CINXE.COM

<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <meta name="robots" content="max-image-preview:large"> <meta name="access" content="Yes"> <meta name="360-site-verification" content="1268d79b5e96aecf3ff2a7dac04ad990" /> <title>Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria | BMC Infectious Diseases</title> <meta name="citation_abstract" content="Early rising asexual parasitaemia (ERAP), initially defined as ‘an increase in the parasite count over the baseline pre-treatment level during the first 24 h of treatment’ of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs). ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8 h of initiating treatment. Parasitaemia was quantified pre-treatment and 1–2 hourly for 8 h, and less frequently thereafter for 6 weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping. ERAP occurred in 205 of 416 children. A parasitaemia <100,000/μL and parasitaemia 1 day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81–130.1) and 2.5 h (95% CI 2.2–2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2 h (95% CI 0.2–0.3), 1 h (95% CI 0.9–1.1), and 0.9 h−1 (95% CI 0.8–1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones versus time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential. ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria. Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015."/> <meta name="journal_id" content="12879"/> <meta name="dc.title" content="Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria"/> <meta name="dc.source" content="BMC Infectious Diseases 2017 17:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="BioMed Central"/> <meta name="dc.date" content="2017-01-31"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2017 The Author(s)."/> <meta name="dc.rights" content="2017 The Author(s)."/> <meta name="dc.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="dc.description" content="Early rising asexual parasitaemia (ERAP), initially defined as ‘an increase in the parasite count over the baseline pre-treatment level during the first 24&nbsp;h of treatment’ of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs). ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8&nbsp;h of initiating treatment. Parasitaemia was quantified pre-treatment and 1–2 hourly for 8&nbsp;h, and less frequently thereafter for 6&nbsp;weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping. ERAP occurred in 205 of 416 children. A parasitaemia &lt;100,000/μL and parasitaemia 1&nbsp;day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81–130.1) and 2.5&nbsp;h (95% CI 2.2–2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2&nbsp;h (95% CI 0.2–0.3), 1&nbsp;h (95% CI 0.9–1.1), and 0.9&nbsp;h−1 (95% CI 0.8–1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones versus time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential. ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria. Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015."/> <meta name="prism.issn" content="1471-2334"/> <meta name="prism.publicationName" content="BMC Infectious Diseases"/> <meta name="prism.publicationDate" content="2017-01-31"/> <meta name="prism.volume" content="17"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="20"/> <meta name="prism.copyright" content="2017 The Author(s)."/> <meta name="prism.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="prism.url" content="https://link.springer.com/articles/10.1186/s12879-016-2173-z"/> <meta name="prism.doi" content="doi:10.1186/s12879-016-2173-z"/> <meta name="citation_pdf_url" content="https://bmcinfectdis.biomedcentral.com/counter/pdf/10.1186/s12879-016-2173-z"/> <meta name="citation_fulltext_html_url" content="https://link.springer.com/articles/10.1186/s12879-016-2173-z"/> <meta name="citation_journal_title" content="BMC Infectious Diseases"/> <meta name="citation_journal_abbrev" content="BMC Infect Dis"/> <meta name="citation_publisher" content="BioMed Central"/> <meta name="citation_issn" content="1471-2334"/> <meta name="citation_title" content="Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria"/> <meta name="citation_volume" content="17"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2017/12"/> <meta name="citation_online_date" content="2017/01/31"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="20"/> <meta name="citation_article_type" content="Research article"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1186/s12879-016-2173-z"/> <meta name="DOI" content="10.1186/s12879-016-2173-z"/> <meta name="size" content="321689"/> <meta name="citation_doi" content="10.1186/s12879-016-2173-z"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1186/s12879-016-2173-z&api_key="/> <meta name="description" content="Early rising asexual parasitaemia (ERAP), initially defined as ‘an increase in the parasite count over the baseline pre-treatment level during the first 24&nbsp;h of treatment’ of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs). ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8&nbsp;h of initiating treatment. Parasitaemia was quantified pre-treatment and 1–2 hourly for 8&nbsp;h, and less frequently thereafter for 6&nbsp;weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping. ERAP occurred in 205 of 416 children. A parasitaemia &lt;100,000/μL and parasitaemia 1&nbsp;day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81–130.1) and 2.5&nbsp;h (95% CI 2.2–2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2&nbsp;h (95% CI 0.2–0.3), 1&nbsp;h (95% CI 0.9–1.1), and 0.9&nbsp;h−1 (95% CI 0.8–1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones versus time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential. ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria. Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015."/> <meta name="dc.creator" content="Sowunmi, Akintunde"/> <meta name="dc.creator" content="Akano, Kazeem"/> <meta name="dc.creator" content="Ayede, Adejumoke I."/> <meta name="dc.creator" content="Adewoye, Elsie O."/> <meta name="dc.creator" content="Ntadom, Godwin"/> <meta name="dc.creator" content="Fatunmbi, Bayo"/> <meta name="dc.creator" content="Gbotosho, Grace O."/> <meta name="dc.creator" content="Folarin, Onikepe A."/> <meta name="dc.creator" content="Happi, Christian T."/> <meta name="dc.subject" content="Infectious Diseases"/> <meta name="dc.subject" content="Parasitology"/> <meta name="dc.subject" content="Medical Microbiology"/> <meta name="dc.subject" content="Tropical Medicine"/> <meta name="dc.subject" content="Internal Medicine"/> <meta name="citation_reference" content="citation_journal_title=Southeast Asian J Trop Med Public Health; citation_title=Frequency of early risisng parasitaemia in falciparum malaria treated with artemisinin derivatives; citation_author=U Silachamroon, W Phumratanaprapin, S Krudsood, S Treeprasertsuk, V Budsaratid, K Pornpininworakij, P Wilairatana, S Looareesuwan; citation_volume=32; citation_publication_date=2001; citation_pages=50-6; citation_id=CR1"/> <meta name="citation_reference" content="citation_journal_title=Malaria J; citation_title=Early variations in Plasmodium falciparum dynamics in Nigerian children after treatment with two artemisinin-based combinations: implications on delayed parasite clearance; citation_author=OS Michael, GO Gbotosho, OA Folarin, T Okuboyejo, A Sowunmi, AMJ Oduola, CT Happi; citation_volume=9; citation_publication_date=2010; citation_pages=335; citation_doi=10.1186/1475-2875-9-335; citation_id=CR2"/> <meta name="citation_reference" content="Sowunmi A, Okuboyejo TM, Gbotosho GO, Happi CT. Early changes in Plasmodium falciparum asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs. Malaria Chemother Control Elimin. 2012;1. doi: 10.4303/mcce/235498 ."/> <meta name="citation_reference" content="citation_title=World malaria report; citation_publication_date=2015; citation_id=CR4; citation_publisher=World Health Organization"/> <meta name="citation_reference" content="citation_title=World malaria report; citation_publication_date=2014; citation_id=CR5; citation_publisher=World Health Organization"/> <meta name="citation_reference" content="citation_journal_title=Acta Trop; citation_title=Factors contributing to anaemia after uncomplicated Plasmodium falciparum malaria in children; citation_author=A Sowunmi, GO Gbotosho, CT Happi, BA Fateye; citation_volume=133; citation_publication_date=2010; citation_pages=155-61; citation_doi=10.1016/j.actatropica.2009.10.011; citation_id=CR6"/> <meta name="citation_reference" content="citation_journal_title=BMC Infect Dis; citation_title=Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria; citation_author=A Sowunmi, K Akano, AI Ayede, G Ntadom, T Aderoyeje, EO Adewoye, B Fatunmbi; citation_volume=16; citation_publication_date=2016; citation_pages=240; citation_doi=10.1186/s12879-016-1565-4; citation_id=CR7"/> <meta name="citation_reference" content="citation_journal_title=BMC Infect Dis; citation_title=A longitudinal study of anaemia in children with Plasmodium falciparum infection in the Mount Cameroon region: prevalence, risk factors and perceptions by caregivers; citation_author=IUN Sumbele, M Samje, T Nkuo-Akenji; citation_volume=13; citation_publication_date=2013; citation_pages=123; citation_doi=10.1186/1471-2334-13-123; citation_id=CR8"/> <meta name="citation_reference" content="citation_journal_title=Ann Trop Med Parasitol; citation_title=Effects of artesunate plus sulfadoxine-pyrimethamine on haematological recovery and anaemia in Kenyan children with uncomplicated Plasmodium falciparum malaria; citation_author=CO Obonyo, W Taylor, H Ekvall, A Kaneko, F Kuile, P Olliaro, A Bjorkman, AJ Oloo; citation_volume=101; citation_publication_date=2007; citation_pages=281-95; citation_doi=10.1179/136485907X176337; citation_id=CR9"/> <meta name="citation_reference" content="citation_journal_title=BMC Inectf Dis; citation_title=Temporal changes in haematocrit following artemisinin-based combination treatments of uncomplicated falciparum malaria in children; citation_author=A Sowunmi, K Akano, AI Ayede, G Ntadom, T Aderoyeje, EO Adewoye, B Fatunmbi; citation_volume=15; citation_publication_date=2015; citation_pages=454; citation_doi=10.1186/s12879-015-1219-y; citation_id=CR10"/> <meta name="citation_reference" content="citation_journal_title=Trans R Soc Trop Med Hyg; citation_title=Severe and complicated malaria; citation_author=; citation_volume=84; citation_issue=Suppl 2; citation_publication_date=1990; citation_pages=1-65; citation_doi=10.1016/0035-9203(90)90363-J; citation_id=CR11"/> <meta name="citation_reference" content="citation_journal_title=Trans R Soc Trop Med Hyg; citation_title=Severe falciparum malaria; citation_author=; citation_volume=94; citation_issue=Suppl 1; citation_publication_date=2000; citation_pages=1-90; citation_doi=10.1016/S0035-9203(00)90300-6; citation_id=CR12"/> <meta name="citation_reference" content="citation_journal_title=Trop Med Int Health; citation_title=Severe malaria; citation_author=; citation_volume=19; citation_issue=Suppl 1; citation_publication_date=2014; citation_pages=7-131; citation_id=CR13"/> <meta name="citation_reference" content="citation_journal_title=Lancet; citation_title=Genetic neutropenia in people of African origin; citation_author=AG Shaper, P Lewis; citation_volume=i; citation_publication_date=1971; citation_pages=1021-3; citation_doi=10.1016/S0140-6736(71)90335-7; citation_id=CR14"/> <meta name="citation_reference" content="citation_journal_title=Trop Geogr Med; citation_title=Neutropenia in African; citation_author=GC Ezeilo; citation_volume=23; citation_publication_date=1971; citation_pages=264-7; citation_id=CR15"/> <meta name="citation_reference" content="citation_journal_title=Afr J Med Med Sci; citation_title=Leukocyte counts in falciparum in African children from an endemic area; citation_author=A Sowunmi, JA Akindele, MA Balogun; citation_volume=24; citation_publication_date=1995; citation_pages=145-9; citation_id=CR16"/> <meta name="citation_reference" content="citation_journal_title=Trans R Soc Trop Med Hyg; citation_title=Clinical trials of artemisinin and its derivatives in the treatment of malaria in China; citation_author=G Li, X Guo, L Fu, H Jian, X Wang; citation_volume=88; citation_issue=Supplement; citation_publication_date=1994; citation_pages=S5-6; citation_doi=10.1016/0035-9203(94)90460-X; citation_id=CR17"/> <meta name="citation_reference" content="citation_title=Gametocytes; citation_inbook_title=Malaria: principles and practice of malariology; citation_publication_date=1988; citation_pages=253-303; citation_id=CR18; citation_author=R Carter; citation_author=PM Graves; citation_publisher=Chuchill Livinstone"/> <meta name="citation_reference" content="citation_journal_title=Trans R Soc Trop Med Hyg; citation_title=Effects of gametocyte sex ratio on infectivity of Plasmodium falciparum to Anopheles gambiae ; citation_author=V Robert, AF Read, J Essong, T Tchuinkam, B Mulder, JP Verhave, P Carnevale; citation_volume=90; citation_publication_date=1996; citation_pages=621-4; citation_doi=10.1016/S0035-9203(96)90408-3; citation_id=CR19"/> <meta name="citation_reference" content="citation_title=Gametocytes and sexual developments; citation_inbook_title=Malaria: parasite biology, pathogenesis and protection; citation_publication_date=1998; citation_pages=25-48; citation_id=CR20; citation_author=RE Sinden; citation_publisher=ASM Press"/> <meta name="citation_reference" content="citation_journal_title=Trends Parasitol; citation_title=Evolution of gametocyte sex ratio in malaria and related apicomplexan (protozoan) parasites; citation_author=SA West, SE Reece, AF Read; citation_volume=17; citation_publication_date=2001; citation_pages=525-31; citation_doi=10.1016/S1471-4922(01)02058-X; citation_id=CR21"/> <meta name="citation_reference" content="citation_journal_title=J Parasitol; citation_title=Fertility insurance and the sex ratios of malaria and related hemosporins blood parasites; citation_author=SA West, TG Smith, S Nee, AF Read; citation_volume=17; citation_publication_date=2002; citation_pages=258-63; citation_doi=10.1645/0022-3395(2002)088[0258:FIATSR]2.0.CO;2; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=Parasitol International; citation_title=Population structure of Plasmodium falciparum gametocyte sex ratios in malarious children in an endemic area; citation_author=A Sowunmi, GO Gbotosho, CT Happi, OA Folarin, ST Balogun; citation_volume=58; citation_publication_date=2009; citation_pages=438-43; citation_doi=10.1016/j.parint.2009.08.007; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=J Infect Dis; citation_title=In vitro-reduced susceptibility to artemether in P. falciparum and its asscociation with polymorphisms on transporter genes; citation_author=C Bustamante, OA Folarin, GO Gbotosho, CN Batista, EA Mesquita, RM Brindeiro, A Tanuri, CJ Struchiner, A Sowunmi, A Oduola, DF Wirth, MG Zalis, CT Happi; citation_volume=206; citation_publication_date=2012; citation_pages=324-32; citation_doi=10.1093/infdis/jis359; citation_id=CR24"/> <meta name="citation_reference" content="citation_journal_title=Am J Trop Med Hyg; citation_title=Factors contributing to anemia after uncomplicated falciparum malaria; citation_author=RC Price, JA Simpson, F Nosten, C Luxemberger, L Hkirjaroen, F Kuile, T Chongsuphajaisiddhi, NJ White; citation_volume=65; citation_publication_date=2001; citation_pages=614-22; citation_id=CR25"/> <meta name="citation_reference" content="citation_journal_title=Acta Trop; citation_title=Effects of amodiaquine, artesunate, and artesunate-amodiaquine on Plasmodium falciparum malaria-associated anaemia in children; citation_author=A Sowunmi, ST Balogun, GO Gbotosho, CT Happi; citation_volume=109; citation_publication_date=2009; citation_pages=55-60; citation_doi=10.1016/j.actatropica.2008.09.022; citation_id=CR26"/> <meta name="citation_reference" content="citation_journal_title=Am J Trop Med Hyg; citation_title=Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five year-old Nigerian children; citation_author=S Oguche, HU Okafor, I Watila, M Meremikwu, P Agomo, W Ogala, C Agomo, G Ntadom, O Banjo, T Okuboyejo, G Ogunrinde, F Odey, O Aina, T Sofola, A Sowunmi; citation_volume=91; citation_publication_date=2014; citation_pages=925-35; citation_doi=10.4269/ajtmh.13-0248; citation_id=CR27"/> <meta name="citation_reference" content="citation_journal_title=Am J Ther; citation_title=Fall in haematocrit per 1000 parasites cleared from peripheral blood; a simple method for estimating drug-related fall in haematocrit after treatment of malaria infections; citation_author=GO Gbotosho, TM Okuboyejo, CT Happi, A Sowunmi; citation_volume=21; citation_publication_date=2014; citation_pages=193-7; citation_doi=10.1097/MJT.0b013e31822119d9; citation_id=CR28"/> <meta name="citation_reference" content="citation_title=Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria; citation_publication_date=2003; citation_id=CR29; citation_publisher=World Health Organization"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob Agent Chemother; citation_title=Assessment of the pharmacodynamics properties of antimalarial drugs in vivo; citation_author=NJ White; citation_volume=41; citation_publication_date=1997; citation_pages=1413-22; citation_id=CR30"/> <meta name="citation_reference" content="citation_title=Clinical pharmacokinetics: concepts and applications; citation_publication_date=1980; citation_id=CR31; citation_author=M Rowland; citation_author=TN Tozer; citation_publisher=Lea and Ferbiger"/> <meta name="citation_reference" content="citation_journal_title=Clin Drug Invest; citation_title=Comparative Plasmodium falciparum kinetics during treatment with amodiaquine and chloroquine in children; citation_author=A Sowunmi, AG Falade, AA Adedeji, AI Ayede, BA Fateye, CO Sowunmi, AMJ Oduola; citation_volume=21; citation_publication_date=2001; citation_pages=371-81; citation_doi=10.2165/00044011-200121050-00007; citation_id=CR32"/> <meta name="citation_reference" content="citation_journal_title=Am J Trop Med Hyg; citation_title=Therapeutic efficacies of artemisinin-based combination therapies in Nigerian children with uncomplicated falciparum malaria during five years of adoption as first-line treatments; citation_author=GO Gbotosho, A Sowunmi, CT Happi, TM Okuboyejo; citation_volume=84; citation_publication_date=2011; citation_pages=936-43; citation_doi=10.4269/ajtmh.2011.10-0722; citation_id=CR33"/> <meta name="citation_reference" content="citation_title=A word processing data base and statistics program for public health on IBM-compatible microcomputers; citation_publication_date=1994; citation_id=CR34; citation_publisher=Centers for Disease Control and Prevention"/> <meta name="citation_reference" content="SPSS for Windows Release 20.0 (standard version). Chicago IL: SPSS Inc.; 2011."/> <meta name="citation_reference" content="citation_journal_title=Malaria J; citation_title=Hyperparasitaemia anf low dosing are important source of anti-malarial drug resistance; citation_author=NJ White, W Pongtavornpinyo, RJ Maude, S Saralamba, R Aguas, K Stepniewska, SJ Lee, AM Dondorp, LJ White, NPJ Day; citation_volume=8; citation_publication_date=2009; citation_pages=253; citation_doi=10.1186/1475-2875-8-253; citation_id=CR36"/> <meta name="citation_reference" content="citation_journal_title=Parasitol Res; citation_title=Stage-specific gametocytocidal effect in vitro of the artemisinin drug quinghaosu on Plasmodium falciparum ; citation_author=N Kumar, H Zheng; citation_volume=76; citation_publication_date=1990; citation_pages=214-8; citation_doi=10.1007/BF00930817; citation_id=CR37"/> <meta name="citation_reference" content="citation_journal_title=Proc Nat Acad Sci; citation_title=Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue; citation_author=SH Adjaley, GL Johnston, T Li, RT Eastman, EH Ekland, AG Eappen, A Richman, BKL Sim, MCS Lee, SL Hoffman, DA Fidock; citation_volume=47; citation_publication_date=2011; citation_pages=E1214-23; citation_doi=10.1073/pnas.1112037108; citation_id=CR38"/> <meta name="citation_reference" content="citation_journal_title=Antimicrobial Agents Chemother; citation_title=Activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual and sexual stage parasites in falciparum malaria in children; citation_author=A Sowunmi, T Balogun, GO Gbotosho, CT Happi, AA Adedeji, FA Fehintola; citation_volume=51; citation_publication_date=2007; citation_pages=1694-9; citation_doi=10.1128/AAC.00077-07; citation_id=CR39"/> <meta name="citation_reference" content="citation_journal_title=Acta Trop; citation_title= Plasmodium falciparum gametocyte sex ratios in symptomatic children treated with antimalarial drugs; citation_author=A Sowunmi, ST Balogun, GO Gbotosho, CT Happi; citation_volume=100; citation_publication_date=2009; citation_pages=108-17; citation_doi=10.1016/j.actatropica.2008.10.010; citation_id=CR40"/> <meta name="citation_reference" content="citation_journal_title=Am J Pathol; citation_title=Human cerebral malaria: a qualitative ultrastructural analysis of parasitized erythrocyte sequestration; citation_author=GG MacPherson, MJ Warrell, NJ White, S Looareesuwan, DA Warrell; citation_volume=119; citation_publication_date=1985; citation_pages=386-401; citation_id=CR41"/> <meta name="citation_reference" content="citation_journal_title=Nat Med; citation_title=Differentiating the pathologies of cerebral malaria by post-mortem parasite counts; citation_author=TE Taylor, WJ Fu, RA Carr, RO Whitten, JS Mueller, NG Fosiko, S Lewallen, NG Lomba, ME Molyneux; citation_volume=10; citation_publication_date=2004; citation_pages=143-5; citation_doi=10.1038/nm986; citation_id=CR42"/> <meta name="citation_reference" content="citation_journal_title=Malaria J; citation_title=Human malarial disease: a consequence of inflammatory cytokine release; citation_author=IA Clarke, AC Budd, SM Alleva, WB Cowden; citation_volume=6; citation_publication_date=2006; citation_pages=85; citation_doi=10.1186/1475-2875-5-85; citation_id=CR43"/> <meta name="citation_reference" content="citation_journal_title=J inf Dis; citation_title=In vivo parasitological measures of artemisinin susceptibility; citation_author=K Stepniewska, E Ashley, SJ Lee, N Anstey, KI Barnes, TQ Binh, U D’Alessandro, NPJ Day, PJ Vries, G Dorsey, J_P Guthmann, M Mayxay, PN Newton, P Olliaro, L Osorio, RN Price, M Rowland, F Smithuis, WRJ Taylor, F Nosten, NJ White; citation_volume=201; citation_publication_date=2010; citation_pages=570-6; citation_doi=10.1086/650301; citation_id=CR44"/> <meta name="citation_reference" content="Global Malaria Programme WHO. Update on artemisinin resistance – April 2012. 2012. Available from: http://www.who.int/malaria/publications/atoz/updateartemsininresistanceapr2012/en/ ."/> <meta name="citation_author" content="Sowunmi, Akintunde"/> <meta name="citation_author_institution" content="Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author_institution" content="Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author_institution" content="Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria"/> <meta name="citation_author" content="Akano, Kazeem"/> <meta name="citation_author_institution" content="Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author" content="Ayede, Adejumoke I."/> <meta name="citation_author_institution" content="Department of Paediatrics, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author" content="Adewoye, Elsie O."/> <meta name="citation_author_institution" content="Department of Physiology, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author" content="Ntadom, Godwin"/> <meta name="citation_author_institution" content="National Malaria Elimination Programme, Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author" content="Fatunmbi, Bayo"/> <meta name="citation_author_institution" content="World Health Organization, Regional Office for the Western Pacific, Phnom Penh, Cambodia"/> <meta name="citation_author" content="Gbotosho, Grace O."/> <meta name="citation_author_institution" content="Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author_institution" content="Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author" content="Folarin, Onikepe A."/> <meta name="citation_author_institution" content="Department of Biological Sciences, Redeemer’s University, Ede, Nigeria"/> <meta name="citation_author_institution" content="African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer’s University, Ede, Nigeria"/> <meta name="citation_author" content="Happi, Christian T."/> <meta name="citation_author_institution" content="Department of Biological Sciences, Redeemer’s University, Ede, Nigeria"/> <meta name="citation_author_institution" content="African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer’s University, Ede, Nigeria"/> <meta property="og:url" content="https://link.springer.com/article/10.1186/s12879-016-2173-z"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="SpringerLink"/> <meta property="og:title" content="Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria - BMC Infectious Diseases"/> <meta property="og:description" content="Background Early rising asexual parasitaemia (ERAP), initially defined as ‘an increase in the parasite count over the baseline pre-treatment level during the first 24 h of treatment’ of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs). Methods ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8 h of initiating treatment. Parasitaemia was quantified pre-treatment and 1–2 hourly for 8 h, and less frequently thereafter for 6 weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping. Results ERAP occurred in 205 of 416 children. A parasitaemia <100,000/μL and parasitaemia 1 day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81–130.1) and 2.5 h (95% CI 2.2–2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2 h (95% CI 0.2–0.3), 1 h (95% CI 0.9–1.1), and 0.9 h−1 (95% CI 0.8–1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones versus time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential. Conclusion ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria. Trials registration Pan African Clinical Trial Registry PACTR201508001188143 , 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig1_HTML.gif"/> <meta name="format-detection" content="telephone=no"> <link rel="apple-touch-icon" sizes="180x180" href=/oscar-static/img/favicons/darwin/apple-touch-icon-92e819bf8a.png> <link rel="icon" type="image/png" sizes="192x192" href=/oscar-static/img/favicons/darwin/android-chrome-192x192-6f081ca7e5.png> <link rel="icon" type="image/png" sizes="32x32" href=/oscar-static/img/favicons/darwin/favicon-32x32-1435da3e82.png> <link rel="icon" type="image/png" sizes="16x16" href=/oscar-static/img/favicons/darwin/favicon-16x16-ed57f42bd2.png> <link rel="shortcut icon" data-test="shortcut-icon" href=/oscar-static/img/favicons/darwin/favicon-c6d59aafac.ico> <meta name="theme-color" content="#e6e6e6">   <link rel="stylesheet" media="print" href=/oscar-static/app-springerlink/css/print-b8af42253b.css> <style> html{text-size-adjust:100%;line-height:1.15}body{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;line-height:1.8;margin:0}details,main{display:block}h1{font-size:2em;margin:.67em 0}a{background-color:transparent;color:#025e8d}sub{bottom:-.25em;font-size:75%;line-height:0;position:relative;vertical-align:baseline}img{border:0;height:auto;max-width:100%;vertical-align:middle}button,input{font-family:inherit;font-size:100%;line-height:1.15;margin:0;overflow:visible}button{text-transform:none}[type=button],[type=submit],button{-webkit-appearance:button}[type=search]{-webkit-appearance:textfield;outline-offset:-2px}summary{display:list-item}[hidden]{display:none}button{cursor:pointer}svg{height:1rem;width:1rem} </style> <style>@media only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark) { body{background:#fff;color:#222;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;line-height:1.8;min-height:100%}a{color:#025e8d;text-decoration:underline;text-decoration-skip-ink:auto}button{cursor:pointer}img{border:0;height:auto;max-width:100%;vertical-align:middle}html{box-sizing:border-box;font-size:100%;height:100%;overflow-y:scroll}h1{font-size:2.25rem}h2{font-size:1.75rem}h1,h2,h4{font-weight:700;line-height:1.2}h4{font-size:1.25rem}body{font-size:1.125rem}*{box-sizing:inherit}p{margin-bottom:2rem;margin-top:0}p:last-of-type{margin-bottom:0}.c-ad{text-align:center}@media only screen and (min-width:480px){.c-ad{padding:8px}}.c-ad--728x90{display:none}.c-ad--728x90 .c-ad__inner{min-height:calc(1.5em + 94px)}@media only screen and (min-width:876px){.js .c-ad--728x90{display:none}}.c-ad__label{color:#333;font-size:.875rem;font-weight:400;line-height:1.5;margin-bottom:4px}.c-ad__label,.c-status-message{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif}.c-status-message{align-items:center;box-sizing:border-box;display:flex;position:relative;width:100%}.c-status-message :last-child{margin-bottom:0}.c-status-message--boxed{background-color:#fff;border:1px solid #ccc;line-height:1.4;padding:16px}.c-status-message__heading{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:.875rem;font-weight:700}.c-status-message__icon{fill:currentcolor;display:inline-block;flex:0 0 auto;height:1.5em;margin-right:8px;transform:translate(0);vertical-align:text-top;width:1.5em}.c-status-message__icon--top{align-self:flex-start}.c-status-message--info .c-status-message__icon{color:#003f8d}.c-status-message--boxed.c-status-message--info{border-bottom:4px solid #003f8d}.c-status-message--error .c-status-message__icon{color:#c40606}.c-status-message--boxed.c-status-message--error{border-bottom:4px solid #c40606}.c-status-message--success .c-status-message__icon{color:#00b8b0}.c-status-message--boxed.c-status-message--success{border-bottom:4px solid #00b8b0}.c-status-message--warning .c-status-message__icon{color:#edbc53}.c-status-message--boxed.c-status-message--warning{border-bottom:4px solid #edbc53}.eds-c-header{background-color:#fff;border-bottom:2px solid #01324b;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:1rem;line-height:1.5;padding:8px 0 0}.eds-c-header__container{align-items:center;display:flex;flex-wrap:nowrap;gap:8px 16px;justify-content:space-between;margin:0 auto 8px;max-width:1280px;padding:0 8px;position:relative}.eds-c-header__nav{border-top:2px solid #c5e0f4;padding-top:4px;position:relative}.eds-c-header__nav-container{align-items:center;display:flex;flex-wrap:wrap;margin:0 auto 4px;max-width:1280px;padding:0 8px;position:relative}.eds-c-header__nav-container>:not(:last-child){margin-right:32px}.eds-c-header__link-container{align-items:center;display:flex;flex:1 0 auto;gap:8px 16px;justify-content:space-between}.eds-c-header__list{list-style:none;margin:0;padding:0}.eds-c-header__list-item{font-weight:700;margin:0 auto;max-width:1280px;padding:8px}.eds-c-header__list-item:not(:last-child){border-bottom:2px solid #c5e0f4}.eds-c-header__item{color:inherit}@media only screen and (min-width:768px){.eds-c-header__item--menu{display:none;visibility:hidden}.eds-c-header__item--menu:first-child+*{margin-block-start:0}}.eds-c-header__item--inline-links{display:none;visibility:hidden}@media only screen and (min-width:768px){.eds-c-header__item--inline-links{display:flex;gap:16px 16px;visibility:visible}}.eds-c-header__item--divider:before{border-left:2px solid #c5e0f4;content:"";height:calc(100% - 16px);margin-left:-15px;position:absolute;top:8px}.eds-c-header__brand{padding:16px 8px}.eds-c-header__brand a{display:block;line-height:1;text-decoration:none}.eds-c-header__brand img{height:1.5rem;width:auto}.eds-c-header__link{color:inherit;display:inline-block;font-weight:700;padding:16px 8px;position:relative;text-decoration-color:transparent;white-space:nowrap;word-break:normal}.eds-c-header__icon{fill:currentcolor;display:inline-block;font-size:1.5rem;height:1em;transform:translate(0);vertical-align:bottom;width:1em}.eds-c-header__icon+*{margin-left:8px}.eds-c-header__expander{background-color:#f0f7fc}.eds-c-header__search{display:block;padding:24px 0}@media only screen and (min-width:768px){.eds-c-header__search{max-width:70%}}.eds-c-header__search-container{position:relative}.eds-c-header__search-label{color:inherit;display:inline-block;font-weight:700;margin-bottom:8px}.eds-c-header__search-input{background-color:#fff;border:1px solid #000;padding:8px 48px 8px 8px;width:100%}.eds-c-header__search-button{background-color:transparent;border:0;color:inherit;height:100%;padding:0 8px;position:absolute;right:0}.has-tethered.eds-c-header__expander{border-bottom:2px solid #01324b;left:0;margin-top:-2px;top:100%;width:100%;z-index:10}@media only screen and (min-width:768px){.has-tethered.eds-c-header__expander--menu{display:none;visibility:hidden}}.has-tethered .eds-c-header__heading{display:none;visibility:hidden}.has-tethered .eds-c-header__heading:first-child+*{margin-block-start:0}.has-tethered .eds-c-header__search{margin:auto}.eds-c-header__heading{margin:0 auto;max-width:1280px;padding:16px 16px 0}.eds-c-pagination{align-items:center;display:flex;flex-wrap:wrap;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:.875rem;gap:16px 0;justify-content:center;line-height:1.4;list-style:none;margin:0;padding:32px 0}@media only screen and (min-width:480px){.eds-c-pagination{padding:32px 16px}}.eds-c-pagination__item{margin-right:8px}.eds-c-pagination__item--prev{margin-right:16px}.eds-c-pagination__item--next .eds-c-pagination__link,.eds-c-pagination__item--prev .eds-c-pagination__link{padding:16px 8px}.eds-c-pagination__item--next{margin-left:8px}.eds-c-pagination__item:last-child{margin-right:0}.eds-c-pagination__link{align-items:center;color:#222;cursor:pointer;display:inline-block;font-size:1rem;margin:0;padding:16px 24px;position:relative;text-align:center;transition:all .2s ease 0s}.eds-c-pagination__link:visited{color:#222}.eds-c-pagination__link--disabled{border-color:#555;color:#555;cursor:default}.eds-c-pagination__link--active{background-color:#01324b;background-image:none;border-radius:8px;color:#fff}.eds-c-pagination__link--active:focus,.eds-c-pagination__link--active:hover,.eds-c-pagination__link--active:visited{color:#fff}.eds-c-pagination__link-container{align-items:center;display:flex}.eds-c-pagination__icon{fill:#222;height:1.5rem;width:1.5rem}.eds-c-pagination__icon--disabled{fill:#555}.eds-c-pagination__visually-hidden{clip:rect(0,0,0,0);border:0;clip-path:inset(50%);height:1px;overflow:hidden;padding:0;position:absolute!important;white-space:nowrap;width:1px}.c-breadcrumbs{color:#333;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:1rem;list-style:none;margin:0;padding:0}.c-breadcrumbs>li{display:inline}svg.c-breadcrumbs__chevron{fill:#333;height:10px;margin:0 .25rem;width:10px}.c-breadcrumbs--contrast,.c-breadcrumbs--contrast .c-breadcrumbs__link{color:#fff}.c-breadcrumbs--contrast svg.c-breadcrumbs__chevron{fill:#fff}@media only screen and (max-width:479px){.c-breadcrumbs .c-breadcrumbs__item{display:none}.c-breadcrumbs .c-breadcrumbs__item:last-child,.c-breadcrumbs .c-breadcrumbs__item:nth-last-child(2){display:inline}}.c-skip-link{background:#01324b;bottom:auto;color:#fff;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:1rem;padding:8px;position:absolute;text-align:center;transform:translateY(-100%);width:100%;z-index:9999}@media (prefers-reduced-motion:reduce){.c-skip-link{transition:top .3s ease-in-out 0s}}@media print{.c-skip-link{display:none}}.c-skip-link:active,.c-skip-link:hover,.c-skip-link:link,.c-skip-link:visited{color:#fff}.c-skip-link:focus{transform:translateY(0)}.l-with-sidebar{display:flex;flex-wrap:wrap}.l-with-sidebar>*{margin:0}.l-with-sidebar__sidebar{flex-basis:var(--with-sidebar--basis,400px);flex-grow:1}.l-with-sidebar>:not(.l-with-sidebar__sidebar){flex-basis:0px;flex-grow:999;min-width:var(--with-sidebar--min,53%)}.l-with-sidebar>:first-child{padding-right:4rem}@supports (gap:1em){.l-with-sidebar>:first-child{padding-right:0}.l-with-sidebar{gap:var(--with-sidebar--gap,4rem)}}.c-header__link{color:inherit;display:inline-block;font-weight:700;padding:16px 8px;position:relative;text-decoration-color:transparent;white-space:nowrap;word-break:normal}.app-masthead__colour-4{--background-color:#ff9500;--gradient-light:rgba(0,0,0,.5);--gradient-dark:rgba(0,0,0,.8)}.app-masthead{background:var(--background-color,#0070a8);position:relative}.app-masthead:after{background:radial-gradient(circle at top right,var(--gradient-light,rgba(0,0,0,.4)),var(--gradient-dark,rgba(0,0,0,.7)));bottom:0;content:"";left:0;position:absolute;right:0;top:0}@media only screen and (max-width:479px){.app-masthead:after{background:linear-gradient(225deg,var(--gradient-light,rgba(0,0,0,.4)),var(--gradient-dark,rgba(0,0,0,.7)))}}.app-masthead__container{color:var(--masthead-color,#fff);margin:0 auto;max-width:1280px;padding:0 16px;position:relative;z-index:1}.u-button{align-items:center;background-color:#01324b;background-image:none;border:4px solid transparent;border-radius:32px;cursor:pointer;display:inline-flex;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:.875rem;font-weight:700;justify-content:center;line-height:1.3;margin:0;padding:16px 32px;position:relative;transition:all .2s ease 0s;width:auto}.u-button svg,.u-button--contrast svg,.u-button--primary svg,.u-button--secondary svg,.u-button--tertiary svg{fill:currentcolor}.u-button,.u-button:visited{color:#fff}.u-button,.u-button:hover{box-shadow:0 0 0 1px #01324b;text-decoration:none}.u-button:hover{border:4px solid #fff}.u-button:focus{border:4px solid #fc0;box-shadow:none;outline:0;text-decoration:none}.u-button:focus,.u-button:hover{background-color:#fff;background-image:none;color:#01324b}.app-masthead--pastel .c-pdf-download .u-button--primary:focus svg path,.app-masthead--pastel .c-pdf-download .u-button--primary:hover svg path,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:focus svg path,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:hover svg path,.u-button--primary:focus svg path,.u-button--primary:hover svg path,.u-button:focus svg path,.u-button:hover svg path{fill:#01324b}.u-button--primary{background-color:#01324b;background-image:none;border:4px solid transparent;box-shadow:0 0 0 1px #01324b;color:#fff;font-weight:700}.u-button--primary:visited{color:#fff}.u-button--primary:hover{border:4px solid #fff;box-shadow:0 0 0 1px #01324b;text-decoration:none}.u-button--primary:focus{border:4px solid #fc0;box-shadow:none;outline:0;text-decoration:none}.u-button--primary:focus,.u-button--primary:hover{background-color:#fff;background-image:none;color:#01324b}.u-button--secondary{background-color:#fff;border:4px solid #fff;color:#01324b;font-weight:700}.u-button--secondary:visited{color:#01324b}.u-button--secondary:hover{border:4px solid #01324b;box-shadow:none}.u-button--secondary:focus,.u-button--secondary:hover{background-color:#01324b;color:#fff}.app-masthead--pastel .c-pdf-download .u-button--secondary:focus svg path,.app-masthead--pastel .c-pdf-download .u-button--secondary:hover svg path,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--secondary:focus svg path,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--secondary:hover svg path,.u-button--secondary:focus svg path,.u-button--secondary:hover svg path,.u-button--tertiary:focus svg path,.u-button--tertiary:hover svg path{fill:#fff}.u-button--tertiary{background-color:#ebf1f5;border:4px solid transparent;box-shadow:none;color:#666;font-weight:700}.u-button--tertiary:visited{color:#666}.u-button--tertiary:hover{border:4px solid #01324b;box-shadow:none}.u-button--tertiary:focus,.u-button--tertiary:hover{background-color:#01324b;color:#fff}.u-button--contrast{background-color:transparent;background-image:none;color:#fff;font-weight:400}.u-button--contrast:visited{color:#fff}.u-button--contrast,.u-button--contrast:focus,.u-button--contrast:hover{border:4px solid #fff}.u-button--contrast:focus,.u-button--contrast:hover{background-color:#fff;background-image:none;color:#000}.u-button--contrast:focus svg path,.u-button--contrast:hover svg path{fill:#000}.u-button--disabled,.u-button:disabled{background-color:transparent;background-image:none;border:4px solid #ccc;color:#000;cursor:default;font-weight:400;opacity:.7}.u-button--disabled svg,.u-button:disabled svg{fill:currentcolor}.u-button--disabled:visited,.u-button:disabled:visited{color:#000}.u-button--disabled:focus,.u-button--disabled:hover,.u-button:disabled:focus,.u-button:disabled:hover{border:4px solid #ccc;text-decoration:none}.u-button--disabled:focus,.u-button--disabled:hover,.u-button:disabled:focus,.u-button:disabled:hover{background-color:transparent;background-image:none;color:#000}.u-button--disabled:focus svg path,.u-button--disabled:hover svg path,.u-button:disabled:focus svg path,.u-button:disabled:hover svg path{fill:#000}.u-button--small,.u-button--xsmall{font-size:.875rem;padding:2px 8px}.u-button--small{padding:8px 16px}.u-button--large{font-size:1.125rem;padding:10px 35px}.u-button--full-width{display:flex;width:100%}.u-button--icon-left svg{margin-right:8px}.u-button--icon-right svg{margin-left:8px}.u-clear-both{clear:both}.u-container{margin:0 auto;max-width:1280px;padding:0 16px}.u-justify-content-space-between{justify-content:space-between}.u-display-none{display:none}.js .u-js-hide,.u-hide{display:none;visibility:hidden}.u-visually-hidden{clip:rect(0,0,0,0);border:0;clip-path:inset(50%);height:1px;overflow:hidden;padding:0;position:absolute!important;white-space:nowrap;width:1px}.u-icon{fill:currentcolor;display:inline-block;height:1em;transform:translate(0);vertical-align:text-top;width:1em}.u-list-reset{list-style:none;margin:0;padding:0}.u-ma-16{margin:16px}.u-mt-0{margin-top:0}.u-mt-24{margin-top:24px}.u-mt-32{margin-top:32px}.u-mb-8{margin-bottom:8px}.u-mb-32{margin-bottom:32px}.u-button-reset{background-color:transparent;border:0;padding:0}.u-sans-serif{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif}.u-serif{font-family:Merriweather,serif}h1,h2,h4{-webkit-font-smoothing:antialiased}p{overflow-wrap:break-word;word-break:break-word}.u-h4{font-size:1.25rem;font-weight:700;line-height:1.2}.u-mbs-0{margin-block-start:0!important}.c-article-header{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif}.c-article-identifiers{color:#6f6f6f;display:flex;flex-wrap:wrap;font-size:1rem;line-height:1.3;list-style:none;margin:0 0 8px;padding:0}.c-article-identifiers__item{border-right:1px solid #6f6f6f;list-style:none;margin-right:8px;padding-right:8px}.c-article-identifiers__item:last-child{border-right:0;margin-right:0;padding-right:0}@media only screen and (min-width:876px){.c-article-title{font-size:1.875rem;line-height:1.2}}.c-article-author-list{display:inline;font-size:1rem;list-style:none;margin:0 8px 0 0;padding:0;width:100%}.c-article-author-list__item{display:inline;padding-right:0}.c-article-author-list__show-more{display:none;margin-right:4px}.c-article-author-list__button,.js .c-article-author-list__item--hide,.js .c-article-author-list__show-more{display:none}.js .c-article-author-list--long .c-article-author-list__show-more,.js .c-article-author-list--long+.c-article-author-list__button{display:inline}@media only screen and (max-width:767px){.js .c-article-author-list__item--hide-small-screen{display:none}.js .c-article-author-list--short .c-article-author-list__show-more,.js .c-article-author-list--short+.c-article-author-list__button{display:inline}}#uptodate-client,.js .c-article-author-list--expanded .c-article-author-list__show-more{display:none!important}.js .c-article-author-list--expanded .c-article-author-list__item--hide-small-screen{display:inline!important}.c-article-author-list__button,.c-button-author-list{background:#ebf1f5;border:4px solid #ebf1f5;border-radius:20px;color:#666;font-size:.875rem;line-height:1.4;padding:2px 11px 2px 8px;text-decoration:none}.c-article-author-list__button svg,.c-button-author-list svg{margin:1px 4px 0 0}.c-article-author-list__button:hover,.c-button-author-list:hover{background:#025e8d;border-color:transparent;color:#fff}.c-article-body .c-article-access-provider{padding:8px 16px}.c-article-body .c-article-access-provider,.c-notes{border:1px solid #d5d5d5;border-image:initial;border-left:none;border-right:none;margin:24px 0}.c-article-body .c-article-access-provider__text{color:#555}.c-article-body .c-article-access-provider__text,.c-notes__text{font-size:1rem;margin-bottom:0;padding-bottom:2px;padding-top:2px;text-align:center}.c-article-body .c-article-author-affiliation__address{color:inherit;font-weight:700;margin:0}.c-article-body .c-article-author-affiliation__authors-list{list-style:none;margin:0;padding:0}.c-article-body .c-article-author-affiliation__authors-item{display:inline;margin-left:0}.c-article-authors-search{margin-bottom:24px;margin-top:0}.c-article-authors-search__item,.c-article-authors-search__title{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif}.c-article-authors-search__title{color:#626262;font-size:1.05rem;font-weight:700;margin:0;padding:0}.c-article-authors-search__item{font-size:1rem}.c-article-authors-search__text{margin:0}.c-code-block{border:1px solid #fff;font-family:monospace;margin:0 0 24px;padding:20px}.c-code-block__heading{font-weight:400;margin-bottom:16px}.c-code-block__line{display:block;overflow-wrap:break-word;white-space:pre-wrap}.c-article-share-box{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;margin-bottom:24px}.c-article-share-box__description{font-size:1rem;margin-bottom:8px}.c-article-share-box__no-sharelink-info{font-size:.813rem;font-weight:700;margin-bottom:24px;padding-top:4px}.c-article-share-box__only-read-input{border:1px solid #d5d5d5;box-sizing:content-box;display:inline-block;font-size:.875rem;font-weight:700;height:24px;margin-bottom:8px;padding:8px 10px}.c-article-share-box__additional-info{color:#626262;font-size:.813rem}.c-article-share-box__button{background:#fff;box-sizing:content-box;text-align:center}.c-article-share-box__button--link-like{background-color:transparent;border:0;color:#025e8d;cursor:pointer;font-size:.875rem;margin-bottom:8px;margin-left:10px}.c-article-associated-content__container .c-article-associated-content__collection-label{font-size:.875rem;line-height:1.4}.c-article-associated-content__container .c-article-associated-content__collection-title{line-height:1.3}.c-reading-companion{clear:both;min-height:389px}.c-reading-companion__figures-list,.c-reading-companion__references-list{list-style:none;min-height:389px;padding:0}.c-reading-companion__references-list--numeric{list-style:decimal inside}.c-reading-companion__figure-item{border-top:1px solid #d5d5d5;font-size:1rem;padding:16px 8px 16px 0}.c-reading-companion__figure-item:first-child{border-top:none;padding-top:8px}.c-reading-companion__reference-item{font-size:1rem}.c-reading-companion__reference-item:first-child{border-top:none}.c-reading-companion__reference-item a{word-break:break-word}.c-reading-companion__reference-citation{display:inline}.c-reading-companion__reference-links{font-size:.813rem;font-weight:700;list-style:none;margin:8px 0 0;padding:0;text-align:right}.c-reading-companion__reference-links>a{display:inline-block;padding-left:8px}.c-reading-companion__reference-links>a:first-child{display:inline-block;padding-left:0}.c-reading-companion__figure-title{display:block;font-size:1.25rem;font-weight:700;line-height:1.2;margin:0 0 8px}.c-reading-companion__figure-links{display:flex;justify-content:space-between;margin:8px 0 0}.c-reading-companion__figure-links>a{align-items:center;display:flex}.c-article-section__figure-caption{display:block;margin-bottom:8px;word-break:break-word}.c-article-section__figure .video,p.app-article-masthead__access--above-download{margin:0 0 16px}.c-article-section__figure-description{font-size:1rem}.c-article-section__figure-description>*{margin-bottom:0}.c-cod{display:block;font-size:1rem;width:100%}.c-cod__form{background:#ebf0f3}.c-cod__prompt{font-size:1.125rem;line-height:1.3;margin:0 0 24px}.c-cod__label{display:block;margin:0 0 4px}.c-cod__row{display:flex;margin:0 0 16px}.c-cod__row:last-child{margin:0}.c-cod__input{border:1px solid #d5d5d5;border-radius:2px;flex-shrink:0;margin:0;padding:13px}.c-cod__input--submit{background-color:#025e8d;border:1px solid #025e8d;color:#fff;flex-shrink:1;margin-left:8px;transition:background-color .2s ease-out 0s,color .2s ease-out 0s}.c-cod__input--submit-single{flex-basis:100%;flex-shrink:0;margin:0}.c-cod__input--submit:focus,.c-cod__input--submit:hover{background-color:#fff;color:#025e8d}.save-data .c-article-author-institutional-author__sub-division,.save-data .c-article-equation__number,.save-data .c-article-figure-description,.save-data .c-article-fullwidth-content,.save-data .c-article-main-column,.save-data .c-article-satellite-article-link,.save-data .c-article-satellite-subtitle,.save-data .c-article-table-container,.save-data .c-blockquote__body,.save-data .c-code-block__heading,.save-data .c-reading-companion__figure-title,.save-data .c-reading-companion__reference-citation,.save-data .c-site-messages--nature-briefing-email-variant .serif,.save-data .c-site-messages--nature-briefing-email-variant.serif,.save-data .serif,.save-data .u-serif,.save-data h1,.save-data h2,.save-data h3{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif}.c-pdf-download__link{display:flex;flex:1 1 0%;padding:13px 24px}.c-pdf-download__link:hover{text-decoration:none}@media only screen and (min-width:768px){.c-context-bar--sticky .c-pdf-download__link{align-items:center;flex:1 1 183px}}@media only screen and (max-width:320px){.c-context-bar--sticky .c-pdf-download__link{padding:16px}}.c-article-body .c-article-recommendations-list,.c-book-body .c-article-recommendations-list{display:flex;flex-direction:row;gap:16px 16px;margin:0;max-width:100%;padding:16px 0 0}.c-article-body .c-article-recommendations-list__item,.c-book-body .c-article-recommendations-list__item{flex:1 1 0%}@media only screen and (max-width:767px){.c-article-body .c-article-recommendations-list,.c-book-body .c-article-recommendations-list{flex-direction:column}}.c-article-body .c-article-recommendations-card__authors{display:none;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:.875rem;line-height:1.5;margin:0 0 8px}@media only screen and (max-width:767px){.c-article-body .c-article-recommendations-card__authors{display:block;margin:0}}.c-article-body .c-article-history{margin-top:24px}.app-article-metrics-bar p{margin:0}.app-article-masthead{display:flex;flex-direction:column;gap:16px 16px;padding:16px 0 24px}.app-article-masthead__info{display:flex;flex-direction:column;flex-grow:1}.app-article-masthead__brand{border-top:1px solid hsla(0,0%,100%,.8);display:flex;flex-direction:column;flex-shrink:0;gap:8px 8px;min-height:96px;padding:16px 0 0}.app-article-masthead__brand img{border:1px solid #fff;border-radius:8px;box-shadow:0 4px 15px 0 hsla(0,0%,50%,.25);height:auto;left:0;position:absolute;width:72px}.app-article-masthead__journal-link{display:block;font-size:1.125rem;font-weight:700;margin:0 0 8px;max-width:400px;padding:0 0 0 88px;position:relative}.app-article-masthead__journal-title{-webkit-box-orient:vertical;-webkit-line-clamp:3;display:-webkit-box;overflow:hidden}.app-article-masthead__submission-link{align-items:center;display:flex;font-size:1rem;gap:4px 4px;margin:0 0 0 88px}.app-article-masthead__access{align-items:center;display:flex;flex-wrap:wrap;font-size:.875rem;font-weight:300;gap:4px 4px;margin:0}.app-article-masthead__buttons{display:flex;flex-flow:column wrap;gap:16px 16px}.app-article-masthead__access svg,.app-masthead--pastel .c-pdf-download .u-button--primary svg,.app-masthead--pastel .c-pdf-download .u-button--secondary svg,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary svg,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--secondary svg{fill:currentcolor}.app-article-masthead a{color:#fff}.app-masthead--pastel .c-pdf-download .u-button--primary,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary{background-color:#025e8d;background-image:none;border:2px solid transparent;box-shadow:none;color:#fff;font-weight:700}.app-masthead--pastel .c-pdf-download .u-button--primary:visited,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:visited{color:#fff}.app-masthead--pastel .c-pdf-download .u-button--primary:hover,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:hover{text-decoration:none}.app-masthead--pastel .c-pdf-download .u-button--primary:focus,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:focus{border:4px solid #fc0;box-shadow:none;outline:0;text-decoration:none}.app-masthead--pastel .c-pdf-download .u-button--primary:focus,.app-masthead--pastel .c-pdf-download .u-button--primary:hover,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:focus,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:hover{background-color:#fff;background-image:none;color:#01324b}.app-masthead--pastel .c-pdf-download .u-button--primary:hover,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--primary:hover{background:0 0;border:2px solid #025e8d;box-shadow:none;color:#025e8d}.app-masthead--pastel .c-pdf-download .u-button--secondary,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--secondary{background:0 0;border:2px solid #025e8d;color:#025e8d;font-weight:700}.app-masthead--pastel .c-pdf-download .u-button--secondary:visited,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--secondary:visited{color:#01324b}.app-masthead--pastel .c-pdf-download .u-button--secondary:hover,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--secondary:hover{background-color:#01324b;background-color:#025e8d;border:2px solid transparent;box-shadow:none;color:#fff}.app-masthead--pastel .c-pdf-download .u-button--secondary:focus,.c-context-bar--sticky .c-context-bar__container .c-pdf-download .u-button--secondary:focus{background-color:#fff;background-image:none;border:4px solid #fc0;color:#01324b}@media only screen and (min-width:768px){.app-article-masthead{flex-direction:row;gap:64px 64px;padding:24px 0}.app-article-masthead__brand{border:0;padding:0}.app-article-masthead__brand img{height:auto;position:static;width:auto}.app-article-masthead__buttons{align-items:center;flex-direction:row;margin-top:auto}.app-article-masthead__journal-link{display:flex;flex-direction:column;gap:24px 24px;margin:0 0 8px;padding:0}.app-article-masthead__submission-link{margin:0}}@media only screen and (min-width:1024px){.app-article-masthead__brand{flex-basis:400px}}.app-article-masthead .c-article-identifiers{font-size:.875rem;font-weight:300;line-height:1;margin:0 0 8px;overflow:hidden;padding:0}.app-article-masthead .c-article-identifiers--cite-list{margin:0 0 16px}.app-article-masthead .c-article-identifiers *{color:#fff}.app-article-masthead .c-cod{display:none}.app-article-masthead .c-article-identifiers__item{border-left:1px solid #fff;border-right:0;margin:0 17px 8px -9px;padding:0 0 0 8px}.app-article-masthead .c-article-identifiers__item--cite{border-left:0}.app-article-metrics-bar{display:flex;flex-wrap:wrap;font-size:1rem;padding:16px 0 0;row-gap:24px}.app-article-metrics-bar__item{padding:0 16px 0 0}.app-article-metrics-bar__count{font-weight:700}.app-article-metrics-bar__label{font-weight:400;padding-left:4px}.app-article-metrics-bar__icon{height:auto;margin-right:4px;margin-top:-4px;width:auto}.app-article-metrics-bar__arrow-icon{margin:4px 0 0 4px}.app-article-metrics-bar a{color:#000}.app-article-metrics-bar .app-article-metrics-bar__item--metrics{padding-right:0}.app-overview-section .c-article-author-list,.app-overview-section__authors{line-height:2}.app-article-metrics-bar{margin-top:8px}.c-book-toc-pagination+.c-book-section__back-to-top{margin-top:0}.c-article-body .c-article-access-provider__text--chapter{color:#222;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;padding:20px 0}.c-article-body .c-article-access-provider__text--chapter svg.c-status-message__icon{fill:#003f8d;vertical-align:middle}.c-article-body-section__content--separator{padding-top:40px}.c-pdf-download__link{max-height:44px}.app-article-access .u-button--primary,.app-article-access .u-button--primary:visited{color:#fff}.c-article-sidebar{display:none}@media only screen and (min-width:1024px){.c-article-sidebar{display:block}}.c-cod__form{border-radius:12px}.c-cod__label{font-size:.875rem}.c-cod .c-status-message{align-items:center;justify-content:center;margin-bottom:16px;padding-bottom:16px}@media only screen and (min-width:1024px){.c-cod .c-status-message{align-items:inherit}}.c-cod .c-status-message__icon{margin-top:4px}.c-cod .c-cod__prompt{font-size:1rem;margin-bottom:16px}.c-article-body .app-article-access,.c-book-body .app-article-access{display:block}@media only screen and (min-width:1024px){.c-article-body .app-article-access,.c-book-body .app-article-access{display:none}}.c-article-body .app-card-service{margin-bottom:32px}@media only screen and (min-width:1024px){.c-article-body .app-card-service{display:none}}.app-article-access .buybox__buy .u-button--secondary,.app-article-access .u-button--primary,.c-cod__row .u-button--primary{background-color:#025e8d;border:2px solid #025e8d;box-shadow:none;font-size:1rem;font-weight:700;gap:8px 8px;justify-content:center;line-height:1.5;padding:8px 24px}.app-article-access .buybox__buy .u-button--secondary,.app-article-access .u-button--primary:hover,.c-cod__row .u-button--primary:hover{background-color:#fff;color:#025e8d}.app-article-access .buybox__buy .u-button--secondary:hover{background-color:#025e8d;color:#fff}.buybox__buy .c-notes__text{color:#666;font-size:.875rem;padding:0 16px 8px}.c-cod__input{flex-basis:auto;width:100%}.c-article-title{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:2.25rem;font-weight:700;line-height:1.2;margin:12px 0}.c-reading-companion__figure-item figure{margin:0}@media only screen and (min-width:768px){.c-article-title{margin:16px 0}}.app-article-access{border:1px solid #c5e0f4;border-radius:12px}.app-article-access__heading{border-bottom:1px solid #c5e0f4;font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:1.125rem;font-weight:700;margin:0;padding:16px;text-align:center}.app-article-access .buybox__info svg{vertical-align:middle}.c-article-body .app-article-access p{margin-bottom:0}.app-article-access .buybox__info{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif;font-size:1rem;margin:0}.app-article-access{margin:0 0 32px}@media only screen and (min-width:1024px){.app-article-access{margin:0 0 24px}}.c-status-message{font-size:1rem}.c-article-body{font-size:1.125rem}.c-article-body dl,.c-article-body ol,.c-article-body p,.c-article-body ul{margin-bottom:32px;margin-top:0}.c-article-access-provider__text:last-of-type,.c-article-body .c-notes__text:last-of-type{margin-bottom:0}.c-article-body ol p,.c-article-body ul p{margin-bottom:16px}.c-article-section__figure-caption{font-family:Merriweather Sans,Helvetica Neue,Helvetica,Arial,sans-serif}.c-reading-companion__figure-item{border-top-color:#c5e0f4}.c-reading-companion__sticky{max-width:400px}.c-article-section .c-article-section__figure-description>*{font-size:1rem;margin-bottom:16px}.c-reading-companion__reference-item{border-top:1px solid #d5d5d5;padding:16px 0}.c-reading-companion__reference-item:first-child{padding-top:0}.c-article-share-box__button,.js .c-article-authors-search__item .c-article-button{background:0 0;border:2px solid #025e8d;border-radius:32px;box-shadow:none;color:#025e8d;font-size:1rem;font-weight:700;line-height:1.5;margin:0;padding:8px 24px;transition:all .2s ease 0s}.c-article-authors-search__item .c-article-button{width:100%}.c-pdf-download .u-button{background-color:#fff;border:2px solid #fff;color:#01324b;justify-content:center}.c-context-bar__container .c-pdf-download .u-button svg,.c-pdf-download .u-button svg{fill:currentcolor}.c-pdf-download .u-button:visited{color:#01324b}.c-pdf-download .u-button:hover{border:4px solid #01324b;box-shadow:none}.c-pdf-download .u-button:focus,.c-pdf-download .u-button:hover{background-color:#01324b}.c-pdf-download .u-button:focus svg path,.c-pdf-download .u-button:hover svg path{fill:#fff}.c-context-bar__container .c-pdf-download .u-button{background-image:none;border:2px solid;color:#fff}.c-context-bar__container .c-pdf-download .u-button:visited{color:#fff}.c-context-bar__container .c-pdf-download .u-button:hover{text-decoration:none}.c-context-bar__container .c-pdf-download .u-button:focus{box-shadow:none;outline:0;text-decoration:none}.c-context-bar__container .c-pdf-download .u-button:focus,.c-context-bar__container .c-pdf-download .u-button:hover{background-color:#fff;background-image:none;color:#01324b}.c-context-bar__container .c-pdf-download .u-button:focus svg path,.c-context-bar__container .c-pdf-download .u-button:hover svg path{fill:#01324b}.c-context-bar__container .c-pdf-download .u-button,.c-pdf-download .u-button{box-shadow:none;font-size:1rem;font-weight:700;line-height:1.5;padding:8px 24px}.c-context-bar__container .c-pdf-download .u-button{background-color:#025e8d}.c-pdf-download .u-button:hover{border:2px solid #fff}.c-pdf-download .u-button:focus,.c-pdf-download .u-button:hover{background:0 0;box-shadow:none;color:#fff}.c-context-bar__container .c-pdf-download .u-button:hover{border:2px solid #025e8d;box-shadow:none;color:#025e8d}.c-context-bar__container .c-pdf-download .u-button:focus,.c-pdf-download .u-button:focus{border:2px solid #025e8d}.c-article-share-box__button:focus:focus,.c-article__pill-button:focus:focus,.c-context-bar__container .c-pdf-download .u-button:focus:focus,.c-pdf-download .u-button:focus:focus{outline:3px solid #08c;will-change:transform}.c-pdf-download__link .u-icon{padding-top:0}.c-bibliographic-information__column button{margin-bottom:16px}.c-article-body .c-article-author-affiliation__list p,.c-article-body .c-article-author-information__list p,figure{margin:0}.c-article-share-box__button{margin-right:16px}.c-status-message--boxed{border-radius:12px}.c-article-associated-content__collection-title{font-size:1rem}.app-card-service__description,.c-article-body .app-card-service__description{color:#222;margin-bottom:0;margin-top:8px}.app-article-access__subscriptions a,.app-article-access__subscriptions a:visited,.app-book-series-listing__item a,.app-book-series-listing__item a:hover,.app-book-series-listing__item a:visited,.c-article-author-list a,.c-article-author-list a:visited,.c-article-buy-box a,.c-article-buy-box a:visited,.c-article-peer-review a,.c-article-peer-review a:visited,.c-article-satellite-subtitle a,.c-article-satellite-subtitle a:visited,.c-breadcrumbs__link,.c-breadcrumbs__link:hover,.c-breadcrumbs__link:visited{color:#000}.c-article-author-list svg{height:24px;margin:0 0 0 6px;width:24px}.c-article-header{margin-bottom:32px}@media only screen and (min-width:876px){.js .c-ad--conditional{display:block}}.u-lazy-ad-wrapper{background-color:#fff;display:none;min-height:149px}@media only screen and (min-width:876px){.u-lazy-ad-wrapper{display:block}}p.c-ad__label{margin-bottom:4px}.c-ad--728x90{background-color:#fff;border-bottom:2px solid #cedbe0} } </style> <style>@media only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark) { .eds-c-header__brand img{height:24px;width:203px}.app-article-masthead__journal-link img{height:93px;width:72px}@media only screen and (min-width:769px){.app-article-masthead__journal-link img{height:161px;width:122px}} } </style> <link rel="stylesheet" data-test="critical-css-handler" data-inline-css-source="critical-css" href=/oscar-static/app-springerlink/css/core-darwin-8c08f3c2fc.css media="print" onload="this.media='all';this.onload=null"> <link rel="stylesheet" data-test="critical-css-handler" data-inline-css-source="critical-css" href="/oscar-static/app-springerlink/css/enhanced-darwin-article-72ba046d97.css" media="print" onload="this.media='only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark)';this.onload=null"> <script type="text/javascript"> config = { env: 'live', site: 'bmcinfectdis.biomedcentral.com', siteWithPath: 'bmcinfectdis.biomedcentral.com' + window.location.pathname, twitterHashtag: '', cmsPrefix: 'https://studio-cms.springernature.com/studio/', figshareScriptUrl: 'https://widgets.figshare.com/static/figshare.js', hasFigshareInvoked: false, publisherBrand: 'BioMed Central', mustardcut: false }; </script> <script> window.dataLayer = [{"GA Key":"UA-26408784-1","DOI":"10.1186/s12879-016-2173-z","Page":"article","springerJournal":false,"Publishing Model":"Open Access","Country":"HK","japan":false,"doi":"10.1186-s12879-016-2173-z","Journal Id":12879,"Journal Title":"BMC Infectious Diseases","imprint":"BioMed Central","Keywords":"Early rising asexual parasitaemia, Artemisinin-based combination treatments, Children, Nigeria","kwrd":["Early_rising_asexual_parasitaemia","Artemisinin-based_combination_treatments","Children","Nigeria"],"Labs":"Y","ksg":"Krux.segments","kuid":"Krux.uid","Has Body":"Y","Features":[],"Open Access":"Y","hasAccess":"Y","bypassPaywall":"N","user":{"license":{"businessPartnerID":[],"businessPartnerIDString":""}},"Access Type":"open","Bpids":"","Bpnames":"","BPID":["1"],"VG Wort Identifier":"vgzm.415900-10.1186-s12879-016-2173-z","Full HTML":"Y","Subject Codes":["SCH","SCH33096","SCB19002","SCB16003","SCH61006","SCH33002"],"pmc":["H","H33096","B19002","B16003","H61006","H33002"],"session":{"authentication":{"loginStatus":"N"},"attributes":{"edition":"academic"}},"content":{"serial":{"eissn":"1471-2334"},"type":"Article","category":{"pmc":{"primarySubject":"Medicine \u0026 Public Health","primarySubjectCode":"H","secondarySubjects":{"1":"Infectious Diseases","2":"Parasitology","3":"Medical Microbiology","4":"Tropical Medicine","5":"Internal Medicine"},"secondarySubjectCodes":{"1":"H33096","2":"B19002","3":"B16003","4":"H61006","5":"H33002"}},"sucode":"SC11","articleType":"Research article"},"attributes":{"deliveryPlatform":"oscar"}},"page":{"attributes":{"environment":"live"},"category":{"pageType":"article"}},"Event Category":"Article"}]; </script> <script data-test="springer-link-article-datalayer"> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ ga4MeasurementId: 'G-B3E4QL2TPR', ga360TrackingId: 'UA-26408784-1', twitterId: 'o47a7', baiduId: 'aef3043f025ccf2305af8a194652d70b', ga4ServerUrl: 'https://collect.springer.com', imprint: 'springerlink', page: { attributes:{ featureFlags: [{ name: 'darwin-orion', active: true }, { name: 'chapter-books-recs', active: true } ], darwinAvailable: true } } }); </script> <script> (function(w, d) { w.config = w.config || {}; w.config.mustardcut = false; if (w.matchMedia && w.matchMedia('only print, only all and (prefers-color-scheme: no-preference), only all and (prefers-color-scheme: light), only all and (prefers-color-scheme: dark)').matches) { w.config.mustardcut = true; d.classList.add('js'); d.classList.remove('grade-c'); d.classList.remove('no-js'); } })(window, document.documentElement); </script> <script class="js-entry"> if (window.config.mustardcut) { (function(w, d) { window.Component = {}; window.suppressShareButton = false; window.onArticlePage = true; var currentScript = d.currentScript || d.head.querySelector('script.js-entry'); function catchNoModuleSupport() { var scriptEl = d.createElement('script'); return (!('noModule' in scriptEl) && 'onbeforeload' in scriptEl) } var headScripts = [ {'src': '/oscar-static/js/polyfill-es5-bundle-572d4fec60.js', 'async': false} ]; var bodyScripts = [ {'src': '/oscar-static/js/global-article-es5-bundle-dad1690b0d.js', 'async': false, 'module': false}, {'src': '/oscar-static/js/global-article-es6-bundle-e7d03c4cb3.js', 'async': false, 'module': true} ]; function createScript(script) { var scriptEl = d.createElement('script'); scriptEl.src = script.src; scriptEl.async = script.async; if (script.module === true) { scriptEl.type = "module"; if (catchNoModuleSupport()) { scriptEl.src = ''; } } else if (script.module === false) { scriptEl.setAttribute('nomodule', true) } if (script.charset) { scriptEl.setAttribute('charset', script.charset); } return scriptEl; } for (var i = 0; i < headScripts.length; ++i) { var scriptEl = createScript(headScripts[i]); currentScript.parentNode.insertBefore(scriptEl, currentScript.nextSibling); } d.addEventListener('DOMContentLoaded', function() { for (var i = 0; i < bodyScripts.length; ++i) { var scriptEl = createScript(bodyScripts[i]); d.body.appendChild(scriptEl); } }); // Webfont repeat view var config = w.config; if (config && config.publisherBrand && sessionStorage.fontsLoaded === 'true') { d.documentElement.className += ' webfonts-loaded'; } })(window, document); } </script> <script data-src="https://cdn.optimizely.com/js/27195530232.js" data-cc-script="C03"></script> <script data-test="gtm-head"> window.initGTM = function() { if (window.config.mustardcut) { (function (w, d, s, l, i) { w[l] = w[l] || []; w[l].push({'gtm.start': new Date().getTime(), event: 'gtm.js'}); var f = d.getElementsByTagName(s)[0], j = d.createElement(s), dl = l != 'dataLayer' ? '&l=' + l : ''; j.async = true; j.src = 'https://www.googletagmanager.com/gtm.js?id=' + i + dl; f.parentNode.insertBefore(j, f); })(window, document, 'script', 'dataLayer', 'GTM-MRVXSHQ'); } } </script> <script> (function (w, d, t) { function cc() { var h = w.location.hostname; var e = d.createElement(t), s = d.getElementsByTagName(t)[0]; if (h.indexOf('springer.com') > -1 && h.indexOf('biomedcentral.com') === -1 && h.indexOf('springeropen.com') === -1) { if (h.indexOf('link-qa.springer.com') > -1 || h.indexOf('test-www.springer.com') > -1) { e.src = 'https://cmp.springer.com/production_live/en/consent-bundle-17-52.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } else { e.src = 'https://cmp.springer.com/production_live/en/consent-bundle-17-52.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } } else if (h.indexOf('biomedcentral.com') > -1) { if (h.indexOf('biomedcentral.com.qa') > -1) { e.src = 'https://cmp.biomedcentral.com/production_live/en/consent-bundle-15-36.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } else { e.src = 'https://cmp.biomedcentral.com/production_live/en/consent-bundle-15-36.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } } else if (h.indexOf('springeropen.com') > -1) { if (h.indexOf('springeropen.com.qa') > -1) { e.src = 'https://cmp.springernature.com/production_live/en/consent-bundle-16-35.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } else { e.src = 'https://cmp.springernature.com/production_live/en/consent-bundle-16-35.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-MRVXSHQ')"); } } else if (h.indexOf('springernature.com') > -1) { if (h.indexOf('beta-qa.springernature.com') > -1) { e.src = 'https://cmp.springernature.com/production_live/en/consent-bundle-49-43.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-NK22KLS')"); } else { e.src = 'https://cmp.springernature.com/production_live/en/consent-bundle-49-43.js'; e.setAttribute('onload', "initGTM(window,document,'script','dataLayer','GTM-NK22KLS')"); } } else { e.src = '/oscar-static/js/cookie-consent-es5-bundle-cb57c2c98a.js'; e.setAttribute('data-consent', h); } s.insertAdjacentElement('afterend', e); } cc(); })(window, document, 'script'); </script> <link rel="canonical" href="https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-016-2173-z"/> <script type="application/ld+json">{"mainEntity":{"headline":"Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria","description":"Early rising asexual parasitaemia (ERAP), initially defined as ‘an increase in the parasite count over the baseline pre-treatment level during the first 24 h of treatment’ of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs). ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8 h of initiating treatment. Parasitaemia was quantified pre-treatment and 1–2 hourly for 8 h, and less frequently thereafter for 6 weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping. ERAP occurred in 205 of 416 children. A parasitaemia <100,000/μL and parasitaemia 1 day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81–130.1) and 2.5 h (95% CI 2.2–2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2 h (95% CI 0.2–0.3), 1 h (95% CI 0.9–1.1), and 0.9 h−1 (95% CI 0.8–1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones versus time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential. ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria. Pan African Clinical Trial Registry \n PACTR201508001188143\n \n , 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015.","datePublished":"2017-01-31T00:00:00Z","dateModified":"2017-01-31T00:00:00Z","pageStart":"1","pageEnd":"20","license":"http://creativecommons.org/publicdomain/zero/1.0/","sameAs":"https://doi.org/10.1186/s12879-016-2173-z","keywords":["Early rising asexual parasitaemia","Artemisinin-based combination treatments","Children","Nigeria","Infectious Diseases","Parasitology","Medical Microbiology","Tropical Medicine","Internal Medicine"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig1_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig2_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig3_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig4_HTML.gif"],"isPartOf":{"name":"BMC Infectious Diseases","issn":["1471-2334"],"volumeNumber":"17","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"BioMed Central","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Akintunde Sowunmi","affiliation":[{"name":"University of Ibadan","address":{"name":"Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Ibadan","address":{"name":"Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University College Hospital","address":{"name":"Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"email":"akinsowunmi@hotmail.com","@type":"Person"},{"name":"Kazeem Akano","affiliation":[{"name":"University of Ibadan","address":{"name":"Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Adejumoke I. Ayede","affiliation":[{"name":"University of Ibadan","address":{"name":"Department of Paediatrics, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Elsie O. Adewoye","affiliation":[{"name":"University of Ibadan","address":{"name":"Department of Physiology, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Godwin Ntadom","affiliation":[{"name":"National Malaria Elimination Programme, Federal Ministry of Health","address":{"name":"National Malaria Elimination Programme, Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Bayo Fatunmbi","affiliation":[{"name":"World Health Organization, Regional Office for the Western Pacific","address":{"name":"World Health Organization, Regional Office for the Western Pacific, Phnom Penh, Cambodia","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Grace O. Gbotosho","affiliation":[{"name":"University of Ibadan","address":{"name":"Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Ibadan","address":{"name":"Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Onikepe A. Folarin","affiliation":[{"name":"Redeemer’s University","address":{"name":"Department of Biological Sciences, Redeemer’s University, Ede, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Redeemer’s University","address":{"name":"African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer’s University, Ede, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Christian T. Happi","affiliation":[{"name":"Redeemer’s University","address":{"name":"Department of Biological Sciences, Redeemer’s University, Ede, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Redeemer’s University","address":{"name":"African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer’s University, Ede, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"}],"isAccessibleForFree":true,"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> </head> <body class="" >  <noscript> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript>   <noscript data-test="gtm-body"> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript>  <div class="u-visually-hidden" aria-hidden="true" data-test="darwin-icons"> <?xml version="1.0" encoding="UTF-8"?><!DOCTYPE svg PUBLIC "-//W3C//DTD SVG 1.1//EN" "http://www.w3.org/Graphics/SVG/1.1/DTD/svg11.dtd"><svg xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink"><symbol id="icon-eds-i-accesses-medium" viewBox="0 0 24 24"><path d="M15.59 1a1 1 0 0 1 .706.291l5.41 5.385a1 1 0 0 1 .294.709v13.077c0 .674-.269 1.32-.747 1.796a2.549 2.549 0 0 1-1.798.742H15a1 1 0 0 1 0-2h4.455a.549.549 0 0 0 .387-.16.535.535 0 0 0 .158-.378V7.8L15.178 3H5.545a.543.543 0 0 0-.538.451L5 3.538v8.607a1 1 0 0 1-2 0V3.538A2.542 2.542 0 0 1 5.545 1h10.046ZM8 13c2.052 0 4.66 1.61 6.36 3.4l.124.141c.333.41.516.925.516 1.459 0 .6-.232 1.178-.64 1.599C12.666 21.388 10.054 23 8 23c-2.052 0-4.66-1.61-6.353-3.393A2.31 2.31 0 0 1 1 18c0-.6.232-1.178.64-1.6C3.34 14.61 5.948 13 8 13Zm0 2c-1.369 0-3.552 1.348-4.917 2.785A.31.31 0 0 0 3 18c0 .083.031.161.09.222C4.447 19.652 6.631 21 8 21c1.37 0 3.556-1.35 4.917-2.785A.31.31 0 0 0 13 18a.32.32 0 0 0-.048-.17l-.042-.052C11.553 16.348 9.369 15 8 15Zm0 1a2 2 0 1 1 0 4 2 2 0 0 1 0-4Z"/></symbol><symbol id="icon-eds-i-altmetric-medium" viewBox="0 0 24 24"><path d="M12 1c5.978 0 10.843 4.77 10.996 10.712l.004.306-.002.022-.002.248C22.843 18.23 17.978 23 12 23 5.925 23 1 18.075 1 12S5.925 1 12 1Zm-1.726 9.246L8.848 12.53a1 1 0 0 1-.718.461L8.003 13l-4.947.014a9.001 9.001 0 0 0 17.887-.001L16.553 13l-2.205 3.53a1 1 0 0 1-1.735-.068l-.05-.11-2.289-6.106ZM12 3a9.001 9.001 0 0 0-8.947 8.013l4.391-.012L9.652 7.47a1 1 0 0 1 1.784.179l2.288 6.104 1.428-2.283a1 1 0 0 1 .722-.462l.129-.008 4.943.012A9.001 9.001 0 0 0 12 3Z"/></symbol><symbol id="icon-eds-i-arrow-bend-down-medium" viewBox="0 0 24 24"><path d="m11.852 20.989.058.007L12 21l.075-.003.126-.017.111-.03.111-.044.098-.052.104-.074.082-.073 6-6a1 1 0 0 0-1.414-1.414L13 17.585v-12.2C13 4.075 11.964 3 10.667 3H4a1 1 0 1 0 0 2h6.667c.175 0 .333.164.333.385v12.2l-4.293-4.292a1 1 0 0 0-1.32-.083l-.094.083a1 1 0 0 0 0 1.414l6 6c.035.036.073.068.112.097l.11.071.114.054.105.035.118.025Z"/></symbol><symbol id="icon-eds-i-arrow-bend-down-small" viewBox="0 0 16 16"><path d="M1 2a1 1 0 0 0 1 1h5v8.585L3.707 8.293a1 1 0 0 0-1.32-.083l-.094.083a1 1 0 0 0 0 1.414l5 5 .063.059.093.069.081.048.105.048.104.035.105.022.096.01h.136l.122-.018.113-.03.103-.04.1-.053.102-.07.052-.043 5.04-5.037a1 1 0 1 0-1.415-1.414L9 11.583V3a2 2 0 0 0-2-2H2a1 1 0 0 0-1 1Z"/></symbol><symbol id="icon-eds-i-arrow-bend-up-medium" viewBox="0 0 24 24"><path d="m11.852 3.011.058-.007L12 3l.075.003.126.017.111.03.111.044.098.052.104.074.082.073 6 6a1 1 0 1 1-1.414 1.414L13 6.415v12.2C13 19.925 11.964 21 10.667 21H4a1 1 0 0 1 0-2h6.667c.175 0 .333-.164.333-.385v-12.2l-4.293 4.292a1 1 0 0 1-1.32.083l-.094-.083a1 1 0 0 1 0-1.414l6-6c.035-.036.073-.068.112-.097l.11-.071.114-.054.105-.035.118-.025Z"/></symbol><symbol id="icon-eds-i-arrow-bend-up-small" viewBox="0 0 16 16"><path d="M1 13.998a1 1 0 0 1 1-1h5V4.413L3.707 7.705a1 1 0 0 1-1.32.084l-.094-.084a1 1 0 0 1 0-1.414l5-5 .063-.059.093-.068.081-.05.105-.047.104-.035.105-.022L7.94 1l.136.001.122.017.113.03.103.04.1.053.102.07.052.043 5.04 5.037a1 1 0 1 1-1.415 1.414L9 4.415v8.583a2 2 0 0 1-2 2H2a1 1 0 0 1-1-1Z"/></symbol><symbol id="icon-eds-i-arrow-diagonal-medium" viewBox="0 0 24 24"><path d="M14 3h6l.075.003.126.017.111.03.111.044.098.052.096.067.09.08c.036.035.068.073.097.112l.071.11.054.114.035.105.03.148L21 4v6a1 1 0 0 1-2 0V6.414l-4.293 4.293a1 1 0 0 1-1.414-1.414L17.584 5H14a1 1 0 0 1-.993-.883L13 4a1 1 0 0 1 1-1ZM4 13a1 1 0 0 1 1 1v3.584l4.293-4.291a1 1 0 1 1 1.414 1.414L6.414 19H10a1 1 0 0 1 .993.883L11 20a1 1 0 0 1-1 1l-6.075-.003-.126-.017-.111-.03-.111-.044-.098-.052-.096-.067-.09-.08a1.01 1.01 0 0 1-.097-.112l-.071-.11-.054-.114-.035-.105-.025-.118-.007-.058L3 20v-6a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-arrow-diagonal-small" viewBox="0 0 16 16"><path d="m2 15-.082-.004-.119-.016-.111-.03-.111-.044-.098-.052-.096-.067-.09-.08a1.008 1.008 0 0 1-.097-.112l-.071-.11-.031-.062-.034-.081-.024-.076-.025-.118-.007-.058L1 14.02V9a1 1 0 1 1 2 0v2.584l2.793-2.791a1 1 0 1 1 1.414 1.414L4.414 13H7a1 1 0 0 1 .993.883L8 14a1 1 0 0 1-1 1H2ZM14 1l.081.003.12.017.111.03.111.044.098.052.096.067.09.08c.036.035.068.073.097.112l.071.11.031.062.034.081.024.076.03.148L15 2v5a1 1 0 0 1-2 0V4.414l-2.96 2.96A1 1 0 1 1 8.626 5.96L11.584 3H9a1 1 0 0 1-.993-.883L8 2a1 1 0 0 1 1-1h5Z"/></symbol><symbol id="icon-eds-i-arrow-down-medium" viewBox="0 0 24 24"><path d="m20.707 12.728-7.99 7.98a.996.996 0 0 1-.561.281l-.157.011a.998.998 0 0 1-.788-.384l-7.918-7.908a1 1 0 0 1 1.414-1.416L11 17.576V4a1 1 0 0 1 2 0v13.598l6.293-6.285a1 1 0 0 1 1.32-.082l.095.083a1 1 0 0 1-.001 1.414Z"/></symbol><symbol id="icon-eds-i-arrow-down-small" viewBox="0 0 16 16"><path d="m1.293 8.707 6 6 .063.059.093.069.081.048.105.049.104.034.056.013.118.017L8 15l.076-.003.122-.017.113-.03.085-.032.063-.03.098-.058.06-.043.05-.043 6.04-6.037a1 1 0 0 0-1.414-1.414L9 11.583V2a1 1 0 1 0-2 0v9.585L2.707 7.293a1 1 0 0 0-1.32-.083l-.094.083a1 1 0 0 0 0 1.414Z"/></symbol><symbol id="icon-eds-i-arrow-left-medium" viewBox="0 0 24 24"><path d="m11.272 3.293-7.98 7.99a.996.996 0 0 0-.281.561L3 12.001c0 .32.15.605.384.788l7.908 7.918a1 1 0 0 0 1.416-1.414L6.424 13H20a1 1 0 0 0 0-2H6.402l6.285-6.293a1 1 0 0 0 .082-1.32l-.083-.095a1 1 0 0 0-1.414.001Z"/></symbol><symbol id="icon-eds-i-arrow-left-small" viewBox="0 0 16 16"><path d="m7.293 1.293-6 6-.059.063-.069.093-.048.081-.049.105-.034.104-.013.056-.017.118L1 8l.003.076.017.122.03.113.032.085.03.063.058.098.043.06.043.05 6.037 6.04a1 1 0 0 0 1.414-1.414L4.417 9H14a1 1 0 0 0 0-2H4.415l4.292-4.293a1 1 0 0 0 .083-1.32l-.083-.094a1 1 0 0 0-1.414 0Z"/></symbol><symbol id="icon-eds-i-arrow-right-medium" viewBox="0 0 24 24"><path d="m12.728 3.293 7.98 7.99a.996.996 0 0 1 .281.561l.011.157c0 .32-.15.605-.384.788l-7.908 7.918a1 1 0 0 1-1.416-1.414L17.576 13H4a1 1 0 0 1 0-2h13.598l-6.285-6.293a1 1 0 0 1-.082-1.32l.083-.095a1 1 0 0 1 1.414.001Z"/></symbol><symbol id="icon-eds-i-arrow-right-small" viewBox="0 0 16 16"><path d="m8.707 1.293 6 6 .059.063.069.093.048.081.049.105.034.104.013.056.017.118L15 8l-.003.076-.017.122-.03.113-.032.085-.03.063-.058.098-.043.06-.043.05-6.037 6.04a1 1 0 0 1-1.414-1.414L11.583 9H2a1 1 0 1 1 0-2h9.585L7.293 2.707a1 1 0 0 1-.083-1.32l.083-.094a1 1 0 0 1 1.414 0Z"/></symbol><symbol id="icon-eds-i-arrow-up-medium" viewBox="0 0 24 24"><path d="m3.293 11.272 7.99-7.98a.996.996 0 0 1 .561-.281L12.001 3c.32 0 .605.15.788.384l7.918 7.908a1 1 0 0 1-1.414 1.416L13 6.424V20a1 1 0 0 1-2 0V6.402l-6.293 6.285a1 1 0 0 1-1.32.082l-.095-.083a1 1 0 0 1 .001-1.414Z"/></symbol><symbol id="icon-eds-i-arrow-up-small" viewBox="0 0 16 16"><path d="m1.293 7.293 6-6 .063-.059.093-.069.081-.048.105-.049.104-.034.056-.013.118-.017L8 1l.076.003.122.017.113.03.085.032.063.03.098.058.06.043.05.043 6.04 6.037a1 1 0 0 1-1.414 1.414L9 4.417V14a1 1 0 0 1-2 0V4.415L2.707 8.707a1 1 0 0 1-1.32.083l-.094-.083a1 1 0 0 1 0-1.414Z"/></symbol><symbol id="icon-eds-i-article-medium" viewBox="0 0 24 24"><path d="M8 7a1 1 0 0 0 0 2h4a1 1 0 1 0 0-2H8ZM8 11a1 1 0 1 0 0 2h8a1 1 0 1 0 0-2H8ZM7 16a1 1 0 0 1 1-1h8a1 1 0 1 1 0 2H8a1 1 0 0 1-1-1Z"/><path d="M5.545 1A2.542 2.542 0 0 0 3 3.538v16.924A2.542 2.542 0 0 0 5.545 23h12.91A2.542 2.542 0 0 0 21 20.462V3.5A2.5 2.5 0 0 0 18.5 1H5.545ZM5 3.538C5 3.245 5.24 3 5.545 3H18.5a.5.5 0 0 1 .5.5v16.962c0 .293-.24.538-.546.538H5.545A.542.542 0 0 1 5 20.462V3.538Z" clip-rule="evenodd"/></symbol><symbol id="icon-eds-i-book-medium" viewBox="0 0 24 24"><path d="M18.5 1A2.5 2.5 0 0 1 21 3.5v12c0 1.16-.79 2.135-1.86 2.418l-.14.031V21h1a1 1 0 0 1 .993.883L21 22a1 1 0 0 1-1 1H6.5A3.5 3.5 0 0 1 3 19.5v-15A3.5 3.5 0 0 1 6.5 1h12ZM17 18H6.5a1.5 1.5 0 0 0-1.493 1.356L5 19.5A1.5 1.5 0 0 0 6.5 21H17v-3Zm1.5-15h-12A1.5 1.5 0 0 0 5 4.5v11.837l.054-.025a3.481 3.481 0 0 1 1.254-.307L6.5 16h12a.5.5 0 0 0 .492-.41L19 15.5v-12a.5.5 0 0 0-.5-.5ZM15 6a1 1 0 0 1 0 2H9a1 1 0 1 1 0-2h6Z"/></symbol><symbol id="icon-eds-i-book-series-medium" viewBox="0 0 24 24"><path fill-rule="evenodd" d="M1 3.786C1 2.759 1.857 2 2.82 2H6.18c.964 0 1.82.759 1.82 1.786V4h3.168c.668 0 1.298.364 1.616.938.158-.109.333-.195.523-.252l3.216-.965c.923-.277 1.962.204 2.257 1.187l4.146 13.82c.296.984-.307 1.957-1.23 2.234l-3.217.965c-.923.277-1.962-.203-2.257-1.187L13 10.005v10.21c0 1.04-.878 1.785-1.834 1.785H7.833c-.291 0-.575-.07-.83-.195A1.849 1.849 0 0 1 6.18 22H2.821C1.857 22 1 21.241 1 20.214V3.786ZM3 4v11h3V4H3Zm0 16v-3h3v3H3Zm15.075-.04-.814-2.712 2.874-.862.813 2.712-2.873.862Zm1.485-5.49-2.874.862-2.634-8.782 2.873-.862 2.635 8.782ZM8 20V6h3v14H8Z" clip-rule="evenodd"/></symbol><symbol id="icon-eds-i-calendar-acceptance-medium" viewBox="0 0 24 24"><path d="M17 2a1 1 0 0 1 1 1v1h1.5C20.817 4 22 5.183 22 6.5v13c0 1.317-1.183 2.5-2.5 2.5h-15C3.183 22 2 20.817 2 19.5v-13C2 5.183 3.183 4 4.5 4a1 1 0 1 1 0 2c-.212 0-.5.288-.5.5v13c0 .212.288.5.5.5h15c.212 0 .5-.288.5-.5v-13c0-.212-.288-.5-.5-.5H18v1a1 1 0 0 1-2 0V3a1 1 0 0 1 1-1Zm-.534 7.747a1 1 0 0 1 .094 1.412l-4.846 5.538a1 1 0 0 1-1.352.141l-2.77-2.076a1 1 0 0 1 1.2-1.6l2.027 1.519 4.236-4.84a1 1 0 0 1 1.411-.094ZM7.5 2a1 1 0 0 1 1 1v1H14a1 1 0 0 1 0 2H8.5v1a1 1 0 1 1-2 0V3a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-calendar-date-medium" viewBox="0 0 24 24"><path d="M17 2a1 1 0 0 1 1 1v1h1.5C20.817 4 22 5.183 22 6.5v13c0 1.317-1.183 2.5-2.5 2.5h-15C3.183 22 2 20.817 2 19.5v-13C2 5.183 3.183 4 4.5 4a1 1 0 1 1 0 2c-.212 0-.5.288-.5.5v13c0 .212.288.5.5.5h15c.212 0 .5-.288.5-.5v-13c0-.212-.288-.5-.5-.5H18v1a1 1 0 0 1-2 0V3a1 1 0 0 1 1-1ZM8 15a1 1 0 1 1 0 2 1 1 0 0 1 0-2Zm4 0a1 1 0 1 1 0 2 1 1 0 0 1 0-2Zm-4-4a1 1 0 1 1 0 2 1 1 0 0 1 0-2Zm4 0a1 1 0 1 1 0 2 1 1 0 0 1 0-2Zm4 0a1 1 0 1 1 0 2 1 1 0 0 1 0-2ZM7.5 2a1 1 0 0 1 1 1v1H14a1 1 0 0 1 0 2H8.5v1a1 1 0 1 1-2 0V3a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-calendar-decision-medium" viewBox="0 0 24 24"><path d="M17 2a1 1 0 0 1 1 1v1h1.5C20.817 4 22 5.183 22 6.5v13c0 1.317-1.183 2.5-2.5 2.5h-15C3.183 22 2 20.817 2 19.5v-13C2 5.183 3.183 4 4.5 4a1 1 0 1 1 0 2c-.212 0-.5.288-.5.5v13c0 .212.288.5.5.5h15c.212 0 .5-.288.5-.5v-13c0-.212-.288-.5-.5-.5H18v1a1 1 0 0 1-2 0V3a1 1 0 0 1 1-1Zm-2.935 8.246 2.686 2.645c.34.335.34.883 0 1.218l-2.686 2.645a.858.858 0 0 1-1.213-.009.854.854 0 0 1 .009-1.21l1.05-1.035H7.984a.992.992 0 0 1-.984-1c0-.552.44-1 .984-1h5.928l-1.051-1.036a.854.854 0 0 1-.085-1.121l.076-.088a.858.858 0 0 1 1.213-.009ZM7.5 2a1 1 0 0 1 1 1v1H14a1 1 0 0 1 0 2H8.5v1a1 1 0 1 1-2 0V3a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-calendar-impact-factor-medium" viewBox="0 0 24 24"><path d="M17 2a1 1 0 0 1 1 1v1h1.5C20.817 4 22 5.183 22 6.5v13c0 1.317-1.183 2.5-2.5 2.5h-15C3.183 22 2 20.817 2 19.5v-13C2 5.183 3.183 4 4.5 4a1 1 0 1 1 0 2c-.212 0-.5.288-.5.5v13c0 .212.288.5.5.5h15c.212 0 .5-.288.5-.5v-13c0-.212-.288-.5-.5-.5H18v1a1 1 0 0 1-2 0V3a1 1 0 0 1 1-1Zm-3.2 6.924a.48.48 0 0 1 .125.544l-1.52 3.283h2.304c.27 0 .491.215.491.483a.477.477 0 0 1-.13.327l-4.18 4.484a.498.498 0 0 1-.69.031.48.48 0 0 1-.125-.544l1.52-3.284H9.291a.487.487 0 0 1-.491-.482c0-.121.047-.238.13-.327l4.18-4.484a.498.498 0 0 1 .69-.031ZM7.5 2a1 1 0 0 1 1 1v1H14a1 1 0 0 1 0 2H8.5v1a1 1 0 1 1-2 0V3a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-call-papers-medium" viewBox="0 0 24 24"><g><path d="m20.707 2.883-1.414 1.414a1 1 0 0 0 1.414 1.414l1.414-1.414a1 1 0 0 0-1.414-1.414Z"/><path d="M6 16.054c0 2.026 1.052 2.943 3 2.943a1 1 0 1 1 0 2c-2.996 0-5-1.746-5-4.943v-1.227a4.068 4.068 0 0 1-1.83-1.189 4.553 4.553 0 0 1-.87-1.455 4.868 4.868 0 0 1-.3-1.686c0-1.17.417-2.298 1.17-3.14.38-.426.834-.767 1.338-1 .51-.237 1.06-.36 1.617-.36L6.632 6H7l7.932-2.895A2.363 2.363 0 0 1 18 5.36v9.28a2.36 2.36 0 0 1-3.069 2.25l.084.03L7 14.997H6v1.057Zm9.637-11.057a.415.415 0 0 0-.083.008L8 7.638v5.536l7.424 1.786.104.02c.035.01.072.02.109.02.2 0 .363-.16.363-.36V5.36c0-.2-.163-.363-.363-.363Zm-9.638 3h-.874a1.82 1.82 0 0 0-.625.111l-.15.063a2.128 2.128 0 0 0-.689.517c-.42.47-.661 1.123-.661 1.81 0 .34.06.678.176.992.114.308.28.585.485.816.4.447.925.691 1.464.691h.874v-5Z" clip-rule="evenodd"/><path d="M20 8.997h2a1 1 0 1 1 0 2h-2a1 1 0 1 1 0-2ZM20.707 14.293l1.414 1.414a1 1 0 0 1-1.414 1.414l-1.414-1.414a1 1 0 0 1 1.414-1.414Z"/></g></symbol><symbol id="icon-eds-i-card-medium" viewBox="0 0 24 24"><path d="M19.615 2c.315 0 .716.067 1.14.279.76.38 1.245 1.107 1.245 2.106v15.23c0 .315-.067.716-.279 1.14-.38.76-1.107 1.245-2.106 1.245H4.385a2.56 2.56 0 0 1-1.14-.279C2.485 21.341 2 20.614 2 19.615V4.385c0-.315.067-.716.279-1.14C2.659 2.485 3.386 2 4.385 2h15.23Zm0 2H4.385c-.213 0-.265.034-.317.14A.71.71 0 0 0 4 4.385v15.23c0 .213.034.265.14.317a.71.71 0 0 0 .245.068h15.23c.213 0 .265-.034.317-.14a.71.71 0 0 0 .068-.245V4.385c0-.213-.034-.265-.14-.317A.71.71 0 0 0 19.615 4ZM17 16a1 1 0 0 1 0 2H7a1 1 0 0 1 0-2h10Zm0-3a1 1 0 0 1 0 2H7a1 1 0 0 1 0-2h10Zm-.5-7A1.5 1.5 0 0 1 18 7.5v3a1.5 1.5 0 0 1-1.5 1.5h-9A1.5 1.5 0 0 1 6 10.5v-3A1.5 1.5 0 0 1 7.5 6h9ZM16 8H8v2h8V8Z"/></symbol><symbol id="icon-eds-i-cart-medium" viewBox="0 0 24 24"><path d="M5.76 1a1 1 0 0 1 .994.902L7.155 6h13.34c.18 0 .358.02.532.057l.174.045a2.5 2.5 0 0 1 1.693 3.103l-2.069 7.03c-.36 1.099-1.398 1.823-2.49 1.763H8.65c-1.272.015-2.352-.927-2.546-2.244L4.852 3H2a1 1 0 0 1-.993-.883L1 2a1 1 0 0 1 1-1h3.76Zm2.328 14.51a.555.555 0 0 0 .55.488l9.751.001a.533.533 0 0 0 .527-.357l2.059-7a.5.5 0 0 0-.48-.642H7.351l.737 7.51ZM18 19a2 2 0 1 1 0 4 2 2 0 0 1 0-4ZM8 19a2 2 0 1 1 0 4 2 2 0 0 1 0-4Z"/></symbol><symbol id="icon-eds-i-check-circle-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 2a9 9 0 1 0 0 18 9 9 0 0 0 0-18Zm5.125 4.72a1 1 0 0 1 .156 1.405l-6 7.5a1 1 0 0 1-1.421.143l-3-2.5a1 1 0 0 1 1.28-1.536l2.217 1.846 5.362-6.703a1 1 0 0 1 1.406-.156Z"/></symbol><symbol id="icon-eds-i-check-filled-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm5.125 6.72a1 1 0 0 0-1.406.155l-5.362 6.703-2.217-1.846a1 1 0 1 0-1.28 1.536l3 2.5a1 1 0 0 0 1.42-.143l6-7.5a1 1 0 0 0-.155-1.406Z"/></symbol><symbol id="icon-eds-i-chevron-down-medium" viewBox="0 0 24 24"><path d="M3.305 8.28a1 1 0 0 0-.024 1.415l7.495 7.762c.314.345.757.543 1.224.543.467 0 .91-.198 1.204-.522l7.515-7.783a1 1 0 1 0-1.438-1.39L12 15.845l-7.28-7.54A1 1 0 0 0 3.4 8.2l-.096.082Z"/></symbol><symbol id="icon-eds-i-chevron-down-small" viewBox="0 0 16 16"><path d="M13.692 5.278a1 1 0 0 1 .03 1.414L9.103 11.51a1.491 1.491 0 0 1-2.188.019L2.278 6.692a1 1 0 0 1 1.444-1.384L8 9.771l4.278-4.463a1 1 0 0 1 1.318-.111l.096.081Z"/></symbol><symbol id="icon-eds-i-chevron-left-medium" viewBox="0 0 24 24"><path d="M15.72 3.305a1 1 0 0 0-1.415-.024l-7.762 7.495A1.655 1.655 0 0 0 6 12c0 .467.198.91.522 1.204l7.783 7.515a1 1 0 1 0 1.39-1.438L8.155 12l7.54-7.28A1 1 0 0 0 15.8 3.4l-.082-.096Z"/></symbol><symbol id="icon-eds-i-chevron-left-small" viewBox="0 0 16 16"><path d="M10.722 2.308a1 1 0 0 0-1.414-.03L4.49 6.897a1.491 1.491 0 0 0-.019 2.188l4.838 4.637a1 1 0 1 0 1.384-1.444L6.229 8l4.463-4.278a1 1 0 0 0 .111-1.318l-.081-.096Z"/></symbol><symbol id="icon-eds-i-chevron-right-medium" viewBox="0 0 24 24"><path d="M8.28 3.305a1 1 0 0 1 1.415-.024l7.762 7.495c.345.314.543.757.543 1.224 0 .467-.198.91-.522 1.204l-7.783 7.515a1 1 0 1 1-1.39-1.438L15.845 12l-7.54-7.28A1 1 0 0 1 8.2 3.4l.082-.096Z"/></symbol><symbol id="icon-eds-i-chevron-right-small" viewBox="0 0 16 16"><path d="M5.278 2.308a1 1 0 0 1 1.414-.03l4.819 4.619a1.491 1.491 0 0 1 .019 2.188l-4.838 4.637a1 1 0 1 1-1.384-1.444L9.771 8 5.308 3.722a1 1 0 0 1-.111-1.318l.081-.096Z"/></symbol><symbol id="icon-eds-i-chevron-up-medium" viewBox="0 0 24 24"><path d="M20.695 15.72a1 1 0 0 0 .024-1.415l-7.495-7.762A1.655 1.655 0 0 0 12 6c-.467 0-.91.198-1.204.522l-7.515 7.783a1 1 0 1 0 1.438 1.39L12 8.155l7.28 7.54a1 1 0 0 0 1.319.106l.096-.082Z"/></symbol><symbol id="icon-eds-i-chevron-up-small" viewBox="0 0 16 16"><path d="M13.692 10.722a1 1 0 0 0 .03-1.414L9.103 4.49a1.491 1.491 0 0 0-2.188-.019L2.278 9.308a1 1 0 0 0 1.444 1.384L8 6.229l4.278 4.463a1 1 0 0 0 1.318.111l.096-.081Z"/></symbol><symbol id="icon-eds-i-citations-medium" viewBox="0 0 24 24"><path d="M15.59 1a1 1 0 0 1 .706.291l5.41 5.385a1 1 0 0 1 .294.709v13.077c0 .674-.269 1.32-.747 1.796a2.549 2.549 0 0 1-1.798.742h-5.843a1 1 0 1 1 0-2h5.843a.549.549 0 0 0 .387-.16.535.535 0 0 0 .158-.378V7.8L15.178 3H5.545a.543.543 0 0 0-.538.451L5 3.538v8.607a1 1 0 0 1-2 0V3.538A2.542 2.542 0 0 1 5.545 1h10.046ZM5.483 14.35c.197.26.17.62-.049.848l-.095.083-.016.011c-.36.24-.628.45-.804.634-.393.409-.59.93-.59 1.562.077-.019.192-.028.345-.028.442 0 .84.158 1.195.474.355.316.532.716.532 1.2 0 .501-.173.9-.518 1.198-.345.298-.767.446-1.266.446-.672 0-1.209-.195-1.612-.585-.403-.39-.604-.976-.604-1.757 0-.744.11-1.39.33-1.938.222-.549.49-1.009.807-1.38a4.28 4.28 0 0 1 .992-.88c.07-.043.148-.087.232-.133a.881.881 0 0 1 1.121.245Zm5 0c.197.26.17.62-.049.848l-.095.083-.016.011c-.36.24-.628.45-.804.634-.393.409-.59.93-.59 1.562.077-.019.192-.028.345-.028.442 0 .84.158 1.195.474.355.316.532.716.532 1.2 0 .501-.173.9-.518 1.198-.345.298-.767.446-1.266.446-.672 0-1.209-.195-1.612-.585-.403-.39-.604-.976-.604-1.757 0-.744.11-1.39.33-1.938.222-.549.49-1.009.807-1.38a4.28 4.28 0 0 1 .992-.88c.07-.043.148-.087.232-.133a.881.881 0 0 1 1.121.245Z"/></symbol><symbol id="icon-eds-i-clipboard-check-medium" viewBox="0 0 24 24"><path d="M14.4 1c1.238 0 2.274.865 2.536 2.024L18.5 3C19.886 3 21 4.14 21 5.535v14.93C21 21.86 19.886 23 18.5 23h-13C4.114 23 3 21.86 3 20.465V5.535C3 4.14 4.114 3 5.5 3h1.57c.27-1.147 1.3-2 2.53-2h4.8Zm4.115 4-1.59.024A2.601 2.601 0 0 1 14.4 7H9.6c-1.23 0-2.26-.853-2.53-2H5.5c-.27 0-.5.234-.5.535v14.93c0 .3.23.535.5.535h13c.27 0 .5-.234.5-.535V5.535c0-.3-.23-.535-.485-.535Zm-1.909 4.205a1 1 0 0 1 .19 1.401l-5.334 7a1 1 0 0 1-1.344.23l-2.667-1.75a1 1 0 1 1 1.098-1.672l1.887 1.238 4.769-6.258a1 1 0 0 1 1.401-.19ZM14.4 3H9.6a.6.6 0 0 0-.6.6v.8a.6.6 0 0 0 .6.6h4.8a.6.6 0 0 0 .6-.6v-.8a.6.6 0 0 0-.6-.6Z"/></symbol><symbol id="icon-eds-i-clipboard-report-medium" viewBox="0 0 24 24"><path d="M14.4 1c1.238 0 2.274.865 2.536 2.024L18.5 3C19.886 3 21 4.14 21 5.535v14.93C21 21.86 19.886 23 18.5 23h-13C4.114 23 3 21.86 3 20.465V5.535C3 4.14 4.114 3 5.5 3h1.57c.27-1.147 1.3-2 2.53-2h4.8Zm4.115 4-1.59.024A2.601 2.601 0 0 1 14.4 7H9.6c-1.23 0-2.26-.853-2.53-2H5.5c-.27 0-.5.234-.5.535v14.93c0 .3.23.535.5.535h13c.27 0 .5-.234.5-.535V5.535c0-.3-.23-.535-.485-.535Zm-2.658 10.929a1 1 0 0 1 0 2H8a1 1 0 0 1 0-2h7.857Zm0-3.929a1 1 0 0 1 0 2H8a1 1 0 0 1 0-2h7.857ZM14.4 3H9.6a.6.6 0 0 0-.6.6v.8a.6.6 0 0 0 .6.6h4.8a.6.6 0 0 0 .6-.6v-.8a.6.6 0 0 0-.6-.6Z"/></symbol><symbol id="icon-eds-i-close-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 2a9 9 0 1 0 0 18 9 9 0 0 0 0-18ZM8.707 7.293 12 10.585l3.293-3.292a1 1 0 0 1 1.414 1.414L13.415 12l3.292 3.293a1 1 0 0 1-1.414 1.414L12 13.415l-3.293 3.292a1 1 0 1 1-1.414-1.414L10.585 12 7.293 8.707a1 1 0 0 1 1.414-1.414Z"/></symbol><symbol id="icon-eds-i-cloud-upload-medium" viewBox="0 0 24 24"><path d="m12.852 10.011.028-.004L13 10l.075.003.126.017.086.022.136.052.098.052.104.074.082.073 3 3a1 1 0 0 1 0 1.414l-.094.083a1 1 0 0 1-1.32-.083L14 13.416V20a1 1 0 0 1-2 0v-6.586l-1.293 1.293a1 1 0 0 1-1.32.083l-.094-.083a1 1 0 0 1 0-1.414l3-3 .112-.097.11-.071.114-.054.105-.035.118-.025Zm.587-7.962c3.065.362 5.497 2.662 5.992 5.562l.013.085.207.073c2.117.782 3.496 2.845 3.337 5.097l-.022.226c-.297 2.561-2.503 4.491-5.124 4.502a1 1 0 1 1-.009-2c1.619-.007 2.967-1.186 3.147-2.733.179-1.542-.86-2.979-2.487-3.353-.512-.149-.894-.579-.981-1.165-.21-2.237-2-4.035-4.308-4.308-2.31-.273-4.497 1.06-5.25 3.19l-.049.113c-.234.468-.718.756-1.176.743-1.418.057-2.689.857-3.32 2.084a3.668 3.668 0 0 0 .262 3.798c.796 1.136 2.169 1.764 3.583 1.635a1 1 0 1 1 .182 1.992c-2.125.194-4.193-.753-5.403-2.48a5.668 5.668 0 0 1-.403-5.86c.85-1.652 2.449-2.79 4.323-3.092l.287-.039.013-.028c1.207-2.741 4.125-4.404 7.186-4.042Z"/></symbol><symbol id="icon-eds-i-collection-medium" viewBox="0 0 24 24"><path d="M21 7a1 1 0 0 1 1 1v12.5a2.5 2.5 0 0 1-2.5 2.5H8a1 1 0 0 1 0-2h11.5a.5.5 0 0 0 .5-.5V8a1 1 0 0 1 1-1Zm-5.5-5A2.5 2.5 0 0 1 18 4.5v12a2.5 2.5 0 0 1-2.5 2.5h-11A2.5 2.5 0 0 1 2 16.5v-12A2.5 2.5 0 0 1 4.5 2h11Zm0 2h-11a.5.5 0 0 0-.5.5v12a.5.5 0 0 0 .5.5h11a.5.5 0 0 0 .5-.5v-12a.5.5 0 0 0-.5-.5ZM13 13a1 1 0 0 1 0 2H7a1 1 0 0 1 0-2h6Zm0-3.5a1 1 0 0 1 0 2H7a1 1 0 0 1 0-2h6ZM13 6a1 1 0 0 1 0 2H7a1 1 0 1 1 0-2h6Z"/></symbol><symbol id="icon-eds-i-conference-series-medium" viewBox="0 0 24 24"><path fill-rule="evenodd" d="M4.5 2A2.5 2.5 0 0 0 2 4.5v11A2.5 2.5 0 0 0 4.5 18h2.37l-2.534 2.253a1 1 0 0 0 1.328 1.494L9.88 18H11v3a1 1 0 1 0 2 0v-3h1.12l4.216 3.747a1 1 0 0 0 1.328-1.494L17.13 18h2.37a2.5 2.5 0 0 0 2.5-2.5v-11A2.5 2.5 0 0 0 19.5 2h-15ZM20 6V4.5a.5.5 0 0 0-.5-.5h-15a.5.5 0 0 0-.5.5V6h16ZM4 8v7.5a.5.5 0 0 0 .5.5h15a.5.5 0 0 0 .5-.5V8H4Z" clip-rule="evenodd"/></symbol><symbol id="icon-eds-i-delivery-medium" viewBox="0 0 24 24"><path d="M8.51 20.598a3.037 3.037 0 0 1-3.02 0A2.968 2.968 0 0 1 4.161 19L3.5 19A2.5 2.5 0 0 1 1 16.5v-11A2.5 2.5 0 0 1 3.5 3h10a2.5 2.5 0 0 1 2.45 2.004L16 5h2.527c.976 0 1.855.585 2.27 1.49l2.112 4.62a1 1 0 0 1 .091.416v4.856C23 17.814 21.889 19 20.484 19h-.523a1.01 1.01 0 0 1-.121-.007 2.96 2.96 0 0 1-1.33 1.605 3.037 3.037 0 0 1-3.02 0A2.968 2.968 0 0 1 14.161 19H9.838a2.968 2.968 0 0 1-1.327 1.597Zm-2.024-3.462a.955.955 0 0 0-.481.73L5.999 18l.001.022a.944.944 0 0 0 .388.777l.098.065c.316.181.712.181 1.028 0A.97.97 0 0 0 8 17.978a.95.95 0 0 0-.486-.842 1.037 1.037 0 0 0-1.028 0Zm10 0a.955.955 0 0 0-.481.73l-.005.156a.944.944 0 0 0 .388.777l.098.065c.316.181.712.181 1.028 0a.97.97 0 0 0 .486-.886.95.95 0 0 0-.486-.842 1.037 1.037 0 0 0-1.028 0ZM21 12h-5v3.17a3.038 3.038 0 0 1 2.51.232 2.993 2.993 0 0 1 1.277 1.45l.058.155.058-.005.581-.002c.27 0 .516-.263.516-.618V12Zm-7.5-7h-10a.5.5 0 0 0-.5.5v11a.5.5 0 0 0 .5.5h.662a2.964 2.964 0 0 1 1.155-1.491l.172-.107a3.037 3.037 0 0 1 3.022 0A2.987 2.987 0 0 1 9.843 17H13.5a.5.5 0 0 0 .5-.5v-11a.5.5 0 0 0-.5-.5Zm5.027 2H16v3h4.203l-1.224-2.677a.532.532 0 0 0-.375-.316L18.527 7Z"/></symbol><symbol id="icon-eds-i-download-medium" viewBox="0 0 24 24"><path d="M22 18.5a3.5 3.5 0 0 1-3.5 3.5h-13A3.5 3.5 0 0 1 2 18.5V18a1 1 0 0 1 2 0v.5A1.5 1.5 0 0 0 5.5 20h13a1.5 1.5 0 0 0 1.5-1.5V18a1 1 0 0 1 2 0v.5Zm-3.293-7.793-6 6-.063.059-.093.069-.081.048-.105.049-.104.034-.056.013-.118.017L12 17l-.076-.003-.122-.017-.113-.03-.085-.032-.063-.03-.098-.058-.06-.043-.05-.043-6.04-6.037a1 1 0 0 1 1.414-1.414l4.294 4.29L11 3a1 1 0 0 1 2 0l.001 10.585 4.292-4.292a1 1 0 0 1 1.32-.083l.094.083a1 1 0 0 1 0 1.414Z"/></symbol><symbol id="icon-eds-i-edit-medium" viewBox="0 0 24 24"><path d="M17.149 2a2.38 2.38 0 0 1 1.699.711l2.446 2.46a2.384 2.384 0 0 1 .005 3.38L10.01 19.906a1 1 0 0 1-.434.257l-6.3 1.8a1 1 0 0 1-1.237-1.237l1.8-6.3a1 1 0 0 1 .257-.434L15.443 2.718A2.385 2.385 0 0 1 17.15 2Zm-3.874 5.689-7.586 7.536-1.234 4.319 4.318-1.234 7.54-7.582-3.038-3.039ZM17.149 4a.395.395 0 0 0-.286.126L14.695 6.28l3.029 3.029 2.162-2.173a.384.384 0 0 0 .106-.197L20 6.864c0-.103-.04-.2-.119-.278l-2.457-2.47A.385.385 0 0 0 17.149 4Z"/></symbol><symbol id="icon-eds-i-education-medium" viewBox="0 0 24 24"><path fill-rule="evenodd" d="M12.41 2.088a1 1 0 0 0-.82 0l-10 4.5a1 1 0 0 0 0 1.824L3 9.047v7.124A3.001 3.001 0 0 0 4 22a3 3 0 0 0 1-5.83V9.948l1 .45V14.5a1 1 0 0 0 .087.408L7 14.5c-.913.408-.912.41-.912.41l.001.003.003.006.007.015a1.988 1.988 0 0 0 .083.16c.054.097.131.225.236.373.21.297.53.68.993 1.057C8.351 17.292 9.824 18 12 18c2.176 0 3.65-.707 4.589-1.476.463-.378.783-.76.993-1.057a4.162 4.162 0 0 0 .319-.533l.007-.015.003-.006v-.003h.002s0-.002-.913-.41l.913.408A1 1 0 0 0 18 14.5v-4.103l4.41-1.985a1 1 0 0 0 0-1.824l-10-4.5ZM16 11.297l-3.59 1.615a1 1 0 0 1-.82 0L8 11.297v2.94a3.388 3.388 0 0 0 .677.739C9.267 15.457 10.294 16 12 16s2.734-.543 3.323-1.024a3.388 3.388 0 0 0 .677-.739v-2.94ZM4.437 7.5 12 4.097 19.563 7.5 12 10.903 4.437 7.5ZM3 19a1 1 0 1 1 2 0 1 1 0 0 1-2 0Z" clip-rule="evenodd"/></symbol><symbol id="icon-eds-i-error-diamond-medium" viewBox="0 0 24 24"><path d="M12.002 1c.702 0 1.375.279 1.871.775l8.35 8.353a2.646 2.646 0 0 1 .001 3.744l-8.353 8.353a2.646 2.646 0 0 1-3.742 0l-8.353-8.353a2.646 2.646 0 0 1 0-3.744l8.353-8.353.156-.142c.424-.362.952-.58 1.507-.625l.21-.008Zm0 2a.646.646 0 0 0-.38.123l-.093.08-8.34 8.34a.646.646 0 0 0-.18.355L3 12c0 .171.068.336.19.457l8.353 8.354a.646.646 0 0 0 .914 0l8.354-8.354a.646.646 0 0 0-.001-.914l-8.351-8.354A.646.646 0 0 0 12.002 3ZM12 14.5a1.5 1.5 0 0 1 .144 2.993L12 17.5a1.5 1.5 0 0 1 0-3ZM12 6a1 1 0 0 1 1 1v5a1 1 0 0 1-2 0V7a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-error-filled-medium" viewBox="0 0 24 24"><path d="M12.002 1c.702 0 1.375.279 1.871.775l8.35 8.353a2.646 2.646 0 0 1 .001 3.744l-8.353 8.353a2.646 2.646 0 0 1-3.742 0l-8.353-8.353a2.646 2.646 0 0 1 0-3.744l8.353-8.353.156-.142c.424-.362.952-.58 1.507-.625l.21-.008ZM12 14.5a1.5 1.5 0 0 0 0 3l.144-.007A1.5 1.5 0 0 0 12 14.5ZM12 6a1 1 0 0 0-1 1v5a1 1 0 0 0 2 0V7a1 1 0 0 0-1-1Z"/></symbol><symbol id="icon-eds-i-external-link-medium" viewBox="0 0 24 24"><path d="M9 2a1 1 0 1 1 0 2H4.6c-.371 0-.6.209-.6.5v15c0 .291.229.5.6.5h14.8c.371 0 .6-.209.6-.5V15a1 1 0 0 1 2 0v4.5c0 1.438-1.162 2.5-2.6 2.5H4.6C3.162 22 2 20.938 2 19.5v-15C2 3.062 3.162 2 4.6 2H9Zm6 0h6l.075.003.126.017.111.03.111.044.098.052.096.067.09.08c.036.035.068.073.097.112l.071.11.054.114.035.105.03.148L22 3v6a1 1 0 0 1-2 0V5.414l-6.693 6.693a1 1 0 0 1-1.414-1.414L18.584 4H15a1 1 0 0 1-.993-.883L14 3a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-external-link-small" viewBox="0 0 16 16"><path d="M5 1a1 1 0 1 1 0 2l-2-.001V13L13 13v-2a1 1 0 0 1 2 0v2c0 1.15-.93 2-2.067 2H3.067C1.93 15 1 14.15 1 13V3c0-1.15.93-2 2.067-2H5Zm4 0h5l.075.003.126.017.111.03.111.044.098.052.096.067.09.08.044.047.073.093.051.083.054.113.035.105.03.148L15 2v5a1 1 0 0 1-2 0V4.414L9.107 8.307a1 1 0 0 1-1.414-1.414L11.584 3H9a1 1 0 0 1-.993-.883L8 2a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-file-download-medium" viewBox="0 0 24 24"><path d="M14.5 1a1 1 0 0 1 .707.293l5.5 5.5A1 1 0 0 1 21 7.5v12.962A2.542 2.542 0 0 1 18.455 23H5.545A2.542 2.542 0 0 1 3 20.462V3.538A2.542 2.542 0 0 1 5.545 1H14.5Zm-.415 2h-8.54A.542.542 0 0 0 5 3.538v16.924c0 .296.243.538.545.538h12.91a.542.542 0 0 0 .545-.538V7.915L14.085 3ZM12 7a1 1 0 0 1 1 1v6.585l2.293-2.292a1 1 0 0 1 1.32-.083l.094.083a1 1 0 0 1 0 1.414l-4 4a1.008 1.008 0 0 1-.112.097l-.11.071-.114.054-.105.035-.149.03L12 18l-.075-.003-.126-.017-.111-.03-.111-.044-.098-.052-.096-.067-.09-.08-4-4a1 1 0 0 1 1.414-1.414L11 14.585V8a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-file-report-medium" viewBox="0 0 24 24"><path d="M14.5 1a1 1 0 0 1 .707.293l5.5 5.5A1 1 0 0 1 21 7.5v12.962c0 .674-.269 1.32-.747 1.796a2.549 2.549 0 0 1-1.798.742H5.545c-.674 0-1.32-.267-1.798-.742A2.535 2.535 0 0 1 3 20.462V3.538A2.542 2.542 0 0 1 5.545 1H14.5Zm-.415 2h-8.54A.542.542 0 0 0 5 3.538v16.924c0 .142.057.278.158.379.102.102.242.159.387.159h12.91a.549.549 0 0 0 .387-.16.535.535 0 0 0 .158-.378V7.915L14.085 3ZM16 17a1 1 0 0 1 0 2H8a1 1 0 0 1 0-2h8Zm0-3a1 1 0 0 1 0 2H8a1 1 0 0 1 0-2h8Zm-4.793-6.207L13 9.585l1.793-1.792a1 1 0 0 1 1.32-.083l.094.083a1 1 0 0 1 0 1.414l-2.5 2.5a1 1 0 0 1-1.414 0L10.5 9.915l-1.793 1.792a1 1 0 0 1-1.32.083l-.094-.083a1 1 0 0 1 0-1.414l2.5-2.5a1 1 0 0 1 1.414 0Z"/></symbol><symbol id="icon-eds-i-file-text-medium" viewBox="0 0 24 24"><path d="M14.5 1a1 1 0 0 1 .707.293l5.5 5.5A1 1 0 0 1 21 7.5v12.962A2.542 2.542 0 0 1 18.455 23H5.545A2.542 2.542 0 0 1 3 20.462V3.538A2.542 2.542 0 0 1 5.545 1H14.5Zm-.415 2h-8.54A.542.542 0 0 0 5 3.538v16.924c0 .296.243.538.545.538h12.91a.542.542 0 0 0 .545-.538V7.915L14.085 3ZM16 15a1 1 0 0 1 0 2H8a1 1 0 0 1 0-2h8Zm0-4a1 1 0 0 1 0 2H8a1 1 0 0 1 0-2h8Zm-5-4a1 1 0 0 1 0 2H8a1 1 0 1 1 0-2h3Z"/></symbol><symbol id="icon-eds-i-file-upload-medium" viewBox="0 0 24 24"><path d="M14.5 1a1 1 0 0 1 .707.293l5.5 5.5A1 1 0 0 1 21 7.5v12.962A2.542 2.542 0 0 1 18.455 23H5.545A2.542 2.542 0 0 1 3 20.462V3.538A2.542 2.542 0 0 1 5.545 1H14.5Zm-.415 2h-8.54A.542.542 0 0 0 5 3.538v16.924c0 .296.243.538.545.538h12.91a.542.542 0 0 0 .545-.538V7.915L14.085 3Zm-2.233 4.011.058-.007L12 7l.075.003.126.017.111.03.111.044.098.052.104.074.082.073 4 4a1 1 0 0 1 0 1.414l-.094.083a1 1 0 0 1-1.32-.083L13 10.415V17a1 1 0 0 1-2 0v-6.585l-2.293 2.292a1 1 0 0 1-1.32.083l-.094-.083a1 1 0 0 1 0-1.414l4-4 .112-.097.11-.071.114-.054.105-.035.118-.025Z"/></symbol><symbol id="icon-eds-i-filter-medium" viewBox="0 0 24 24"><path d="M21 2a1 1 0 0 1 .82 1.573L15 13.314V18a1 1 0 0 1-.31.724l-.09.076-4 3A1 1 0 0 1 9 21v-7.684L2.18 3.573a1 1 0 0 1 .707-1.567L3 2h18Zm-1.921 2H4.92l5.9 8.427a1 1 0 0 1 .172.45L11 13v6l2-1.5V13a1 1 0 0 1 .117-.469l.064-.104L19.079 4Z"/></symbol><symbol id="icon-eds-i-funding-medium" viewBox="0 0 24 24"><path fill-rule="evenodd" d="M23 8A7 7 0 1 0 9 8a7 7 0 0 0 14 0ZM9.006 12.225A4.07 4.07 0 0 0 6.12 11.02H2a.979.979 0 1 0 0 1.958h4.12c.558 0 1.094.222 1.489.617l2.207 2.288c.27.27.27.687.012.944a.656.656 0 0 1-.928 0L7.744 15.67a.98.98 0 0 0-1.386 1.384l1.157 1.158c.535.536 1.244.791 1.946.765l.041.002h6.922c.874 0 1.597.748 1.597 1.688 0 .203-.146.354-.309.354H7.755c-.487 0-.96-.178-1.339-.504L2.64 17.259a.979.979 0 0 0-1.28 1.482L5.137 22c.733.631 1.66.979 2.618.979h9.957c1.26 0 2.267-1.043 2.267-2.312 0-2.006-1.584-3.646-3.555-3.646h-4.529a2.617 2.617 0 0 0-.681-2.509l-2.208-2.287ZM16 3a5 5 0 1 0 0 10 5 5 0 0 0 0-10Zm.979 3.5a.979.979 0 1 0-1.958 0v3a.979.979 0 1 0 1.958 0v-3Z" clip-rule="evenodd"/></symbol><symbol id="icon-eds-i-hashtag-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 2a9 9 0 1 0 0 18 9 9 0 0 0 0-18ZM9.52 18.189a1 1 0 1 1-1.964-.378l.437-2.274H6a1 1 0 1 1 0-2h2.378l.592-3.076H6a1 1 0 0 1 0-2h3.354l.51-2.65a1 1 0 1 1 1.964.378l-.437 2.272h3.04l.51-2.65a1 1 0 1 1 1.964.378l-.438 2.272H18a1 1 0 0 1 0 2h-1.917l-.592 3.076H18a1 1 0 0 1 0 2h-2.893l-.51 2.652a1 1 0 1 1-1.964-.378l.437-2.274h-3.04l-.51 2.652Zm.895-4.652h3.04l.591-3.076h-3.04l-.591 3.076Z"/></symbol><symbol id="icon-eds-i-home-medium" viewBox="0 0 24 24"><path d="M5 22a1 1 0 0 1-1-1v-8.586l-1.293 1.293a1 1 0 0 1-1.32.083l-.094-.083a1 1 0 0 1 0-1.414l10-10a1 1 0 0 1 1.414 0l10 10a1 1 0 0 1-1.414 1.414L20 12.415V21a1 1 0 0 1-1 1H5Zm7-17.585-6 5.999V20h5v-4a1 1 0 0 1 2 0v4h5v-9.585l-6-6Z"/></symbol><symbol id="icon-eds-i-image-medium" viewBox="0 0 24 24"><path d="M19.615 2A2.385 2.385 0 0 1 22 4.385v15.23A2.385 2.385 0 0 1 19.615 22H4.385A2.385 2.385 0 0 1 2 19.615V4.385A2.385 2.385 0 0 1 4.385 2h15.23Zm0 2H4.385A.385.385 0 0 0 4 4.385v15.23c0 .213.172.385.385.385h1.244l10.228-8.76a1 1 0 0 1 1.254-.037L20 13.392V4.385A.385.385 0 0 0 19.615 4Zm-3.07 9.283L8.703 20h10.912a.385.385 0 0 0 .385-.385v-3.713l-3.455-2.619ZM9.5 6a3.5 3.5 0 1 1 0 7 3.5 3.5 0 0 1 0-7Zm0 2a1.5 1.5 0 1 0 0 3 1.5 1.5 0 0 0 0-3Z"/></symbol><symbol id="icon-eds-i-impact-factor-medium" viewBox="0 0 24 24"><path d="M16.49 2.672c.74.694.986 1.765.632 2.712l-.04.1-1.549 3.54h1.477a2.496 2.496 0 0 1 2.485 2.34l.005.163c0 .618-.23 1.21-.642 1.675l-7.147 7.961a2.48 2.48 0 0 1-3.554.165 2.512 2.512 0 0 1-.633-2.712l.042-.103L9.108 15H7.46c-1.393 0-2.379-1.11-2.455-2.369L5 12.473c0-.593.142-1.145.628-1.692l7.307-7.944a2.48 2.48 0 0 1 3.555-.165ZM14.43 4.164l-7.33 7.97c-.083.093-.101.214-.101.34 0 .277.19.526.46.526h4.163l.097-.009c.015 0 .03.003.046.009.181.078.264.32.186.5l-2.554 5.817a.512.512 0 0 0 .127.552.48.48 0 0 0 .69-.033l7.155-7.97a.513.513 0 0 0 .13-.34.497.497 0 0 0-.49-.502h-3.988a.355.355 0 0 1-.328-.497l2.555-5.844a.512.512 0 0 0-.127-.552.48.48 0 0 0-.69.033Z"/></symbol><symbol id="icon-eds-i-info-circle-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 2a9 9 0 1 0 0 18 9 9 0 0 0 0-18Zm0 7a1 1 0 0 1 1 1v5h1.5a1 1 0 0 1 0 2h-5a1 1 0 0 1 0-2H11v-4h-.5a1 1 0 0 1-.993-.883L9.5 11a1 1 0 0 1 1-1H12Zm0-4.5a1.5 1.5 0 0 1 .144 2.993L12 8.5a1.5 1.5 0 0 1 0-3Z"/></symbol><symbol id="icon-eds-i-info-filled-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 9h-1.5a1 1 0 0 0-1 1l.007.117A1 1 0 0 0 10.5 12h.5v4H9.5a1 1 0 0 0 0 2h5a1 1 0 0 0 0-2H13v-5a1 1 0 0 0-1-1Zm0-4.5a1.5 1.5 0 0 0 0 3l.144-.007A1.5 1.5 0 0 0 12 5.5Z"/></symbol><symbol id="icon-eds-i-journal-medium" viewBox="0 0 24 24"><path d="M18.5 1A2.5 2.5 0 0 1 21 3.5v14a2.5 2.5 0 0 1-2.5 2.5h-13a.5.5 0 1 0 0 1H20a1 1 0 0 1 0 2H5.5A2.5 2.5 0 0 1 3 20.5v-17A2.5 2.5 0 0 1 5.5 1h13ZM7 3H5.5a.5.5 0 0 0-.5.5v14.549l.016-.002c.104-.02.211-.035.32-.042L5.5 18H7V3Zm11.5 0H9v15h9.5a.5.5 0 0 0 .5-.5v-14a.5.5 0 0 0-.5-.5ZM16 5a1 1 0 0 1 1 1v4a1 1 0 0 1-1 1h-5a1 1 0 0 1-1-1V6a1 1 0 0 1 1-1h5Zm-1 2h-3v2h3V7Z"/></symbol><symbol id="icon-eds-i-mail-medium" viewBox="0 0 24 24"><path d="M20.462 3C21.875 3 23 4.184 23 5.619v12.762C23 19.816 21.875 21 20.462 21H3.538C2.125 21 1 19.816 1 18.381V5.619C1 4.184 2.125 3 3.538 3h16.924ZM21 8.158l-7.378 6.258a2.549 2.549 0 0 1-3.253-.008L3 8.16v10.222c0 .353.253.619.538.619h16.924c.285 0 .538-.266.538-.619V8.158ZM20.462 5H3.538c-.264 0-.5.228-.534.542l8.65 7.334c.2.165.492.165.684.007l8.656-7.342-.001-.025c-.044-.3-.274-.516-.531-.516Z"/></symbol><symbol id="icon-eds-i-mail-send-medium" viewBox="0 0 24 24"><path d="M20.444 5a2.562 2.562 0 0 1 2.548 2.37l.007.078.001.123v7.858A2.564 2.564 0 0 1 20.444 18H9.556A2.564 2.564 0 0 1 7 15.429l.001-7.977.007-.082A2.561 2.561 0 0 1 9.556 5h10.888ZM21 9.331l-5.46 3.51a1 1 0 0 1-1.08 0L9 9.332v6.097c0 .317.251.571.556.571h10.888a.564.564 0 0 0 .556-.571V9.33ZM20.444 7H9.556a.543.543 0 0 0-.32.105l5.763 3.706 5.766-3.706a.543.543 0 0 0-.32-.105ZM4.308 5a1 1 0 1 1 0 2H2a1 1 0 1 1 0-2h2.308Zm0 5.5a1 1 0 0 1 0 2H2a1 1 0 0 1 0-2h2.308Zm0 5.5a1 1 0 0 1 0 2H2a1 1 0 0 1 0-2h2.308Z"/></symbol><symbol id="icon-eds-i-mentions-medium" viewBox="0 0 24 24"><path d="m9.452 1.293 5.92 5.92 2.92-2.92a1 1 0 0 1 1.415 1.414l-2.92 2.92 5.92 5.92a1 1 0 0 1 0 1.415 10.371 10.371 0 0 1-10.378 2.584l.652 3.258A1 1 0 0 1 12 23H2a1 1 0 0 1-.874-1.486l4.789-8.62C4.194 9.074 4.9 4.43 8.038 1.292a1 1 0 0 1 1.414 0Zm-2.355 13.59L3.699 21h7.081l-.689-3.442a10.392 10.392 0 0 1-2.775-2.396l-.22-.28Zm1.69-11.427-.07.09a8.374 8.374 0 0 0 11.737 11.737l.089-.071L8.787 3.456Z"/></symbol><symbol id="icon-eds-i-menu-medium" viewBox="0 0 24 24"><path d="M21 4a1 1 0 0 1 0 2H3a1 1 0 1 1 0-2h18Zm-4 7a1 1 0 0 1 0 2H3a1 1 0 0 1 0-2h14Zm4 7a1 1 0 0 1 0 2H3a1 1 0 0 1 0-2h18Z"/></symbol><symbol id="icon-eds-i-metrics-medium" viewBox="0 0 24 24"><path d="M3 22a1 1 0 0 1-1-1V3a1 1 0 0 1 1-1h6a1 1 0 0 1 1 1v7h4V8a1 1 0 0 1 1-1h6a1 1 0 0 1 1 1v13a1 1 0 0 1-.883.993L21 22H3Zm17-2V9h-4v11h4Zm-6-8h-4v8h4v-8ZM8 4H4v16h4V4Z"/></symbol><symbol id="icon-eds-i-news-medium" viewBox="0 0 24 24"><path d="M17.384 3c.975 0 1.77.787 1.77 1.762v13.333c0 .462.354.846.815.899l.107.006.109-.006a.915.915 0 0 0 .809-.794l.006-.105V8.19a1 1 0 0 1 2 0v9.905A2.914 2.914 0 0 1 20.077 21H3.538a2.547 2.547 0 0 1-1.644-.601l-.147-.135A2.516 2.516 0 0 1 1 18.476V4.762C1 3.787 1.794 3 2.77 3h14.614Zm-.231 2H3v13.476c0 .11.035.216.1.304l.054.063c.101.1.24.157.384.157l13.761-.001-.026-.078a2.88 2.88 0 0 1-.115-.655l-.004-.17L17.153 5ZM14 15.021a.979.979 0 1 1 0 1.958H6a.979.979 0 1 1 0-1.958h8Zm0-8c.54 0 .979.438.979.979v4c0 .54-.438.979-.979.979H6A.979.979 0 0 1 5.021 12V8c0-.54.438-.979.979-.979h8Zm-.98 1.958H6.979v2.041h6.041V8.979Z"/></symbol><symbol id="icon-eds-i-newsletter-medium" viewBox="0 0 24 24"><path d="M21 10a1 1 0 0 1 1 1v9.5a2.5 2.5 0 0 1-2.5 2.5h-15A2.5 2.5 0 0 1 2 20.5V11a1 1 0 0 1 2 0v.439l8 4.888 8-4.889V11a1 1 0 0 1 1-1Zm-1 3.783-7.479 4.57a1 1 0 0 1-1.042 0l-7.48-4.57V20.5a.5.5 0 0 0 .501.5h15a.5.5 0 0 0 .5-.5v-6.717ZM15 9a1 1 0 0 1 0 2H9a1 1 0 0 1 0-2h6Zm2.5-8A2.5 2.5 0 0 1 20 3.5V9a1 1 0 0 1-2 0V3.5a.5.5 0 0 0-.5-.5h-11a.5.5 0 0 0-.5.5V9a1 1 0 1 1-2 0V3.5A2.5 2.5 0 0 1 6.5 1h11ZM15 5a1 1 0 0 1 0 2H9a1 1 0 1 1 0-2h6Z"/></symbol><symbol id="icon-eds-i-notifcation-medium" viewBox="0 0 24 24"><path d="M14 20a1 1 0 0 1 0 2h-4a1 1 0 0 1 0-2h4ZM3 18l-.133-.007c-1.156-.124-1.156-1.862 0-1.986l.3-.012C4.32 15.923 5 15.107 5 14V9.5C5 5.368 8.014 2 12 2s7 3.368 7 7.5V14c0 1.107.68 1.923 1.832 1.995l.301.012c1.156.124 1.156 1.862 0 1.986L21 18H3Zm9-14C9.17 4 7 6.426 7 9.5V14c0 .671-.146 1.303-.416 1.858L6.51 16h10.979l-.073-.142a4.192 4.192 0 0 1-.412-1.658L17 14V9.5C17 6.426 14.83 4 12 4Z"/></symbol><symbol id="icon-eds-i-publish-medium" viewBox="0 0 24 24"><g><path d="M16.296 1.291A1 1 0 0 0 15.591 1H5.545A2.542 2.542 0 0 0 3 3.538V13a1 1 0 1 0 2 0V3.538l.007-.087A.543.543 0 0 1 5.545 3h9.633L20 7.8v12.662a.534.534 0 0 1-.158.379.548.548 0 0 1-.387.159H11a1 1 0 1 0 0 2h8.455c.674 0 1.32-.267 1.798-.742A2.534 2.534 0 0 0 22 20.462V7.385a1 1 0 0 0-.294-.709l-5.41-5.385Z"/><path d="M10.762 16.647a1 1 0 0 0-1.525-1.294l-4.472 5.271-2.153-1.665a1 1 0 1 0-1.224 1.582l2.91 2.25a1 1 0 0 0 1.374-.144l5.09-6ZM16 10a1 1 0 1 1 0 2H8a1 1 0 1 1 0-2h8ZM12 7a1 1 0 0 0-1-1H8a1 1 0 1 0 0 2h3a1 1 0 0 0 1-1Z"/></g></symbol><symbol id="icon-eds-i-refresh-medium" viewBox="0 0 24 24"><g><path d="M7.831 5.636H6.032A8.76 8.76 0 0 1 9 3.631 8.549 8.549 0 0 1 12.232 3c.603 0 1.192.063 1.76.182C17.979 4.017 21 7.632 21 12a1 1 0 1 0 2 0c0-5.296-3.674-9.746-8.591-10.776A10.61 10.61 0 0 0 5 3.851V2.805a1 1 0 0 0-.987-1H4a1 1 0 0 0-1 1v3.831a1 1 0 0 0 1 1h3.831a1 1 0 0 0 .013-2h-.013ZM17.968 18.364c-1.59 1.632-3.784 2.636-6.2 2.636C6.948 21 3 16.993 3 12a1 1 0 1 0-2 0c0 6.053 4.799 11 10.768 11 2.788 0 5.324-1.082 7.232-2.85v1.045a1 1 0 1 0 2 0v-3.831a1 1 0 0 0-1-1h-3.831a1 1 0 0 0 0 2h1.799Z"/></g></symbol><symbol id="icon-eds-i-search-medium" viewBox="0 0 24 24"><path d="M11 1c5.523 0 10 4.477 10 10 0 2.4-.846 4.604-2.256 6.328l3.963 3.965a1 1 0 0 1-1.414 1.414l-3.965-3.963A9.959 9.959 0 0 1 11 21C5.477 21 1 16.523 1 11S5.477 1 11 1Zm0 2a8 8 0 1 0 0 16 8 8 0 0 0 0-16Z"/></symbol><symbol id="icon-eds-i-settings-medium" viewBox="0 0 24 24"><path d="M11.382 1h1.24a2.508 2.508 0 0 1 2.334 1.63l.523 1.378 1.59.933 1.444-.224c.954-.132 1.89.3 2.422 1.101l.095.155.598 1.066a2.56 2.56 0 0 1-.195 2.848l-.894 1.161v1.896l.92 1.163c.6.768.707 1.812.295 2.674l-.09.17-.606 1.08a2.504 2.504 0 0 1-2.531 1.25l-1.428-.223-1.589.932-.523 1.378a2.512 2.512 0 0 1-2.155 1.625L12.65 23h-1.27a2.508 2.508 0 0 1-2.334-1.63l-.524-1.379-1.59-.933-1.443.225c-.954.132-1.89-.3-2.422-1.101l-.095-.155-.598-1.066a2.56 2.56 0 0 1 .195-2.847l.891-1.161v-1.898l-.919-1.162a2.562 2.562 0 0 1-.295-2.674l.09-.17.606-1.08a2.504 2.504 0 0 1 2.531-1.25l1.43.223 1.618-.938.524-1.375.07-.167A2.507 2.507 0 0 1 11.382 1Zm.003 2a.509.509 0 0 0-.47.338l-.65 1.71a1 1 0 0 1-.434.51L7.6 6.85a1 1 0 0 1-.655.123l-1.762-.275a.497.497 0 0 0-.498.252l-.61 1.088a.562.562 0 0 0 .04.619l1.13 1.43a1 1 0 0 1 .216.62v2.585a1 1 0 0 1-.207.61L4.15 15.339a.568.568 0 0 0-.036.634l.601 1.072a.494.494 0 0 0 .484.26l1.78-.278a1 1 0 0 1 .66.126l2.2 1.292a1 1 0 0 1 .43.507l.648 1.71a.508.508 0 0 0 .467.338h1.263a.51.51 0 0 0 .47-.34l.65-1.708a1 1 0 0 1 .428-.507l2.201-1.292a1 1 0 0 1 .66-.126l1.763.275a.497.497 0 0 0 .498-.252l.61-1.088a.562.562 0 0 0-.04-.619l-1.13-1.43a1 1 0 0 1-.216-.62v-2.585a1 1 0 0 1 .207-.61l1.105-1.437a.568.568 0 0 0 .037-.634l-.601-1.072a.494.494 0 0 0-.484-.26l-1.78.278a1 1 0 0 1-.66-.126l-2.2-1.292a1 1 0 0 1-.43-.507l-.649-1.71A.508.508 0 0 0 12.62 3h-1.234ZM12 8a4 4 0 1 1 0 8 4 4 0 0 1 0-8Zm0 2a2 2 0 1 0 0 4 2 2 0 0 0 0-4Z"/></symbol><symbol id="icon-eds-i-shipping-medium" viewBox="0 0 24 24"><path d="M16.515 2c1.406 0 2.706.728 3.352 1.902l2.02 3.635.02.042.036.089.031.105.012.058.01.073.004.075v11.577c0 .64-.244 1.255-.683 1.713a2.356 2.356 0 0 1-1.701.731H4.386a2.356 2.356 0 0 1-1.702-.731 2.476 2.476 0 0 1-.683-1.713V7.948c.01-.217.083-.43.22-.6L4.2 3.905C4.833 2.755 6.089 2.032 7.486 2h9.029ZM20 9H4v10.556a.49.49 0 0 0 .075.26l.053.07a.356.356 0 0 0 .257.114h15.23c.094 0 .186-.04.258-.115a.477.477 0 0 0 .127-.33V9Zm-2 7.5a1 1 0 0 1 0 2h-4a1 1 0 0 1 0-2h4ZM16.514 4H13v3h6.3l-1.183-2.13c-.288-.522-.908-.87-1.603-.87ZM11 3.999H7.51c-.679.017-1.277.36-1.566.887L4.728 7H11V3.999Z"/></symbol><symbol id="icon-eds-i-step-guide-medium" viewBox="0 0 24 24"><path d="M11.394 9.447a1 1 0 1 0-1.788-.894l-.88 1.759-.019-.02a1 1 0 1 0-1.414 1.415l1 1a1 1 0 0 0 1.601-.26l1.5-3ZM12 11a1 1 0 0 1 1-1h3a1 1 0 1 1 0 2h-3a1 1 0 0 1-1-1ZM12 17a1 1 0 0 1 1-1h3a1 1 0 1 1 0 2h-3a1 1 0 0 1-1-1ZM10.947 14.105a1 1 0 0 1 .447 1.342l-1.5 3a1 1 0 0 1-1.601.26l-1-1a1 1 0 1 1 1.414-1.414l.02.019.879-1.76a1 1 0 0 1 1.341-.447Z"/><path d="M5.545 1A2.542 2.542 0 0 0 3 3.538v16.924A2.542 2.542 0 0 0 5.545 23h12.91A2.542 2.542 0 0 0 21 20.462V7.5a1 1 0 0 0-.293-.707l-5.5-5.5A1 1 0 0 0 14.5 1H5.545ZM5 3.538C5 3.245 5.24 3 5.545 3h8.54L19 7.914v12.547c0 .294-.24.539-.546.539H5.545A.542.542 0 0 1 5 20.462V3.538Z" clip-rule="evenodd"/></symbol><symbol id="icon-eds-i-submission-medium" viewBox="0 0 24 24"><g><path d="M5 3.538C5 3.245 5.24 3 5.545 3h9.633L20 7.8v12.662a.535.535 0 0 1-.158.379.549.549 0 0 1-.387.159H6a1 1 0 0 1-1-1v-2.5a1 1 0 1 0-2 0V20a3 3 0 0 0 3 3h13.455c.673 0 1.32-.266 1.798-.742A2.535 2.535 0 0 0 22 20.462V7.385a1 1 0 0 0-.294-.709l-5.41-5.385A1 1 0 0 0 15.591 1H5.545A2.542 2.542 0 0 0 3 3.538V7a1 1 0 0 0 2 0V3.538Z"/><path d="m13.707 13.707-4 4a1 1 0 0 1-1.414 0l-.083-.094a1 1 0 0 1 .083-1.32L10.585 14 2 14a1 1 0 1 1 0-2l8.583.001-2.29-2.294a1 1 0 0 1 1.414-1.414l4.037 4.04.043.05.043.06.059.098.03.063.031.085.03.113.017.122L14 13l-.004.087-.017.118-.013.056-.034.104-.049.105-.048.081-.07.093-.058.063Z"/></g></symbol><symbol id="icon-eds-i-table-1-medium" viewBox="0 0 24 24"><path d="M4.385 22a2.56 2.56 0 0 1-1.14-.279C2.485 21.341 2 20.614 2 19.615V4.385c0-.315.067-.716.279-1.14C2.659 2.485 3.386 2 4.385 2h15.23c.315 0 .716.067 1.14.279.76.38 1.245 1.107 1.245 2.106v15.23c0 .315-.067.716-.279 1.14-.38.76-1.107 1.245-2.106 1.245H4.385ZM4 19.615c0 .213.034.265.14.317a.71.71 0 0 0 .245.068H8v-4H4v3.615ZM20 16H10v4h9.615c.213 0 .265-.034.317-.14a.71.71 0 0 0 .068-.245V16Zm0-2v-4H10v4h10ZM4 14h4v-4H4v4ZM19.615 4H10v4h10V4.385c0-.213-.034-.265-.14-.317A.71.71 0 0 0 19.615 4ZM8 4H4.385l-.082.002c-.146.01-.19.047-.235.138A.71.71 0 0 0 4 4.385V8h4V4Z"/></symbol><symbol id="icon-eds-i-table-2-medium" viewBox="0 0 24 24"><path d="M4.384 22A2.384 2.384 0 0 1 2 19.616V4.384A2.384 2.384 0 0 1 4.384 2h15.232A2.384 2.384 0 0 1 22 4.384v15.232A2.384 2.384 0 0 1 19.616 22H4.384ZM10 15H4v4.616c0 .212.172.384.384.384H10v-5Zm5 0h-3v5h3v-5Zm5 0h-3v5h2.616a.384.384 0 0 0 .384-.384V15ZM10 9H4v4h6V9Zm5 0h-3v4h3V9Zm5 0h-3v4h3V9Zm-.384-5H4.384A.384.384 0 0 0 4 4.384V7h16V4.384A.384.384 0 0 0 19.616 4Z"/></symbol><symbol id="icon-eds-i-tag-medium" viewBox="0 0 24 24"><path d="m12.621 1.998.127.004L20.496 2a1.5 1.5 0 0 1 1.497 1.355L22 3.5l-.005 7.669c.038.456-.133.905-.447 1.206l-9.02 9.018a2.075 2.075 0 0 1-2.932 0l-6.99-6.99a2.075 2.075 0 0 1 .001-2.933L11.61 2.47c.246-.258.573-.418.881-.46l.131-.011Zm.286 2-8.885 8.886a.075.075 0 0 0 0 .106l6.987 6.988c.03.03.077.03.106 0l8.883-8.883L19.999 4l-7.092-.002ZM16 6.5a1.5 1.5 0 0 1 .144 2.993L16 9.5a1.5 1.5 0 0 1 0-3Z"/></symbol><symbol id="icon-eds-i-trash-medium" viewBox="0 0 24 24"><path d="M12 1c2.717 0 4.913 2.232 4.997 5H21a1 1 0 0 1 0 2h-1v12.5c0 1.389-1.152 2.5-2.556 2.5H6.556C5.152 23 4 21.889 4 20.5V8H3a1 1 0 1 1 0-2h4.003l.001-.051C7.114 3.205 9.3 1 12 1Zm6 7H6v12.5c0 .238.19.448.454.492l.102.008h10.888c.315 0 .556-.232.556-.5V8Zm-4 3a1 1 0 0 1 1 1v6.005a1 1 0 0 1-2 0V12a1 1 0 0 1 1-1Zm-4 0a1 1 0 0 1 1 1v6a1 1 0 0 1-2 0v-6a1 1 0 0 1 1-1Zm2-8c-1.595 0-2.914 1.32-2.996 3h5.991v-.02C14.903 4.31 13.589 3 12 3Z"/></symbol><symbol id="icon-eds-i-user-account-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 16c-1.806 0-3.52.994-4.664 2.698A8.947 8.947 0 0 0 12 21a8.958 8.958 0 0 0 4.664-1.301C15.52 17.994 13.806 17 12 17Zm0-14a9 9 0 0 0-6.25 15.476C7.253 16.304 9.54 15 12 15s4.747 1.304 6.25 3.475A9 9 0 0 0 12 3Zm0 3a4 4 0 1 1 0 8 4 4 0 0 1 0-8Zm0 2a2 2 0 1 0 0 4 2 2 0 0 0 0-4Z"/></symbol><symbol id="icon-eds-i-user-add-medium" viewBox="0 0 24 24"><path d="M9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm9 10a1 1 0 0 1 1 1v3h3a1 1 0 0 1 0 2h-3v3a1 1 0 0 1-2 0v-3h-3a1 1 0 0 1 0-2h3v-3a1 1 0 0 1 1-1Zm-5.545-.15a1 1 0 1 1-.91 1.78 5.713 5.713 0 0 0-5.705.282c-1.67 1.068-2.728 2.927-2.832 4.956L3.004 20 11.5 20a1 1 0 0 1 .993.883L12.5 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876c.028-2.812 1.446-5.416 3.763-6.897a7.713 7.713 0 0 1 7.692-.378Z"/></symbol><symbol id="icon-eds-i-user-assign-medium" viewBox="0 0 24 24"><path d="M16.226 13.298a1 1 0 0 1 1.414-.01l.084.093a1 1 0 0 1-.073 1.32L15.39 17H22a1 1 0 0 1 0 2h-6.611l2.262 2.298a1 1 0 0 1-1.425 1.404l-3.939-4a1 1 0 0 1 0-1.404l3.94-4Zm-3.771-.449a1 1 0 1 1-.91 1.781 5.713 5.713 0 0 0-5.705.282c-1.67 1.068-2.728 2.927-2.832 4.956L3.004 20 10.5 20a1 1 0 0 1 .993.883L11.5 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876c.028-2.812 1.446-5.416 3.763-6.897a7.713 7.713 0 0 1 7.692-.378ZM9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Z"/></symbol><symbol id="icon-eds-i-user-block-medium" viewBox="0 0 24 24"><path d="M9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm9 10a5 5 0 1 1 0 10 5 5 0 0 1 0-10Zm-5.545-.15a1 1 0 1 1-.91 1.78 5.713 5.713 0 0 0-5.705.282c-1.67 1.068-2.728 2.927-2.832 4.956L3.004 20 11.5 20a1 1 0 0 1 .993.883L12.5 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876c.028-2.812 1.446-5.416 3.763-6.897a7.713 7.713 0 0 1 7.692-.378ZM15 18a3 3 0 0 0 4.294 2.707l-4.001-4c-.188.391-.293.83-.293 1.293Zm3-3c-.463 0-.902.105-1.294.293l4.001 4A3 3 0 0 0 18 15Z"/></symbol><symbol id="icon-eds-i-user-check-medium" viewBox="0 0 24 24"><path d="M9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm13.647 12.237a1 1 0 0 1 .116 1.41l-5.091 6a1 1 0 0 1-1.375.144l-2.909-2.25a1 1 0 1 1 1.224-1.582l2.153 1.665 4.472-5.271a1 1 0 0 1 1.41-.116Zm-8.139-.977c.22.214.428.44.622.678a1 1 0 1 1-1.548 1.266 6.025 6.025 0 0 0-1.795-1.49.86.86 0 0 1-.163-.048l-.079-.036a5.721 5.721 0 0 0-2.62-.63l-.194.006c-2.76.134-5.022 2.177-5.592 4.864l-.035.175-.035.213c-.03.201-.05.405-.06.61L3.003 20 10 20a1 1 0 0 1 .993.883L11 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876l.005-.223.02-.356.02-.222.03-.248.022-.15c.02-.133.044-.265.071-.397.44-2.178 1.725-4.105 3.595-5.301a7.75 7.75 0 0 1 3.755-1.215l.12-.004a7.908 7.908 0 0 1 5.87 2.252Z"/></symbol><symbol id="icon-eds-i-user-delete-medium" viewBox="0 0 24 24"><path d="M9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6ZM4.763 13.227a7.713 7.713 0 0 1 7.692-.378 1 1 0 1 1-.91 1.781 5.713 5.713 0 0 0-5.705.282c-1.67 1.068-2.728 2.927-2.832 4.956L3.004 20H11.5a1 1 0 0 1 .993.883L12.5 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876c.028-2.812 1.446-5.416 3.763-6.897Zm11.421 1.543 2.554 2.553 2.555-2.553a1 1 0 0 1 1.414 1.414l-2.554 2.554 2.554 2.555a1 1 0 0 1-1.414 1.414l-2.555-2.554-2.554 2.554a1 1 0 0 1-1.414-1.414l2.553-2.555-2.553-2.554a1 1 0 0 1 1.414-1.414Z"/></symbol><symbol id="icon-eds-i-user-edit-medium" viewBox="0 0 24 24"><path d="m19.876 10.77 2.831 2.83a1 1 0 0 1 0 1.415l-7.246 7.246a1 1 0 0 1-.572.284l-3.277.446a1 1 0 0 1-1.125-1.13l.461-3.277a1 1 0 0 1 .283-.567l7.23-7.246a1 1 0 0 1 1.415-.001Zm-7.421 2.08a1 1 0 1 1-.91 1.78 5.713 5.713 0 0 0-5.705.282c-1.67 1.068-2.728 2.927-2.832 4.956L3.004 20 7.5 20a1 1 0 0 1 .993.883L8.5 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876c.028-2.812 1.446-5.416 3.763-6.897a7.713 7.713 0 0 1 7.692-.378Zm6.715.042-6.29 6.3-.23 1.639 1.633-.222 6.302-6.302-1.415-1.415ZM9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Z"/></symbol><symbol id="icon-eds-i-user-linked-medium" viewBox="0 0 24 24"><path d="M15.65 6c.31 0 .706.066 1.122.274C17.522 6.65 18 7.366 18 8.35v12.3c0 .31-.066.706-.274 1.122-.375.75-1.092 1.228-2.076 1.228H3.35a2.52 2.52 0 0 1-1.122-.274C1.478 22.35 1 21.634 1 20.65V8.35c0-.31.066-.706.274-1.122C1.65 6.478 2.366 6 3.35 6h12.3Zm0 2-12.376.002c-.134.007-.17.04-.21.12A.672.672 0 0 0 3 8.35v12.3c0 .198.028.24.122.287.09.044.2.063.228.063h.887c.788-2.269 2.814-3.5 5.263-3.5 2.45 0 4.475 1.231 5.263 3.5h.887c.198 0 .24-.028.287-.122.044-.09.063-.2.063-.228V8.35c0-.198-.028-.24-.122-.287A.672.672 0 0 0 15.65 8ZM9.5 19.5c-1.36 0-2.447.51-3.06 1.5h6.12c-.613-.99-1.7-1.5-3.06-1.5ZM20.65 1A2.35 2.35 0 0 1 23 3.348V15.65A2.35 2.35 0 0 1 20.65 18H20a1 1 0 0 1 0-2h.65a.35.35 0 0 0 .35-.35V3.348A.35.35 0 0 0 20.65 3H8.35a.35.35 0 0 0-.35.348V4a1 1 0 1 1-2 0v-.652A2.35 2.35 0 0 1 8.35 1h12.3ZM9.5 10a3.5 3.5 0 1 1 0 7 3.5 3.5 0 0 1 0-7Zm0 2a1.5 1.5 0 1 0 0 3 1.5 1.5 0 0 0 0-3Z"/></symbol><symbol id="icon-eds-i-user-multiple-medium" viewBox="0 0 24 24"><path d="M9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm6 0a5 5 0 0 1 0 10 1 1 0 0 1-.117-1.993L15 9a3 3 0 0 0 0-6 1 1 0 0 1 0-2ZM9 3a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm8.857 9.545a7.99 7.99 0 0 1 2.651 1.715A8.31 8.31 0 0 1 23 20.134V21a1 1 0 0 1-1 1h-3a1 1 0 0 1 0-2h1.995l-.005-.153a6.307 6.307 0 0 0-1.673-3.945l-.204-.209a5.99 5.99 0 0 0-1.988-1.287 1 1 0 1 1 .732-1.861Zm-3.349 1.715A8.31 8.31 0 0 1 17 20.134V21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.877c.044-4.343 3.387-7.908 7.638-8.115a7.908 7.908 0 0 1 5.87 2.252ZM9.016 14l-.285.006c-3.104.15-5.58 2.718-5.725 5.9L3.004 20h11.991l-.005-.153a6.307 6.307 0 0 0-1.673-3.945l-.204-.209A5.924 5.924 0 0 0 9.3 14.008L9.016 14Z"/></symbol><symbol id="icon-eds-i-user-notify-medium" viewBox="0 0 24 24"><path d="M9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm10 18v1a1 1 0 0 1-2 0v-1h-3a1 1 0 0 1 0-2v-2.818C14 13.885 15.777 12 18 12s4 1.885 4 4.182V19a1 1 0 0 1 0 2h-3Zm-6.545-8.15a1 1 0 1 1-.91 1.78 5.713 5.713 0 0 0-5.705.282c-1.67 1.068-2.728 2.927-2.832 4.956L3.004 20 11.5 20a1 1 0 0 1 .993.883L12.5 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876c.028-2.812 1.446-5.416 3.763-6.897a7.713 7.713 0 0 1 7.692-.378ZM18 14c-1.091 0-2 .964-2 2.182V19h4v-2.818c0-1.165-.832-2.098-1.859-2.177L18 14Z"/></symbol><symbol id="icon-eds-i-user-remove-medium" viewBox="0 0 24 24"><path d="M9 1a5 5 0 1 1 0 10A5 5 0 0 1 9 1Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm3.455 9.85a1 1 0 1 1-.91 1.78 5.713 5.713 0 0 0-5.705.282c-1.67 1.068-2.728 2.927-2.832 4.956L3.004 20 11.5 20a1 1 0 0 1 .993.883L12.5 21a1 1 0 0 1-1 1H2a1 1 0 0 1-1-1v-.876c.028-2.812 1.446-5.416 3.763-6.897a7.713 7.713 0 0 1 7.692-.378ZM22 17a1 1 0 0 1 0 2h-8a1 1 0 0 1 0-2h8Z"/></symbol><symbol id="icon-eds-i-user-single-medium" viewBox="0 0 24 24"><path d="M12 1a5 5 0 1 1 0 10 5 5 0 0 1 0-10Zm0 2a3 3 0 1 0 0 6 3 3 0 0 0 0-6Zm-.406 9.008a8.965 8.965 0 0 1 6.596 2.494A9.161 9.161 0 0 1 21 21.025V22a1 1 0 0 1-1 1H4a1 1 0 0 1-1-1v-.985c.05-4.825 3.815-8.777 8.594-9.007Zm.39 1.992-.299.006c-3.63.175-6.518 3.127-6.678 6.775L5 21h13.998l-.009-.268a7.157 7.157 0 0 0-1.97-4.573l-.214-.213A6.967 6.967 0 0 0 11.984 14Z"/></symbol><symbol id="icon-eds-i-warning-circle-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 2a9 9 0 1 0 0 18 9 9 0 0 0 0-18Zm0 11.5a1.5 1.5 0 0 1 .144 2.993L12 17.5a1.5 1.5 0 0 1 0-3ZM12 6a1 1 0 0 1 1 1v5a1 1 0 0 1-2 0V7a1 1 0 0 1 1-1Z"/></symbol><symbol id="icon-eds-i-warning-filled-medium" viewBox="0 0 24 24"><path d="M12 1c6.075 0 11 4.925 11 11s-4.925 11-11 11S1 18.075 1 12 5.925 1 12 1Zm0 13.5a1.5 1.5 0 0 0 0 3l.144-.007A1.5 1.5 0 0 0 12 14.5ZM12 6a1 1 0 0 0-1 1v5a1 1 0 0 0 2 0V7a1 1 0 0 0-1-1Z"/></symbol><symbol id="icon-chevron-left-medium" viewBox="0 0 24 24"><path d="M15.7194 3.3054C15.3358 2.90809 14.7027 2.89699 14.3054 3.28061L6.54342 10.7757C6.19804 11.09 6 11.5335 6 12C6 12.4665 6.19804 12.91 6.5218 13.204L14.3054 20.7194C14.7027 21.103 15.3358 21.0919 15.7194 20.6946C16.103 20.2973 16.0919 19.6642 15.6946 19.2806L8.155 12L15.6946 4.71939C16.0614 4.36528 16.099 3.79863 15.8009 3.40105L15.7194 3.3054Z"/></symbol><symbol id="icon-chevron-right-medium" viewBox="0 0 24 24"><path d="M8.28061 3.3054C8.66423 2.90809 9.29729 2.89699 9.6946 3.28061L17.4566 10.7757C17.802 11.09 18 11.5335 18 12C18 12.4665 17.802 12.91 17.4782 13.204L9.6946 20.7194C9.29729 21.103 8.66423 21.0919 8.28061 20.6946C7.89699 20.2973 7.90809 19.6642 8.3054 19.2806L15.845 12L8.3054 4.71939C7.93865 4.36528 7.90098 3.79863 8.19908 3.40105L8.28061 3.3054Z"/></symbol><symbol id="icon-eds-alerts" viewBox="0 0 32 32"><path d="M28 12.667c.736 0 1.333.597 1.333 1.333v13.333A3.333 3.333 0 0 1 26 30.667H6a3.333 3.333 0 0 1-3.333-3.334V14a1.333 1.333 0 1 1 2.666 0v1.252L16 21.769l10.667-6.518V14c0-.736.597-1.333 1.333-1.333Zm-1.333 5.71-9.972 6.094c-.427.26-.963.26-1.39 0l-9.972-6.094v8.956c0 .368.299.667.667.667h20a.667.667 0 0 0 .667-.667v-8.956ZM19.333 12a1.333 1.333 0 1 1 0 2.667h-6.666a1.333 1.333 0 1 1 0-2.667h6.666Zm4-10.667a3.333 3.333 0 0 1 3.334 3.334v6.666a1.333 1.333 0 1 1-2.667 0V4.667A.667.667 0 0 0 23.333 4H8.667A.667.667 0 0 0 8 4.667v6.666a1.333 1.333 0 1 1-2.667 0V4.667a3.333 3.333 0 0 1 3.334-3.334h14.666Zm-4 5.334a1.333 1.333 0 0 1 0 2.666h-6.666a1.333 1.333 0 1 1 0-2.666h6.666Z"/></symbol><symbol id="icon-eds-arrow-up" viewBox="0 0 24 24"><path fill-rule="evenodd" d="m13.002 7.408 4.88 4.88a.99.99 0 0 0 1.32.08l.09-.08c.39-.39.39-1.03 0-1.42l-6.58-6.58a1.01 1.01 0 0 0-1.42 0l-6.58 6.58a1 1 0 0 0-.09 1.32l.08.1a1 1 0 0 0 1.42-.01l4.88-4.87v11.59a.99.99 0 0 0 .88.99l.12.01c.55 0 1-.45 1-1V7.408z" class="layer"/></symbol><symbol id="icon-eds-checklist" viewBox="0 0 32 32"><path d="M19.2 1.333a3.468 3.468 0 0 1 3.381 2.699L24.667 4C26.515 4 28 5.52 28 7.38v19.906c0 1.86-1.485 3.38-3.333 3.38H7.333c-1.848 0-3.333-1.52-3.333-3.38V7.38C4 5.52 5.485 4 7.333 4h2.093A3.468 3.468 0 0 1 12.8 1.333h6.4ZM9.426 6.667H7.333c-.36 0-.666.312-.666.713v19.906c0 .401.305.714.666.714h17.334c.36 0 .666-.313.666-.714V7.38c0-.4-.305-.713-.646-.714l-2.121.033A3.468 3.468 0 0 1 19.2 9.333h-6.4a3.468 3.468 0 0 1-3.374-2.666Zm12.715 5.606c.586.446.7 1.283.253 1.868l-7.111 9.334a1.333 1.333 0 0 1-1.792.306l-3.556-2.333a1.333 1.333 0 1 1 1.463-2.23l2.517 1.651 6.358-8.344a1.333 1.333 0 0 1 1.868-.252ZM19.2 4h-6.4a.8.8 0 0 0-.8.8v1.067a.8.8 0 0 0 .8.8h6.4a.8.8 0 0 0 .8-.8V4.8a.8.8 0 0 0-.8-.8Z"/></symbol><symbol id="icon-eds-citation" viewBox="0 0 36 36"><path d="M23.25 1.5a1.5 1.5 0 0 1 1.06.44l8.25 8.25a1.5 1.5 0 0 1 .44 1.06v19.5c0 2.105-1.645 3.75-3.75 3.75H18a1.5 1.5 0 0 1 0-3h11.25c.448 0 .75-.302.75-.75V11.873L22.628 4.5H8.31a.811.811 0 0 0-.8.68l-.011.13V16.5a1.5 1.5 0 0 1-3 0V5.31A3.81 3.81 0 0 1 8.31 1.5h14.94ZM8.223 20.358a.984.984 0 0 1-.192 1.378l-.048.034c-.54.36-.942.676-1.206.951-.59.614-.885 1.395-.885 2.343.115-.028.288-.042.518-.042.662 0 1.26.237 1.791.711.533.474.799 1.074.799 1.799 0 .753-.259 1.352-.777 1.799-.518.446-1.151.669-1.9.669-1.006 0-1.812-.293-2.417-.878C3.302 28.536 3 27.657 3 26.486c0-1.115.165-2.085.496-2.907.331-.823.734-1.513 1.209-2.071.475-.558.971-.997 1.49-1.318a6.01 6.01 0 0 1 .347-.2 1.321 1.321 0 0 1 1.681.368Zm7.5 0a.984.984 0 0 1-.192 1.378l-.048.034c-.54.36-.942.676-1.206.951-.59.614-.885 1.395-.885 2.343.115-.028.288-.042.518-.042.662 0 1.26.237 1.791.711.533.474.799 1.074.799 1.799 0 .753-.259 1.352-.777 1.799-.518.446-1.151.669-1.9.669-1.006 0-1.812-.293-2.417-.878-.604-.586-.906-1.465-.906-2.636 0-1.115.165-2.085.496-2.907.331-.823.734-1.513 1.209-2.071.475-.558.971-.997 1.49-1.318a6.01 6.01 0 0 1 .347-.2 1.321 1.321 0 0 1 1.681.368Z"/></symbol><symbol id="icon-eds-i-access-indicator" viewBox="0 0 16 16"><circle cx="4.5" cy="11.5" r="3.5" style="fill:currentColor"/><path fill-rule="evenodd" d="M4 3v3a1 1 0 0 1-2 0V2.923C2 1.875 2.84 1 3.909 1h5.909a1 1 0 0 1 .713.298l3.181 3.231a1 1 0 0 1 .288.702v7.846c0 .505-.197.993-.554 1.354a1.902 1.902 0 0 1-1.355.569H10a1 1 0 1 1 0-2h2V5.64L9.4 3H4Z" clip-rule="evenodd" style="fill:#222"/></symbol><symbol id="icon-eds-i-github-medium" viewBox="0 0 24 24"><path d="M 11.964844 0 C 5.347656 0 0 5.269531 0 11.792969 C 0 17.003906 3.425781 21.417969 8.179688 22.976562 C 8.773438 23.09375 8.992188 22.722656 8.992188 22.410156 C 8.992188 22.136719 8.972656 21.203125 8.972656 20.226562 C 5.644531 20.929688 4.953125 18.820312 4.953125 18.820312 C 4.417969 17.453125 3.625 17.101562 3.625 17.101562 C 2.535156 16.378906 3.703125 16.378906 3.703125 16.378906 C 4.914062 16.457031 5.546875 17.589844 5.546875 17.589844 C 6.617188 19.386719 8.339844 18.878906 9.03125 18.566406 C 9.132812 17.804688 9.449219 17.277344 9.785156 16.984375 C 7.132812 16.710938 4.339844 15.695312 4.339844 11.167969 C 4.339844 9.878906 4.8125 8.824219 5.566406 8.003906 C 5.445312 7.710938 5.03125 6.5 5.683594 4.878906 C 5.683594 4.878906 6.695312 4.566406 8.972656 6.089844 C 9.949219 5.832031 10.953125 5.703125 11.964844 5.699219 C 12.972656 5.699219 14.003906 5.835938 14.957031 6.089844 C 17.234375 4.566406 18.242188 4.878906 18.242188 4.878906 C 18.898438 6.5 18.480469 7.710938 18.363281 8.003906 C 19.136719 8.824219 19.589844 9.878906 19.589844 11.167969 C 19.589844 15.695312 16.796875 16.691406 14.125 16.984375 C 14.558594 17.355469 14.933594 18.058594 14.933594 19.171875 C 14.933594 20.753906 14.914062 22.019531 14.914062 22.410156 C 14.914062 22.722656 15.132812 23.09375 15.726562 22.976562 C 20.480469 21.414062 23.910156 17.003906 23.910156 11.792969 C 23.929688 5.269531 18.558594 0 11.964844 0 Z M 11.964844 0 "/></symbol><symbol id="icon-eds-i-limited-access" viewBox="0 0 16 16"><path fill-rule="evenodd" d="M4 3v3a1 1 0 0 1-2 0V2.923C2 1.875 2.84 1 3.909 1h5.909a1 1 0 0 1 .713.298l3.181 3.231a1 1 0 0 1 .288.702V6a1 1 0 1 1-2 0v-.36L9.4 3H4ZM3 8a1 1 0 0 1 1 1v1a1 1 0 1 1-2 0V9a1 1 0 0 1 1-1Zm10 0a1 1 0 0 1 1 1v1a1 1 0 1 1-2 0V9a1 1 0 0 1 1-1Zm-3.5 6a1 1 0 0 1-1 1h-1a1 1 0 1 1 0-2h1a1 1 0 0 1 1 1Zm2.441-1a1 1 0 0 1 2 0c0 .73-.246 1.306-.706 1.664a1.61 1.61 0 0 1-.876.334l-.032.002H11.5a1 1 0 1 1 0-2h.441ZM4 13a1 1 0 0 0-2 0c0 .73.247 1.306.706 1.664a1.609 1.609 0 0 0 .876.334l.032.002H4.5a1 1 0 1 0 0-2H4Z" clip-rule="evenodd"/></symbol><symbol id="icon-eds-i-subjects-medium" viewBox="0 0 24 24"><g id="icon-subjects-copy" stroke="none" stroke-width="1" fill-rule="evenodd"><path d="M13.3846154,2 C14.7015971,2 15.7692308,3.06762994 15.7692308,4.38461538 L15.7692308,7.15384615 C15.7692308,8.47082629 14.7015955,9.53846154 13.3846154,9.53846154 L13.1038388,9.53925278 C13.2061091,9.85347965 13.3815528,10.1423885 13.6195822,10.3804178 C13.9722182,10.7330539 14.436524,10.9483278 14.9293854,10.9918129 L15.1153846,11 C16.2068332,11 17.2535347,11.433562 18.0254647,12.2054189 C18.6411944,12.8212361 19.0416785,13.6120766 19.1784166,14.4609738 L19.6153846,14.4615385 C20.932386,14.4615385 22,15.5291672 22,16.8461538 L22,19.6153846 C22,20.9323924 20.9323924,22 19.6153846,22 L16.8461538,22 C15.5291672,22 14.4615385,20.932386 14.4615385,19.6153846 L14.4615385,16.8461538 C14.4615385,15.5291737 15.5291737,14.4615385 16.8461538,14.4615385 L17.126925,14.460779 C17.0246537,14.1465537 16.8492179,13.857633 16.6112344,13.6196157 C16.2144418,13.2228606 15.6764136,13 15.1153846,13 C14.0239122,13 12.9771569,12.5664197 12.2053686,11.7946314 C12.1335167,11.7227795 12.0645962,11.6485444 11.9986839,11.5721119 C11.9354038,11.6485444 11.8664833,11.7227795 11.7946314,11.7946314 C11.0228431,12.5664197 9.97608778,13 8.88461538,13 C8.323576,13 7.78552852,13.2228666 7.38881294,13.6195822 C7.15078359,13.8576115 6.97533988,14.1465203 6.8730696,14.4607472 L7.15384615,14.4615385 C8.47082629,14.4615385 9.53846154,15.5291737 9.53846154,16.8461538 L9.53846154,19.6153846 C9.53846154,20.932386 8.47083276,22 7.15384615,22 L4.38461538,22 C3.06762347,22 2,20.9323876 2,19.6153846 L2,16.8461538 C2,15.5291721 3.06762994,14.4615385 4.38461538,14.4615385 L4.8215823,14.4609378 C4.95831893,13.6120029 5.3588057,12.8211623 5.97459937,12.2053686 C6.69125996,11.488708 7.64500941,11.0636656 8.6514968,11.0066017 L8.88461538,11 C9.44565477,11 9.98370225,10.7771334 10.3804178,10.3804178 C10.6184472,10.1423885 10.7938909,9.85347965 10.8961612,9.53925278 L10.6153846,9.53846154 C9.29840448,9.53846154 8.23076923,8.47082629 8.23076923,7.15384615 L8.23076923,4.38461538 C8.23076923,3.06762994 9.29840286,2 10.6153846,2 L13.3846154,2 Z M7.15384615,16.4615385 L4.38461538,16.4615385 C4.17220099,16.4615385 4,16.63374 4,16.8461538 L4,19.6153846 C4,19.8278134 4.17218833,20 4.38461538,20 L7.15384615,20 C7.36626945,20 7.53846154,19.8278103 7.53846154,19.6153846 L7.53846154,16.8461538 C7.53846154,16.6337432 7.36625679,16.4615385 7.15384615,16.4615385 Z M19.6153846,16.4615385 L16.8461538,16.4615385 C16.6337432,16.4615385 16.4615385,16.6337432 16.4615385,16.8461538 L16.4615385,19.6153846 C16.4615385,19.8278103 16.6337306,20 16.8461538,20 L19.6153846,20 C19.8278229,20 20,19.8278229 20,19.6153846 L20,16.8461538 C20,16.6337306 19.8278103,16.4615385 19.6153846,16.4615385 Z M13.3846154,4 L10.6153846,4 C10.4029708,4 10.2307692,4.17220099 10.2307692,4.38461538 L10.2307692,7.15384615 C10.2307692,7.36625679 10.402974,7.53846154 10.6153846,7.53846154 L13.3846154,7.53846154 C13.597026,7.53846154 13.7692308,7.36625679 13.7692308,7.15384615 L13.7692308,4.38461538 C13.7692308,4.17220099 13.5970292,4 13.3846154,4 Z" id="Shape" fill-rule="nonzero"/></g></symbol><symbol id="icon-eds-small-arrow-left" viewBox="0 0 16 17"><path stroke="currentColor" stroke-linecap="round" stroke-linejoin="round" stroke-width="2" d="M14 8.092H2m0 0L8 2M2 8.092l6 6.035"/></symbol><symbol id="icon-eds-small-arrow-right" viewBox="0 0 16 16"><g fill-rule="evenodd" stroke="currentColor" stroke-linecap="round" stroke-linejoin="round" stroke-width="2"><path d="M2 8.092h12M8 2l6 6.092M8 14.127l6-6.035"/></g></symbol><symbol id="icon-orcid-logo" viewBox="0 0 40 40"><path fill-rule="evenodd" d="M12.281 10.453c.875 0 1.578-.719 1.578-1.578 0-.86-.703-1.578-1.578-1.578-.875 0-1.578.703-1.578 1.578 0 .86.703 1.578 1.578 1.578Zm-1.203 18.641h2.406V12.359h-2.406v16.735Z"/><path fill-rule="evenodd" d="M17.016 12.36h6.5c6.187 0 8.906 4.421 8.906 8.374 0 4.297-3.36 8.375-8.875 8.375h-6.531V12.36Zm6.234 14.578h-3.828V14.53h3.703c4.688 0 6.828 2.844 6.828 6.203 0 2.063-1.25 6.203-6.703 6.203Z" clip-rule="evenodd"/></symbol></svg> </div> <a class="c-skip-link" href="#main">Skip to main content</a> <div class="u-lazy-ad-wrapper u-mbs-0"> <div class="c-ad c-ad--728x90 c-ad--conditional" data-test="springer-doubleclick-ad"> <div class="c-ad c-ad__inner" > <p class="c-ad__label">Advertisement</p> <div id="div-gpt-ad-LB1" class="div-gpt-ad grade-c-hide" data-gpt data-gpt-unitpath="/270604982/springerlink/12879/article" data-gpt-sizes="728x90" data-gpt-targeting="pos=top;articleid=s12879-016-2173-z;" data-ad-type="top" style="min-width:728px;min-height:90px"> <noscript> <a href="//pubads.g.doubleclick.net/gampad/jump?iu=/270604982/springerlink/12879/article&sz=728x90&pos=top&articleid=s12879-016-2173-z"> <img data-test="gpt-advert-fallback-img" src="//pubads.g.doubleclick.net/gampad/ad?iu=/270604982/springerlink/12879/article&sz=728x90&pos=top&articleid=s12879-016-2173-z" alt="Advertisement" width="728" height="90"> </a> </noscript> </div> </div> </div> </div> <header class="eds-c-header" data-eds-c-header> <div class="eds-c-header__container" data-eds-c-header-expander-anchor> <div class="eds-c-header__brand"> <a href="https://link.springer.com" data-test=springerlink-logo data-track="click_imprint_logo" data-track-context="unified header" data-track-action="click logo link" data-track-category="unified header" data-track-label="link" > <img src="/oscar-static/images/darwin/header/img/logo-springer-nature-link-3149409f62.svg" alt="Springer Nature Link"> </a> </div> <a class="c-header__link eds-c-header__link" id="identity-account-widget" href='https://idp.springer.com/auth/personal/springernature?redirect_uri=https://link.springer.com/article/10.1186/s12879-016-2173-z?'><span class="eds-c-header__widget-fragment-title">Log in</span></a> </div> <nav class="eds-c-header__nav" aria-label="header navigation"> <div class="eds-c-header__nav-container"> <div class="eds-c-header__item eds-c-header__item--menu"> <a href="#eds-c-header-nav" class="eds-c-header__link" data-eds-c-header-expander> <svg class="eds-c-header__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-menu-medium"></use> </svg><span>Menu</span> </a> </div> <div class="eds-c-header__item eds-c-header__item--inline-links"> <a class="eds-c-header__link" href="https://link.springer.com/journals/" data-track="nav_find_a_journal" data-track-context="unified header" data-track-action="click find a journal" data-track-category="unified header" data-track-label="link" > Find a journal </a> <a class="eds-c-header__link" href="https://www.springernature.com/gp/authors" data-track="nav_how_to_publish" data-track-context="unified header" data-track-action="click publish with us link" data-track-category="unified header" data-track-label="link" > Publish with us </a> <a class="eds-c-header__link" href="https://link.springernature.com/home/" data-track="nav_track_your_research" data-track-context="unified header" data-track-action="click track your research" data-track-category="unified header" data-track-label="link" > Track your research </a> </div> <div class="eds-c-header__link-container"> <div class="eds-c-header__item eds-c-header__item--divider"> <a href="#eds-c-header-popup-search" class="eds-c-header__link" data-eds-c-header-expander data-eds-c-header-test-search-btn> <svg class="eds-c-header__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-search-medium"></use> </svg><span>Search</span> </a> </div> <div id="ecommerce-header-cart-icon-link" class="eds-c-header__item ecommerce-cart" style="display:inline-block"> <a class="eds-c-header__link" href="https://order.springer.com/public/cart" style="appearance:none;border:none;background:none;color:inherit;position:relative"> <svg id="eds-i-cart" class="eds-c-header__icon" xmlns="http://www.w3.org/2000/svg" height="24" width="24" viewBox="0 0 24 24" aria-hidden="true" focusable="false"> <path fill="currentColor" fill-rule="nonzero" d="M2 1a1 1 0 0 0 0 2l1.659.001 2.257 12.808a2.599 2.599 0 0 0 2.435 2.185l.167.004 9.976-.001a2.613 2.613 0 0 0 2.61-1.748l.03-.106 1.755-7.82.032-.107a2.546 2.546 0 0 0-.311-1.986l-.108-.157a2.604 2.604 0 0 0-2.197-1.076L6.042 5l-.56-3.17a1 1 0 0 0-.864-.82l-.12-.007L2.001 1ZM20.35 6.996a.63.63 0 0 1 .54.26.55.55 0 0 1 .082.505l-.028.1L19.2 15.63l-.022.05c-.094.177-.282.299-.526.317l-10.145.002a.61.61 0 0 1-.618-.515L6.394 6.999l13.955-.003ZM18 19a2 2 0 1 0 0 4 2 2 0 0 0 0-4ZM8 19a2 2 0 1 0 0 4 2 2 0 0 0 0-4Z"></path> </svg><span>Cart</span><span class="cart-info" style="display:none;position:absolute;top:10px;right:45px;background-color:#C65301;color:#fff;width:18px;height:18px;font-size:11px;border-radius:50%;line-height:17.5px;text-align:center"></span></a> <script>(function () { var exports = {}; if (window.fetch) { "use strict"; Object.defineProperty(exports, "__esModule", { value: true }); exports.headerWidgetClientInit = void 0; var headerWidgetClientInit = function (getCartInfo) { document.body.addEventListener("updatedCart", function () { updateCartIcon(); }, false); return updateCartIcon(); function updateCartIcon() { return getCartInfo() .then(function (res) { return res.json(); }) .then(refreshCartState) .catch(function (_) { }); } function refreshCartState(json) { var indicator = document.querySelector("#ecommerce-header-cart-icon-link .cart-info"); /* istanbul ignore else */ if (indicator && json.itemCount) { indicator.style.display = 'block'; indicator.textContent = json.itemCount > 9 ? '9+' : json.itemCount.toString(); var moreThanOneItem = json.itemCount > 1; indicator.setAttribute('title', "there ".concat(moreThanOneItem ? "are" : "is", " ").concat(json.itemCount, " item").concat(moreThanOneItem ? "s" : "", " in your cart")); } return json; } }; exports.headerWidgetClientInit = headerWidgetClientInit; headerWidgetClientInit( function () { return window.fetch("https://cart.springer.com/cart-info", { credentials: "include", headers: { Accept: "application/json" } }) } ) }})()</script> </div> </div> </div> </nav> </header> <article lang="en" id="main" class="app-masthead__colour-default"> <section class="app-masthead " aria-label="article masthead"> <div class="app-masthead__container"> <div class="app-article-masthead u-sans-serif js-context-bar-sticky-point-masthead" data-track-component="article" data-test="masthead-component"> <div class="app-article-masthead__info"> <nav aria-label="breadcrumbs" data-test="breadcrumbs"> <ol class="c-breadcrumbs c-breadcrumbs--contrast" itemscope itemtype="https://schema.org/BreadcrumbList"> <li class="c-breadcrumbs__item" id="breadcrumb0" itemprop="itemListElement" itemscope="" itemtype="https://schema.org/ListItem"> <a href="/" class="c-breadcrumbs__link" itemprop="item" data-track="click_breadcrumb" data-track-context="article page" data-track-category="article" data-track-action="breadcrumbs" data-track-label="breadcrumb1"><span itemprop="name">Home</span></a><meta itemprop="position" content="1"> <svg class="c-breadcrumbs__chevron" role="img" aria-hidden="true" focusable="false" width="10" height="10" viewBox="0 0 10 10"> <path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/> </svg> </li> <li class="c-breadcrumbs__item" id="breadcrumb1" itemprop="itemListElement" itemscope="" itemtype="https://schema.org/ListItem"> <a href="/journal/12879" class="c-breadcrumbs__link" itemprop="item" data-track="click_breadcrumb" data-track-context="article page" data-track-category="article" data-track-action="breadcrumbs" data-track-label="breadcrumb2"><span itemprop="name">BMC Infectious Diseases</span></a><meta itemprop="position" content="2"> <svg class="c-breadcrumbs__chevron" role="img" aria-hidden="true" focusable="false" width="10" height="10" viewBox="0 0 10 10"> <path d="m5.96738168 4.70639573 2.39518594-2.41447274c.37913917-.38219212.98637524-.38972225 1.35419292-.01894278.37750606.38054586.37784436.99719163-.00013556 1.37821513l-4.03074001 4.06319683c-.37758093.38062133-.98937525.38100976-1.367372-.00003075l-4.03091981-4.06337806c-.37759778-.38063832-.38381821-.99150444-.01600053-1.3622839.37750607-.38054587.98772445-.38240057 1.37006824.00302197l2.39538588 2.4146743.96295325.98624457z" fill-rule="evenodd" transform="matrix(0 -1 1 0 0 10)"/> </svg> </li> <li class="c-breadcrumbs__item" id="breadcrumb2" itemprop="itemListElement" itemscope="" itemtype="https://schema.org/ListItem"> <span itemprop="name">Article</span><meta itemprop="position" content="3"> </li> </ol> </nav> <h1 class="c-article-title" data-test="article-title" data-article-title="">Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria</h1> <ul class="c-article-identifiers"> <li class="c-article-identifiers__item" data-test="article-category">Research article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item"> Published: <time datetime="2017-01-31">31 January 2017</time> </li> </ul> <ul class="c-article-identifiers c-article-identifiers--cite-list"> <li class="c-article-identifiers__item"> <span data-test="journal-volume">Volume 17</span>, article number <span data-test="article-number">110</span>, (<span data-test="article-publication-year">2017</span>) </li> <li class="c-article-identifiers__item c-article-identifiers__item--cite"> <a href="#citeas" data-track="click" data-track-action="cite this article" data-track-category="article body" data-track-label="link">Cite this article</a> </li> </ul> <div class="app-article-masthead__buttons" data-test="download-article-link-wrapper" data-track-context="masthead"> <div class="c-pdf-container"> <div class="c-pdf-download u-clear-both u-mb-16"> <a href="/content/pdf/10.1186/s12879-016-2173-z.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="pdf-link" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="button" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-eds-i-download-medium"/></svg> </a> </div> </div> <p class="app-article-masthead__access"> <svg width="16" height="16" focusable="false" role="img" aria-hidden="true"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-check-filled-medium"></use></svg> You have full access to this <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link">open access</a> article</p> </div> </div> <div class="app-article-masthead__brand"> <a href="/journal/12879" class="app-article-masthead__journal-link" data-track="click_journal_home" data-track-action="journal homepage" data-track-context="article page" data-track-label="link"> <picture> <source type="image/webp" media="(min-width: 768px)" width="120" height="159" srcset="https://media.springernature.com/w120/springer-static/cover-hires/journal/12879?as=webp, https://media.springernature.com/w316/springer-static/cover-hires/journal/12879?as=webp 2x"> <img width="72" height="95" src="https://media.springernature.com/w72/springer-static/cover-hires/journal/12879?as=webp" srcset="https://media.springernature.com/w144/springer-static/cover-hires/journal/12879?as=webp 2x" alt=""> </picture> <span class="app-article-masthead__journal-title">BMC Infectious Diseases</span> </a> <a href="https://bmcinfectdis.biomedcentral.com/about" class="app-article-masthead__submission-link" data-track="click_aims_and_scope" data-track-action="aims and scope" data-track-context="article page" data-track-label="link"> Aims and scope <svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-arrow-right-medium"></use></svg> </a> <a href="https://submission.nature.com/new-submission/12879/3" class="app-article-masthead__submission-link" data-track="click_submit_manuscript" data-track-context="article masthead on springerlink article page" data-track-action="submit manuscript" data-track-label="link"> Submit manuscript <svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-arrow-right-medium"></use></svg> </a> </div> </div> </div> </section> <div class="c-article-main u-container u-mt-24 u-mb-32 l-with-sidebar" id="main-content" data-component="article-container"> <main class="u-serif js-main-column" data-track-component="article body"> <div class="c-context-bar u-hide" data-test="context-bar" data-context-bar aria-hidden="true"> <div class="c-context-bar__container u-container"> <div class="c-context-bar__title"> Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria </div> <div data-test="inCoD" data-track-context="sticky banner"> <div class="c-pdf-container"> <div class="c-pdf-download u-clear-both u-mb-16"> <a href="/content/pdf/10.1186/s12879-016-2173-z.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="pdf-link" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="button" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-eds-i-download-medium"/></svg> </a> </div> </div> </div> </div> </div> <div class="c-article-header"> <header> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Akintunde-Sowunmi-Aff1-Aff2-Aff9" data-author-popup="auth-Akintunde-Sowunmi-Aff1-Aff2-Aff9" data-author-search="Sowunmi, Akintunde" data-corresp-id="c1">Akintunde Sowunmi<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff9">9</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Kazeem-Akano-Aff1" data-author-popup="auth-Kazeem-Akano-Aff1" data-author-search="Akano, Kazeem">Kazeem Akano</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Adejumoke_I_-Ayede-Aff3" data-author-popup="auth-Adejumoke_I_-Ayede-Aff3" data-author-search="Ayede, Adejumoke I.">Adejumoke I. Ayede</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Elsie_O_-Adewoye-Aff4" data-author-popup="auth-Elsie_O_-Adewoye-Aff4" data-author-search="Adewoye, Elsie O.">Elsie O. Adewoye</a><sup class="u-js-hide"><a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Godwin-Ntadom-Aff5" data-author-popup="auth-Godwin-Ntadom-Aff5" data-author-search="Ntadom, Godwin">Godwin Ntadom</a><sup class="u-js-hide"><a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Bayo-Fatunmbi-Aff6" data-author-popup="auth-Bayo-Fatunmbi-Aff6" data-author-search="Fatunmbi, Bayo">Bayo Fatunmbi</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Grace_O_-Gbotosho-Aff1-Aff2" data-author-popup="auth-Grace_O_-Gbotosho-Aff1-Aff2" data-author-search="Gbotosho, Grace O.">Grace O. Gbotosho</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Onikepe_A_-Folarin-Aff7-Aff8" data-author-popup="auth-Onikepe_A_-Folarin-Aff7-Aff8" data-author-search="Folarin, Onikepe A.">Onikepe A. Folarin</a><sup class="u-js-hide"><a href="#Aff7">7</a>,<a href="#Aff8">8</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 9 authors for this article" title="Show all 9 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Christian_T_-Happi-Aff7-Aff8" data-author-popup="auth-Christian_T_-Happi-Aff7-Aff8" data-author-search="Happi, Christian T.">Christian T. Happi</a><sup class="u-js-hide"><a href="#Aff7">7</a>,<a href="#Aff8">8</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <div data-test="article-metrics"> <ul class="app-article-metrics-bar u-list-reset"> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-accesses-medium"></use> </svg>1828 <span class="app-article-metrics-bar__label">Accesses</span></p> </li> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-citations-medium"></use> </svg>6 <span class="app-article-metrics-bar__label">Citations</span></p> </li> <li class="app-article-metrics-bar__item app-article-metrics-bar__item--metrics"> <p class="app-article-metrics-bar__details"><a href="/article/10.1186/s12879-016-2173-z/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Explore all metrics <svg class="u-icon app-article-metrics-bar__arrow-icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-arrow-right-medium"></use> </svg></a></p> </li> </ul> </div> <div class="u-mt-32"> </div> </header> </div> <div data-article-body="true" data-track-component="article body" class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Background</h3><p>Early rising asexual parasitaemia (ERAP), initially defined as ‘an increase in the parasite count over the baseline pre-treatment level during the first 24 h of treatment’ of falciparum malaria with artemisinin derivatives is well documented, but there is no characterization of its risk factors, kinetics, molecular features or relationship to late-appearing anaemia (LAA) in acute falciparum malaria in African children following oral artemisinin-based combination therapies (ACTs).</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Methods</h3><p>ERAP was defined as ≥5% increase in pre-treatment parasitaemia within 8 h of initiating treatment. Parasitaemia was quantified pre-treatment and 1–2 hourly for 8 h, and less frequently thereafter for 6 weeks following randomized treatment of acutely malarious children with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine. Risk factors were determined by stepwise multiple logistic regression model. Kinetics of release into and of elimination of asexual parasites and DNA clones from peripheral blood were evaluated by method of residuals and non-compartment model, respectively. Parasite population changes were evaluated morphologically and by molecular genotyping.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Results</h3><p>ERAP occurred in 205 of 416 children. A parasitaemia <100,000/μL and parasitaemia 1 day post-treatment initiation were independent predictors of ERAP. In children with ERAP: mean and peak time of increase in parasitaemia were 105.6% (95% CI 81–130.1) and 2.5 h (95% CI 2.2–2.7), respectively. Mean lag time, half-time and rate constant of release were 0.2 h (95% CI 0.2–0.3), 1 h (95% CI 0.9–1.1), and 0.9 h<sup>−1</sup> (95% CI 0.8–1), respectively. Schizonts and young gametocytes were seen only in peripheral blood of few children with ERAP. In age-, gender-, baseline parasitaemia- and treatment-matched children with and without ERAP, parasite DNA clearance time and area under curve of number of DNA clones <i>versus</i> time were significantly higher in children with ERAP indicating peripheral retention of released parasites followed by elimination. DNA clone elimination was monoexponential.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Conclusion</h3><p>ERAP is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose of ACTs of acute childhood falciparum malaria.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Trials registration</h3><p>Pan African Clinical Trial Registry <a href="http://www.pactr.org">PACTR201508001188143</a>, 3 July 2015; PACTR201510001189370, 3 July 2015; PACTR201508001191898, 7 July 2015 and PACTR201508001193368, 8 July 2015.</p></div></div></section> <div class="app-peer-review"> <a class="app-peer-review__link" href="/article/10.1186/s12879-016-2173-z/peer-review" data-track="click" data-track-category="article body" data-track-action="open peer review reports" data-track-label="10.1186/s12879-016-2173-z"> <svg class="u-icon app-peer-review__icon" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-file-report-medium"></use> </svg> View this article's peer review reports </a> </div> <div data-test="cobranding-download"> </div> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1186%2Fs40249-018-0503-7/MediaObjects/40249_2018_503_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1186/s40249-018-0503-7?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1186/s40249-018-0503-7">Parasite reduction ratio one day after initiation of artemisinin-based combination therapies and its relationship with parasite clearance time in acutely malarious children </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">07 December 2018</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1186%2Fs12879-016-1565-4/MediaObjects/12879_2016_1565_Fig1_HTML.gif" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1186/s12879-016-1565-4?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1186/s12879-016-1565-4">Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">01 June 2016</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1186%2Fs40249-016-0165-2/MediaObjects/40249_2016_165_Fig1_HTML.gif" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1186/s40249-016-0165-2?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1186/s40249-016-0165-2">Therapeutic efficacy and effects of artesunate-amodiaquine and artemether-lumefantrine on malaria-associated anaemia in Nigerian children aged two years and under </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">06 July 2016</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1733236082, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Background"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Background</h2><div class="c-article-section__content" id="Sec1-content"><p>Early rising asexual parasitaemia (ERAP), originally described as an increase in parasite count over the baseline pre-treatment level occurring within 24 h following treatment of falciparum malaria with artemisinin-like drugs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Silachamroon U, Phumratanaprapin W, Krudsood S, Treeprasertsuk S, Budsaratid V, Pornpininworakij K, Wilairatana P, Looareesuwan S. Frequency of early risisng parasitaemia in falciparum malaria treated with artemisinin derivatives. Southeast Asian J Trop Med Public Health. 2001;32:50–6." href="/article/10.1186/s12879-016-2173-z#ref-CR1" id="ref-link-section-d86078652e1034">1</a>], may occur in 25–45% of malarious patients following artemisinin-based combination treatments (ACTs) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Silachamroon U, Phumratanaprapin W, Krudsood S, Treeprasertsuk S, Budsaratid V, Pornpininworakij K, Wilairatana P, Looareesuwan S. Frequency of early risisng parasitaemia in falciparum malaria treated with artemisinin derivatives. Southeast Asian J Trop Med Public Health. 2001;32:50–6." href="/article/10.1186/s12879-016-2173-z#ref-CR1" id="ref-link-section-d86078652e1037">1</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sowunmi A, Okuboyejo TM, Gbotosho GO, Happi CT. Early changes in Plasmodium falciparum asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs. Malaria Chemother Control Elimin. 2012;1. doi:
 10.4303/mcce/235498
 
 ." href="/article/10.1186/s12879-016-2173-z#ref-CR3" id="ref-link-section-d86078652e1040">3</a>]. Although prognosis is favourable in malarious Thai and Nigerian patients with ERAP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Silachamroon U, Phumratanaprapin W, Krudsood S, Treeprasertsuk S, Budsaratid V, Pornpininworakij K, Wilairatana P, Looareesuwan S. Frequency of early risisng parasitaemia in falciparum malaria treated with artemisinin derivatives. Southeast Asian J Trop Med Public Health. 2001;32:50–6." href="/article/10.1186/s12879-016-2173-z#ref-CR1" id="ref-link-section-d86078652e1043">1</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sowunmi A, Okuboyejo TM, Gbotosho GO, Happi CT. Early changes in Plasmodium falciparum asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs. Malaria Chemother Control Elimin. 2012;1. doi:
 10.4303/mcce/235498
 
 ." href="/article/10.1186/s12879-016-2173-z#ref-CR3" id="ref-link-section-d86078652e1046">3</a>], the factors contributing to ERAP, and the additional burden posed by it are little evaluated. Given that early increases in parasitaemia may be accompanied by changes in asexual and sexual parasite populations following ACTs and may be relatively short-lasting by morphological assessment [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sowunmi A, Okuboyejo TM, Gbotosho GO, Happi CT. Early changes in Plasmodium falciparum asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs. Malaria Chemother Control Elimin. 2012;1. doi:
 10.4303/mcce/235498
 
 ." href="/article/10.1186/s12879-016-2173-z#ref-CR3" id="ref-link-section-d86078652e1050">3</a>], evaluation of ERAP by polymerase chain reaction (PCR) genotyping and kinetics of parasite population changes are urgently needed as they may provide insight into the possible cause(s) and consequences of ERAP and the possible mechanisms of ACTs-related ERAP.</p><p>Of the estimated 214 million clinical episodes of malaria reported annually, 188 million clinical episodes occur in Africa mainly in children [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="World Health Organization. World malaria report. Geneva: World Health Organization; 2015." href="/article/10.1186/s12879-016-2173-z#ref-CR4" id="ref-link-section-d86078652e1056">4</a>]. In Nigeria, an estimated over 37 million clinical episodes of falciparum malaria are reported annually [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="World Health Organization. World malaria report. Geneva: World Health Organization; 2014." href="/article/10.1186/s12879-016-2173-z#ref-CR5" id="ref-link-section-d86078652e1059">5</a>]. Although acute falciparum infections are associated with anaemia in 25–80% of African children at presentation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Sowunmi A, Gbotosho GO, Happi CT, Fateye BA. Factors contributing to anaemia after uncomplicated Plasmodium falciparum malaria in children. Acta Trop. 2010;133:155–61." href="/article/10.1186/s12879-016-2173-z#ref-CR6" id="ref-link-section-d86078652e1062">6</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Sumbele IUN, Samje M, Nkuo-Akenji T. A longitudinal study of anaemia in children with Plasmodium falciparum infection in the Mount Cameroon region: prevalence, risk factors and perceptions by caregivers. BMC Infect Dis. 2013;13:123." href="/article/10.1186/s12879-016-2173-z#ref-CR8" id="ref-link-section-d86078652e1065">8</a>], it is increasingly apparent additional burden of anaemia may be imposed by a late-appearing anaemia (LAA) following successful ACTs of apparently uncomplicated infections [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e1068">7</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Obonyo CO, Taylor W, Ekvall H, Kaneko A, ter Kuile F, Olliaro P, Bjorkman A, Oloo AJ. Effects of artesunate plus sulfadoxine-pyrimethamine on haematological recovery and anaemia in Kenyan children with uncomplicated Plasmodium falciparum malaria. Ann Trop Med Parasitol. 2007;101:281–95." href="/article/10.1186/s12879-016-2173-z#ref-CR9" id="ref-link-section-d86078652e1072">9</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Temporal changes in haematocrit following artemisinin-based combination treatments of uncomplicated falciparum malaria in children. BMC Inectf Dis. 2015;15:454." href="/article/10.1186/s12879-016-2173-z#ref-CR10" id="ref-link-section-d86078652e1075">10</a>]. The extent of this additional burden and its relationship to ERAP, if any, following ACTs in African children remain unknown.</p><p>In order to determine the factors contributing to ERAP, its release and disposition kinetics, its consequences and other additional burden it may pose, and the association between ERAP and LAA, larger number of well-characterized patients and comparison with patients without ERAP are needed. For these reasons, we added asexual parasite kinetic analyses and molecular genotyping to the clinical and parasitological characterization of children with ERAP following a first dose of ACTs of apparently uncomplicated <i>Plasmodium falciparum</i> malaria in children. The aims of the study were to determine in malarious children with ERAP: its frequency and the factors contributing to it; its consequences; the kinetics of release into and of the disposition of asexual stage parasites from peripheral blood during ERAP; asexual stage and gametocyte stage population changes; asexual stage genotyping during ERAP; and the relationship, if any, between ERAP and LAA following ACTs.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Methods</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">Study location</h3><p>The study was conducted between January 2008 and December 2015 in Ibadan, an endemic area of malaria in southwestern Nigeria. It was part of a larger and longer study of the efficacies of artemisinin-based combination treatments - artesunate-amodiaquine (AA), artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHP). Details of the study have been described elsewhere [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e1096">7</a>]. The study protocol was approved by The Ethics Committee of The Ministry of Health, Ibadan and by National Health Research Ethics Committee, Abuja, Nigeria [Pan African Clinical Trial Registry PACTR201508001188143; PACTR201510001189370; PACTR201508001191898; PACTR201508001193368].</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec4">Patients</h3><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec5">Inclusion and exclusion criteria</h4><p>Patients were enrolled in the study if they met the following criteria: age 6 months–15 years, symptoms compatible with acute uncomplicated malaria with <i>Plasmodium falciparum</i> mono-infections ≥2000 μL<sup>−1</sup> of blood, no history of antimalarial drug ingestion in the 2 weeks prior to enrolment, absence of severe malaria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="World Health Organization. Severe and complicated malaria. Trans R Soc Trop Med Hyg. 1990;84 Suppl 2:1–65." href="/article/10.1186/s12879-016-2173-z#ref-CR11" id="ref-link-section-d86078652e1116">11</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="World Health Organization. Severe malaria. Trop Med Int Health. 2014;19 Suppl 1:7–131." href="/article/10.1186/s12879-016-2173-z#ref-CR13" id="ref-link-section-d86078652e1119">13</a>], written informed consent given by parents or guardians and ability to comply with a 42-day follow-up period. Patients with uncomplicated hyperparasitaemia (parasitaemia >250,000 μL<sup>−1</sup>) were not excluded from the study [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="World Health Organization. Severe malaria. Trop Med Int Health. 2014;19 Suppl 1:7–131." href="/article/10.1186/s12879-016-2173-z#ref-CR13" id="ref-link-section-d86078652e1125">13</a>]. Patients with severe malnutrition (i. e. weight for age < 60% and bilateral oedema) and those with sickle cell anaemia were excluded from the study. Patient selection and enrolment were done by a physician who did not participate in patient evaluation once treatment began [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e1128">7</a>].</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec6">Drug treatment</h4><p>Patients were randomised to and received artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine orally as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e1139">7</a>] (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab1">1</a>). Each randomization envelope was opened at the time of treatment by the attending nurse or physician. Each tablet of artemether-lumefantrine (Coartem®, Novatis, Basel, Switzerland) contains 20 mg of artemether and 120 mg of lumefantrine. Each tablet of dihydroartemisinin-piperaquine (Duo-cotecxin®, Zhejiang Holley Nanhu, China) contains 40 mg of dihydroartemisinin and 320 mg of piperaquine. The formulations of artesunate-amodiaquine (Coarsucam®, Sanofi Aventis, France) are 25 mg/67.5 mg, 50 mg/135 mg, 100 mg/270 mg of fixed dose combination. All drugs were given within 3 min of obtaining enrolment (pre-treatment, baseline) blood slides for quantification of parasitaemia.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Treatment regimens</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1186/s12879-016-2173-z/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec7">Patient evaluation</h4><p>Clinical evaluation and monitoring for adverse events were done at the following times: before treatment (day 0; that is, the day treatment began) and at 1, 2, 3, 7, 14, 21, 28, 35 and 42 days after start of treatment. Clinical evaluation consisted of physical examination and measurement of body temperature, heart and respiratory rates. Side effects were defined as symptoms and signs that first occurred or became worse after treatment started and were checked for at every visit. Any new events occurring during treatment were also considered as side effects.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec8">Parasitological evaluation</h4><p>Thick and thin blood films prepared from a finger prick were obtained at the following times: before treatment (0 h), and at 1, 2, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168, 336, 504 and 672 h and then on days 35 and 42 after initiation of treatment. Blood slides were stained with Giemsa and examined by light microscopy under oil immersion objective lens at 1000 × magnification by two assessors who did not know the drug regimen of the patients. A senior member of the study team reviewed the slides if there was any disagreement between the two microscopists. In addition, the slide of every fourth child enrolled in the study was reviewed by the senior member.</p><p>Parasitaemias, asexual or sexual, in thick films were estimated by counting asexual and sexual parasites relative to 500 leukocytes, or 500 asexual or sexual forms whichever occurred first. From this figure, the parasite density was calculated assuming a leukocyte count of 6,000 μL<sup>−1</sup> of blood [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Shaper AG, Lewis P. Genetic neutropenia in people of African origin. Lancet. 1971;i:1021–3." href="/article/10.1186/s12879-016-2173-z#ref-CR14" id="ref-link-section-d86078652e1259">14</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Sowunmi A, Akindele JA, Balogun MA. Leukocyte counts in falciparum in African children from an endemic area. Afr J Med Med Sci. 1995;24:145–9." href="/article/10.1186/s12879-016-2173-z#ref-CR16" id="ref-link-section-d86078652e1262">16</a>]. A slide was considered parasite negative if no asexual or sexual parasite was detected after examination of 200 microscope fields.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec9">Definition of ERAP</h4><p>ERAP was defined as ≥5% increase in pre-treatment asexual parasitaemia occurring within 8 h of initiating ACTs.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec10">Staging of asexual and sexual parasites development in peripheral blood</h4><p>Stages of asexual parasite development in peripheral blood were estimated as follows: R1: width of cytoplasm/diameter of nucleus <0.5, that is, ring form aged 0- < 6 h. R2: width of cytoplasm/diameter of nucleus >0.5- < 1, that is, ring form aged 6- < 18 h. R3: width of cytoplasm/diameter of nucleus >1, that is, ring form aged 18–24 h. Late trophozoite, that is aged >24–40 h and containing 2 nuclei. Schizonts, that is, >40 h and containing at least 3 nuclei [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Li G, Guo X, Fu L, Jian H, Wang X. Clinical trials of artemisinin and its derivatives in the treatment of malaria in China. Trans R Soc Trop Med Hyg. 1994;88(Supplement):S5–6." href="/article/10.1186/s12879-016-2173-z#ref-CR17" id="ref-link-section-d86078652e1282">17</a>]. Gametocytes were sexed according to the following morphological criteria: males (microgametocytes) are smaller than females (macrogametocytes), the nucleus is larger in males than in females, the end of the cells are rounder in males and pointed in females, with Giemsa the cytoplasm stains purple in males and deep blue in females, and the granules of malaria pigment are centrally located in females and more widely spread scattered in males [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Carter R, Graves PM. Gametocytes. In: Wernsdorfer WH, Mc Gregor I, editors. Malaria: principles and practice of malariology, vol. 1. Edinburgh: Chuchill Livinstone; 1988. p. 253–303." href="/article/10.1186/s12879-016-2173-z#ref-CR18" id="ref-link-section-d86078652e1285">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Robert V, Read AF, Essong J, Tchuinkam T, Mulder B, Verhave JP, Carnevale P. Effects of gametocyte sex ratio on infectivity of Plasmodium falciparum to Anopheles gambiae. Trans R Soc Trop Med Hyg. 1996;90:621–4." href="/article/10.1186/s12879-016-2173-z#ref-CR19" id="ref-link-section-d86078652e1288">19</a>]. Gametocytes were classified morphologically as male or female if at least three of the five criteria stated above were present. Gametocytes were considered immature or young when they are Stage I–III, or mature when they are Stage IV–V [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Sinden RE. Gametocytes and sexual developments. In: Sherman IW, editor. Malaria: parasite biology, pathogenesis and protection. Washinton DC: ASM Press; 1998. p. 25–48." href="/article/10.1186/s12879-016-2173-z#ref-CR20" id="ref-link-section-d86078652e1291">20</a>]. Gametocytes were classified as stage II if they were elongated in the erythrocytes or had a D-shape and were distinguished from late trophozoite with 2 nuclei. Gametocytes sex ratio, the proportion of gametocytes that is male [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="West SA, Reece SE, Read AF. Evolution of gametocyte sex ratio in malaria and related apicomplexan (protozoan) parasites. Trends Parasitol. 2001;17:525–31." href="/article/10.1186/s12879-016-2173-z#ref-CR21" id="ref-link-section-d86078652e1294">21</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="West SA, Smith TG, Nee S, Read AF. Fertility insurance and the sex ratios of malaria and related hemosporins blood parasites. J Parasitol. 2002;17:258–63." href="/article/10.1186/s12879-016-2173-z#ref-CR22" id="ref-link-section-d86078652e1298">22</a>], was not evaluated.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec11">PCR genotyping</h4><p>PCR genotyping was done as described previously [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Sowunmi A, Gbotosho GO, Happi CT, Folarin OA, Balogun ST. Population structure of Plasmodium falciparum gametocyte sex ratios in malarious children in an endemic area. Parasitol International. 2009;58:438–43." href="/article/10.1186/s12879-016-2173-z#ref-CR23" id="ref-link-section-d86078652e1309">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Bustamante C, Folarin OA, Gbotosho GO, Batista CN, Mesquita EA, Brindeiro RM, Tanuri A, Struchiner CJ, Sowunmi A, Oduola A, Wirth DF, Zalis MG, Happi CT. In vitro-reduced susceptibility to artemether in P. falciparum and its asscociation with polymorphisms on transporter genes. J Infect Dis. 2012;206:324–32." href="/article/10.1186/s12879-016-2173-z#ref-CR24" id="ref-link-section-d86078652e1312">24</a>]. <i>P. falciparum</i> loci that exhibited repeated numbers of polymorphisms to distinguish between different parasite populations were used for characterization of population structure. Block 2 of merozoite surface protein-1 (MSP-1), block 3 of MSP-2, and region II of glutamine-rich protein (GLURP) were amplified by nested polymerase chain reaction (PCR) using primers and amplification conditions described previously [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Sowunmi A, Gbotosho GO, Happi CT, Folarin OA, Balogun ST. Population structure of Plasmodium falciparum gametocyte sex ratios in malarious children in an endemic area. Parasitol International. 2009;58:438–43." href="/article/10.1186/s12879-016-2173-z#ref-CR23" id="ref-link-section-d86078652e1318">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Bustamante C, Folarin OA, Gbotosho GO, Batista CN, Mesquita EA, Brindeiro RM, Tanuri A, Struchiner CJ, Sowunmi A, Oduola A, Wirth DF, Zalis MG, Happi CT. In vitro-reduced susceptibility to artemether in P. falciparum and its asscociation with polymorphisms on transporter genes. J Infect Dis. 2012;206:324–32." href="/article/10.1186/s12879-016-2173-z#ref-CR24" id="ref-link-section-d86078652e1321">24</a>]. Ten microlitres of the PCR products was resolved by electrophoresis on a 2% agarose gel and sized against 1000-basepair (bp) molecular weight marker (New England Biolabs, Beverly, MA). Primers sequences and PCR conditions for the nested PCR strategy were as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Sowunmi A, Gbotosho GO, Happi CT, Folarin OA, Balogun ST. Population structure of Plasmodium falciparum gametocyte sex ratios in malarious children in an endemic area. Parasitol International. 2009;58:438–43." href="/article/10.1186/s12879-016-2173-z#ref-CR23" id="ref-link-section-d86078652e1325">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Bustamante C, Folarin OA, Gbotosho GO, Batista CN, Mesquita EA, Brindeiro RM, Tanuri A, Struchiner CJ, Sowunmi A, Oduola A, Wirth DF, Zalis MG, Happi CT. In vitro-reduced susceptibility to artemether in P. falciparum and its asscociation with polymorphisms on transporter genes. J Infect Dis. 2012;206:324–32." href="/article/10.1186/s12879-016-2173-z#ref-CR24" id="ref-link-section-d86078652e1328">24</a>]. Each <i>P. falciparum</i> infection was characterized on the basis of the fragment size of the PCR products for each locus and determining size of the alleles of MSP-1, MSP-2 and GLURP. Infections were defined as polyclonal if parasites from the same patient showed more than one allele on one or more genes. If an isolate had one allele at each of the 3 loci, the clone was taken to be one. Extracted parasite DNA was not quantified but intensity of parasite DNA band and time of maximal intensity was noted on electrophoresis in each patient. Because qPCR was not performed, internal controls like human housekeeping genes were not used. However, DNA concentration in different time point samples were quantified using a NanoDrop 2000c. Equal volumes of DNA were used in a 25 μL final volume of PCR reaction. Parasite DNA clearance time was defined as time from commencement of treatment until there was no detectable parasite DNA by genotyping.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec12">Haematological evaluation</h4><p>Capillary blood collected before treatment and during follow-up was used to measure haematocrit using a microhaematocrit tube and microcentrifuge (Hawksley, Lancing, UK). Anaemia was defined as a haematocrit < 30% [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Sowunmi A, Gbotosho GO, Happi CT, Fateye BA. Factors contributing to anaemia after uncomplicated Plasmodium falciparum malaria in children. Acta Trop. 2010;133:155–61." href="/article/10.1186/s12879-016-2173-z#ref-CR6" id="ref-link-section-d86078652e1342">6</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Price RC, Simpson JA, Nosten F, Luxemberger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ. Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg. 2001;65:614–22." href="/article/10.1186/s12879-016-2173-z#ref-CR25" id="ref-link-section-d86078652e1345">25</a>]. Late-appearing anaemia (LAA)] was defined as anaemia occurring after 2 weeks of starting treatment [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e1348">7</a>]. A diagnosis of late-appearing anaemia was made if the following criteria were met following initiation of artemisinin-based combination treatments: clearance of parasitaemia and other symptoms within 1 week, haematocrit ≥ 30% at 1 and/or 2 weeks, a fall in haematocrit to < 30% occurring at 3–6 weeks, absence of concomitant illness at 1–6 weeks, and absence of asexual parasitaemia by both microscopy and PCR at 3–6 weeks [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e1351">7</a>]. Anaemia recovery time (in anaemic patients at presentation) was defined as time elapsing from start of drug administration to attainment of a haematocrit value ≥ 30% [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Sowunmi A, Balogun ST, Gbotosho GO, Happi CT. Effects of amodiaquine, artesunate, and artesunate-amodiaquine on Plasmodium falciparum malaria-associated anaemia in children. Acta Trop. 2009;109:55–60." href="/article/10.1186/s12879-016-2173-z#ref-CR26" id="ref-link-section-d86078652e1354">26</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Ntadom G, Banjo O, Okuboyejo T, Ogunrinde G, Odey F, Aina O, Sofola T, Sowunmi A. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five year-old Nigerian children. Am J Trop Med Hyg. 2014;91:925–35." href="/article/10.1186/s12879-016-2173-z#ref-CR27" id="ref-link-section-d86078652e1358">27</a>]. Fall in haematocrit (FIH) per 1000 asexual parasites cleared from peripheral blood following treatment [FIH/1000 asexual parasites cpb] was defined as relative difference in haematocrit at baseline (pre-treatment) and the first 1 or 2 days after treatment began as numerator, and the corresponding relative difference in parasitaemia as the denominator, and expressing it per 1000 asexual parasites cleared from peripheral blood [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Gbotosho GO, Okuboyejo TM, Happi CT, Sowunmi A. Fall in haematocrit per 1000 parasites cleared from peripheral blood; a simple method for estimating drug-related fall in haematocrit after treatment of malaria infections. Am J Ther. 2014;21:193–7." href="/article/10.1186/s12879-016-2173-z#ref-CR28" id="ref-link-section-d86078652e1361">28</a>].</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec13">Evaluation of response to treatment</h4><p>Response to drug treatment was assessed using a modified version of the World Health Organization in vivo clinical classification criteria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="World Health Organization. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: World Health Organization; 2003." href="/article/10.1186/s12879-016-2173-z#ref-CR29" id="ref-link-section-d86078652e1372">29</a>]. The clinical classification system consisted of the following categories of response: adequate clinical and parasitological response (ACPR), late parasitological failure (LPF), late clinical failure (LCF), and early treatment failure (ETF). The primary outcomes were the 42-day uncorrected and PCR-corrected efficacy. The secondary outcomes were the fever clearance time, parasite clearance time and recovery from malaria-associated anaemia.</p><p>The cure rates on days 28 and 42 were adjusted on the basis of the PCR (polymerase chain reaction) genotyping results of paired samples of patients with recurrent parasitaemia after day 7 of starting treatment as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Sowunmi A, Gbotosho GO, Happi CT, Folarin OA, Balogun ST. Population structure of Plasmodium falciparum gametocyte sex ratios in malarious children in an endemic area. Parasitol International. 2009;58:438–43." href="/article/10.1186/s12879-016-2173-z#ref-CR23" id="ref-link-section-d86078652e1378">23</a>]. Fever clearance time (FCT) in patients with presenting body temperature ≥ 37.5 °C was defined as time elapsing from start of treatment until temperature fell below 37.5 °C and remained so for at least 48 h. Parasite clearance time (PCT) was defined as time elapsing from start of drug administration until there was no patent parasitaemia for at least 72 h. Asexual parasite reduction ratio (PRR) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="White NJ. Assessment of the pharmacodynamics properties of antimalarial drugs in vivo. Antimicrob Agent Chemother. 1997;41:1413–22." href="/article/10.1186/s12879-016-2173-z#ref-CR30" id="ref-link-section-d86078652e1381">30</a>] was defined as the ratio of day 0/day 2 parasitaemia (and for convenience, referred to as PRR<sub>D2</sub>). Asexual parasite reduction ratio on day 1 (PRR<sub>D1</sub>) was defined as the ratio of day 0/day 1 parasitaemia.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec14">Kinetics of release of asexual parasites into and of their disposition from peripheral blood in children with ERAP, and of the disposition of asexual parasites in children without ERAP</h4><p>In order to characterize the release of asexual parasites into peripheral blood from ‘deep tissue’, a graphic procedure similar to that for testing whether drug absorption is a first–order process, and if so, to determine the absorption half-life - the method of residuals, was adapted [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. Philadelphia: Lea and Ferbiger; 1980." href="/article/10.1186/s12879-016-2173-z#ref-CR31" id="ref-link-section-d86078652e1396">31</a>]. Asexual parasites in deep tissue was assumed to be the administered ‘drug’ and the rate of increase and decrease in peripheral blood asexual parasites, the ‘drug’ absorbed into circulation as follows: in each patient, on a semi-log plot of parasite density (concentration) versus time, the linear portion of the decline phase was back extrapolated. The concentration along the extrapolated line was denoted as <span class="mathjax-tex">\( \overleftarrow{C} \)</span>. The observed parasite concentration during the rising phase, denoted as <i>C</i>, was subtracted from the corresponding extrapolated value at each time point, that is, <span class="mathjax-tex">\( \overleftarrow{C}- C \)</span> (the residuals). The residuals <span class="mathjax-tex">\( \left(\overleftarrow{C}- C\right) \)</span> was plotted against time on the same semi-logarithmic graph paper. Release half-time (the equivalent of absorption half-time) was determined from this plot. Rate constant for release (K<sub>erap</sub>) [the equivalent of absorption rate constant] was calculated as 0.693/t<sub>½erap</sub>. Lag time for release (the equivalent of time between drug administration and onset of absorption) was the time when the plot of <span class="mathjax-tex">\( \overleftarrow{C}- C \)</span> meets <span class="mathjax-tex">\( \overleftarrow{C} \)</span>. This time was assumed to be the interval between time of administration of first dose of ACTs and the onset of release of asexual parasites from deep tissue into peripheral blood (see reference [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. Philadelphia: Lea and Ferbiger; 1980." href="/article/10.1186/s12879-016-2173-z#ref-CR31" id="ref-link-section-d86078652e1545">31</a>] for the underlying basis of the method of residuals and its equations). Areas under curve (AUC) of the plot of parasitaemia versus time, and of the plot of clone number versus time were estimated by trapezoidal method [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. Philadelphia: Lea and Ferbiger; 1980." href="/article/10.1186/s12879-016-2173-z#ref-CR31" id="ref-link-section-d86078652e1548">31</a>]. Kinetics of elimination of parasitaemia were evaluated as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Sowunmi A, Falade AG, Adedeji AA, Ayede AI, Fateye BA, Sowunmi CO, Oduola AMJ. Comparative Plasmodium falciparum kinetics during treatment with amodiaquine and chloroquine in children. Clin Drug Invest. 2001;21:371–81." href="/article/10.1186/s12879-016-2173-z#ref-CR32" id="ref-link-section-d86078652e1552">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Gbotosho GO, Sowunmi A, Happi CT, Okuboyejo TM. Therapeutic efficacies of artemisinin-based combination therapies in Nigerian children with uncomplicated falciparum malaria during five years of adoption as first-line treatments. Am J Trop Med Hyg. 2011;84:936–43." href="/article/10.1186/s12879-016-2173-z#ref-CR33" id="ref-link-section-d86078652e1555">33</a>].</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec15">Statistical analysis</h3><p>Data were analyzed using version 6 of Epi-Info software [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Epi Info Version 6. A word processing data base and statistics program for public health on IBM-compatible microcomputers. Atlanta: Centers for Disease Control and Prevention; 1994." href="/article/10.1186/s12879-016-2173-z#ref-CR34" id="ref-link-section-d86078652e1567">34</a>] and the statistical program SPSS for Windows version 20.0. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="SPSS for Windows Release 20.0 (standard version). Chicago IL: SPSS Inc.; 2011." href="/article/10.1186/s12879-016-2173-z#ref-CR35" id="ref-link-section-d86078652e1570">35</a>]. Variables considered in the analysis were related to the densities of <i>P. falciparum</i> asexual and sexual forms. Proportions were compared by calculating <i>χ</i> <sup>2</sup> using Yates’ correction, Fisher’s exact or Mantel Haenszel tests. Normally distributed, continuous data were compared by Student’s <i>t</i> test and analysis of variance (ANOVA). Data not conforming to a normal distribution were compared by the Mann–Whitney U tests and the Kruskal Wallis tests. The relationship between two variables that are continuous and normally distributed, and those that are discrete and not normally distributed were evaluated by Pearson correlation coefficient and Spearman’s rank correlation coefficient, respectively. A stepwise multiple logistic regression model was used to test the association between early rising asexual parasitaemia and factors that were significant at univariate analysis: parasitaemia <100,000/uL, parasitaemia 1 day after treatment began, and parasite reduction ratio <10<sup>4</sup> 1 day after treatment began. Because the study was conducted over a period of 7 years, time in years since the commencement of the study was included as a dichotomous covariate in the model for early rising asexual parasitaemia. <i>P</i> values of <0.05 were taken to indicate significant differences. Data were double entered serially using patients’ codes and were only analyzed at the end of the study.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec16-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec16">Results</h2><div class="c-article-section__content" id="Sec16-content"><h3 class="c-article__sub-heading" id="Sec17">Characteristics of patients enrolled in the study and treatment outcomes</h3><p>The characteristics of children enrolled in the study are shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab2">2</a>. These characteristics are similar in children with and without ERAP. However, children with ERAP had significantly lower enrolment geometric mean parasitaemia [52,392 μL<sup>−1</sup> (range 2,220–536,912, <i>n</i> = 205) <i>versus</i> 61,933 μL<sup>−1</sup> (range 1,800–1,096,636, <i>n</i> = 211), respectively, <i>P</i> = 0.01] and proportion with a parasitaemia >100,000 μL<sup>−1</sup> (19.6% <i>versus</i> 40.3%, <i>P</i> < 0.0001).</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-2"><figure><figcaption class="c-article-table__figcaption"><b id="Tab2" data-test="table-caption">Table 2 Clinical, parasitological and other parameters at enrolment in children with or without early rising asexual parasitaemia following artemisinin-based combination treatments</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1186/s12879-016-2173-z/tables/2" aria-label="Full size table 2"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <h3 class="c-article__sub-heading" id="Sec18">Frequency of early rising asexual parasitaemia</h3><p>Two hundred and five of 416 children (49%) had ERAP and it occurred with similar frequencies in those treated with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine [107 of 240 (45%) <i>versus</i> 64 of 120 (53%) <i>versus</i> 34 of 56 (61%), respectively, <i>P</i> = 0.054]. ERAP was significantly more frequent in the first 4 h following initiation of treatment compared to > 4 h after start of treatment (187 of 416 <i>versus</i> 18 of 416 (<i>P</i> < 0.0001) (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig1">1</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Fig. 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig1_HTML.gif?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig1_HTML.gif" alt="figure 1" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>Frequency and time distribution of children with early rising asexual parasitaemia following artemisinin-based combination treatments</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <h3 class="c-article__sub-heading" id="Sec19">Factors contributing to early rising asexual parasitaemia</h3><p>Factors at presentation associated with ERAP following ACTs are presented in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab3">3</a>. In a univariate analysis, an enrolment parasitaemia <100,000 μL<sup>−1</sup>, parasite positivity on day 1 and parasite reduction ratio <10<sup>4</sup> one day after treatment began were related to ERAP. Gender, age, duration of illness, temperature at presentation, fever 1 day after treatment began, anaemia at presentation and 1 day after treatment began, FIH/1000 asexual parasites cpb, fever clearance time, parasite reduction ratio 2 days after treatment began, and year and season of enrolment were not related to ERAP. In a multivariate analysis, an enrolment parasitaemia <100,000 μL<sup>−1</sup> and parasite positivity 1 day after treatment began were independent predictors of ERAP.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-3"><figure><figcaption class="c-article-table__figcaption"><b id="Tab3" data-test="table-caption">Table 3 Risk factors for early rising asexual parasitaemia in malarious children following artemisinin-based combination treatments</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1186/s12879-016-2173-z/tables/3" aria-label="Full size table 3"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <h3 class="c-article__sub-heading" id="Sec20">Time-course of parasitaemia in patients with or without early rising asexual parasitaemia</h3><p>The time-course of parasitaemia in children with or without ERAP is shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig2">2</a>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Fig. 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig2_HTML.gif?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig2_HTML.gif" alt="figure 2" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>Time-course of parasitaemia in malarious children with early rising asexual parasitaemia (<i>red line</i>), without early rising asexual parasitaemia (<i>blue line</i>), and in all children (<i>black line</i>) following treatment with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <ol class="u-list-style-none"> <li> <span class="u-custom-list-number">(a).</span> <p> <i> Increase in pre-treatment parasitaemia after first dose of ACTs</i> </p> <p>Overall, mean maximum increase in parasitaemia over baseline (pre-treatment) was 96% (95% CI 73.4–118.6, <i>n</i> = 226) in all children. In children with ERAP, overall, mean maximum increase in pre-treatment parasitaemia was 105.6% (95% CI 81–130.1, <i>n</i> = 205), and it was similar with all 3 treatments [92.5% (95% CI 62.2–122.4, <i>n</i> = 107) <i>versus</i> 125.5% (95% CI 69.9–181.2, <i>n</i> = 64) <i>versus</i> 109.3% (95% CI 56.8–161.1, <i>n</i> = 34) in artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinin-piperaquine treatment groups, respectively, <i>P</i> = 0.5]. In children without ERAP mean maximum increase in parasitaemia was 2.5% (95% CI 1.9–3.1, <i>n</i> = 21). At presentation, geometric mean parasitaemia was significantly higher in children without ERAP compared with those with ERAP [61,933 μL<sup>−1</sup>(range 1,800–1,096,636) <i>versus</i> 52,392 μL<sup>−1</sup> (range 2,220–536,912), <i>P</i> = 0.01]. However at other times following the first dose of ACTs, geometric mean parasitaemia was significantly higher in children with ERAP compared with those without [geometric mean 70,313 μL<sup>−1</sup> (range 2,136 – 763,500) <i>versus</i> 37,425 μL<sup>−1</sup> (range 177 – 473,059), <i>P</i> < 0.0001; geometric mean 61,965 μL<sup>−1</sup> (range 2,976 – 838,500) <i>versus</i> 29,719 μL<sup>−1</sup> (range 60 – 358,800), <i>P</i> < 0.0001; geometric mean 52,778 μL<sup>−1</sup> (range 210 – 785,610) <i>versus</i> 20,873 μL<sup>−1</sup> (range 30 – 326,400), <i>P</i> < 0.0001; geometric mean 33,660 μL<sup>−1</sup> (range 980 – 53,100) <i>versus</i> 8,834 μL<sup>−1</sup> (60 – 141,556), <i>P</i> < 0.0001; geometric mean 28,360 μL<sup>−1</sup> (range 36 – 616,119) <i>versus</i> 11,406 μL<sup>−1</sup> (range 23 – 367,647), <i>P</i> = 0.002 at 1, 2, 4, 6 and 8 h, respectively].</p> </li> <li> <span class="u-custom-list-number">(b).</span> <p> <i> Time to peak parasitaemia after first dose of ACTs</i> </p> <p>Overall, time to peak parasitaemia in all children after the first dose was 1.3 h (95% CI 1.1–1.5, <i>n</i> = 226). In children with ERAP, mean peak asexual parasitaemia occurred at 2.5 h (95% CI 2.2–2.7, <i>n</i> = 205), and it was similar with all 3 treatments [2.3 h (95% CI 2–2.7, <i>n</i> = 107) <i>versus</i> 2.5 h (95% CI 2–3, <i>n</i> = 64) <i>versus</i> 2.8 h (95% CI 2.2–3.5, <i>n</i> = 34) in artesunate-amodiaquine, artemether-lumefantrine and dihydroartemisinin-piperaquine treatment groups, respectively, <i>P</i> = 0.39]. In children without ERAP, time to peak parasitaemia occurred at 0.2 h (95% CI 0.1–0.3, <i>n</i> = 21), and it was significantly lower than in those with ERAP (<i>P</i> < 0.0001).</p> </li> <li> <span class="u-custom-list-number">(c).</span> <p> <i> Parasite and fever clearance</i> </p> <p>Overall, mean parasite clearance time was 29 h (95% CI 27.2–30.8, <i>n</i> = 416). Parasite clearance was significantly faster in children without compared to those with ERAP [27.9 h (95% CI 26.5–29.3, <i>n</i> = 211) versus 32.1 h (95% CI 30.2–33.9, <i>n</i> = 205), respectively, <i>P</i> < 0.0001]. In those with ERAP, parasite clearance was significantly faster in artesunate-amodiaquine-treated children compared with artemether-lumefantrine- or dihydroartemisinin-piperaquine-treated children [28.1 h (95% CI 26.7–29.5, <i>n</i> = 240) <i>versus</i> 30.6 h (95% CI 28.4–32.8, <i>n</i> = 120) <i>versus</i> 36.4 h (95% CI 32.5–40.3, <i>n</i> = 56), respectively, <i>P</i> = 0.04]. In those without ERAP, parasite clearance was significantly slower in dihydroartemisinin-piperaquine-treated children compared with artesunate-amodiaquine- or artemether-lumefantrine-treated children [34.6 h (95% CI 28.6–41.2, <i>n</i> = 22) <i>versus</i> 27.4 h (95% CI 25.7–29.2, <i>n</i> = 133) <i>versus</i> 26.1 h (95% CI 24.3–28, <i>n</i> = 56), respectively, <i>P</i> = 0.002]. Overall, PCR corrected ACPR on days 28–42 was 97.8% (95% CI 95–100) and it was similar in children with and without ERAP [97.3% (95% CI 94.1–100) <i>versus</i> 98.2% (95% CI 95.4–100), respectively; <i>P</i> = 0.38]. No child had early treatment failure (ETF). Late parasitological failure (LPF) occurred in 13 children (8 of 205 children <i>versus</i> 5 of 211 children in those with and without ERAP, respectively). There was no significant difference in the proportions of children with late parasitological failure in the two groups (<i>P</i> = 0.37). Overall parasite positivity on day 3 was 3 of 416 and it similar in children with and without ERAP (2 of 205 <i>versus</i> 1 of 211, respectively, <i>P</i> = 0.62). Overall, mean fever clearance time was 1.1 day (95% CI 1.06–1.1, <i>n</i> = 295). Fever clearance was similar in children with or without ERAP [1.1 day (95% CI 1–1.2, <i>n</i> = 154) <i>versus</i> 1.1 day (95% CI 1–1.1, <i>n</i> = 141), respectively, <i>P</i> = 0.62].</p> </li> <li> <span class="u-custom-list-number">(d).</span> <p> <i> Parasite reduction ratio</i> </p> <p>Parasite reduction ratio 1 and 2 days after treatment began was significantly higher in children without compared with those with ERAP [2.8 × 10<sup>4</sup> (7.8 × 10<sup>0</sup>–1.1 × 10<sup>6</sup>) <i>versus</i> 6.2 × 10<sup>3</sup> (5.6 × 10<sup>−1</sup>–5.4 × 10<sup>5</sup>), respectively, <i>P</i> < 0.0001 and 5.7 × 10<sup>4</sup> (1.6 × 10<sup>1</sup>–1.1 × 10<sup>6</sup>) <i>versus</i> 4.6 × 10<sup>3</sup> (3.5 × 10<sup>1</sup>–5.4 × 10<sup>5</sup>), respectively, <i>P</i> < 0.005]. In children with ERAP, parasite reduction ratio 1 day after treatment began was significantly lower in dihydroartemisinin-piperaquine-treated children compared with artesunate-amodiaquine- or artemether-lumefantrine-treated children [1.6 × 10<sup>3</sup> (5.6 × 10<sup>−1</sup>–1.2 × 10<sup>5</sup>) <i>versus</i> 1.3 × 10<sup>4</sup> (2.8 × 10<sup>0</sup>–4.7 × 10<sup>5</sup>) <i>versus</i> [3.7 × 10<sup>4</sup> (8.0 × 10<sup>−1</sup>–5.4 × 10<sup>5</sup>), respectively, <i>P</i> = 0.01]. However, parasite reduction ratio 2 days after treatment began was similar in all 3 treatment groups [4.8 × 10<sup>4</sup> (1.4 × 10<sup>2</sup>–4.7 × 10<sup>5</sup>) <i>versus</i> 5.4 × 10<sup>4</sup> (1.8 × 10<sup>3</sup>–5.4 × 10<sup>5</sup>) <i>versus</i> [4.6 × 10<sup>4</sup>(3.5 × 10<sup>1</sup>–4.2 × 10<sup>5</sup>), respectively, <i>P</i> = 0.09]. <i>Post hoc</i> comparison showed that parasite reduction ratio 2 days after treatment began was significantly higher in artemether-lumefantrine-treated children compared with dihydroartemisinin-piperaquine-treated children (<i>P</i> = 0.03).</p> </li> </ol> <h3 class="c-article__sub-heading" id="Sec21">Kinetics of release of asexual parasites in children with ERAP</h3><p>Data for evaluation of estimates of lag time, half-time and the corresponding release rate constant were available in all 205 children with ERAP. Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig3">3</a> is a semi-logarithmic plot of parasitaemia <i>versus</i> time by the method of residuals in all 205 children with ERAP.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Fig. 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig3_HTML.gif?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig3_HTML.gif" alt="figure 3" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>Estimates of lag time, half-time and rate constant of release of asexual parasitaemia by the method of residuals following a first dose of artemisinin-based combination treatments of falciparum malaria (mean lag time, half-time and rate constant of release were 0.2 h, 1 h and 0.9 h<sup>−1</sup>, respectively)</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <ol class="u-list-style-none"> <li> <span class="u-custom-list-number">(a).</span> <p> <i> Lag time</i>: Overall, mean lag time was 0.2 h (95% CI 0.2-0.3, range 0.02-0.9) and it was similar with all 3 treatments: [0.2 h (95% CI 0.2–0.3, range 0.02–0.9, <i>n</i> = 107) <i>versus</i> 0.2 h (95% CI 0.2–0.3, range 0.02–0.8, <i>n</i> = 64) <i>versus</i> 0.2 h (95% CI 0.2–0.3, range 0.02–0.7, <i>n</i> = 34), respectively for AA, AL, and DHP, <i>P</i> = 1.0].</p> </li> <li> <span class="u-custom-list-number">(b).</span> <p> <i> Half time</i>: Overall, mean half-time of release of parasites into peripheral circulation was 1 h (95% CI 0.9–1.1, range 0.1–4.9) and it was similar with all 3 treatments: [1 h (95% CI 0.9–1.1, range 0.1–4.9, <i>n</i> = 107) <i>versus</i> 1.2 h (95% CI 0.9–1.4, range 0.3–4.4, <i>n</i> = 64) <i>versus</i> 1 h (95% CI 0.8–1.2, range 0.5–3.6, <i>n</i> = 34), respectively for AA, AL, and DHP, <i>P</i> = 0.34].</p> </li> <li> <span class="u-custom-list-number">(c).</span> <p> <i> Rate constant of release</i>: Overall, mean rate constant for release of parasites into peripheral circulation was 0.9 h<sup>−1</sup> (95% CI 0.8–1, range 0.1–5.6) and it was similar with all 3 treatments: [0.9 h<sup>−1</sup> (95% CI 0.8–1.1, range 0.1–5.6, <i>n</i> = 107) <i>versus</i> 0.8 h<sup>−1</sup>(95% CI 0.7–0.9, range 0.2–2.4, <i>n</i> = 64) <i>versus</i> 0.9 h<sup>−1</sup> (95% CI 0.7–0.9, range 0.2–1.5, <i>n</i> = 34), respectively for AA, AL, and DHP, <i>P</i> = 0.45].</p> </li> <li> <span class="u-custom-list-number">(d).</span> <p> <i> Factors influencing kinetics of the release of asexual parasitaemia during early rising asexual parasitaemia</i>: Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab4">4</a> shows the clinical and parasitological parameters that can influence the kinetics of release of asexual parasitaemia in children with early rising asexual parasitaemia. Of these parameters, only the parasite clearance time significantly affected both the lag time and the half-time of release of asexual parasitaemia. With respect to the influence of parasite clearance, there is a reciprocal relationship between lag time and half-time of release if parasite clearance time was ≤ 1 day.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-4"><figure><figcaption class="c-article-table__figcaption"><b id="Tab4" data-test="table-caption">Table 4 Factors influencing the kinetics of release of asexual parasites in children with early rising asexual parasitaemia</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1186/s12879-016-2173-z/tables/4" aria-label="Full size table 4"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> </li> </ol> <h3 class="c-article__sub-heading" id="Sec22">Kinetics of the disposition of parasitaemia in children with or without early rising asexual parasitaemia</h3><p>Overall, geometric mean AUC from initiation of treatment to clearance of parasitaemia in all children was 5.4 × 10<sup>5</sup> μL<sup>−1</sup>.h (95%CI 9.0 × 10<sup>5</sup>–1.1 × 10<sup>6</sup>, range 2.7 × 10<sup>3</sup>–1.1 × 10<sup>7</sup>). Geometric mean AUCs at 0–4, 0–8, 0–24 and 0–48 h after first dose were significantly higher in children with early rising asexual parasitaemia compared with children without early rising asexual parasitaemia (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab5">5</a>, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig3">3</a>). Overall, declines from peak parasitaemias were monoexponential in children with or without ERAP (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig4">4</a>). Overall estimated half-time was 1.2 h (95% CI 1.1–1.2). Mean estimated half-times were similar in children with and without ERAP [1.2 h (95% CI 1.1–1.3) <i>versus</i> 1.2 h (95% CI 1.1–1.3), respectively; <i>P</i> = 0.6] and in all treatment groups [1.2 h (95% CI 1.1–1.2, <i>n</i> = 240) <i>versus</i> 1.2 h (95% CI 1.1–1.2, <i>n</i> = 120) <i>versus</i> 1.3 (95% CI 1.1–1.4, <i>n</i> = 56), <i>P</i> = 0.61] in artesunate-amodiaquine-, artemether-lumefantrine- and dihydroartemisinin-piperaquine-treated children, respectively. Mean estimated half-times were also similar in anaemic and non-anaemic children [1.2 h (95% CI 1.1–1.3, <i>n</i> = 96) <i>versus</i> 1.2 h (95% CI 1.1–1.2, <i>n</i> = 320), respectively; <i>P</i> = 0.49, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig4">4</a>]. In children with ERAP, mean estimated half-times were similar with all 3 treatments [1.2 h (95% CI 1.1–1.2, <i>n</i> = 107) versus 1.2 h (95% CI 1.1–1.3, <i>n</i> = 64) versus 1.3 (95% CI 1.1–1.4, <i>n</i> = 34); <i>P</i> = 0.44] in artesunate-amodiaquine-, artemether-lumefantrine- and dihydroartemisinin-piperaquine-treated children, respectively. Similarly, in children without ERAP, estimated half-times were similar with all 3 treatments [1.2 h (95% CI 1.1–1.3, <i>n</i> = 133) versus 1.2 h (95% CI 1–1.2, <i>n</i> = 56) versus 1.3 (95% CI 1.1–1.5, <i>n</i> = 22); <i>P</i> = 0.64] in artesunate-amodiaquine-, artemether-lumefantrine- and dihydroartemisinin-piperaquine-treated children, respectively. The other pharmacokinetic parameters are summarized in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab5">5</a>.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-5"><figure><figcaption class="c-article-table__figcaption"><b id="Tab5" data-test="table-caption">Table 5 Parameters for disposition of asexual parasitaemia in children with or without early rising asexual parasitaemia following artemisinin-based combination treatments</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1186/s12879-016-2173-z/tables/5" aria-label="Full size table 5"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Fig. 4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 4</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig4_HTML.gif?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig4_HTML.gif" alt="figure 4" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>Semilogarithmic plots of asexual parasitaemia <i>versus</i> time (<b>a</b>) in all children (<i>black line</i>), children with (<i>green line</i>) and without (<i>blue line</i>) early rising asexual parasitaemia, and (<b>b</b>) in anaemic (<i>blue line</i>) and non-anaemic (<i>green line</i>) children treated with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <h3 class="c-article__sub-heading" id="Sec23">Stages of sexual and asexual parasitaemias in peripheral blood</h3> <ol class="u-list-style-none"> <li> <span class="u-custom-list-number">(a).</span> <p> <i> Before treatment</i> </p> <p>Before treatment, gametocytaemia was detected in peripheral blood of 12 children (3%): 6 children each with or without early rising asexual parasitaemia. Only mature gametocytes (Stages IV and V) were detectable in peripheral blood. Ring forms of varying stages were found in the peripheral blood of all children. Late sequestering trophozoites and schizonts were not found in peripheral blood of any child.</p> </li> <li> <span class="u-custom-list-number">(b).</span> <p> <i> Following first dose of ACTs</i> </p> <p>In the first 8 h following treatment, in children without ERAP, different stages of ring forms were found in peripheral blood of all children but schizonts were found in peripheral blood of 1 child. However, young gametocytes were not found in peripheral blood. In children who subsequently developed ERAP, different stages of ring forms were found in peripheral blood of all children. However, schizonts were found in peripheral blood films of 4 children and young gametocytes in peripheral blood films of another 8 children (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig5">5</a>). After 2 weeks following treatment, gametocytes were not found in peripheral blood of any child.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Fig. 5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 5</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig5_HTML.gif?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig5_HTML.gif" alt="figure 5" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p>Light micrograph of <i>Plasmodium falciparum</i> in the first 8 h after a first dose of artemisinin-based combination treatments<i>.</i> Panel <b>a</b> shows female and male gametocytes, Panel <b>b</b> shows immature gametocytes, and Panel <b>c</b> shows schizonts found in peripheral blood of children with early rising asexual parasitaemia</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> </li> </ol> <h3 class="c-article__sub-heading" id="Sec24">Molecular genotyping</h3><p>Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab6">6</a> shows the features of the 170 children (85 pairs) with and without ERAP who were matched for clinical and parasitological parameters at presentation. Asexual parasitaemia was significantly higher in children with ERAP compared to those without from 1 to 8 h after initiation of treatment (P ≤ 0.02 at all times, Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab6">6</a>). However, parasite clearance time determined by microscopy was similar in children with and without ERAP.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-6"><figure><figcaption class="c-article-table__figcaption"><b id="Tab6" data-test="table-caption">Table 6 Features of children with or without early rising asexual parasitaemia matched for gender, enrolment parasitaemia, treatment and same day presentation who were treated with artesunate-amodiaquine, artemether-lumefantrine or dihydroartemisinin-piperaquine</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1186/s12879-016-2173-z/tables/6" aria-label="Full size table 6"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> <ol class="u-list-style-none"> <li> <span class="u-custom-list-number">(a).</span> <p> <i> Parasite DNA clones before and after first dose of artemisinin-based combination treatments</i> </p> <p>Before treatment, of the 12 children with ERAP, 10 children had 1 clone infection and 1 each had 2 and 3 clone infections. In children without ERAP, 8 children had 1 clone infection and 4 had 2 clone infections. Following first dose of ACTs in children with ERAP, clone number increased in 4 children (from 1 to 2 clones in 2 children, 1 to 5 clones in 1 child and 2 to 3 clones in 1 child). In children without ERAP, clone numbers remained unchanged in 11 of 12 children. However, clone number reduced in 1 child from 2 to 1 at 4 h after first dose of ACT. The time course of changes in parasite DNA clones before and following artemisinin-based combination treatments are shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig6">6</a>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-6" data-title="Fig. 6"><figure><figcaption><b id="Fig6" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 6</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig6_HTML.gif?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig6_HTML.gif" alt="figure 6" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-6-desc"><p>Time-course of changes in parasite DNA clones in age-, gender-, parasitaemia- and treatment-matched children with [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Silachamroon U, Phumratanaprapin W, Krudsood S, Treeprasertsuk S, Budsaratid V, Pornpininworakij K, Wilairatana P, Looareesuwan S. Frequency of early risisng parasitaemia in falciparum malaria treated with artemisinin derivatives. Southeast Asian J Trop Med Public Health. 2001;32:50–6." href="/article/10.1186/s12879-016-2173-z#ref-CR1" id="ref-link-section-d86078652e7091">1</a>] and without [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Michael OS, Gbotosho GO, Folarin OA, Okuboyejo T, Sowunmi A, Oduola AMJ, Happi CT. Early variations in Plasmodium falciparum dynamics in Nigerian children after treatment with two artemisinin-based combinations: implications on delayed parasite clearance. Malaria J. 2010;9:335." href="/article/10.1186/s12879-016-2173-z#ref-CR2" id="ref-link-section-d86078652e7094">2</a>] early rising asexual parasitaemia following artemisinin-based combination treatment. Panel <b>a</b> shows individual (<i>black lines</i>) and mean (<i>red line</i>) of area under curves (AUC of clone number <i>versus</i> time) in children with ERAP. Panel <b>b</b> shows individual (<i>black lines</i>) and mean (<i>red line</i>) of area under curves (AUC of clone number <i>versus</i> time) in children without ERAP. Panels <b>c</b> and <b>d</b> show semilog plots of mean clone number <i>versus</i> time in children with and without ERAP, respectively. Declines from peak clone number were monoexponential (mean estimated half-times were 3.4 h (95% CI 3.1–3.7) and 3.1 h (95% CI 2.7–3.4), respectively)</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/6" data-track-dest="link:Figure6 Full size image" aria-label="Full size image figure 6" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> </li> <li> <span class="u-custom-list-number">(b).</span> <p> <i> Time to clearance of parasite DNA clones following treatment</i> </p> <p>Parasite DNA clone clearance time was significantly longer in children with compared to those without early rising asexual parasitaemia [54 h (95% CI 44.5–63.5) <i>versus</i> 36 h (95% CI 28–43.9), respectively; <i>P</i> = 0.004, see Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig6">6</a> Panels a and b].</p> </li> <li> <span class="u-custom-list-number">(c).</span> <p> <i> Relationship between time-course of parasitaemia and changes in intensity of parasite DNA bands</i> </p> <p>In general, irrespective of clone number at enrolment, DNA band intensity did not change in the first 6–8 h in children without ERAP. In children with ERAP, band intensities increased within 1–4 h following initiation of treatment and there was a significant correlation between time of maximum parasitaemia and time of maximal parasite DNA intensity (r = 0.62, <i>P</i> = 0.03). Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig7">7</a> shows the relationship between parasite DNA band intensity, time course of parasitaemia, and parasite lag time, half-time and rate constant of release of parasitaemia in a child with ERAP and the corresponding pair without ERAP.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-7" data-title="Fig. 7"><figure><figcaption><b id="Fig7" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 7</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/7" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig7_HTML.gif?as=webp"><img aria-describedby="Fig7" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig7_HTML.gif" alt="figure 7" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-7-desc"><p>Features of molecular, time course, and release kinetics of asexual parasitaemia in age-, pre-treatment parasitaemia- and same treatment-matched malarious children with (1) and without (2) early rising asexual parasitaemia after first dose of dihydroartemisinin-piperaquine. Panel <b>a</b> shows increase in parasite clones from one to two and maximum parasite DNA band intensity 2 h post-initiation of treatment followed by decreasing intensity after 6 h. Parasite DNA clearance time was 48 h. Panel <b>b</b> shows stable number of clones (two in all) pre- and post-initiation of treatment and no change in DNA band intensity in the first 6 h followed by decrease in intensity. Parasite DNA clearance time was 24 h. Panel <b>c</b> shows peak parasitaemia at 2 h coincides with maximum DNA band intensity in Panel <b>a</b>. Panel <b>d</b> shows decreasing parasitaemia parallels DNA band intensity in Panel <b>b</b>. Panel <b>e</b> shows release kinetics estimated by method of residuals (lag time, half-time, and rate constant of 0.2 h, 0.5 h and 1.5 h<sup>−1</sup>, respectively, and monoexponential terminal elimination half-time of 2.3 h. Panel <b>f</b> shows only monoexponential terminal elimination half time of 1.7 h</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/7" data-track-dest="link:Figure7 Full size image" aria-label="Full size image figure 7" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> </li> <li> <span class="u-custom-list-number">(d).</span> <p> <i> Area under curve (AUC) of number of DNA clones</i> versus <i>time</i> </p> <p>Area under curve of DNA clone number from time of commencement of treatment till clearance was significantly higher in children with ERAP compared to those without ERAP [62.2 no.h (95% CI 36.5–87.8) <i>versus</i> 28.8 no.h (95% CI 21.5–36), <i>P</i> = 0.02) [Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig6">6</a>]. Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig8">8</a> shows increase in DNA clone number, area under curve of number of clone and the disposition of DNA clone in a child with ERAP and the corresponding pair without ERAP. Declines in clone number were monoexponential with similar half-times in the matched pairs of children with and without ERAP (3.4 h (95% CI 3.1–3.7) v 3.1 h (95% CI 2.7–3.4), <i>P</i> = 0.15, Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig6">6</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig8">8</a>)</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-8" data-title="Fig. 8"><figure><figcaption><b id="Fig8" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 8</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/8" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig8_HTML.gif?as=webp"><img aria-describedby="Fig8" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-016-2173-z/MediaObjects/12879_2016_2173_Fig8_HTML.gif" alt="figure 8" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-8-desc"><p>Parasite DNA clone number, area under curve of number of DNA clones <i>versus</i> time, and elimination kinetics of parasite DNA clones in age-, pre-treatment parasitaemia- and same treatment-matched malarious children with (1) and without (2) ERAP treated with artesunate-amodiaquine. Panel <b>a</b> shows increase in parasite DNA clones from one to five 1 h post-initiation of treatment. Parasite DNA clearance time was 48 h. Panel <b>b</b> shows stable number of DNA clone (one at all times) pre- and post-initiation of treatment and no change in parasite DNA clone number following treatment. Parasite DNA clearance time was 24 h. Panels <b>c</b> and <b>d</b> show area under curve of number of clones <i>versus</i> time in children with and without ERAP, respectively. Panel <b>e</b> and <b>f</b> show monoexponential terminal elimination of DNA clones in children with and without ERAP, respectively. Note: Declines in DNA clone numbers were monoexponential</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1186/s12879-016-2173-z/figures/8" data-track-dest="link:Figure8 Full size image" aria-label="Full size image figure 8" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div> </li> </ol> <h3 class="c-article__sub-heading" id="Sec25">Relationship between early rising asexual parasitaemia and late-appearing anaemia</h3><p>In a univariate analysis, a haematocrit <30% was not associated with early rising asexual parasitaemia (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab3">3</a>). The proportions of children with or without early rising parasitaemia who subsequently developed late-appearing anaemia were similar: 28 of 205 (14%) <i>versus</i> 24 of 211 (11%). <i>P</i> =0.48. Similarly, the proportions of children with anaemia at presentation and who subsequently developed late-appearing anaemia in children with or without early rising asexual parasitaemia were also similar: 9 of 49 (18%) <i>versus</i> 8 of 47 (17%). <i>P</i> = 0.86. When matched for age, gender, same day presentation and same treatment, the proportion of children with or without early rising parasitaemia who developed late-appearing anaemia were also similar 12 of 85 (14%) <i>versus</i> 9 of 85 (11%). <i>P</i> = 0.64 (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab6">6</a>).</p><h3 class="c-article__sub-heading" id="Sec26">Reported adverse events</h3><p>Eighty two of 205 (40%) children and 66 of 211 (31%) children with and without early rising asexual parasitaemia, respectively, reported at least 1 adverse event in the first week of starting treatment. There was no significant difference in the proportions reporting adverse events in the 2 groups (<i>P</i> = 0.08). In children with early rising asexual parasitaemia, 23 (11%), 15 (7%), 11 (5%), 2 (1%), 15 (7%), 15 (7%), 9 (4%), 11 (5%) and 3 (1%) children reported abdominal pain, fever, vomiting, weakness, headache, cough, anorexia, running nose and diarrhoea, respectively. In children without early rising asexual parasitaemia, 17 (8%), 13 (6%), 5 (2%), 1 (0.5%), 12 (6%), 16 (8%), 5 (2%), 7 (3%) and 4 (2%) children reported abdominal pain, fever, vomiting, weakness, headache, cough, anorexia, running nose and diarrhoea, respectively. There was no significant difference in the proportions reporting each of these adverse events in the children with and those without early rising asexual parasitaemia.</p></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec27-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec27">Discussion</h2><div class="c-article-section__content" id="Sec27-content"><p>In this study, we described the clinical and parasitological features, the risk factors for, the kinetics of the release and of the disposition of asexual parasitaemia, the parasite population changes, the molecular features of and the relationship between early rising asexual parasitaemia and late-appearing anaemia following artemisinin-based combination treatments in a cohort of children resident in an endemic area. Using a definition of early rising asexual parasitaemia of ≥5% increase in baseline (enrolment) parasitaemia occurring within the first 8 h of initiating artemisinin-based combination treatments showed half of the children had significant increases in baseline parasitaemia that peaked 2.5 h after first dose. Time to peak parasitaemia was significantly longer and the peak parasitaemia significantly higher in children with compared to those without early rising asexual parasitaemia.</p><p>Of the three factors associated with early rising asexual parasitaemia (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab3">3</a>), enrolment parasitaemia <100,000/uL and parasitaemia 1 day post-treatment initiation were independent predictors of early rising asexual parasitaemia. Taken together, these factors would suggest: (i). In these children, a relatively ‘low’ baseline peripheral asexual parasitaemia may indicate a relatively ‘large’ parasite biomass in deep tissues that was, following treatment, quickly mobilized after a first dose; (ii). Mobilization resulted in significantly higher peak asexual parasitaemia compared to that in children without early rising asexual parasitaemia in the first 4–8 h post-treatment initiation (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig2">2</a>); (iii). The higher peripheral parasitaemia was then cleared relatively slowly. The last supports reports of slower clearance of high parasitaemias compared to lower parasitaemias by artemisinin-like drugs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Gbotosho GO, Sowunmi A, Happi CT, Okuboyejo TM. Therapeutic efficacies of artemisinin-based combination therapies in Nigerian children with uncomplicated falciparum malaria during five years of adoption as first-line treatments. Am J Trop Med Hyg. 2011;84:936–43." href="/article/10.1186/s12879-016-2173-z#ref-CR33" id="ref-link-section-d86078652e7388">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="White NJ, Pongtavornpinyo W, Maude RJ, Saralamba S, Aguas R, Stepniewska K, Lee SJ, Dondorp AM, White LJ, Day NPJ. Hyperparasitaemia anf low dosing are important source of anti-malarial drug resistance. Malaria J. 2009;8:253." href="/article/10.1186/s12879-016-2173-z#ref-CR36" id="ref-link-section-d86078652e7391">36</a>]. The significant association of dihydroartemisinin-piperaquine compared with artemether-lumefantrine treatment with early rising asexual parasitaemia may in part be due to the lag time required for converting artemether to its metabolite, dihydroartemisinin. The significantly slower clearance of parasitaemia and lower parasite reduction ratio one day after treatment began in children treated with dihydroartemisinin-piperaquine may also be contributory to its significant association with early rising asexual parasitaemia (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1186/s12879-016-2173-z#Tab3">3</a>).</p><p>The rapid release of asexual parasites into peripheral blood by 12 min of initiating treatment with all 3 artemisinins coupled with the short release half-time indicate release kinetics are rapid first order processes attributable to first dose of artemisinins. Of the factors that may affect release kinetics, it would appear parasite clearance time, which showed a reciprocal relationship between lag time and half-time of release, is the most intriguing. The reason(s) is (are) unclear. However, anaemia did not affect release kinetics indicating release kinetics are not impaired in anaemic children. Evidently, there is no artemisinin resistance in <i>P. falciparum</i> in the study area ([<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Ntadom G, Banjo O, Okuboyejo T, Ogunrinde G, Odey F, Aina O, Sofola T, Sowunmi A. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five year-old Nigerian children. Am J Trop Med Hyg. 2014;91:925–35." href="/article/10.1186/s12879-016-2173-z#ref-CR27" id="ref-link-section-d86078652e7403">27</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Gbotosho GO, Sowunmi A, Happi CT, Okuboyejo TM. Therapeutic efficacies of artemisinin-based combination therapies in Nigerian children with uncomplicated falciparum malaria during five years of adoption as first-line treatments. Am J Trop Med Hyg. 2011;84:936–43." href="/article/10.1186/s12879-016-2173-z#ref-CR33" id="ref-link-section-d86078652e7406">33</a>] and as shown in the present study) and is unclear if the ‘first dose phenomenon’ will be modified by development of artemisinin resistance should this occur in the future.</p><p>Pre-treatment gametocyte carriage was low (3%) in this cohort of children. Nonetheless, young gametocytes were demonstrable after first dose only in few children with early rising asexual parasitaemia. Theoretically, their mobilization into peripheral circulation can be advantageous in two ways: exposing them to higher drug concentrations and enhancing the gametocytocidal effects of the first doses of artemisinins and their partner drugs, all of which are gametocytocidal to young gametocytes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Kumar N, Zheng H. Stage-specific gametocytocidal effect in vitro of the artemisinin drug quinghaosu on Plasmodium falciparum. Parasitol Res. 1990;76:214–8." href="/article/10.1186/s12879-016-2173-z#ref-CR37" id="ref-link-section-d86078652e7412">37</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Adjaley SH, Johnston GL, Li T, Eastman RT, Ekland EH, Eappen AG, Richman A, Sim BKL, Lee MCS, Hoffman SL, Fidock DA. Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue. Proc Nat Acad Sci. 2011;47:E1214–23." href="/article/10.1186/s12879-016-2173-z#ref-CR38" id="ref-link-section-d86078652e7415">38</a>]; and preventing further development in bone marrow to mature gametocytes which are not sensitive to killing effects of the artemisinin-based combination treatments evaluated. It has been shown that a male-biased sex ratio is more infective to mosquitoes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Robert V, Read AF, Essong J, Tchuinkam T, Mulder B, Verhave JP, Carnevale P. Effects of gametocyte sex ratio on infectivity of Plasmodium falciparum to Anopheles gambiae. Trans R Soc Trop Med Hyg. 1996;90:621–4." href="/article/10.1186/s12879-016-2173-z#ref-CR19" id="ref-link-section-d86078652e7418">19</a>], and a selective alteration of gametocyte sex ratios during early rising sexual parasitaemia (ERSP) can produce a female biased sex ratio [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sowunmi A, Okuboyejo TM, Gbotosho GO, Happi CT. Early changes in Plasmodium falciparum asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs. Malaria Chemother Control Elimin. 2012;1. doi:
 10.4303/mcce/235498
 
 ." href="/article/10.1186/s12879-016-2173-z#ref-CR3" id="ref-link-section-d86078652e7421">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Sowunmi A, Balogun T, Gbotosho GO, Happi CT, Adedeji AA, Fehintola FA. Activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual and sexual stage parasites in falciparum malaria in children. Antimicrobial Agents Chemother. 2007;51:1694–9." href="/article/10.1186/s12879-016-2173-z#ref-CR39" id="ref-link-section-d86078652e7424">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Sowunmi A, Balogun ST, Gbotosho GO, Happi CT. Plasmodium falciparum gametocyte sex ratios in symptomatic children treated with antimalarial drugs. Acta Trop. 2009;100:108–17." href="/article/10.1186/s12879-016-2173-z#ref-CR40" id="ref-link-section-d86078652e7428">40</a>], which is less likely to be infective to mosquitoes. However, gametocyte sex ratio changes were not evaluated in the present study because gametocytaemia was less than 10/μL, the lower threshold for estimating sex ratio [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Sowunmi A, Balogun T, Gbotosho GO, Happi CT, Adedeji AA, Fehintola FA. Activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual and sexual stage parasites in falciparum malaria in children. Antimicrobial Agents Chemother. 2007;51:1694–9." href="/article/10.1186/s12879-016-2173-z#ref-CR39" id="ref-link-section-d86078652e7431">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Sowunmi A, Balogun ST, Gbotosho GO, Happi CT. Plasmodium falciparum gametocyte sex ratios in symptomatic children treated with antimalarial drugs. Acta Trop. 2009;100:108–17." href="/article/10.1186/s12879-016-2173-z#ref-CR40" id="ref-link-section-d86078652e7434">40</a>] in patients with demonstrable peripheral gametocytes. Demonstrable sequestering forms of asexual parasites (late trophozoites and schizonts) in peripheral blood also suggests mobilization from deep tissue to peripheral blood.</p><p>Overall, as expected, the area under curve of asexual parasitaemia <i>versus</i> time but not the terminal elimination half-times of parasitaemia was significantly higher in children with early rising asexual parasitaemia compared to those without. The significantly higher area under curve in the first 8–24 h post-treatment initiation indicates large peripheral asexual parasite burden in children with early rising asexual parasitaemia is largely due to a ‘first dose artemisinin phenomenon’. Also, as expected, in age-and treatment-matched children with and without early rising asexual parasitaemia, parasite clearance determined by microscopy was rapid and similar in both groups. However, parasite DNA clearance was significantly longer in children with early rising asexual parasitaemia indicating PCR is more sensitive than microscopy in detecting low peripheral parasitaemia. Taken together, the significantly higher area under curve and significantly slower clearance of parasite DNA indicate significant retention, in the peripheral blood, of asexual parasites that were likely released from deep tissue sites into peripheral blood in children with early rising asexual parasitaemia. Similarly, the significantly higher area under curve of the plot of number of clones <i>versus</i> time at 8 h or after initiation of treatment indicates significant retention of parasite clones in the peripheral blood of children with early rising asexual parasitaemia. Thus, taken together, the significant magnitude and duration of parasitaemia and parasite clones in peripheral blood during the early hours following initiation of treatment are molecular features of first dose of artemisinins and are not indicative of in vivo reduced artemisinin susceptibility in this endemic area. The monoexponential declines in clone number in children with or without early rising asexual parasitaemia who had multiple clones at initiation of treatment or following first dose indicate clone elimination is a first order process (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1186/s12879-016-2173-z#Fig7">7</a>). Overall, the molecular features allow the development of the ‘concept of clone retention’ (measured as area under curve) and ‘clone elimination half-time’ (determined by a monoexponential declines from peak clone number) following a first dose of an artemisinin-like drugs.</p><p>Overall, although a disadvantage of early rising asexual parasitaemia is increasing circulating parasite biomass, a distinct advantage of this first dose phenomenon is a reduced likelihood of and lower sequestering or sequestered parasite biomass. This, in addition to relatively rapid clearance of parasitaemia, should lead to reduced likelihood of progression of non-severe to severe malaria in these children because severe malaria has been attributable to parasite sequestration in vital organs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria: a qualitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985;119:386–401." href="/article/10.1186/s12879-016-2173-z#ref-CR41" id="ref-link-section-d86078652e7453">41</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, Lewallen S, Lomba NG, Molyneux ME. Differentiating the pathologies of cerebral malaria by post-mortem parasite counts. Nat Med. 2004;10:143–5." href="/article/10.1186/s12879-016-2173-z#ref-CR42" id="ref-link-section-d86078652e7456">42</a>], or to release of, and imbalance between pro-inflammatory and anti-inflammatory cytokines by sequestered parasites in deep tissue [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Clarke IA, Budd AC, Alleva SM, Cowden WB. Human malarial disease: a consequence of inflammatory cytokine release. Malaria J. 2006;6:85." href="/article/10.1186/s12879-016-2173-z#ref-CR43" id="ref-link-section-d86078652e7459">43</a>]. In this context, controlled studies are required to evaluate the risks and consequences of progression to severe malaria in children with uncomplicated malaria who subsequently develop or did not develop early rising asexual parasitaemia following initiation of artemisinin-based combination treatments.</p><p>Although early rising asexual parasitaemia has been attributed to mobilization of parasites from deep tissues [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Michael OS, Gbotosho GO, Folarin OA, Okuboyejo T, Sowunmi A, Oduola AMJ, Happi CT. Early variations in Plasmodium falciparum dynamics in Nigerian children after treatment with two artemisinin-based combinations: implications on delayed parasite clearance. Malaria J. 2010;9:335." href="/article/10.1186/s12879-016-2173-z#ref-CR2" id="ref-link-section-d86078652e7465">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Sowunmi A, Okuboyejo TM, Gbotosho GO, Happi CT. Early changes in Plasmodium falciparum asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs. Malaria Chemother Control Elimin. 2012;1. doi:
 10.4303/mcce/235498
 
 ." href="/article/10.1186/s12879-016-2173-z#ref-CR3" id="ref-link-section-d86078652e7468">3</a>], it could also have resulted from large numbers of schizonts bursting to release young ring forms into peripheral circulation after first dose of artemisinins. Can this also be an artemisinin effects? This is possible. The broad stage effects of artemisinins from rings aged 6 h and above [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Li G, Guo X, Fu L, Jian H, Wang X. Clinical trials of artemisinin and its derivatives in the treatment of malaria in China. Trans R Soc Trop Med Hyg. 1994;88(Supplement):S5–6." href="/article/10.1186/s12879-016-2173-z#ref-CR17" id="ref-link-section-d86078652e7471">17</a>], would act on these young rings in the first 8 h of the first dose. It is also possible that, acting by unknown mechanism, artemisinin-like drugs are more likely to cause more peripheral circulating rather than deep tissue retention of asexual parasites in children with early rising asexual parasitaemia. In this regard, studies are urgently needed on the effects of artemisinins on binding of asexual parasite-infected red blood cells to tissue proteins.</p><p>A postulate of the present study was increase mobilization of asexual parasites from deep tissue into peripheral circulation would increase the number of infected red blood cells pitted by the spleen. This process could lead to increase in number of once-infected red blood cells in peripheral circulation. The once-infected red blood cells may thereafter be destroyed 7–21 days later causing a relatively asymptomatic late-appearing anaemia following artemisinin-based combination treatments in patients with early rising asexual parasites compared with those without. This postulate was not realised in children with early rising asexual parasites compared with those without as evidenced by similar frequency of late-appearing anaemia in children with or without early rising asexual parasitaemia. Additionally, anaemia had no effect on asexual parasite release kinetics in children with early rising asexual parasitaemia. When compared with the recently described features of late-appearing anaemia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e7477">7</a>], there are significant differences in risk factors for the two conditions. The differences are particularly striking with respect to age, presence of anaemia at enrolment or 1 day after treatment began, parasite reduction ratios, and parasite clearance times, which are diametrically opposite in these two conditions associated with artemisinin-based combination treatments (see reference [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240." href="/article/10.1186/s12879-016-2173-z#ref-CR7" id="ref-link-section-d86078652e7480">7</a>]). Perhaps the lack of association between early rising asexual parasites and late-appearing anaemia is one of the ‘beneficial effects’ of artemisinin-like drugs. Studies are now necessary to quantify once- infected red blood cells in patients with or without early rising asexual parasites following artemisinin-based combination treatments.</p><p>There is need to justify the definition of early rising parasitaemia used in the present study. Firstly, a ≥5% increase in parasitaemia from baseline in a relatively short time frame is unlikely to be a random effect. Secondly, in a manner similar to a two-way analysis of variance, it is likely to represent a significant increase in parasitaemia from baseline in a short time frame that would result in two populations of children: those with and those without early rising asexual parasitaemia after a first dose of artemisinins. Thirdly, the lag time of 12 min after a first dose and ≥5% increase in baseline parasitaemia indicate it is a first dose artemisinin effect and it is unlikely to be due to reduced sensitivity or resistance in the parasites that are released into peripheral circulation. Fourthly, with an estimated half-life of 1 h or less, >99% of an administered first dose of oral artemisinin would have been eliminated in 8 h lending credence to this critical time frame, and attributing the response most likely but not exclusively to artemisinin-like drug action. Finally, the definition is not in agreement with in vivo measures of artemisinin resistance measured as parasite positivity rate 3 days after commencement of treatment >3% in patients with pre-treatment parasitaemia <100,000/μL or >10% of patients with detectable <i>P. falciparum</i> parasitaemia 72 h after initiation of direct observed therapy [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, Binh TQ, D’Alessandro U, Day NPJ, de Vries PJ, Dorsey G, Guthmann J_P, Mayxay M, Newton PN, Olliaro P, Osorio L, Price RN, Rowland M, Smithuis F, Taylor WRJ, Nosten F, White NJ. In vivo parasitological measures of artemisinin susceptibility. J inf Dis. 2010;201:570–6." href="/article/10.1186/s12879-016-2173-z#ref-CR44" id="ref-link-section-d86078652e7489">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Global Malaria Programme WHO. Update on artemisinin resistance – April 2012. 2012. Available from: 
 http://www.who.int/malaria/publications/atoz/updateartemsininresistanceapr2012/en/
 
 ." href="/article/10.1186/s12879-016-2173-z#ref-CR45" id="ref-link-section-d86078652e7492">45</a>]. The similar frequency of early rising asexual parasitaemia and non-early rising asexual parasitaemia in the population of children evaluated would suggest there is a possible genetic basis for this ‘first dose phenomenon’. Whether the genetic basis is host- or parasite-related is conjectural. More studies are now needed to explore the basis of this phenomenon.</p><p>There are limitations of the study. These include not using a quantitative method (qPCR) to assess the amount of DNA in patients samples during the various time points, in samples obtained in children with or without early rising asexual parasitaemia to justify the increased intensity observed on PCR gels and not estimating once-infected red blood cells in the postulate to establish the relationship between early rising asexual parasitaemia and late- appearing anaemia.</p></div></div></section><section data-title="Conclusion"><div class="c-article-section" id="Sec28-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec28">Conclusion</h2><div class="c-article-section__content" id="Sec28-content"><p>In conclusion, early rising asexual parasitaemia is common, occurs rapidly as first order process and may be due to mobilization of parasites from deep tissue following a first dose ACTs of acute childhood falciparum malaria.</p></div></div></section> </div> <section data-title="Abbreviations"><div class="c-article-section" id="abbreviations-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="abbreviations">Abbreviations</h2><div class="c-article-section__content" id="abbreviations-content"><dl class="c-abbreviation_list"><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>%:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Percent</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>°C:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Degree Celsius</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>μL:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Microliter</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>AA:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Artesunate-amodiaquine</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>ACTs:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Artemisinin-based combination treatments</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>AL:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Artemether-lumefantrine</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>AOR:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Adjusted odds ratio</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>AUC:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Area under curve</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>bp:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Base pair</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>cbp:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Cleared from peripheral blood</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>CL<sub>Bpd</sub> :</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Volume of blood cleared of parasitaemia per unit of time</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>C<sub>maxpd</sub> :</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Maximum parasite density</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>DHP:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Dihydroartemisinin-piperaquine</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>DNA:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Deoxyribonucleic acid</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>ERAP:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Early rising asexual parasitaemia</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>FCT:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Fever clearance time</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>FIH:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Fall in haematocrit</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>g:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Gram</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>GMPD:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Geometric mean parasite density</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>h:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Hour</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>HCT:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Haematocrit</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>kg:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Kilogram</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>L:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Litre</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>LAA:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Late-appearing anaemia</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>M/F:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>male/female</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>mg:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>milligram</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>OR:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Odds ratio</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>PCR:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Polymerase chain reaction</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>PCT:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Parasite clearance time</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>PRR:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Parasite reduction ratio</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>qPCR:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Quantitative polymerase chain reaction</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>T<sub>maxpd</sub> :</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Time to reach maximum parasite density</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>v:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>versus</p> </dd></dl></div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">Silachamroon U, Phumratanaprapin W, Krudsood S, Treeprasertsuk S, Budsaratid V, Pornpininworakij K, Wilairatana P, Looareesuwan S. Frequency of early risisng parasitaemia in falciparum malaria treated with artemisinin derivatives. Southeast Asian J Trop Med Public Health. 2001;32:50–6.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DC%2BD38%2FislOmtQ%3D%3D" aria-label="CAS reference 1">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11485095" aria-label="PubMed reference 1">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 1" href="http://scholar.google.com/scholar_lookup?&title=Frequency%20of%20early%20risisng%20parasitaemia%20in%20falciparum%20malaria%20treated%20with%20artemisinin%20derivatives&journal=Southeast%20Asian%20J%20Trop%20Med%20Public%20Health&volume=32&pages=50-6&publication_year=2001&author=Silachamroon%2CU&author=Phumratanaprapin%2CW&author=Krudsood%2CS&author=Treeprasertsuk%2CS&author=Budsaratid%2CV&author=Pornpininworakij%2CK&author=Wilairatana%2CP&author=Looareesuwan%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="2."><p class="c-article-references__text" id="ref-CR2">Michael OS, Gbotosho GO, Folarin OA, Okuboyejo T, Sowunmi A, Oduola AMJ, Happi CT. Early variations in <i>Plasmodium falciparum</i> dynamics in Nigerian children after treatment with two artemisinin-based combinations: implications on delayed parasite clearance. Malaria J. 2010;9:335.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/1475-2875-9-335" data-track-item_id="10.1186/1475-2875-9-335" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/1475-2875-9-335" aria-label="Article reference 2" data-doi="10.1186/1475-2875-9-335">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXhsFejsrzJ" aria-label="CAS reference 2">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 2" href="http://scholar.google.com/scholar_lookup?&title=Early%20variations%20in%20Plasmodium%20falciparum%20dynamics%20in%20Nigerian%20children%20after%20treatment%20with%20two%20artemisinin-based%20combinations%3A%20implications%20on%20delayed%20parasite%20clearance&journal=Malaria%20J&doi=10.1186%2F1475-2875-9-335&volume=9&publication_year=2010&author=Michael%2COS&author=Gbotosho%2CGO&author=Folarin%2COA&author=Okuboyejo%2CT&author=Sowunmi%2CA&author=Oduola%2CAMJ&author=Happi%2CCT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="3."><p class="c-article-references__text" id="ref-CR3">Sowunmi A, Okuboyejo TM, Gbotosho GO, Happi CT. Early changes in <i>Plasmodium falciparum</i> asexual and sexual populations in children with acute infections following treatment with artemisinin-based combination drugs. Malaria Chemother Control Elimin. 2012;1. doi:<a href="https://doi.org/10.4303/mcce/235498" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.4303/mcce/235498">10.4303/mcce/235498</a>.</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="4."><p class="c-article-references__text" id="ref-CR4">World Health Organization. World malaria report. Geneva: World Health Organization; 2015.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 4" href="http://scholar.google.com/scholar_lookup?&title=World%20malaria%20report&publication_year=2015"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="5."><p class="c-article-references__text" id="ref-CR5">World Health Organization. World malaria report. Geneva: World Health Organization; 2014.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 5" href="http://scholar.google.com/scholar_lookup?&title=World%20malaria%20report&publication_year=2014"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="6."><p class="c-article-references__text" id="ref-CR6">Sowunmi A, Gbotosho GO, Happi CT, Fateye BA. Factors contributing to anaemia after uncomplicated <i>Plasmodium falciparum</i> malaria in children. Acta Trop. 2010;133:155–61.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.actatropica.2009.10.011" data-track-item_id="10.1016/j.actatropica.2009.10.011" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.actatropica.2009.10.011" aria-label="Article reference 6" data-doi="10.1016/j.actatropica.2009.10.011">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 6" href="http://scholar.google.com/scholar_lookup?&title=Factors%20contributing%20to%20anaemia%20after%20uncomplicated%20Plasmodium%20falciparum%20malaria%20in%20children&journal=Acta%20Trop&doi=10.1016%2Fj.actatropica.2009.10.011&volume=133&pages=155-61&publication_year=2010&author=Sowunmi%2CA&author=Gbotosho%2CGO&author=Happi%2CCT&author=Fateye%2CBA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="7."><p class="c-article-references__text" id="ref-CR7">Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Clinical illness and outcomes in Nigerian children with late-appearing anaemia after artemisinin-based combination treatments of uncomplicated falciparum malaria. BMC Infect Dis. 2016;16:240.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12879-016-1565-4" data-track-item_id="10.1186/s12879-016-1565-4" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12879-016-1565-4" aria-label="Article reference 7" data-doi="10.1186/s12879-016-1565-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27246468" aria-label="PubMed reference 7">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888541" aria-label="PubMed Central reference 7">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 7" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20illness%20and%20outcomes%20in%20Nigerian%20children%20with%20late-appearing%20anaemia%20after%20artemisinin-based%20combination%20treatments%20of%20uncomplicated%20falciparum%20malaria&journal=BMC%20Infect%20Dis&doi=10.1186%2Fs12879-016-1565-4&volume=16&publication_year=2016&author=Sowunmi%2CA&author=Akano%2CK&author=Ayede%2CAI&author=Ntadom%2CG&author=Aderoyeje%2CT&author=Adewoye%2CEO&author=Fatunmbi%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="8."><p class="c-article-references__text" id="ref-CR8">Sumbele IUN, Samje M, Nkuo-Akenji T. A longitudinal study of anaemia in children with <i>Plasmodium falciparum</i> infection in the Mount Cameroon region: prevalence, risk factors and perceptions by caregivers. BMC Infect Dis. 2013;13:123.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/1471-2334-13-123" data-track-item_id="10.1186/1471-2334-13-123" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/1471-2334-13-123" aria-label="Article reference 8" data-doi="10.1186/1471-2334-13-123">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23497273" aria-label="PubMed reference 8">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600988" aria-label="PubMed Central reference 8">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 8" href="http://scholar.google.com/scholar_lookup?&title=A%20longitudinal%20study%20of%20anaemia%20in%20children%20with%20Plasmodium%20falciparum%20infection%20in%20the%20Mount%20Cameroon%20region%3A%20prevalence%2C%20risk%20factors%20and%20perceptions%20by%20caregivers&journal=BMC%20Infect%20Dis&doi=10.1186%2F1471-2334-13-123&volume=13&publication_year=2013&author=Sumbele%2CIUN&author=Samje%2CM&author=Nkuo-Akenji%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="9."><p class="c-article-references__text" id="ref-CR9">Obonyo CO, Taylor W, Ekvall H, Kaneko A, ter Kuile F, Olliaro P, Bjorkman A, Oloo AJ. Effects of artesunate plus sulfadoxine-pyrimethamine on haematological recovery and anaemia in Kenyan children with uncomplicated <i>Plasmodium falciparum</i> malaria. Ann Trop Med Parasitol. 2007;101:281–95.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1179/136485907X176337" data-track-item_id="10.1179/136485907X176337" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1179%2F136485907X176337" aria-label="Article reference 9" data-doi="10.1179/136485907X176337">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXnvVCrurY%3D" aria-label="CAS reference 9">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17524243" aria-label="PubMed reference 9">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 9" href="http://scholar.google.com/scholar_lookup?&title=Effects%20of%20artesunate%20plus%20sulfadoxine-pyrimethamine%20on%20haematological%20recovery%20and%20anaemia%20in%20Kenyan%20children%20with%20uncomplicated%20Plasmodium%20falciparum%20malaria&journal=Ann%20Trop%20Med%20Parasitol&doi=10.1179%2F136485907X176337&volume=101&pages=281-95&publication_year=2007&author=Obonyo%2CCO&author=Taylor%2CW&author=Ekvall%2CH&author=Kaneko%2CA&author=Kuile%2CF&author=Olliaro%2CP&author=Bjorkman%2CA&author=Oloo%2CAJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="10."><p class="c-article-references__text" id="ref-CR10">Sowunmi A, Akano K, Ayede AI, Ntadom G, Aderoyeje T, Adewoye EO, Fatunmbi B. Temporal changes in haematocrit following artemisinin-based combination treatments of uncomplicated falciparum malaria in children. BMC Inectf Dis. 2015;15:454.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12879-015-1219-y" data-track-item_id="10.1186/s12879-015-1219-y" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12879-015-1219-y" aria-label="Article reference 10" data-doi="10.1186/s12879-015-1219-y">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 10" href="http://scholar.google.com/scholar_lookup?&title=Temporal%20changes%20in%20haematocrit%20following%20artemisinin-based%20combination%20treatments%20of%20uncomplicated%20falciparum%20malaria%20in%20children&journal=BMC%20Inectf%20Dis&doi=10.1186%2Fs12879-015-1219-y&volume=15&publication_year=2015&author=Sowunmi%2CA&author=Akano%2CK&author=Ayede%2CAI&author=Ntadom%2CG&author=Aderoyeje%2CT&author=Adewoye%2CEO&author=Fatunmbi%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="11."><p class="c-article-references__text" id="ref-CR11">World Health Organization. Severe and complicated malaria. Trans R Soc Trop Med Hyg. 1990;84 Suppl 2:1–65.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/0035-9203(90)90363-J" data-track-item_id="10.1016/0035-9203(90)90363-J" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0035-9203%2890%2990363-J" aria-label="Article reference 11" data-doi="10.1016/0035-9203(90)90363-J">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 11" href="http://scholar.google.com/scholar_lookup?&title=Severe%20and%20complicated%20malaria&journal=Trans%20R%20Soc%20Trop%20Med%20Hyg&doi=10.1016%2F0035-9203%2890%2990363-J&volume=84&issue=Suppl%202&pages=1-65&publication_year=1990"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="12."><p class="c-article-references__text" id="ref-CR12">World Health Organization. Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94 Suppl 1:1–90.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0035-9203(00)90300-6" data-track-item_id="10.1016/S0035-9203(00)90300-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0035-9203%2800%2990300-6" aria-label="Article reference 12" data-doi="10.1016/S0035-9203(00)90300-6">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 12" href="http://scholar.google.com/scholar_lookup?&title=Severe%20falciparum%20malaria&journal=Trans%20R%20Soc%20Trop%20Med%20Hyg&doi=10.1016%2FS0035-9203%2800%2990300-6&volume=94&issue=Suppl%201&pages=1-90&publication_year=2000"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="13."><p class="c-article-references__text" id="ref-CR13">World Health Organization. Severe malaria. Trop Med Int Health. 2014;19 Suppl 1:7–131.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 13" href="http://scholar.google.com/scholar_lookup?&title=Severe%20malaria&journal=Trop%20Med%20Int%20Health&volume=19&issue=Suppl%201&pages=7-131&publication_year=2014"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="14."><p class="c-article-references__text" id="ref-CR14">Shaper AG, Lewis P. Genetic neutropenia in people of African origin. Lancet. 1971;i:1021–3.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0140-6736(71)90335-7" data-track-item_id="10.1016/S0140-6736(71)90335-7" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0140-6736%2871%2990335-7" aria-label="Article reference 14" data-doi="10.1016/S0140-6736(71)90335-7">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 14" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20neutropenia%20in%20people%20of%20African%20origin&journal=Lancet&doi=10.1016%2FS0140-6736%2871%2990335-7&volume=i&pages=1021-3&publication_year=1971&author=Shaper%2CAG&author=Lewis%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="15."><p class="c-article-references__text" id="ref-CR15">Ezeilo GC. Neutropenia in African. Trop Geogr Med. 1971;23:264–7.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaE38%2FhtlCitA%3D%3D" aria-label="CAS reference 15">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=5098995" aria-label="PubMed reference 15">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 15" href="http://scholar.google.com/scholar_lookup?&title=Neutropenia%20in%20African&journal=Trop%20Geogr%20Med&volume=23&pages=264-7&publication_year=1971&author=Ezeilo%2CGC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="16."><p class="c-article-references__text" id="ref-CR16">Sowunmi A, Akindele JA, Balogun MA. Leukocyte counts in falciparum in African children from an endemic area. Afr J Med Med Sci. 1995;24:145–9.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK283ltValsg%3D%3D" aria-label="CAS reference 16">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8669393" aria-label="PubMed reference 16">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 16" href="http://scholar.google.com/scholar_lookup?&title=Leukocyte%20counts%20in%20falciparum%20in%20African%20children%20from%20an%20endemic%20area&journal=Afr%20J%20Med%20Med%20Sci&volume=24&pages=145-9&publication_year=1995&author=Sowunmi%2CA&author=Akindele%2CJA&author=Balogun%2CMA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="17."><p class="c-article-references__text" id="ref-CR17">Li G, Guo X, Fu L, Jian H, Wang X. Clinical trials of artemisinin and its derivatives in the treatment of malaria in China. Trans R Soc Trop Med Hyg. 1994;88(Supplement):S5–6.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/0035-9203(94)90460-X" data-track-item_id="10.1016/0035-9203(94)90460-X" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0035-9203%2894%2990460-X" aria-label="Article reference 17" data-doi="10.1016/0035-9203(94)90460-X">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8053027" aria-label="PubMed reference 17">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 17" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20trials%20of%20artemisinin%20and%20its%20derivatives%20in%20the%20treatment%20of%20malaria%20in%20China&journal=Trans%20R%20Soc%20Trop%20Med%20Hyg&doi=10.1016%2F0035-9203%2894%2990460-X&volume=88&issue=Supplement&pages=S5-6&publication_year=1994&author=Li%2CG&author=Guo%2CX&author=Fu%2CL&author=Jian%2CH&author=Wang%2CX"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="18."><p class="c-article-references__text" id="ref-CR18">Carter R, Graves PM. Gametocytes. In: Wernsdorfer WH, Mc Gregor I, editors. Malaria: principles and practice of malariology, vol. 1. Edinburgh: Chuchill Livinstone; 1988. p. 253–303.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 18" href="http://scholar.google.com/scholar_lookup?&title=Gametocytes&pages=253-303&publication_year=1988&author=Carter%2CR&author=Graves%2CPM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="19."><p class="c-article-references__text" id="ref-CR19">Robert V, Read AF, Essong J, Tchuinkam T, Mulder B, Verhave JP, Carnevale P. Effects of gametocyte sex ratio on infectivity of <i>Plasmodium falciparum</i> to <i>Anopheles gambiae</i>. Trans R Soc Trop Med Hyg. 1996;90:621–4.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0035-9203(96)90408-3" data-track-item_id="10.1016/S0035-9203(96)90408-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0035-9203%2896%2990408-3" aria-label="Article reference 19" data-doi="10.1016/S0035-9203(96)90408-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK2s7mslykuw%3D%3D" aria-label="CAS reference 19">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=9015496" aria-label="PubMed reference 19">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 19" href="http://scholar.google.com/scholar_lookup?&title=Effects%20of%20gametocyte%20sex%20ratio%20on%20infectivity%20of%20Plasmodium%20falciparum%20to%20Anopheles%20gambiae&journal=Trans%20R%20Soc%20Trop%20Med%20Hyg&doi=10.1016%2FS0035-9203%2896%2990408-3&volume=90&pages=621-4&publication_year=1996&author=Robert%2CV&author=Read%2CAF&author=Essong%2CJ&author=Tchuinkam%2CT&author=Mulder%2CB&author=Verhave%2CJP&author=Carnevale%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="20."><p class="c-article-references__text" id="ref-CR20">Sinden RE. Gametocytes and sexual developments. In: Sherman IW, editor. Malaria: parasite biology, pathogenesis and protection. Washinton DC: ASM Press; 1998. p. 25–48.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 20" href="http://scholar.google.com/scholar_lookup?&title=Gametocytes%20and%20sexual%20developments&pages=25-48&publication_year=1998&author=Sinden%2CRE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="21."><p class="c-article-references__text" id="ref-CR21">West SA, Reece SE, Read AF. Evolution of gametocyte sex ratio in malaria and related apicomplexan (protozoan) parasites. Trends Parasitol. 2001;17:525–31.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S1471-4922(01)02058-X" data-track-item_id="10.1016/S1471-4922(01)02058-X" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS1471-4922%2801%2902058-X" aria-label="Article reference 21" data-doi="10.1016/S1471-4922(01)02058-X">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DC%2BD387jsFGksA%3D%3D" aria-label="CAS reference 21">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11872397" aria-label="PubMed reference 21">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 21" href="http://scholar.google.com/scholar_lookup?&title=Evolution%20of%20gametocyte%20sex%20ratio%20in%20malaria%20and%20related%20apicomplexan%20%28protozoan%29%20parasites&journal=Trends%20Parasitol&doi=10.1016%2FS1471-4922%2801%2902058-X&volume=17&pages=525-31&publication_year=2001&author=West%2CSA&author=Reece%2CSE&author=Read%2CAF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="22."><p class="c-article-references__text" id="ref-CR22">West SA, Smith TG, Nee S, Read AF. Fertility insurance and the sex ratios of malaria and related hemosporins blood parasites. J Parasitol. 2002;17:258–63.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1645/0022-3395(2002)088[0258:FIATSR]2.0.CO;2" data-track-item_id="10.1645/0022-3395(2002)088[0258:FIATSR]2.0.CO;2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1645%2F0022-3395%282002%29088%5B0258%3AFIATSR%5D2.0.CO%3B2" aria-label="Article reference 22" data-doi="10.1645/0022-3395(2002)088[0258:FIATSR]2.0.CO;2">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 22" href="http://scholar.google.com/scholar_lookup?&title=Fertility%20insurance%20and%20the%20sex%20ratios%20of%20malaria%20and%20related%20hemosporins%20blood%20parasites&journal=J%20Parasitol&doi=10.1645%2F0022-3395%282002%29088%5B0258%3AFIATSR%5D2.0.CO%3B2&volume=17&pages=258-63&publication_year=2002&author=West%2CSA&author=Smith%2CTG&author=Nee%2CS&author=Read%2CAF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="23."><p class="c-article-references__text" id="ref-CR23">Sowunmi A, Gbotosho GO, Happi CT, Folarin OA, Balogun ST. Population structure of <i>Plasmodium falciparum</i> gametocyte sex ratios in malarious children in an endemic area. Parasitol International. 2009;58:438–43.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.parint.2009.08.007" data-track-item_id="10.1016/j.parint.2009.08.007" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.parint.2009.08.007" aria-label="Article reference 23" data-doi="10.1016/j.parint.2009.08.007">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 23" href="http://scholar.google.com/scholar_lookup?&title=Population%20structure%20of%20Plasmodium%20falciparum%20gametocyte%20sex%20ratios%20in%20malarious%20children%20in%20an%20endemic%20area&journal=Parasitol%20International&doi=10.1016%2Fj.parint.2009.08.007&volume=58&pages=438-43&publication_year=2009&author=Sowunmi%2CA&author=Gbotosho%2CGO&author=Happi%2CCT&author=Folarin%2COA&author=Balogun%2CST"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="24."><p class="c-article-references__text" id="ref-CR24">Bustamante C, Folarin OA, Gbotosho GO, Batista CN, Mesquita EA, Brindeiro RM, Tanuri A, Struchiner CJ, Sowunmi A, Oduola A, Wirth DF, Zalis MG, Happi CT. In vitro-reduced susceptibility to artemether in <i>P. falciparum</i> and its asscociation with polymorphisms on transporter genes. J Infect Dis. 2012;206:324–32.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/infdis/jis359" data-track-item_id="10.1093/infdis/jis359" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Finfdis%2Fjis359" aria-label="Article reference 24" data-doi="10.1093/infdis/jis359">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC38XhtVeisLbM" aria-label="CAS reference 24">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22615315" aria-label="PubMed reference 24">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490696" aria-label="PubMed Central reference 24">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 24" href="http://scholar.google.com/scholar_lookup?&title=In%20vitro-reduced%20susceptibility%20to%20artemether%20in%20P.%20falciparum%20and%20its%20asscociation%20with%20polymorphisms%20on%20transporter%20genes&journal=J%20Infect%20Dis&doi=10.1093%2Finfdis%2Fjis359&volume=206&pages=324-32&publication_year=2012&author=Bustamante%2CC&author=Folarin%2COA&author=Gbotosho%2CGO&author=Batista%2CCN&author=Mesquita%2CEA&author=Brindeiro%2CRM&author=Tanuri%2CA&author=Struchiner%2CCJ&author=Sowunmi%2CA&author=Oduola%2CA&author=Wirth%2CDF&author=Zalis%2CMG&author=Happi%2CCT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="25."><p class="c-article-references__text" id="ref-CR25">Price RC, Simpson JA, Nosten F, Luxemberger C, Hkirjaroen L, ter Kuile F, Chongsuphajaisiddhi T, White NJ. Factors contributing to anemia after uncomplicated falciparum malaria. Am J Trop Med Hyg. 2001;65:614–22.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DC%2BD3MnntVOmtQ%3D%3D" aria-label="CAS reference 25">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11716124" aria-label="PubMed reference 25">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4337986" aria-label="PubMed Central reference 25">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 25" href="http://scholar.google.com/scholar_lookup?&title=Factors%20contributing%20to%20anemia%20after%20uncomplicated%20falciparum%20malaria&journal=Am%20J%20Trop%20Med%20Hyg&volume=65&pages=614-22&publication_year=2001&author=Price%2CRC&author=Simpson%2CJA&author=Nosten%2CF&author=Luxemberger%2CC&author=Hkirjaroen%2CL&author=Kuile%2CF&author=Chongsuphajaisiddhi%2CT&author=White%2CNJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="26."><p class="c-article-references__text" id="ref-CR26">Sowunmi A, Balogun ST, Gbotosho GO, Happi CT. Effects of amodiaquine, artesunate, and artesunate-amodiaquine on <i>Plasmodium falciparum</i> malaria-associated anaemia in children. Acta Trop. 2009;109:55–60.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.actatropica.2008.09.022" data-track-item_id="10.1016/j.actatropica.2008.09.022" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.actatropica.2008.09.022" aria-label="Article reference 26" data-doi="10.1016/j.actatropica.2008.09.022">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXhsVertb%2FM" aria-label="CAS reference 26">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18992209" aria-label="PubMed reference 26">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 26" href="http://scholar.google.com/scholar_lookup?&title=Effects%20of%20amodiaquine%2C%20artesunate%2C%20and%20artesunate-amodiaquine%20on%20Plasmodium%20falciparum%20malaria-associated%20anaemia%20in%20children&journal=Acta%20Trop&doi=10.1016%2Fj.actatropica.2008.09.022&volume=109&pages=55-60&publication_year=2009&author=Sowunmi%2CA&author=Balogun%2CST&author=Gbotosho%2CGO&author=Happi%2CCT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="27."><p class="c-article-references__text" id="ref-CR27">Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Ntadom G, Banjo O, Okuboyejo T, Ogunrinde G, Odey F, Aina O, Sofola T, Sowunmi A. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five year-old Nigerian children. Am J Trop Med Hyg. 2014;91:925–35.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.4269/ajtmh.13-0248" data-track-item_id="10.4269/ajtmh.13-0248" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.4269%2Fajtmh.13-0248" aria-label="Article reference 27" data-doi="10.4269/ajtmh.13-0248">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXitVyhsLzM" aria-label="CAS reference 27">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25246693" aria-label="PubMed reference 27">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4228889" aria-label="PubMed Central reference 27">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 27" href="http://scholar.google.com/scholar_lookup?&title=Efficacy%20of%20artemisinin-based%20combination%20treatments%20of%20uncomplicated%20falciparum%20malaria%20in%20under-five%20year-old%20Nigerian%20children&journal=Am%20J%20Trop%20Med%20Hyg&doi=10.4269%2Fajtmh.13-0248&volume=91&pages=925-35&publication_year=2014&author=Oguche%2CS&author=Okafor%2CHU&author=Watila%2CI&author=Meremikwu%2CM&author=Agomo%2CP&author=Ogala%2CW&author=Agomo%2CC&author=Ntadom%2CG&author=Banjo%2CO&author=Okuboyejo%2CT&author=Ogunrinde%2CG&author=Odey%2CF&author=Aina%2CO&author=Sofola%2CT&author=Sowunmi%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="28."><p class="c-article-references__text" id="ref-CR28">Gbotosho GO, Okuboyejo TM, Happi CT, Sowunmi A. Fall in haematocrit per 1000 parasites cleared from peripheral blood; a simple method for estimating drug-related fall in haematocrit after treatment of malaria infections. Am J Ther. 2014;21:193–7.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1097/MJT.0b013e31822119d9" data-track-item_id="10.1097/MJT.0b013e31822119d9" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1097%2FMJT.0b013e31822119d9" aria-label="Article reference 28" data-doi="10.1097/MJT.0b013e31822119d9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22020083" aria-label="PubMed reference 28">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 28" href="http://scholar.google.com/scholar_lookup?&title=Fall%20in%20haematocrit%20per%201000%20parasites%20cleared%20from%20peripheral%20blood%3B%20a%20simple%20method%20for%20estimating%20drug-related%20fall%20in%20haematocrit%20after%20treatment%20of%20malaria%20infections&journal=Am%20J%20Ther&doi=10.1097%2FMJT.0b013e31822119d9&volume=21&pages=193-7&publication_year=2014&author=Gbotosho%2CGO&author=Okuboyejo%2CTM&author=Happi%2CCT&author=Sowunmi%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="29."><p class="c-article-references__text" id="ref-CR29">World Health Organization. Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: World Health Organization; 2003.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 29" href="http://scholar.google.com/scholar_lookup?&title=Assessment%20and%20monitoring%20of%20antimalarial%20drug%20efficacy%20for%20the%20treatment%20of%20uncomplicated%20falciparum%20malaria&publication_year=2003"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="30."><p class="c-article-references__text" id="ref-CR30">White NJ. Assessment of the pharmacodynamics properties of antimalarial drugs in vivo. Antimicrob Agent Chemother. 1997;41:1413–22.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2sXktlyrtb4%3D" aria-label="CAS reference 30">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 30" href="http://scholar.google.com/scholar_lookup?&title=Assessment%20of%20the%20pharmacodynamics%20properties%20of%20antimalarial%20drugs%20in%20vivo&journal=Antimicrob%20Agent%20Chemother&volume=41&pages=1413-22&publication_year=1997&author=White%2CNJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="31."><p class="c-article-references__text" id="ref-CR31">Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. Philadelphia: Lea and Ferbiger; 1980.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 31" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20pharmacokinetics%3A%20concepts%20and%20applications&publication_year=1980&author=Rowland%2CM&author=Tozer%2CTN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="32."><p class="c-article-references__text" id="ref-CR32">Sowunmi A, Falade AG, Adedeji AA, Ayede AI, Fateye BA, Sowunmi CO, Oduola AMJ. Comparative <i>Plasmodium falciparum</i> kinetics during treatment with amodiaquine and chloroquine in children. Clin Drug Invest. 2001;21:371–81.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.2165/00044011-200121050-00007" data-track-item_id="10.2165/00044011-200121050-00007" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.2165%2F00044011-200121050-00007" aria-label="Article reference 32" data-doi="10.2165/00044011-200121050-00007">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3MXksVOjurc%3D" aria-label="CAS reference 32">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 32" href="http://scholar.google.com/scholar_lookup?&title=Comparative%20Plasmodium%20falciparum%20kinetics%20during%20treatment%20with%20amodiaquine%20and%20chloroquine%20in%20children&journal=Clin%20Drug%20Invest&doi=10.2165%2F00044011-200121050-00007&volume=21&pages=371-81&publication_year=2001&author=Sowunmi%2CA&author=Falade%2CAG&author=Adedeji%2CAA&author=Ayede%2CAI&author=Fateye%2CBA&author=Sowunmi%2CCO&author=Oduola%2CAMJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="33."><p class="c-article-references__text" id="ref-CR33">Gbotosho GO, Sowunmi A, Happi CT, Okuboyejo TM. Therapeutic efficacies of artemisinin-based combination therapies in Nigerian children with uncomplicated falciparum malaria during five years of adoption as first-line treatments. Am J Trop Med Hyg. 2011;84:936–43.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.4269/ajtmh.2011.10-0722" data-track-item_id="10.4269/ajtmh.2011.10-0722" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.4269%2Fajtmh.2011.10-0722" aria-label="Article reference 33" data-doi="10.4269/ajtmh.2011.10-0722">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=21633031" aria-label="PubMed reference 33">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110368" aria-label="PubMed Central reference 33">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 33" href="http://scholar.google.com/scholar_lookup?&title=Therapeutic%20efficacies%20of%20artemisinin-based%20combination%20therapies%20in%20Nigerian%20children%20with%20uncomplicated%20falciparum%20malaria%20during%20five%20years%20of%20adoption%20as%20first-line%20treatments&journal=Am%20J%20Trop%20Med%20Hyg&doi=10.4269%2Fajtmh.2011.10-0722&volume=84&pages=936-43&publication_year=2011&author=Gbotosho%2CGO&author=Sowunmi%2CA&author=Happi%2CCT&author=Okuboyejo%2CTM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="34."><p class="c-article-references__text" id="ref-CR34">Epi Info Version 6. A word processing data base and statistics program for public health on IBM-compatible microcomputers. Atlanta: Centers for Disease Control and Prevention; 1994.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 34" href="http://scholar.google.com/scholar_lookup?&title=A%20word%20processing%20data%20base%20and%20statistics%20program%20for%20public%20health%20on%20IBM-compatible%20microcomputers&publication_year=1994"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="35."><p class="c-article-references__text" id="ref-CR35">SPSS for Windows Release 20.0 (standard version). Chicago IL: SPSS Inc.; 2011.</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="36."><p class="c-article-references__text" id="ref-CR36">White NJ, Pongtavornpinyo W, Maude RJ, Saralamba S, Aguas R, Stepniewska K, Lee SJ, Dondorp AM, White LJ, Day NPJ. Hyperparasitaemia anf low dosing are important source of anti-malarial drug resistance. Malaria J. 2009;8:253.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/1475-2875-8-253" data-track-item_id="10.1186/1475-2875-8-253" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/1475-2875-8-253" aria-label="Article reference 36" data-doi="10.1186/1475-2875-8-253">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 36" href="http://scholar.google.com/scholar_lookup?&title=Hyperparasitaemia%20anf%20low%20dosing%20are%20important%20source%20of%20anti-malarial%20drug%20resistance&journal=Malaria%20J&doi=10.1186%2F1475-2875-8-253&volume=8&publication_year=2009&author=White%2CNJ&author=Pongtavornpinyo%2CW&author=Maude%2CRJ&author=Saralamba%2CS&author=Aguas%2CR&author=Stepniewska%2CK&author=Lee%2CSJ&author=Dondorp%2CAM&author=White%2CLJ&author=Day%2CNPJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="37."><p class="c-article-references__text" id="ref-CR37">Kumar N, Zheng H. Stage-specific gametocytocidal effect in vitro of the artemisinin drug quinghaosu on <i>Plasmodium falciparum</i>. Parasitol Res. 1990;76:214–8.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/BF00930817" data-track-item_id="10.1007/BF00930817" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/BF00930817" aria-label="Article reference 37" data-doi="10.1007/BF00930817">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK3c7pt1Ojtw%3D%3D" aria-label="CAS reference 37">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2179946" aria-label="PubMed reference 37">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 37" href="http://scholar.google.com/scholar_lookup?&title=Stage-specific%20gametocytocidal%20effect%20in%20vitro%20of%20the%20artemisinin%20drug%20quinghaosu%20on%20Plasmodium%20falciparum&journal=Parasitol%20Res&doi=10.1007%2FBF00930817&volume=76&pages=214-8&publication_year=1990&author=Kumar%2CN&author=Zheng%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="38."><p class="c-article-references__text" id="ref-CR38">Adjaley SH, Johnston GL, Li T, Eastman RT, Ekland EH, Eappen AG, Richman A, Sim BKL, Lee MCS, Hoffman SL, Fidock DA. Quantitative assessment of <i>Plasmodium falciparum</i> sexual development reveals potent transmission-blocking activity by methylene blue. Proc Nat Acad Sci. 2011;47:E1214–23.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.1112037108" data-track-item_id="10.1073/pnas.1112037108" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.1112037108" aria-label="Article reference 38" data-doi="10.1073/pnas.1112037108">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 38" href="http://scholar.google.com/scholar_lookup?&title=Quantitative%20assessment%20of%20Plasmodium%20falciparum%20sexual%20development%20reveals%20potent%20transmission-blocking%20activity%20by%20methylene%20blue&journal=Proc%20Nat%20Acad%20Sci&doi=10.1073%2Fpnas.1112037108&volume=47&pages=E1214-23&publication_year=2011&author=Adjaley%2CSH&author=Johnston%2CGL&author=Li%2CT&author=Eastman%2CRT&author=Ekland%2CEH&author=Eappen%2CAG&author=Richman%2CA&author=Sim%2CBKL&author=Lee%2CMCS&author=Hoffman%2CSL&author=Fidock%2CDA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="39."><p class="c-article-references__text" id="ref-CR39">Sowunmi A, Balogun T, Gbotosho GO, Happi CT, Adedeji AA, Fehintola FA. Activities of amodiaquine, artesunate, and artesunate-amodiaquine against asexual and sexual stage parasites in falciparum malaria in children. Antimicrobial Agents Chemother. 2007;51:1694–9.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1128/AAC.00077-07" data-track-item_id="10.1128/AAC.00077-07" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1128%2FAAC.00077-07" aria-label="Article reference 39" data-doi="10.1128/AAC.00077-07">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXlt1yjs7c%3D" aria-label="CAS reference 39">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 39" href="http://scholar.google.com/scholar_lookup?&title=Activities%20of%20amodiaquine%2C%20artesunate%2C%20and%20artesunate-amodiaquine%20against%20asexual%20and%20sexual%20stage%20parasites%20in%20falciparum%20malaria%20in%20children&journal=Antimicrobial%20Agents%20Chemother&doi=10.1128%2FAAC.00077-07&volume=51&pages=1694-9&publication_year=2007&author=Sowunmi%2CA&author=Balogun%2CT&author=Gbotosho%2CGO&author=Happi%2CCT&author=Adedeji%2CAA&author=Fehintola%2CFA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="40."><p class="c-article-references__text" id="ref-CR40">Sowunmi A, Balogun ST, Gbotosho GO, Happi CT. <i>Plasmodium falciparum</i> gametocyte sex ratios in symptomatic children treated with antimalarial drugs. Acta Trop. 2009;100:108–17.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.actatropica.2008.10.010" data-track-item_id="10.1016/j.actatropica.2008.10.010" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.actatropica.2008.10.010" aria-label="Article reference 40" data-doi="10.1016/j.actatropica.2008.10.010">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 40" href="http://scholar.google.com/scholar_lookup?&title=Plasmodium%20falciparum%20gametocyte%20sex%20ratios%20in%20symptomatic%20children%20treated%20with%20antimalarial%20drugs&journal=Acta%20Trop&doi=10.1016%2Fj.actatropica.2008.10.010&volume=100&pages=108-17&publication_year=2009&author=Sowunmi%2CA&author=Balogun%2CST&author=Gbotosho%2CGO&author=Happi%2CCT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="41."><p class="c-article-references__text" id="ref-CR41">MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria: a qualitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985;119:386–401.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 41" href="http://scholar.google.com/scholar_lookup?&title=Human%20cerebral%20malaria%3A%20a%20qualitative%20ultrastructural%20analysis%20of%20parasitized%20erythrocyte%20sequestration&journal=Am%20J%20Pathol&volume=119&pages=386-401&publication_year=1985&author=MacPherson%2CGG&author=Warrell%2CMJ&author=White%2CNJ&author=Looareesuwan%2CS&author=Warrell%2CDA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="42."><p class="c-article-references__text" id="ref-CR42">Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, Lewallen S, Lomba NG, Molyneux ME. Differentiating the pathologies of cerebral malaria by post-mortem parasite counts. Nat Med. 2004;10:143–5.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nm986" data-track-item_id="10.1038/nm986" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnm986" aria-label="Article reference 42" data-doi="10.1038/nm986">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2cXoslKmtw%3D%3D" aria-label="CAS reference 42">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=14745442" aria-label="PubMed reference 42">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 42" href="http://scholar.google.com/scholar_lookup?&title=Differentiating%20the%20pathologies%20of%20cerebral%20malaria%20by%20post-mortem%20parasite%20counts&journal=Nat%20Med&doi=10.1038%2Fnm986&volume=10&pages=143-5&publication_year=2004&author=Taylor%2CTE&author=Fu%2CWJ&author=Carr%2CRA&author=Whitten%2CRO&author=Mueller%2CJS&author=Fosiko%2CNG&author=Lewallen%2CS&author=Lomba%2CNG&author=Molyneux%2CME"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="43."><p class="c-article-references__text" id="ref-CR43">Clarke IA, Budd AC, Alleva SM, Cowden WB. Human malarial disease: a consequence of inflammatory cytokine release. Malaria J. 2006;6:85.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/1475-2875-5-85" data-track-item_id="10.1186/1475-2875-5-85" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/1475-2875-5-85" aria-label="Article reference 43" data-doi="10.1186/1475-2875-5-85">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 43" href="http://scholar.google.com/scholar_lookup?&title=Human%20malarial%20disease%3A%20a%20consequence%20of%20inflammatory%20cytokine%20release&journal=Malaria%20J&doi=10.1186%2F1475-2875-5-85&volume=6&publication_year=2006&author=Clarke%2CIA&author=Budd%2CAC&author=Alleva%2CSM&author=Cowden%2CWB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="44."><p class="c-article-references__text" id="ref-CR44">Stepniewska K, Ashley E, Lee SJ, Anstey N, Barnes KI, Binh TQ, D’Alessandro U, Day NPJ, de Vries PJ, Dorsey G, Guthmann J_P, Mayxay M, Newton PN, Olliaro P, Osorio L, Price RN, Rowland M, Smithuis F, Taylor WRJ, Nosten F, White NJ. In vivo parasitological measures of artemisinin susceptibility. J inf Dis. 2010;201:570–6.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1086/650301" data-track-item_id="10.1086/650301" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1086%2F650301" aria-label="Article reference 44" data-doi="10.1086/650301">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXjtFGjt74%3D" aria-label="CAS reference 44">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 44" href="http://scholar.google.com/scholar_lookup?&title=In%20vivo%20parasitological%20measures%20of%20artemisinin%20susceptibility&journal=J%20inf%20Dis&doi=10.1086%2F650301&volume=201&pages=570-6&publication_year=2010&author=Stepniewska%2CK&author=Ashley%2CE&author=Lee%2CSJ&author=Anstey%2CN&author=Barnes%2CKI&author=Binh%2CTQ&author=D%E2%80%99Alessandro%2CU&author=Day%2CNPJ&author=Vries%2CPJ&author=Dorsey%2CG&author=Guthmann%2CJ_P&author=Mayxay%2CM&author=Newton%2CPN&author=Olliaro%2CP&author=Osorio%2CL&author=Price%2CRN&author=Rowland%2CM&author=Smithuis%2CF&author=Taylor%2CWRJ&author=Nosten%2CF&author=White%2CNJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="45."><p class="c-article-references__text" id="ref-CR45">Global Malaria Programme WHO. Update on artemisinin resistance – April 2012. 2012. Available from: <a href="http://www.who.int/malaria/publications/atoz/updateartemsininresistanceapr2012/en/" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="http://www.who.int/malaria/publications/atoz/updateartemsininresistanceapr2012/en/">http://www.who.int/malaria/publications/atoz/updateartemsininresistanceapr2012/en/</a>.</p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1186/s12879-016-2173-z?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>We are grateful to the parents/guardians and the children who participated in the study.</p> <h3 class="c-article__sub-heading" id="FPar1">Funding</h3> <p>Antimalarial efficacy studies from which the data were derived were supported by Pfizer Global Pharmaceuticals and Swiss Pharma Nigeria PLC Grants to AS, and by World Bank Malaria Booster Project, and Global Fund for Malaria to The Federal Ministry of Health, Abuja, Nigeria through Drug Therapeutic Efficacy Testing in Ibadan, Nigeria. Molecular analysis of this study was supported by NIH H3Africa grant 5U01HG007480-04 to CTH.</p> <h3 class="c-article__sub-heading" id="FPar2">Availability of data and materials</h3> <p>The dataset supporting the findings of this article is available from the corresponding author upon request.</p> <h3 class="c-article__sub-heading" id="FPar3">Authors’ contributions</h3> <p>AS led the design, conduct, data analysis and manuscript preparation. KA, AIA, GN, BF, TA and EOA participated in data collections and analysis, KA, OAF and CTH performed the molecular genotyping. All authors read and approved the final draft of the manuscript.</p> <h3 class="c-article__sub-heading" id="FPar4">Competing interests</h3> <p>The authors declare they have no competing interests.</p> <h3 class="c-article__sub-heading" id="FPar5">Consent for publication</h3> <p>Not applicable.</p> <h3 class="c-article__sub-heading" id="FPar6">Ethics approval and consent to participate</h3> <p>The study protocol was approved by The Ethics Committee of The Ministry of Health, Ibadan and by National Health Research Committee, Abuja, Nigeria. A written informed consent was obtained from the parents or guardians of the children.</p> </div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria</p><p class="c-article-author-affiliation__authors-list">Akintunde Sowunmi, Kazeem Akano & Grace O. Gbotosho</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria</p><p class="c-article-author-affiliation__authors-list">Akintunde Sowunmi & Grace O. Gbotosho</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Paediatrics, University of Ibadan, Ibadan, Nigeria</p><p class="c-article-author-affiliation__authors-list">Adejumoke I. Ayede</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Physiology, University of Ibadan, Ibadan, Nigeria</p><p class="c-article-author-affiliation__authors-list">Elsie O. Adewoye</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">National Malaria Elimination Programme, Federal Ministry of Health, Abuja, Nigeria</p><p class="c-article-author-affiliation__authors-list">Godwin Ntadom</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">World Health Organization, Regional Office for the Western Pacific, Phnom Penh, Cambodia</p><p class="c-article-author-affiliation__authors-list">Bayo Fatunmbi</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Biological Sciences, Redeemer’s University, Ede, Nigeria</p><p class="c-article-author-affiliation__authors-list">Onikepe A. Folarin & Christian T. Happi</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer’s University, Ede, Nigeria</p><p class="c-article-author-affiliation__authors-list">Onikepe A. Folarin & Christian T. Happi</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Clinical Pharmacology, University College Hospital, Ibadan, Nigeria</p><p class="c-article-author-affiliation__authors-list">Akintunde Sowunmi</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Akintunde-Sowunmi-Aff1-Aff2-Aff9"><span class="c-article-authors-search__title u-h3 js-search-name">Akintunde Sowunmi</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Akintunde%20Sowunmi" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Akintunde%20Sowunmi" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Akintunde%20Sowunmi%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Kazeem-Akano-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Kazeem Akano</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Kazeem%20Akano" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Kazeem%20Akano" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Kazeem%20Akano%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Adejumoke_I_-Ayede-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Adejumoke I. Ayede</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Adejumoke%20I.%20Ayede" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Adejumoke%20I.%20Ayede" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Adejumoke%20I.%20Ayede%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Elsie_O_-Adewoye-Aff4"><span class="c-article-authors-search__title u-h3 js-search-name">Elsie O. Adewoye</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Elsie%20O.%20Adewoye" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Elsie%20O.%20Adewoye" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Elsie%20O.%20Adewoye%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Godwin-Ntadom-Aff5"><span class="c-article-authors-search__title u-h3 js-search-name">Godwin Ntadom</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Godwin%20Ntadom" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Godwin%20Ntadom" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Godwin%20Ntadom%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Bayo-Fatunmbi-Aff6"><span class="c-article-authors-search__title u-h3 js-search-name">Bayo Fatunmbi</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Bayo%20Fatunmbi" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Bayo%20Fatunmbi" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Bayo%20Fatunmbi%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Grace_O_-Gbotosho-Aff1-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Grace O. Gbotosho</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Grace%20O.%20Gbotosho" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Grace%20O.%20Gbotosho" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Grace%20O.%20Gbotosho%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Onikepe_A_-Folarin-Aff7-Aff8"><span class="c-article-authors-search__title u-h3 js-search-name">Onikepe A. Folarin</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Onikepe%20A.%20Folarin" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Onikepe%20A.%20Folarin" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Onikepe%20A.%20Folarin%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Christian_T_-Happi-Aff7-Aff8"><span class="c-article-authors-search__title u-h3 js-search-name">Christian T. Happi</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Christian%20T.%20Happi" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Christian%20T.%20Happi" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Christian%20T.%20Happi%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:akinsowunmi@hotmail.com">Akintunde Sowunmi</a>.</p></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"> <p> <b>Open Access</b> This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<a href="http://creativecommons.org/licenses/by/4.0/" rel="license">http://creativecommons.org/licenses/by/4.0/</a>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<a href="http://creativecommons.org/publicdomain/zero/1.0/" rel="license">http://creativecommons.org/publicdomain/zero/1.0/</a>) applies to the data made available in this article, unless otherwise stated.</p> <p class="c-article-rights"><a data-track="click" data-track-action="view rights and permissions" data-track-label="link" href="https://s100.copyright.com/AppDispatchServlet?title=Early%20rising%20asexual%20parasitaemia%20in%20Nigerian%20children%20following%20a%20first%20dose%20of%20artemisinin-based%20combination%20treatments%20of%20falciparum%20malaria&author=Akintunde%20Sowunmi%20et%20al&contentID=10.1186%2Fs12879-016-2173-z&copyright=The%20Author%28s%29.&publication=1471-2334&publicationDate=2017-01-31&publisherName=SpringerNature&orderBeanReset=true&oa=CC%20BY%20%2B%20CC0">Reprints and permissions</a></p></div></div></section><section aria-labelledby="article-info" data-title="About this article"><div class="c-article-section" id="article-info-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="article-info">About this article</h2><div class="c-article-section__content" id="article-info-content"><div class="c-bibliographic-information"><div class="u-hide-print c-bibliographic-information__column c-bibliographic-information__column--border"><a data-crossmark="10.1186/s12879-016-2173-z" target="_blank" rel="noopener" href="https://crossmark.crossref.org/dialog/?doi=10.1186/s12879-016-2173-z" data-track="click" data-track-action="Click Crossmark" data-track-label="link" data-test="crossmark"><img loading="lazy" width="57" height="81" alt="Check for updates. Verify currency and authenticity via CrossMark" src="data:image/svg+xml;base64,<svg height="81" width="57" xmlns="http://www.w3.org/2000/svg"><g fill="none" fill-rule="evenodd"><path d="m17.35 35.45 21.3-14.2v-17.03h-21.3" fill="#989898"/><path d="m38.65 35.45-21.3-14.2v-17.03h21.3" fill="#747474"/><path d="m28 .5c-12.98 0-23.5 10.52-23.5 23.5s10.52 23.5 23.5 23.5 23.5-10.52 23.5-23.5c0-6.23-2.48-12.21-6.88-16.62-4.41-4.4-10.39-6.88-16.62-6.88zm0 41.25c-9.8 0-17.75-7.95-17.75-17.75s7.95-17.75 17.75-17.75 17.75 7.95 17.75 17.75c0 4.71-1.87 9.22-5.2 12.55s-7.84 5.2-12.55 5.2z" fill="#535353"/><path d="m41 36c-5.81 6.23-15.23 7.45-22.43 2.9-7.21-4.55-10.16-13.57-7.03-21.5l-4.92-3.11c-4.95 10.7-1.19 23.42 8.78 29.71 9.97 6.3 23.07 4.22 30.6-4.86z" fill="#9c9c9c"/><path d="m.2 58.45c0-.75.11-1.42.33-2.01s.52-1.09.91-1.5c.38-.41.83-.73 1.34-.94.51-.22 1.06-.32 1.65-.32.56 0 1.06.11 1.51.35.44.23.81.5 1.1.81l-.91 1.01c-.24-.24-.49-.42-.75-.56-.27-.13-.58-.2-.93-.2-.39 0-.73.08-1.05.23-.31.16-.58.37-.81.66-.23.28-.41.63-.53 1.04-.13.41-.19.88-.19 1.39 0 1.04.23 1.86.68 2.46.45.59 1.06.88 1.84.88.41 0 .77-.07 1.07-.23s.59-.39.85-.68l.91 1c-.38.43-.8.76-1.28.99-.47.22-1 .34-1.58.34-.59 0-1.13-.1-1.64-.31-.5-.2-.94-.51-1.31-.91-.38-.4-.67-.9-.88-1.48-.22-.59-.33-1.26-.33-2.02zm8.4-5.33h1.61v2.54l-.05 1.33c.29-.27.61-.51.96-.72s.76-.31 1.24-.31c.73 0 1.27.23 1.61.71.33.47.5 1.14.5 2.02v4.31h-1.61v-4.1c0-.57-.08-.97-.25-1.21-.17-.23-.45-.35-.83-.35-.3 0-.56.08-.79.22-.23.15-.49.36-.78.64v4.8h-1.61zm7.37 6.45c0-.56.09-1.06.26-1.51.18-.45.42-.83.71-1.14.29-.3.63-.54 1.01-.71.39-.17.78-.25 1.18-.25.47 0 .88.08 1.23.24.36.16.65.38.89.67s.42.63.54 1.03c.12.41.18.84.18 1.32 0 .32-.02.57-.07.76h-4.36c.07.62.29 1.1.65 1.44.36.33.82.5 1.38.5.29 0 .57-.04.83-.13s.51-.21.76-.37l.55 1.01c-.33.21-.69.39-1.09.53-.41.14-.83.21-1.26.21-.48 0-.92-.08-1.34-.25-.41-.16-.76-.4-1.07-.7-.31-.31-.55-.69-.72-1.13-.18-.44-.26-.95-.26-1.52zm4.6-.62c0-.55-.11-.98-.34-1.28-.23-.31-.58-.47-1.06-.47-.41 0-.77.15-1.07.45-.31.29-.5.73-.58 1.3zm2.5.62c0-.57.09-1.08.28-1.53.18-.44.43-.82.75-1.13s.69-.54 1.1-.71c.42-.16.85-.24 1.31-.24.45 0 .84.08 1.17.23s.61.34.85.57l-.77 1.02c-.19-.16-.38-.28-.56-.37-.19-.09-.39-.14-.61-.14-.56 0-1.01.21-1.35.63-.35.41-.52.97-.52 1.67 0 .69.17 1.24.51 1.66.34.41.78.62 1.32.62.28 0 .54-.06.78-.17.24-.12.45-.26.64-.42l.67 1.03c-.33.29-.69.51-1.08.65-.39.15-.78.23-1.18.23-.46 0-.9-.08-1.31-.24-.4-.16-.75-.39-1.05-.7s-.53-.69-.7-1.13c-.17-.45-.25-.96-.25-1.53zm6.91-6.45h1.58v6.17h.05l2.54-3.16h1.77l-2.35 2.8 2.59 4.07h-1.75l-1.77-2.98-1.08 1.23v1.75h-1.58zm13.69 1.27c-.25-.11-.5-.17-.75-.17-.58 0-.87.39-.87 1.16v.75h1.34v1.27h-1.34v5.6h-1.61v-5.6h-.92v-1.2l.92-.07v-.72c0-.35.04-.68.13-.98.08-.31.21-.57.4-.79s.42-.39.71-.51c.28-.12.63-.18 1.04-.18.24 0 .48.02.69.07.22.05.41.1.57.17zm.48 5.18c0-.57.09-1.08.27-1.53.17-.44.41-.82.72-1.13.3-.31.65-.54 1.04-.71.39-.16.8-.24 1.23-.24s.84.08 1.24.24c.4.17.74.4 1.04.71s.54.69.72 1.13c.19.45.28.96.28 1.53s-.09 1.08-.28 1.53c-.18.44-.42.82-.72 1.13s-.64.54-1.04.7-.81.24-1.24.24-.84-.08-1.23-.24-.74-.39-1.04-.7c-.31-.31-.55-.69-.72-1.13-.18-.45-.27-.96-.27-1.53zm1.65 0c0 .69.14 1.24.43 1.66.28.41.68.62 1.18.62.51 0 .9-.21 1.19-.62.29-.42.44-.97.44-1.66 0-.7-.15-1.26-.44-1.67-.29-.42-.68-.63-1.19-.63-.5 0-.9.21-1.18.63-.29.41-.43.97-.43 1.67zm6.48-3.44h1.33l.12 1.21h.05c.24-.44.54-.79.88-1.02.35-.24.7-.36 1.07-.36.32 0 .59.05.78.14l-.28 1.4-.33-.09c-.11-.01-.23-.02-.38-.02-.27 0-.56.1-.86.31s-.55.58-.77 1.1v4.2h-1.61zm-47.87 15h1.61v4.1c0 .57.08.97.25 1.2.17.24.44.35.81.35.3 0 .57-.07.8-.22.22-.15.47-.39.73-.73v-4.7h1.61v6.87h-1.32l-.12-1.01h-.04c-.3.36-.63.64-.98.86-.35.21-.76.32-1.24.32-.73 0-1.27-.24-1.61-.71-.33-.47-.5-1.14-.5-2.02zm9.46 7.43v2.16h-1.61v-9.59h1.33l.12.72h.05c.29-.24.61-.45.97-.63.35-.17.72-.26 1.1-.26.43 0 .81.08 1.15.24.33.17.61.4.84.71.24.31.41.68.53 1.11.13.42.19.91.19 1.44 0 .59-.09 1.11-.25 1.57-.16.47-.38.85-.65 1.16-.27.32-.58.56-.94.73-.35.16-.72.25-1.1.25-.3 0-.6-.07-.9-.2s-.59-.31-.87-.56zm0-2.3c.26.22.5.37.73.45.24.09.46.13.66.13.46 0 .84-.2 1.15-.6.31-.39.46-.98.46-1.77 0-.69-.12-1.22-.35-1.61-.23-.38-.61-.57-1.13-.57-.49 0-.99.26-1.52.77zm5.87-1.69c0-.56.08-1.06.25-1.51.16-.45.37-.83.65-1.14.27-.3.58-.54.93-.71s.71-.25 1.08-.25c.39 0 .73.07 1 .2.27.14.54.32.81.55l-.06-1.1v-2.49h1.61v9.88h-1.33l-.11-.74h-.06c-.25.25-.54.46-.88.64-.33.18-.69.27-1.06.27-.87 0-1.56-.32-2.07-.95s-.76-1.51-.76-2.65zm1.67-.01c0 .74.13 1.31.4 1.7.26.38.65.58 1.15.58.51 0 .99-.26 1.44-.77v-3.21c-.24-.21-.48-.36-.7-.45-.23-.08-.46-.12-.7-.12-.45 0-.82.19-1.13.59-.31.39-.46.95-.46 1.68zm6.35 1.59c0-.73.32-1.3.97-1.71.64-.4 1.67-.68 3.08-.84 0-.17-.02-.34-.07-.51-.05-.16-.12-.3-.22-.43s-.22-.22-.38-.3c-.15-.06-.34-.1-.58-.1-.34 0-.68.07-1 .2s-.63.29-.93.47l-.59-1.08c.39-.24.81-.45 1.28-.63.47-.17.99-.26 1.54-.26.86 0 1.51.25 1.93.76s.63 1.25.63 2.21v4.07h-1.32l-.12-.76h-.05c-.3.27-.63.48-.98.66s-.73.27-1.14.27c-.61 0-1.1-.19-1.48-.56-.38-.36-.57-.85-.57-1.46zm1.57-.12c0 .3.09.53.27.67.19.14.42.21.71.21.28 0 .54-.07.77-.2s.48-.31.73-.56v-1.54c-.47.06-.86.13-1.18.23-.31.09-.57.19-.76.31s-.33.25-.41.4c-.09.15-.13.31-.13.48zm6.29-3.63h-.98v-1.2l1.06-.07.2-1.88h1.34v1.88h1.75v1.27h-1.75v3.28c0 .8.32 1.2.97 1.2.12 0 .24-.01.37-.04.12-.03.24-.07.34-.11l.28 1.19c-.19.06-.4.12-.64.17-.23.05-.49.08-.76.08-.4 0-.74-.06-1.02-.18-.27-.13-.49-.3-.67-.52-.17-.21-.3-.48-.37-.78-.08-.3-.12-.64-.12-1.01zm4.36 2.17c0-.56.09-1.06.27-1.51s.41-.83.71-1.14c.29-.3.63-.54 1.01-.71.39-.17.78-.25 1.18-.25.47 0 .88.08 1.23.24.36.16.65.38.89.67s.42.63.54 1.03c.12.41.18.84.18 1.32 0 .32-.02.57-.07.76h-4.37c.08.62.29 1.1.65 1.44.36.33.82.5 1.38.5.3 0 .58-.04.84-.13.25-.09.51-.21.76-.37l.54 1.01c-.32.21-.69.39-1.09.53s-.82.21-1.26.21c-.47 0-.92-.08-1.33-.25-.41-.16-.77-.4-1.08-.7-.3-.31-.54-.69-.72-1.13-.17-.44-.26-.95-.26-1.52zm4.61-.62c0-.55-.11-.98-.34-1.28-.23-.31-.58-.47-1.06-.47-.41 0-.77.15-1.08.45-.31.29-.5.73-.57 1.3zm3.01 2.23c.31.24.61.43.92.57.3.13.63.2.98.2.38 0 .65-.08.83-.23s.27-.35.27-.6c0-.14-.05-.26-.13-.37-.08-.1-.2-.2-.34-.28-.14-.09-.29-.16-.47-.23l-.53-.22c-.23-.09-.46-.18-.69-.3-.23-.11-.44-.24-.62-.4s-.33-.35-.45-.55c-.12-.21-.18-.46-.18-.75 0-.61.23-1.1.68-1.49.44-.38 1.06-.57 1.83-.57.48 0 .91.08 1.29.25s.71.36.99.57l-.74.98c-.24-.17-.49-.32-.73-.42-.25-.11-.51-.16-.78-.16-.35 0-.6.07-.76.21-.17.15-.25.33-.25.54 0 .14.04.26.12.36s.18.18.31.26c.14.07.29.14.46.21l.54.19c.23.09.47.18.7.29s.44.24.64.4c.19.16.34.35.46.58.11.23.17.5.17.82 0 .3-.06.58-.17.83-.12.26-.29.48-.51.68-.23.19-.51.34-.84.45-.34.11-.72.17-1.15.17-.48 0-.95-.09-1.41-.27-.46-.19-.86-.41-1.2-.68z" fill="#535353"/></g></svg>"></a></div><div class="c-bibliographic-information__column"><h3 class="c-article__sub-heading" id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Sowunmi, A., Akano, K., Ayede, A.I. <i>et al.</i> Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria. <i>BMC Infect Dis</i> <b>17</b>, 110 (2017). https://doi.org/10.1186/s12879-016-2173-z</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1186/s12879-016-2173-z?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2016-09-23">23 September 2016</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2016-12-27">27 December 2016</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2017-01-31">31 January 2017</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span class="u-hide">: </span><span class="c-bibliographic-information__value">https://doi.org/10.1186/s12879-016-2173-z</span></p></li></ul><div data-component="share-box"><div class="c-article-share-box u-display-none" hidden=""><h3 class="c-article__sub-heading">Share this article</h3><p class="c-article-share-box__description">Anyone you share the following link with will be able to read this content:</p><button class="js-get-share-url c-article-share-box__button" type="button" id="get-share-url" data-track="click" data-track-label="button" data-track-external="" data-track-action="get shareable link">Get shareable link</button><div class="js-no-share-url-container u-display-none" hidden=""><p class="js-c-article-share-box__no-sharelink-info c-article-share-box__no-sharelink-info">Sorry, a shareable link is not currently available for this article.</p></div><div class="js-share-url-container u-display-none" hidden=""><p class="js-share-url c-article-share-box__only-read-input" id="share-url" data-track="click" data-track-label="button" data-track-action="select share url"></p><button class="js-copy-share-url c-article-share-box__button--link-like" type="button" id="copy-share-url" data-track="click" data-track-label="button" data-track-action="copy share url" data-track-external="">Copy to clipboard</button></div><p class="js-c-article-share-box__additional-info c-article-share-box__additional-info"> Provided by the Springer Nature SharedIt content-sharing initiative </p></div></div><h3 class="c-article__sub-heading">Keywords</h3><ul class="c-article-subject-list"><li class="c-article-subject-list__subject"><span><a href="/search?query=Early%20rising%20asexual%20parasitaemia&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Early rising asexual parasitaemia</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Artemisinin-based%20combination%20treatments&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Artemisinin-based combination treatments</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Children&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Children</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Nigeria&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Nigeria</a></span></li></ul><div data-component="article-info-list"></div></div></div></div></div></section> </div> </main> <div class="c-article-sidebar u-text-sm u-hide-print l-with-sidebar__sidebar" id="sidebar" data-container-type="reading-companion" data-track-component="reading companion"> <aside> <div data-test="collections"> </div> <div data-test="editorial-summary"> </div> <div class="c-reading-companion"> <div class="c-reading-companion__sticky" data-component="reading-companion-sticky" data-test="reading-companion-sticky"> <div class="c-reading-companion__panel c-reading-companion__sections c-reading-companion__panel--active" id="tabpanel-sections"> <div class="u-lazy-ad-wrapper u-mt-16 u-hide" data-component-mpu><div class="c-ad c-ad--300x250"> <div class="c-ad__inner"> <p class="c-ad__label">Advertisement</p> <div id="div-gpt-ad-MPU1" class="div-gpt-ad grade-c-hide" data-pa11y-ignore data-gpt data-gpt-unitpath="/270604982/springerlink/12879/article" data-gpt-sizes="300x250" data-test="MPU1-ad" data-gpt-targeting="pos=MPU1;articleid=s12879-016-2173-z;"> </div> </div> </div> </div> </div> <div class="c-reading-companion__panel c-reading-companion__figures c-reading-companion__panel--full-width" id="tabpanel-figures"></div> <div class="c-reading-companion__panel c-reading-companion__references c-reading-companion__panel--full-width" id="tabpanel-references"></div> </div> </div> </aside> </div> </div> </article> <div class="app-elements"> <div class="eds-c-header__expander eds-c-header__expander--search" id="eds-c-header-popup-search"> <h2 class="eds-c-header__heading">Search</h2> <div class="u-container"> <search class="eds-c-header__search" role="search" aria-label="Search from the header"> <form method="GET" action="//link.springer.com/search" data-test="header-search" data-track="search" data-track-context="search from header" data-track-action="submit search form" data-track-category="unified header" data-track-label="form" > <label for="eds-c-header-search" class="eds-c-header__search-label">Search by keyword or author</label> <div class="eds-c-header__search-container"> <input id="eds-c-header-search" class="eds-c-header__search-input" autocomplete="off" name="query" type="search" value="" required> <button class="eds-c-header__search-button" type="submit"> <svg class="eds-c-header__icon" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-search-medium"></use> </svg> <span class="u-visually-hidden">Search</span> </button> </div> </form> </search> </div> </div> <div class="eds-c-header__expander eds-c-header__expander--menu" id="eds-c-header-nav"> <h2 class="eds-c-header__heading">Navigation</h2> <ul class="eds-c-header__list"> <li class="eds-c-header__list-item"> <a class="eds-c-header__link" href="https://link.springer.com/journals/" data-track="nav_find_a_journal" data-track-context="unified header" data-track-action="click find a journal" data-track-category="unified header" data-track-label="link" > Find a journal </a> </li> <li class="eds-c-header__list-item"> <a class="eds-c-header__link" href="https://www.springernature.com/gp/authors" data-track="nav_how_to_publish" data-track-context="unified header" data-track-action="click publish with us link" data-track-category="unified header" data-track-label="link" > Publish with us </a> </li> <li class="eds-c-header__list-item"> <a class="eds-c-header__link" href="https://link.springernature.com/home/" data-track="nav_track_your_research" data-track-context="unified header" data-track-action="click track your research" data-track-category="unified header" data-track-label="link" > Track your research </a> </li> </ul> </div> <footer > <div class="eds-c-footer" > <div class="eds-c-footer__container"> <div class="eds-c-footer__grid eds-c-footer__group--separator"> <div class="eds-c-footer__group"> <h3 class="eds-c-footer__heading">Discover content</h3> <ul class="eds-c-footer__list"> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://link.springer.com/journals/a/1" data-track="nav_journals_a_z" data-track-action="journals a-z" data-track-context="unified footer" data-track-label="link">Journals A-Z</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://link.springer.com/books/a/1" data-track="nav_books_a_z" data-track-action="books a-z" data-track-context="unified footer" data-track-label="link">Books A-Z</a></li> </ul> </div> <div class="eds-c-footer__group"> <h3 class="eds-c-footer__heading">Publish with us</h3> <ul class="eds-c-footer__list"> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://link.springer.com/journals" data-track="nav_journal_finder" data-track-action="journal finder" data-track-context="unified footer" data-track-label="link">Journal finder</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.springernature.com/gp/authors" data-track="nav_publish_your_research" data-track-action="publish your research" data-track-context="unified footer" data-track-label="link">Publish your research</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="nav_open_access_publishing" data-track-action="open access publishing" data-track-context="unified footer" data-track-label="link">Open access publishing</a></li> </ul> </div> <div class="eds-c-footer__group"> <h3 class="eds-c-footer__heading">Products and services</h3> <ul class="eds-c-footer__list"> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.springernature.com/gp/products" data-track="nav_our_products" data-track-action="our products" data-track-context="unified footer" data-track-label="link">Our products</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.springernature.com/gp/librarians" data-track="nav_librarians" data-track-action="librarians" data-track-context="unified footer" data-track-label="link">Librarians</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.springernature.com/gp/societies" data-track="nav_societies" data-track-action="societies" data-track-context="unified footer" data-track-label="link">Societies</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.springernature.com/gp/partners" data-track="nav_partners_and_advertisers" data-track-action="partners and advertisers" data-track-context="unified footer" data-track-label="link">Partners and advertisers</a></li> </ul> </div> <div class="eds-c-footer__group"> <h3 class="eds-c-footer__heading">Our imprints</h3> <ul class="eds-c-footer__list"> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.springer.com/" data-track="nav_imprint_Springer" data-track-action="Springer" data-track-context="unified footer" data-track-label="link">Springer</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.nature.com/" data-track="nav_imprint_Nature_Portfolio" data-track-action="Nature Portfolio" data-track-context="unified footer" data-track-label="link">Nature Portfolio</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.biomedcentral.com/" data-track="nav_imprint_BMC" data-track-action="BMC" data-track-context="unified footer" data-track-label="link">BMC</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.palgrave.com/" data-track="nav_imprint_Palgrave_Macmillan" data-track-action="Palgrave Macmillan" data-track-context="unified footer" data-track-label="link">Palgrave Macmillan</a></li> <li class="eds-c-footer__item"><a class="eds-c-footer__link" href="https://www.apress.com/" data-track="nav_imprint_Apress" data-track-action="Apress" data-track-context="unified footer" data-track-label="link">Apress</a></li> </ul> </div> </div> </div> <div class="eds-c-footer__container"> <nav aria-label="footer navigation"> <ul class="eds-c-footer__links"> <li class="eds-c-footer__item"> <button class="eds-c-footer__link" data-cc-action="preferences" data-track="dialog_manage_cookies" data-track-action="Manage cookies" data-track-context="unified footer" data-track-label="link"><span class="eds-c-footer__button-text">Your privacy choices/Manage cookies</span></button> </li> <li class="eds-c-footer__item"> <a class="eds-c-footer__link" href="https://www.springernature.com/gp/legal/ccpa" data-track="nav_california_privacy_statement" data-track-action="california privacy statement" data-track-context="unified footer" data-track-label="link">Your US state privacy rights</a> </li> <li class="eds-c-footer__item"> <a class="eds-c-footer__link" href="https://www.springernature.com/gp/info/accessibility" data-track="nav_accessibility_statement" data-track-action="accessibility statement" data-track-context="unified footer" data-track-label="link">Accessibility statement</a> </li> <li class="eds-c-footer__item"> <a class="eds-c-footer__link" href="https://link.springer.com/termsandconditions" data-track="nav_terms_and_conditions" data-track-action="terms and conditions" data-track-context="unified footer" data-track-label="link">Terms and conditions</a> </li> <li class="eds-c-footer__item"> <a class="eds-c-footer__link" href="https://link.springer.com/privacystatement" data-track="nav_privacy_policy" data-track-action="privacy policy" data-track-context="unified footer" data-track-label="link">Privacy policy</a> </li> <li class="eds-c-footer__item"> <a class="eds-c-footer__link" href="https://support.springernature.com/en/support/home" data-track="nav_help_and_support" data-track-action="help and support" data-track-context="unified footer" data-track-label="link">Help and support</a> </li> <li class="eds-c-footer__item"> <a class="eds-c-footer__link" href="https://support.springernature.com/en/support/solutions/articles/6000255911-subscription-cancellations" data-track-action="cancel contracts here">Cancel contracts here</a> </li> </ul> </nav> <div class="eds-c-footer__user"> <p class="eds-c-footer__user-info"> <span data-test="footer-user-ip">8.222.208.146</span> </p> <p class="eds-c-footer__user-info" data-test="footer-business-partners">Not affiliated</p> </div> <a href="https://www.springernature.com/" class="eds-c-footer__link"> <img src="/oscar-static/images/logo-springernature-white-19dd4ba190.svg" alt="Springer Nature" loading="lazy" width="200" height="20"/> </a> <p class="eds-c-footer__legal" data-test="copyright">© 2024 Springer Nature</p> </div> </div> </footer> </div> </body> </html>