CINXE.COM
Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials | BMC Infectious Diseases | Full Text
<!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"> <title>Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials | BMC Infectious Diseases | Full Text</title> <meta name="citation_abstract" content="Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children. Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28–42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28–42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively. Pre-treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia ≤10,000 μL−1 were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15 months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH >4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000 μL−1, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH >4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1 day post-treatment initiation, haematocrit ≥37%, and parasitaemia >100,000 μL−1. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9–2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children. After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children. Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ]."/> <meta name="journal_id" content="12879"/> <meta name="dc.title" content="Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials"/> <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="2017-12-19"/> <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="Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children. Malarious &lt;5&nbsp;year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6&nbsp;weeks. Anaemia was defined as haematocrit &lt;30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28–42&nbsp;days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28–42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit &lt;30% occurring within 1&nbsp;week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH &gt;4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively. Pre-treatment, 355 of 959 children were anaemic. Duration of illness &gt;2&nbsp;days and parasitaemia ≤10,000&nbsp;μL−1 were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15&nbsp;months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH &gt;4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000&nbsp;μL−1, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH &gt;4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1&nbsp;day post-treatment initiation, haematocrit ≥37%, and parasitaemia &gt;100,000&nbsp;μL−1. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9–2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children. After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH &gt;4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children. Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ]."/> <meta name="prism.issn" content="1471-2334"/> <meta name="prism.publicationName" content="BMC Infectious Diseases"/> <meta name="prism.publicationDate" content="2017-12-19"/> <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="18"/> <meta name="prism.copyright" content="2017 The Author(s)."/> <meta name="prism.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="prism.url" content="https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-017-2876-9"/> <meta name="prism.doi" content="doi:10.1186/s12879-017-2876-9"/> <meta name="citation_pdf_url" content="https://bmcinfectdis.biomedcentral.com/counter/pdf/10.1186/s12879-017-2876-9"/> <meta name="citation_fulltext_html_url" content="https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-017-2876-9"/> <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="Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials"/> <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="2017/12/19"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="18"/> <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/s12879-017-2876-9"/> <meta name="DOI" content="10.1186/s12879-017-2876-9"/> <meta name="size" content="333265"/> <meta name="citation_doi" content="10.1186/s12879-017-2876-9"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1186/s12879-017-2876-9&api_key="/> <meta name="description" content="Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children. Malarious &lt;5&nbsp;year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6&nbsp;weeks. Anaemia was defined as haematocrit &lt;30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28–42&nbsp;days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28–42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit &lt;30% occurring within 1&nbsp;week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH &gt;4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively. Pre-treatment, 355 of 959 children were anaemic. Duration of illness &gt;2&nbsp;days and parasitaemia ≤10,000&nbsp;μL−1 were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15&nbsp;months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH &gt;4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000&nbsp;μL−1, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH &gt;4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1&nbsp;day post-treatment initiation, haematocrit ≥37%, and parasitaemia &gt;100,000&nbsp;μL−1. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9–2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children. After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH &gt;4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children. Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ]."/> <meta name="dc.creator" content="Sowunmi, Akintunde"/> <meta name="dc.creator" content="Fatunmbi, Bayo"/> <meta name="dc.creator" content="Akano, Kazeem"/> <meta name="dc.creator" content="Wewe, Olubunmi A."/> <meta name="dc.creator" content="Agomo, Chimere"/> <meta name="dc.creator" content="Finomo, Finomo"/> <meta name="dc.creator" content="Ebenebe, Joy"/> <meta name="dc.creator" content="Jiya, Nma"/> <meta name="dc.creator" content="Ambe, Jose"/> <meta name="dc.creator" content="Wammanda, Robinson"/> <meta name="dc.creator" content="Ntadom, Godwin"/> <meta name="dc.creator" content="Mokuolu, Olugbenga"/> <meta name="dc.creator" content="Emechebe, George"/> <meta name="dc.creator" content="Ezeigwe, Nnenna"/> <meta name="dc.creator" content="Ayede, Adejumoke I."/> <meta name="dc.creator" content="Adewoye, Elsie O."/> <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.creator" content="Oguche, Stephen"/> <meta name="dc.creator" content="Oyibo, Wellington A."/> <meta name="dc.creator" content="Useh, Francis"/> <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=Am J Trop Med Hyg; citation_title=Major transition in malaria treatment: the adoption and deployment of artemisinin-based combination therapies; citation_author=A Bosman, KNA Mendis; citation_volume=66; citation_issue=Suppl 6; citation_publication_date=2007; citation_pages=193-197; citation_id=CR1"/> <meta name="citation_reference" content="citation_title=World malaria report 2015; citation_publication_date=2015; citation_id=CR2; citation_publisher=WHO"/> <meta name="citation_reference" content="World Health Organization. Antimalarial Drug Combination Therapy. Report of a WHO Technical Consultation. Geneva: World Health Organization. 2001. WHO/CDS/RBM/2001.35."/> <meta name="citation_reference" content="citation_journal_title=PLoS One; citation_title=Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment; citation_author=VI Carrara, J Zwang, EA Ashley, RN Price, K Stepniewka, B Marion, A Brockman, T Anderson, R McGready, L Phaiphun, P Stephane, M van Vugt, R Hutagalung, KM Lwin, AP Phyo, P Piyanuch, M Imwong, S Pukrittayakamee, P Singhasivanon, NJ White, F Nosten; citation_volume=4; citation_publication_date=2009; citation_pages=e4551; citation_doi=10.1371/journal.pone.0004551; citation_id=CR4"/> <meta name="citation_reference" content="citation_journal_title=Clin Infect Dis; citation_title=Declining efficacy of artemisinin combination therapy against P. falciparum malaria on the Thai-Myanmar border (2003-2013): the role of parasite genetic factors; citation_author=AP Phyo, EA Ashley, TJC Anderson, Z Bozdech, VI Carrara, K Sriprawat, S Nair, MM White, J Dziekan, C Ling, S Proux, K Konghahong, A Jeeyapant, CJ Woodrow, M Imwong, R McGready, KM Lwin, NPJ Day, NJ White, F Nosten; citation_volume=63; citation_publication_date=2016; citation_pages=784-791; citation_doi=10.1093/cid/ciw388; citation_id=CR5"/> <meta name="citation_reference" content="citation_title=National Antimalaria Treatment Guideline; citation_publication_date=2005; citation_id=CR6; citation_publisher=Federal Ministry of Health"/> <meta name="citation_reference" content="citation_journal_title=J Parasitol; citation_title=Malaria and helminth co-infection in children living in a malaria endemic setting of Mount Cameroon and predictors of anemia; citation_author=TK Nkuo-Akenji, PC Chi, JF Cho, KK Ndamukong, I Sumbele; citation_volume=92; citation_publication_date=2006; citation_pages=1191-1195; citation_doi=10.1645/GE-895R.1; citation_id=CR7"/> <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, B Fateye; citation_volume=113; citation_publication_date=2010; citation_pages=155-161; citation_doi=10.1016/j.actatropica.2009.10.011; citation_id=CR8"/> <meta name="citation_reference" content="citation_journal_title=BioMed Central of Infectious Diseases; citation_title=Longitudinal study on 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, TA Nkuo-Akenji; citation_volume=13; citation_publication_date=2013; citation_pages=123; citation_doi=10.1186/1471-2334-13-123; citation_id=CR9"/> <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 ter Kuile, T Chongsuphajaisiddhi, NJ White; citation_volume=65; citation_publication_date=2001; citation_pages=614-622; citation_doi=10.4269/ajtmh.2001.65.614; citation_id=CR10"/> <meta name="citation_reference" content="citation_journal_title=Am J Trop Med Hyg; citation_title=Red blood cell deformability as a predictor of anemia in severe falciparum malaria; citation_author=AM Dondorp, BJ Angus, K Chotivanich, K Silamut, R Ruangveerayuth, MR Hardeman, PA Kager, J Vreeken, NJ White; citation_volume=60; citation_publication_date=1999; citation_pages=733-737; citation_doi=10.4269/ajtmh.1999.60.733; citation_id=CR11"/> <meta name="citation_reference" content="citation_journal_title=Blood; citation_title=Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen; citation_author=I Safeukui, JM Correas, V Brousse, D Hirt, G Deplaine, S Mulé, M Lesurtel, N Goasguen, A Sauvanet, A Couvelard, S Kerneis, H Khun, I Vigan-Womas, C Ottone, TJ Molina, JM Tréluyer, O Mercereau-Puijalon, G Milon, PH David, PA Buffet; citation_volume=112; citation_publication_date=2008; citation_pages=2520-2528; citation_doi=10.1182/blood-2008-03-146779; citation_id=CR12"/> <meta name="citation_reference" content="citation_journal_title=Blood; citation_title=The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology; citation_author=PA Buffet, I Safeukui, G Deplaine, V Brousse, V Prendki, M Thellier, GD Turner, O Mercereau-Puijalon; citation_volume=117; citation_publication_date=2011; citation_pages=381-392; citation_doi=10.1182/blood-2010-04-202911; citation_id=CR13"/> <meta name="citation_reference" content="citation_journal_title=J Trop Pediatr; citation_title=Moderate to severe anaemia due to afebrile Plasmodium falciparum infections in children aged 6- 23 months from rural district of Kongoussi, Burkina Faso; citation_author=HZ Ouédraogo, A Zeba, M Dramaix-Wilmet, P Donnen; citation_volume=54; citation_publication_date=2008; citation_pages=395-400; citation_doi=10.1093/tropej/fmn049; citation_id=CR14"/> <meta name="citation_reference" content="citation_journal_title=Malar J; citation_title=Malaria, helminths, co-infection and anaemia in a cohort of children from Mutengene, south western Cameroon; citation_author=C Njua-Yafi, EA Achidi, JK Anchang-Kimbi, TO Apinjoh, RN Mugri, HF Chi, RB Tata, C Njumkeng, EN Nkock, T Nkuo-Akenji; citation_volume=15; citation_publication_date=2016; citation_pages=69; citation_doi=10.1186/s12936-016-1111-2; citation_id=CR15"/> <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=CR16"/> <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=925-935; citation_doi=10.4269/ajtmh.13-0248; citation_id=CR17"/> <meta name="citation_reference" content="World Health Organization. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000; 94 Supp1: 1–90."/> <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=CR19"/> <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=CR20"/> <meta name="citation_reference" content="World Health Organization: Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: world health Organization 2003."/> <meta name="citation_reference" content="citation_journal_title=Infectious Diseases of Poverty; citation_title=Therapeutic efficacy and effects of artesunate-amodiaquine and artemether-lumefantrine on malaria-associated anaemia in Nigerian children aged two years and under; citation_author=A Sowunmi, K Akano, AI Ayede, G Ntadom, EO Adewoye, B Fatunmbi, T Aderoyeje; citation_volume=5; citation_publication_date=2016; citation_pages=70; citation_doi=10.1186/s40249-016-0165-2; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=Am J Trop Med Hyg; citation_title=Therapeutic efficacy and effects of artemether-lumefantrine and artesunate amodiaquine co-formulated or co-packaged on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria; citation_author=GO Gbotosho, A Sowunmi, TM Okuboyejo, CT Happi, OO Folarin, OS Michael, EO Adewoye; citation_volume=84; citation_publication_date=2011; citation_pages=813-819; citation_doi=10.4269/ajtmh.2011.10-0582; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=Am J Ther; citation_title=Use of area under the curve to evaluate the effects of antimalarial drugs on malaria-associated anaemia after treatment; citation_author=A Sowunmi, GO Gbotosho, CT Happi, O Folarin, T Okuboyejo, O Michael, B Fatunmbi; citation_volume=18; citation_publication_date=2011; citation_pages=190-197; citation_doi=10.1097/MJT.0b013e3181d169c9; citation_id=CR24"/> <meta name="citation_reference" content="citation_title=Clinical pharmacokinetics: concept and application; citation_publication_date=1980; citation_id=CR25; citation_author=M Rowland; citation_author=TN Tozer; citation_publisher=PA Lea and Ferbiger"/> <meta name="citation_reference" content="Bain BJ, Bates I. Basic haematological techniques. In: Lewis SM, Bain BJ, Bates I, editors. Practical Haematology. 9th ed. Edinburgh: Churchill Living stone 2001; pg. 19–46."/> <meta name="citation_reference" content="Epi Info Version 6. A Word Processing Data Base and Statistics Program for Public Health on IBM-compatible Microcomputers. Centers for Disease Control and Prevention, Atlanta, GA; 1994."/> <meta name="citation_reference" content="SPSS for Windows Release 20.0 (standard version). SPSS Inc., Chicago IL; 2011."/> <meta name="citation_reference" content="citation_journal_title=Lancet; citation_title=Statistical methods for assessing agreement between two methods of clinical measurement; citation_author=JM Bland, DG Altman; citation_volume=1; citation_publication_date=1986; citation_pages=307-310; citation_doi=10.1016/S0140-6736(86)90837-8; citation_id=CR29"/> <meta name="citation_reference" content="citation_journal_title=BMC Infect Dis; citation_title=Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria; citation_author=A Sowunmi, K Akano, AI Ayede, EO Adewoye, G Ntadom, B Fatunmbi, GO Gbotosho, OA Folarin, CT Happi; citation_volume=17; citation_publication_date=2017; citation_pages=110; citation_doi=10.1186/s12879-016-2173-z; citation_id=CR30"/> <meta name="citation_reference" content="citation_journal_title=Infectious Diseases of Poverty; citation_title=Therapeutic efficacy and effects of artemisinin-based combination treatments on uncomplicated Plasmodium falciparum malaria-associated anaemia in Nigerian children during seven years of adoption as first-line treatments; citation_author=A Sowunmi, K Akano, G Ntadom, AI Ayede, FO Ibironke, T Aderoyeje, EO Adewoye, B Fatunmbi, S Oguche, HU Okafor, I Watila, M Meremikwu, P Agomo, W Ogala, C Agomo, OA Folarin, GO Gbotosho, CT Happi; citation_volume=6; citation_publication_date=2017; citation_pages=36; citation_doi=10.1186/s40249-016-0217-7; citation_id=CR31"/> <meta name="citation_reference" content="citation_journal_title=Antimicrob 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=1694-1699; citation_doi=10.1128/AAC.00077-07; citation_id=CR32"/> <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 Chemotherapy Control and Elimination. 2012;1 doi: 10.4303/mcce/235498 ."/> <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=621-624; citation_doi=10.1016/S0035-9203(96)90408-3; citation_id=CR34"/> <meta name="citation_reference" content="citation_journal_title=Chemotherapy; citation_title=Anaemia following artemisinin-based combination treatments of uncomplicated Plasmodium falciparum malaria in children: temporal patterns of haematocrit and the use of uncomplicated hyperparasitaemia as a model for evaluating late-appearing anaemia; citation_author=A Sowunmi, K Akano, G Ntadom, A Ayede, S Oguche, C Agomo, H Okafor, I Watila, M Meremikwu, W Ogala, P Agomo, E Adewoye, B Fatunmbi, T Aderoyeje, C Happi, G Gbotosho, O Folarin; citation_volume=62; citation_publication_date=2017; citation_pages=231-238; citation_doi=10.1159/000449366; citation_id=CR35"/> <meta name="citation_author" content="Sowunmi, Akintunde"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <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="Fatunmbi, Bayo"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="World Health Organization, Country Office, Kampala, Uganda"/> <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="Wewe, Olubunmi A."/> <meta name="citation_author_institution" content="Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author" content="Agomo, Chimere"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Medical Laboratory Science, University of Lagos, Lagos, Nigeria"/> <meta name="citation_author" content="Finomo, Finomo"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, Federal Medical Centre, Yenagoa, Nigeria"/> <meta name="citation_author" content="Ebenebe, Joy"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, Nnamdi Azikiwe University, Awka, Nigeria"/> <meta name="citation_author" content="Jiya, Nma"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, Uthman Dan Fodio University, Sokoto, Nigeria"/> <meta name="citation_author" content="Ambe, Jose"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, University of Maiduguri, Maiduguri, Nigeria"/> <meta name="citation_author" content="Wammanda, Robinson"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, Ahmadu Bello University, Zaria, Nigeria"/> <meta name="citation_author" content="Ntadom, Godwin"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author" content="Mokuolu, Olugbenga"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, University of Ilorin, Ilorin, Nigeria"/> <meta name="citation_author" content="Emechebe, George"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, Imo State University Teaching Hospital, Orlu, Nigeria"/> <meta name="citation_author" content="Ezeigwe, Nnenna"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, 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="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_institution" content="Department of Pharmacology and Toxicology, University of Ibadan, Ibadan, Nigeria"/> <meta name="citation_author" content="Folarin, Onikepe A."/> <meta name="citation_author_institution" content="Department of Biological Sciences and African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer University, Ede, Nigeria"/> <meta name="citation_author" content="Happi, Christian T."/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Biological Sciences and African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer University, Ede, Nigeria"/> <meta name="citation_author" content="Oguche, Stephen"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Paediatrics, University of Jos, Jos, Nigeria"/> <meta name="citation_author" content="Oyibo, Wellington A."/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Medical Microbiology and Parasitology, University of Lagos, Lagos, Nigeria"/> <meta name="citation_author" content="Useh, Francis"/> <meta name="citation_author_institution" content="Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria"/> <meta name="citation_author_institution" content="Department of Medical Laboratory Science, University of Calabar, Calabar, Nigeria"/> <meta name="format-detection" content="telephone=no"> <link rel="apple-touch-icon" sizes="180x180" href=/static/img/favicons/bmc/apple-touch-icon-582ef1d0f5.png> <link rel="icon" type="image/png" sizes="192x192" href=/static/img/favicons/bmc/android-chrome-192x192-9625b7cdba.png> <link rel="icon" type="image/png" sizes="32x32" href=/static/img/favicons/bmc/favicon-32x32-5d7879efe1.png> <link rel="icon" type="image/png" sizes="16x16" href=/static/img/favicons/bmc/favicon-16x16-c241ac1a2f.png> <link rel="shortcut icon" data-test="shortcut-icon" href=/static/img/favicons/bmc/favicon-1886637b78.ico> <link rel="manifest" href=/static/app-bmc/manifest-3bb9ad383b.json> <meta name="msapplication-config" content=/static/app-bmc/browserconfig-ecd9aa8205.xml> <meta name="msapplication-TileColor" content="#1b3051"> <meta name="msapplication-TileImage" content=/static/img/favicons/bmc/app-icon-144x144.png> <meta name="theme-color" content="#1b3051"> <script>(function(H){H.className=H.className.replace(/\bno-js\b/,'js')})(document.documentElement)</script> <link rel="stylesheet" media="screen" href=/static/app-bmc/css/core-article-f3872e738d.css> <link rel="stylesheet" media="screen" href=/static/app-bmc/css/core-eac3097aa4.css> <link rel="stylesheet" media="print" href=/static/app-bmc/css/print-b8af42253b.css> <!-- This template is only used by BMC for now --> <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) { button{line-height:inherit}html,label{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif}html{-webkit-font-smoothing:subpixel-antialiased;box-sizing:border-box;color:#333;font-size:100%;height:100%;line-height:1.61803;overflow-y:scroll}*{box-sizing:inherit}body{background:#fff;margin:0;max-width:100%;min-height:100%}button,div,form,input,p{margin:0;padding:0}body{padding:0}a{color:#004b83;text-decoration:underline;text-decoration-skip-ink:auto}a>img{vertical-align:middle}h1,h2{color:#1b3051;font-style:normal;font-weight:700}h1{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:28px;line-height:1.4}html.webfonts-loaded h1,html.webfonts-loaded h2,html.webfonts-loaded h3{font-family:Europa,Trebuchet MS}h2{font-size:26px;margin-bottom:.5em}h2,h3{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;line-height:1.4}h3{color:#1b3051;font-size:18px;font-style:normal;margin-bottom:.7em}.c-navbar{background:#f2f2f2;border-bottom:1px solid #d9d9d9;border-top:1px solid #d9d9d9;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:14px;line-height:1.61803;padding:16px 0}.c-navbar--with-submit-button{padding-bottom:24px}@media only screen and (min-width:540px){.c-navbar--with-submit-button{padding-bottom:16px}}.c-navbar__container{display:flex;flex-wrap:wrap;justify-content:space-between;margin:0 auto;max-width:1280px;padding:0 16px}.c-navbar__content{display:flex;flex:0 1 auto}.c-navbar__nav{align-items:center;display:flex;flex-wrap:wrap;gap:16px 16px;list-style:none;margin:0;padding:0}.c-navbar__item{flex:0 0 auto}.c-navbar__link{background:0 0;border:0;color:currentcolor;display:block;text-decoration:none;text-transform:capitalize}.c-navbar__link--is-shown{text-decoration:underline}.c-ad{text-align:center}@media only screen and (min-width:320px){.c-ad{padding:8px}}.c-ad--728x90{background-color:#ccc;display:none}.c-ad--728x90 .c-ad__inner{min-height:calc(1.5em + 94px)}.c-ad--728x90 iframe{height:90px;max-width:970px}@media only screen and (min-width:768px){.js .c-ad--728x90{display:none}.js .u-show-following-ad+.c-ad--728x90{display:block}}.c-ad iframe{border:0;overflow:auto;vertical-align:top}.c-ad__label{color:#333;font-weight:400;line-height:1.5;margin-bottom:4px}.c-ad__label,.c-skip-link{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:.875rem}.c-skip-link{background:#dceaf6;bottom:auto;color:#004b83;padding:8px;position:absolute;text-align:center;transform:translateY(-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:link{color:#004b83}.c-dropdown__button:after{border-color:transparent transparent transparent #fff;border-style:solid;border-width:4px 0 4px 14px;content:"";display:block;height:0;margin-left:3px;width:0}.c-dropdown{display:inline-block;position:relative}.c-dropdown__button{background-color:transparent;border:0;display:inline-block;padding:0;white-space:nowrap}.c-dropdown__button:after{border-color:currentcolor transparent transparent;border-width:5px 4px 0 5px;display:inline-block;margin-left:8px;vertical-align:middle}.c-dropdown__menu{background-color:#fff;border:1px solid #d9d9d9;border-radius:3px;box-shadow:0 2px 6px rgba(0,0,0,.1);font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:14px;line-height:1.4;list-style:none;margin:0;padding:8px 0;position:absolute;top:100%;transform:translateY(8px);width:180px;z-index:100}.c-dropdown__menu:after,.c-dropdown__menu:before{border-style:solid;bottom:100%;content:"";display:block;height:0;left:16px;position:absolute;width:0}.c-dropdown__menu:before{border-color:transparent transparent #d9d9d9;border-width:0 9px 9px;transform:translateX(-1px)}.c-dropdown__menu:after{border-color:transparent transparent #fff;border-width:0 8px 8px}.c-dropdown__menu--right{left:auto;right:0}.c-dropdown__menu--right:after,.c-dropdown__menu--right:before{left:auto;right:16px}.c-dropdown__menu--right:before{transform:translateX(1px)}.c-dropdown__link{background-color:transparent;color:#004b83;display:block;padding:4px 16px}.c-header{background-color:#1b3051;border-bottom:4px solid #1b3051;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:14px;padding:16px 0}.c-header__container,.c-header__menu{align-items:center;display:flex;flex-wrap:wrap}@supports (gap:2em){.c-header__container,.c-header__menu{gap:2em 2em}}.c-header__menu{list-style:none;margin:0;padding:0}.c-header__item{color:#fff}@supports not (gap:2em){.c-header__item{margin-left:24px}}.c-header__container{justify-content:space-between;margin:0 auto;max-width:1280px;padding:0 16px}@supports not (gap:2em){.c-header__brand{margin-right:48px}}.c-header__brand a{display:block;text-decoration:none}.c-header__link{color:#fff}.c-journal-title a{text-decoration:none}html.webfonts-loaded .c-journal-title{font-family:Europa,Trebuchet MS}.c-form-field{margin-bottom:1em}.c-form-field__label{color:#666;display:block;font-size:14px;margin-bottom:.4em}.c-form-field__input{border:1px solid #a6a6a6;border-radius:3px;box-shadow:inset 0 1px 3px 0 rgba(0,0,0,.21);font-size:14px;line-height:1.28571;padding:.75em 1em;vertical-align:middle;width:100%}.c-popup-search{background-color:#25426f;box-shadow:0 3px 3px -3px rgba(0,0,0,.21);padding:16px 0;position:relative;z-index:10}@media only screen and (min-width:1024px){.js .c-popup-search{position:absolute;top:100%;width:100%}.c-popup-search__container{margin:auto;max-width:70%}}.c-logo img{display:block}.ctx-search .c-form-field{margin-bottom:0}.ctx-search .c-form-field__label{color:#fff}.ctx-search .c-form-field__input{border-bottom-right-radius:0;border-top-right-radius:0;margin-right:0}.c-journal-header{overflow:hidden}.c-journal-header__inner{padding-bottom:8px;padding-top:8px}@media only screen and (min-width:540px){.c-journal-header__inner{display:flex;justify-content:space-between}}.c-journal-header__identity{background-size:auto 80px;min-height:16px;padding:6px 0}@media only screen and (min-width:540px){.c-journal-header__identity{background-position:0}}.c-journal-header__identity--default{background:url(/static/images/bmc/identities/patterns/default-7e3a6b1388.svg) 0 0 no-repeat #04caa8}.c-journal-title{color:#1b3051;display:flex;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:26px;font-style:normal;font-weight:700;line-height:1.4;margin-bottom:0}.c-journal-title>a{color:#0061a9;color:#1b3051;display:flex;text-decoration:none}.c-journal-title__text{align-self:center;display:block;flex:0 1 auto}.c-logo,.c-logo>a{align-items:baseline;display:flex}.c-logo__strapline{display:none}@media only screen and (min-width:540px){.c-logo__strapline{display:block;margin:0 0 0 16px;transform:translateY(1px)}}.c-logo{display:block}html.webfonts-loaded .u-h3,html.webfonts-loaded .u-h4{font-family:Europa,Trebuchet MS}.u-button{align-items:center;background-color:#f2f2f2;background-image:linear-gradient(#fff,#f2f2f2);border:1px solid #ccc;border-radius:2px;cursor:pointer;display:inline-flex;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1rem;justify-content:center;line-height:1.3;margin:0;padding:8px;position:relative;text-decoration:none;transition:all .25s ease 0s,color .25s ease 0s,border-color .25s ease 0s;width:auto}.u-button svg,.u-button--primary svg,.u-button--tertiary svg{fill:currentcolor}.u-button{color:#004b83}.u-button--primary,.u-button--tertiary{background-color:#33629d;background-image:linear-gradient(#4d76a9,#33629d);border:1px solid rgba(0,59,132,.5);color:#fff}.u-button--tertiary{font-weight:400}.u-button--full-width{display:flex;width:100%}.u-clearfix:after,.u-clearfix:before{content:"";display:table}.u-clearfix:after{clear:both}.u-color-open-access{color:#b74616}.u-container{margin:0 auto;max-width:1280px;padding:0 16px}.u-display-flex{display:flex;width:100%}.u-align-items-center{align-items:center}.u-justify-content-space-between{justify-content:space-between}.u-flex-static{flex:0 0 auto}.u-display-none{display:none}.js .u-js-hide{display:none;visibility:hidden}@media print{.u-hide-print{display:none}}.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-position-relative{position:relative}.u-mt-32{margin-top:32px}.u-mr-24{margin-right:24px}.u-mr-48{margin-right:48px}.u-mb-32{margin-bottom:32px}.u-ml-8{margin-left:8px}.u-button-reset{background-color:transparent;border:0;padding:0}.u-text-sm{font-size:14px}.u-h3,.u-h4{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;line-height:1.4}.u-h3{color:#1b3051;font-size:18px;font-style:normal;margin-bottom:.7em}.u-h4{color:#1b3051;font-size:18px;font-style:italic;font-weight:700;margin-bottom:.7em}.u-vh-full{min-height:100vh}.u-hide{display:none;visibility:hidden}.u-hide:first-child+*{margin-block-start:0}@media only screen and (min-width:1024px){.u-hide-at-lg{display:none;visibility:hidden}}@media only screen and (max-width:1023px){.u-hide-at-lt-lg{display:none;visibility:hidden}.u-hide-at-lt-lg:first-child+*{margin-block-start:0}}.u-visually-hidden{clip:rect(0,0,0,0);border:0;height:1px;margin:-100%;overflow:hidden;padding:0;position:absolute!important;width:1px}.u-button--tertiary{font-size:.875rem;padding:8px 16px}@media only screen and (max-width:539px){.u-button--alt-colour-on-mobile{background-color:#f2f2f2;background-image:linear-gradient(#fff,#f2f2f2);border:1px solid #ccc;color:#004b83}}body{font-size:1.125rem}.c-header__navigation{display:flex;gap:.5rem .5rem} }</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) { button{line-height:inherit}html,label{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif}html{-webkit-font-smoothing:subpixel-antialiased;box-sizing:border-box;color:#333;font-size:100%;height:100%;line-height:1.61803;overflow-y:scroll}*{box-sizing:inherit}body{background:#fff;margin:0;max-width:100%;min-height:100%}button,div,form,input,p{margin:0;padding:0}body{padding:0}a{color:#004b83;overflow-wrap:break-word;text-decoration:underline;text-decoration-skip-ink:auto;word-break:break-word}a>img{vertical-align:middle}h1,h2{color:#1b3051;font-style:normal;font-weight:700}h1{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:28px;line-height:1.4}html.webfonts-loaded h1,html.webfonts-loaded h2,html.webfonts-loaded h3{font-family:Europa,Trebuchet MS}h2{font-size:26px;margin-bottom:.5em}h2,h3{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;line-height:1.4}h3{color:#1b3051;font-size:18px;font-style:normal;margin-bottom:.7em}p{overflow-wrap:break-word;word-break:break-word}.u-h3{font-size:1.5rem}.u-h3,.u-h4{font-weight:700}.u-h4{font-size:1.25rem}.c-reading-companion__figure-title{font-size:1.25rem;font-weight:700}body{font-size:1.125rem}.c-article-header{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;margin-bottom:40px}.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}.c-article-title{font-size:1.5rem;line-height:1.25;margin-bottom:16px}@media only screen and (min-width:768px){.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 svg{margin-left:4px}.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:539px){.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:#173962;border-color:transparent;color:#fff}.c-article-info-details{font-size:1rem;margin-bottom:8px;margin-top:16px}.c-article-info-details__cite-as{border-left:1px solid #6f6f6f;margin-left:8px;padding-left:8px}.c-article-metrics-bar{display:flex;flex-wrap:wrap;font-size:1rem;line-height:1.3}.c-article-metrics-bar__wrapper{margin:0 0 16px}.c-article-metrics-bar__item{align-items:baseline;border-right:1px solid #6f6f6f;margin-right:8px}.c-article-metrics-bar__item:last-child{border-right:0}.c-article-metrics-bar__count{font-weight:700;margin:0}.c-article-metrics-bar__label{color:#626262;font-style:normal;font-weight:400;margin:0 10px 0 5px}.c-article-metrics-bar__details{margin:0}.c-article-main-column{font-family:Georgia,Palatino,serif;margin-right:8.6%;width:60.2%}@media only screen and (max-width:1023px){.c-article-main-column{margin-right:0;width:100%}}.c-article-extras{float:left;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;width:31.2%}@media only screen and (max-width:1023px){.c-article-extras{display:none}}.c-article-associated-content__container .c-article-associated-content__title,.c-article-section__title{border-bottom:2px solid #d5d5d5;font-size:1.25rem;margin:0;padding-bottom:8px}@media only screen and (min-width:768px){.c-article-associated-content__container .c-article-associated-content__title,.c-article-section__title{font-size:1.5rem;line-height:1.24}}.c-article-associated-content__container .c-article-associated-content__title{margin-bottom:8px}.c-article-section{clear:both}.c-article-section__content{margin-bottom:40px;margin-top:0;padding-top:8px}@media only screen and (max-width:1023px){.c-article-section__content{padding-left:0}}.c-article__sub-heading{color:#222;font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif;font-size:1.125rem;font-style:normal;font-weight:400;line-height:1.3;margin:24px 0 8px}@media only screen and (min-width:768px){.c-article__sub-heading{font-size:1.5rem;line-height:1.24}}.c-article__sub-heading:first-child{margin-top:0}.c-article-authors-search{margin-bottom:24px;margin-top:0}.c-article-authors-search__item,.c-article-authors-search__title{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,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-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__button--link-like{background-color:transparent;border:0;color:#0067c5;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-context-bar{box-shadow:0 0 10px 0 rgba(51,51,51,.2);position:relative;width:100%}.c-context-bar__title{display:none}.c-reading-companion{clear:both;min-height:389px}.c-reading-companion__sticky{max-width:389px}.c-reading-companion__scroll-pane{margin:0;min-height:200px;overflow:hidden auto}.c-reading-companion__tabs{display:flex;flex-flow:row nowrap;font-size:1rem;list-style:none;margin:0 0 8px;padding:0}.c-reading-companion__tabs>li{flex-grow:1}.c-reading-companion__tab{background-color:#eee;border:1px solid #d5d5d5;border-image:initial;border-left-width:0;color:#0067c5;font-size:1rem;padding:8px 8px 8px 15px;text-align:left;width:100%}.c-reading-companion__tabs li:first-child .c-reading-companion__tab{border-left-width:1px}.c-reading-companion__tab--active{background-color:#fff;border-bottom:1px solid #fff;color:#222;font-weight:700}.c-reading-companion__sections-list{list-style:none;padding:0}.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__sections-list{margin:0 0 8px;min-height:50px}.c-reading-companion__section-item{font-size:1rem;padding:0}.c-reading-companion__section-item a{display:block;line-height:1.5;overflow:hidden;padding:8px 0 8px 16px;text-overflow:ellipsis;white-space:nowrap}.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{border-top:1px solid #d5d5d5;font-size:1rem;padding:8px 8px 8px 16px}.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;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-reading-companion__figure-full-link svg{height:.8em;margin-left:2px}.c-reading-companion__panel{border-top:none;display:none;margin-top:0;padding-top:0}.c-reading-companion__panel--active{display:block}.c-pdf-download__link .u-icon{padding-top:2px}.c-pdf-download{display:flex;margin-bottom:16px;max-height:48px}@media only screen and (min-width:540px){.c-pdf-download{max-height:none}}@media only screen and (min-width:1024px){.c-pdf-download{max-height:48px}}.c-pdf-download__link{display:flex;flex:1 1 0%;padding:13px 24px!important}.c-pdf-download__text{padding-right:4px}@media only screen and (max-width:539px){.c-pdf-download__text{text-transform:capitalize}}@media only screen and (min-width:540px){.c-pdf-download__text{padding-right:8px}}.c-pdf-container{display:flex;justify-content:flex-end}@media only screen and (max-width:539px){.c-pdf-container .c-pdf-download{display:flex;flex-basis:100%}}.c-article-associated-content__container a,.c-card__summary a{text-decoration:underline}.u-display-none{display:none}.js .u-js-hide,.u-hide{display:none;visibility:hidden}.u-hide:first-child+*{margin-block-start:0}.u-visually-hidden{clip:rect(0,0,0,0);border:0;height:1px;margin:-100%;overflow:hidden;padding:0;position:absolute!important;width:1px}@media print{.u-hide-print{display:none}}@media only screen and (min-width:1024px){.u-hide-at-lg{display:none;visibility:hidden}}.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}.hide{display:none;visibility:hidden}.c-article-associated-content__container .c-article-associated-content__collection.collection~.c-article-associated-content__collection.collection .c-article-associated-content__collection-label,.c-article-associated-content__container .c-article-associated-content__collection.section~.c-article-associated-content__collection.section .c-article-associated-content__collection-label,.c-article-associated-content__container .c-article-associated-content__title{display:none}.c-article-associated-content__container .c-article-associated-content__collection.collection .c-article-associated-content__collection-label,.c-article-associated-content__container .c-article-associated-content__collection.section .c-article-associated-content__collection-label{display:block}.c-article-associated-content__container .c-article-associated-content__collection.collection,.c-article-associated-content__container .c-article-associated-content__collection.section{margin-bottom:5px}.c-article-associated-content__container .c-article-associated-content__collection.section~.c-article-associated-content__collection.collection{margin-top:28px}.c-article-associated-content__container .c-article-associated-content__collection:first-child{margin-top:0}.c-article-associated-content__container .c-article-associated-content__collection:last-child{margin-bottom:2.4rem}.c-article-associated-content__container .c-article-associated-content__collection-label{color:#1b3051}.c-article-associated-content__container .c-article-associated-content__collection-title{font-size:1.063rem;font-weight:400}.webfonts-loaded .c-article__sub-heading{font-family:-apple-system,BlinkMacSystemFont,Segoe UI,Roboto,Oxygen-Sans,Ubuntu,Cantarell,Helvetica Neue,sans-serif} }</style> <link rel="stylesheet" data-test="critical-css-handler" data-inline-css-source="critical-css" href="/static/app-bmc/css/enhanced-32c9abc865.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"> <link rel="stylesheet" data-test="critical-css-handler" data-inline-css-source="critical-css" href="/static/app-bmc/css/enhanced-article-215af16b37.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/', doi: '10.1186/s12879-017-2876-9', figshareScriptUrl: 'https://widgets.figshare.com/static/figshare.js', hasFigshareInvoked: false, publisherBrand: 'BioMed Central', mustardcut: false }; </script> <script type="text/javascript" data-test="dataLayer"> window.dataLayer = [{"content":{"article":{"doi":"10.1186/s12879-017-2876-9","articleType":"Research article","peerReviewType":"Open","supplement":null,"keywords":"Plasmodium falciparum malaria-associated anaemia;Artemisinin-based combination treatments;Children;Nigeria"},"contentInfo":{"imprint":"BioMed Central","title":"Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials","publishedAt":1513641600000,"publishedAtDate":"2017-12-19","author":["Akintunde Sowunmi","Bayo Fatunmbi","Kazeem Akano","Olubunmi A. Wewe","Chimere Agomo","Finomo Finomo","Joy Ebenebe","Nma Jiya","Jose Ambe","Robinson Wammanda","Godwin Ntadom","Olugbenga Mokuolu","George Emechebe","Nnenna Ezeigwe","Adejumoke I. Ayede","Elsie O. Adewoye","Grace O. Gbotosho","Onikepe A. Folarin","Christian T. Happi","Stephen Oguche","Wellington A. Oyibo","Francis Useh"],"collection":[]},"attributes":{"deliveryPlatform":"oscar","template":"rebrand","cms":null,"copyright":{"creativeCommonsType":"CC BY + CC0","openAccess":true},"environment":"live"},"journal":{"siteKey":"bmcinfectdis.biomedcentral.com","volume":"17","issue":"1","title":"BMC Infectious Diseases","type":"SERIES","journalID":12879,"section":[{"sectionId":"AC_121189b4cbb087649e25aa398a0b501c","sectionName":"Parasitological diseases"}]},"category":{"pmc":{"primarySubject":"Medicine & Public Health"},"contentType":"Research article","publishingSegment":"BMC Series 4","snt":["Diseases","Parasitology","Medical Microbiology","Tropical Medicine","Internal Medicine"]}},"session":{"authentication":{"authenticationID":[]}},"version":"1.0.0","page":{"category":{"pageType":"article"},"attributes":{"featureFlags":[],"environment":"live","darwin":false}},"japan":false,"event":"dataLayerCreated","collection":null,"publisherBrand":"BioMed Central"}]; </script> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ ga4MeasurementId: 'G-PJCTJWPV25', ga360TrackingId: 'UA-54492316-9', twitterId: 'o47a2', baiduId: 'd1b4bc3b5ada4eb7290535e72899bac1', ga4ServerUrl: 'https://collect.biomedcentral.com', imprint: 'biomedcentral' }); </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> (function () { if ( typeof window.CustomEvent === "function" ) return false; function CustomEvent ( event, params ) { params = params || { bubbles: false, cancelable: false, detail: null }; var evt = document.createEvent( 'CustomEvent' ); evt.initCustomEvent( event, params.bubbles, params.cancelable, params.detail ); return evt; } CustomEvent.prototype = window.Event.prototype; window.CustomEvent = CustomEvent; })(); </script> <script class="js-entry"> if (window.config.mustardcut) { (function(w, d) { window.Component = {}; window.suppressShareButton = true; 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': '/static/js/polyfill-es5-bundle-572d4fec60.js', 'async': false} ]; var bodyScripts = [ {'src': '/static/js/app-es5-bundle-d0ac94c97e.js', 'async': false, 'module': false}, {'src': '/static/js/app-es6-bundle-5ee1a6879c.js', 'async': false, 'module': true} , {'src': '/static/js/global-article-es5-bundle-ae3b685a1c.js', 'async': false, 'module': false}, {'src': '/static/js/global-article-es6-bundle-f72e3cd2ca.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() { (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> <meta name="360-site-verification" content="2e1d87196f82c9ac5454a21aede69eda" /> <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 = '/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/s12879-017-2876-9"/> <meta property="og:url" content="https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-017-2876-9"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="BioMed Central"/> <meta property="og:title" content="Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials - BMC Infectious Diseases"/> <meta property="og:description" content="Background Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children. Methods Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28–42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28–42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively. Results Pre-treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia ≤10,000 μL−1 were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15 months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH >4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000 μL−1, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH >4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1 day post-treatment initiation, haematocrit ≥37%, and parasitaemia >100,000 μL−1. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9–2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children. Conclusion After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children. Trial registration Pan African Clinical Trial Registry (PACTR) [ PACTR201709002064150, 1 March 2017 ]."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig1_HTML.gif"/> <script type="application/ld+json">{"mainEntity":{"headline":"Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials","description":"Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children. Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28–42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28–42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively. Pre-treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia ≤10,000 μL−1 were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15 months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH >4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000 μL−1, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH >4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1 day post-treatment initiation, haematocrit ≥37%, and parasitaemia >100,000 μL−1. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9–2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children. After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children. Pan African Clinical Trial Registry (PACTR) [\n PACTR201709002064150, 1 March 2017\n \n ].","datePublished":"2017-12-19T00:00:00Z","dateModified":"2017-12-19T00:00:00Z","pageStart":"1","pageEnd":"18","license":"http://creativecommons.org/publicdomain/zero/1.0/","sameAs":"https://doi.org/10.1186/s12879-017-2876-9","keywords":["\n Plasmodium falciparum malaria-associated anaemia","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%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig1_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig2_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig3_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig4_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig5_HTML.gif","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig6_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":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"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":"Department of Clinical Pharmacology, 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":"Bayo Fatunmbi","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"World Health Organization, Country Office","address":{"name":"World Health Organization, Country Office, Kampala, Uganda","@type":"PostalAddress"},"@type":"Organization"}],"@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":"Olubunmi A. Wewe","affiliation":[{"name":"University of Ibadan","address":{"name":"Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Chimere Agomo","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Lagos","address":{"name":"Department of Medical Laboratory Science, University of Lagos, Lagos, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Finomo Finomo","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Department of Paediatrics, Federal Medical Centre","address":{"name":"Department of Paediatrics, Federal Medical Centre, Yenagoa, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Joy Ebenebe","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Department of Paediatrics, Nnamdi Azikiwe University","address":{"name":"Department of Paediatrics, Nnamdi Azikiwe University, Awka, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Nma Jiya","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Uthman Dan Fodio University","address":{"name":"Department of Paediatrics, Uthman Dan Fodio University, Sokoto, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Jose Ambe","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Maiduguri","address":{"name":"Department of Paediatrics, University of Maiduguri, Maiduguri, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Robinson Wammanda","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Ahmadu Bello University","address":{"name":"Department of Paediatrics, Ahmadu Bello University, Zaria, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Godwin Ntadom","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Ibadan","address":{"name":"Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Olugbenga Mokuolu","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Ilorin","address":{"name":"Department of Paediatrics, University of Ilorin, Ilorin, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"George Emechebe","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Imo State University Teaching Hospital","address":{"name":"Department of Paediatrics, Imo State University Teaching Hospital, Orlu, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Nnenna Ezeigwe","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, 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":"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"},{"name":"University of Ibadan","address":{"name":"Department of Pharmacology and Toxicology, University of Ibadan, Ibadan, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Onikepe A. Folarin","affiliation":[{"name":"Department of Biological Sciences and African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer University","address":{"name":"Department of Biological Sciences and African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer University, Ede, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Christian T. Happi","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"Department of Biological Sciences and African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer University","address":{"name":"Department of Biological Sciences and African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer University, Ede, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Stephen Oguche","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Jos","address":{"name":"Department of Paediatrics, University of Jos, Jos, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Wellington A. Oyibo","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Lagos","address":{"name":"Department of Medical Microbiology and Parasitology, University of Lagos, Lagos, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Francis Useh","affiliation":[{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health","address":{"name":"Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria","@type":"PostalAddress"},"@type":"Organization"},{"name":"University of Calabar","address":{"name":"Department of Medical Laboratory Science, University of Calabar, Calabar, Nigeria","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"}],"isAccessibleForFree":true,"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> </head> <body class="journal journal-fulltext" > <div class="ctm"></div> <!-- Google Tag Manager (noscript) --> <noscript> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript> <!-- End Google Tag Manager (noscript) --> <div class="u-visually-hidden" aria-hidden="true"> <?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"><defs><path id="a" d="M0 .74h56.72v55.24H0z"/></defs><symbol id="icon-access" viewBox="0 0 18 18"><path d="m14 8c.5522847 0 1 .44771525 1 1v7h2.5c.2761424 0 .5.2238576.5.5v1.5h-18v-1.5c0-.2761424.22385763-.5.5-.5h2.5v-7c0-.55228475.44771525-1 1-1s1 .44771525 1 1v6.9996556h8v-6.9996556c0-.55228475.4477153-1 1-1zm-8 0 2 1v5l-2 1zm6 0v7l-2-1v-5zm-2.42653766-7.59857636 7.03554716 4.92488299c.4162533.29137735.5174853.86502537.226108 1.28127873-.1721584.24594054-.4534847.39241464-.7536934.39241464h-14.16284822c-.50810197 0-.92-.41189803-.92-.92 0-.30020869.1464741-.58153499.39241464-.75369337l7.03554714-4.92488299c.34432015-.2410241.80260453-.2410241 1.14692468 0zm-.57346234 2.03988748-3.65526982 2.55868888h7.31053962z" fill-rule="evenodd"/></symbol><symbol id="icon-account" viewBox="0 0 18 18"><path d="m10.2379028 16.9048051c1.3083556-.2032362 2.5118471-.7235183 3.5294683-1.4798399-.8731327-2.5141501-2.0638925-3.935978-3.7673711-4.3188248v-1.27684611c1.1651924-.41183641 2-1.52307546 2-2.82929429 0-1.65685425-1.3431458-3-3-3-1.65685425 0-3 1.34314575-3 3 0 1.30621883.83480763 2.41745788 2 2.82929429v1.27684611c-1.70347856.3828468-2.89423845 1.8046747-3.76737114 4.3188248 1.01762123.7563216 2.22111275 1.2766037 3.52946833 1.4798399.40563808.0629726.81921174.0951949 1.23790281.0951949s.83226473-.0322223 1.2379028-.0951949zm4.3421782-2.1721994c1.4927655-1.4532925 2.419919-3.484675 2.419919-5.7326057 0-4.418278-3.581722-8-8-8s-8 3.581722-8 8c0 2.2479307.92715352 4.2793132 2.41991895 5.7326057.75688473-2.0164459 1.83949951-3.6071894 3.48926591-4.3218837-1.14534283-.70360829-1.90918486-1.96796271-1.90918486-3.410722 0-2.209139 1.790861-4 4-4s4 1.790861 4 4c0 1.44275929-.763842 2.70711371-1.9091849 3.410722 1.6497664.7146943 2.7323812 2.3054378 3.4892659 4.3218837zm-5.580081 3.2673943c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-alert" viewBox="0 0 18 18"><path d="m4 10h2.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-3.08578644l-1.12132034 1.1213203c-.18753638.1875364-.29289322.4418903-.29289322.7071068v.1715729h14v-.1715729c0-.2652165-.1053568-.5195704-.2928932-.7071068l-1.7071068-1.7071067v-3.4142136c0-2.76142375-2.2385763-5-5-5-2.76142375 0-5 2.23857625-5 5zm3 4c0 1.1045695.8954305 2 2 2s2-.8954305 2-2zm-5 0c-.55228475 0-1-.4477153-1-1v-.1715729c0-.530433.21071368-1.0391408.58578644-1.4142135l1.41421356-1.4142136v-3c0-3.3137085 2.6862915-6 6-6s6 2.6862915 6 6v3l1.4142136 1.4142136c.3750727.3750727.5857864.8837805.5857864 1.4142135v.1715729c0 .5522847-.4477153 1-1 1h-4c0 1.6568542-1.3431458 3-3 3-1.65685425 0-3-1.3431458-3-3z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-broad" viewBox="0 0 16 16"><path d="m6.10307866 2.97190702v7.69043288l2.44965196-2.44676915c.38776071-.38730439 1.0088052-.39493524 1.38498697-.01919617.38609051.38563612.38643641 1.01053024-.00013864 1.39665039l-4.12239817 4.11754683c-.38616704.3857126-1.01187344.3861062-1.39846576-.0000311l-4.12258206-4.11773056c-.38618426-.38572979-.39254614-1.00476697-.01636437-1.38050605.38609047-.38563611 1.01018509-.38751562 1.4012233.00306241l2.44985644 2.4469734v-8.67638639c0-.54139983.43698413-.98042709.98493125-.98159081l7.89910522-.0043627c.5451687 0 .9871152.44142642.9871152.98595351s-.4419465.98595351-.9871152.98595351z" fill-rule="evenodd" transform="matrix(-1 0 0 -1 14 15)"/></symbol><symbol id="icon-arrow-down" viewBox="0 0 16 16"><path d="m3.28337502 11.5302405 4.03074001 4.176208c.37758093.3912076.98937525.3916069 1.367372-.0000316l4.03091977-4.1763942c.3775978-.3912252.3838182-1.0190815.0160006-1.4001736-.3775061-.39113013-.9877245-.39303641-1.3700683.003106l-2.39538585 2.4818345v-11.6147896l-.00649339-.11662112c-.055753-.49733869-.46370161-.88337888-.95867408-.88337888-.49497246 0-.90292107.38604019-.95867408.88337888l-.00649338.11662112v11.6147896l-2.39518594-2.4816273c-.37913917-.39282218-.98637524-.40056175-1.35419292-.0194697-.37750607.3911302-.37784433 1.0249269.00013556 1.4165479z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-left" viewBox="0 0 16 16"><path d="m4.46975946 3.28337502-4.17620792 4.03074001c-.39120768.37758093-.39160691.98937525.0000316 1.367372l4.1763942 4.03091977c.39122514.3775978 1.01908149.3838182 1.40017357.0160006.39113012-.3775061.3930364-.9877245-.00310603-1.3700683l-2.48183446-2.39538585h11.61478958l.1166211-.00649339c.4973387-.055753.8833789-.46370161.8833789-.95867408 0-.49497246-.3860402-.90292107-.8833789-.95867408l-.1166211-.00649338h-11.61478958l2.4816273-2.39518594c.39282216-.37913917.40056173-.98637524.01946965-1.35419292-.39113012-.37750607-1.02492687-.37784433-1.41654791.00013556z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-right" viewBox="0 0 16 16"><path d="m11.5302405 12.716625 4.176208-4.03074003c.3912076-.37758093.3916069-.98937525-.0000316-1.367372l-4.1763942-4.03091981c-.3912252-.37759778-1.0190815-.38381821-1.4001736-.01600053-.39113013.37750607-.39303641.98772445.003106 1.37006824l2.4818345 2.39538588h-11.6147896l-.11662112.00649339c-.49733869.055753-.88337888.46370161-.88337888.95867408 0 .49497246.38604019.90292107.88337888.95867408l.11662112.00649338h11.6147896l-2.4816273 2.39518592c-.39282218.3791392-.40056175.9863753-.0194697 1.3541929.3911302.3775061 1.0249269.3778444 1.4165479-.0001355z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-sub" viewBox="0 0 16 16"><path d="m7.89692134 4.97190702v7.69043288l-2.44965196-2.4467692c-.38776071-.38730434-1.0088052-.39493519-1.38498697-.0191961-.38609047.3856361-.38643643 1.0105302.00013864 1.3966504l4.12239817 4.1175468c.38616704.3857126 1.01187344.3861062 1.39846576-.0000311l4.12258202-4.1177306c.3861843-.3857298.3925462-1.0047669.0163644-1.380506-.3860905-.38563612-1.0101851-.38751563-1.4012233.0030624l-2.44985643 2.4469734v-8.67638639c0-.54139983-.43698413-.98042709-.98493125-.98159081l-7.89910525-.0043627c-.54516866 0-.98711517.44142642-.98711517.98595351s.44194651.98595351.98711517.98595351z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-up" viewBox="0 0 16 16"><path d="m12.716625 4.46975946-4.03074003-4.17620792c-.37758093-.39120768-.98937525-.39160691-1.367372.0000316l-4.03091981 4.1763942c-.37759778.39122514-.38381821 1.01908149-.01600053 1.40017357.37750607.39113012.98772445.3930364 1.37006824-.00310603l2.39538588-2.48183446v11.61478958l.00649339.1166211c.055753.4973387.46370161.8833789.95867408.8833789.49497246 0 .90292107-.3860402.95867408-.8833789l.00649338-.1166211v-11.61478958l2.39518592 2.4816273c.3791392.39282216.9863753.40056173 1.3541929.01946965.3775061-.39113012.3778444-1.02492687-.0001355-1.41654791z" fill-rule="evenodd"/></symbol><symbol id="icon-article" viewBox="0 0 18 18"><path d="m13 15v-12.9906311c0-.0073595-.0019884-.0093689.0014977-.0093689l-11.00158888.00087166v13.00506804c0 .5482678.44615281.9940603.99415146.9940603h10.27350412c-.1701701-.2941734-.2675644-.6357129-.2675644-1zm-12 .0059397v-13.00506804c0-.5562408.44704472-1.00087166.99850233-1.00087166h11.00299537c.5510129 0 .9985023.45190985.9985023 1.0093689v2.9906311h3v9.9914698c0 1.1065798-.8927712 2.0085302-1.9940603 2.0085302h-12.01187942c-1.09954652 0-1.99406028-.8927712-1.99406028-1.9940603zm13-9.0059397v9c0 .5522847.4477153 1 1 1s1-.4477153 1-1v-9zm-10-2h7v4h-7zm1 1v2h5v-2zm-1 4h7v1h-7zm0 2h7v1h-7zm0 2h7v1h-7z" fill-rule="evenodd"/></symbol><symbol id="icon-audio" viewBox="0 0 18 18"><path d="m13.0957477 13.5588459c-.195279.1937043-.5119137.193729-.7072234.0000551-.1953098-.193674-.1953346-.5077061-.0000556-.7014104 1.0251004-1.0168342 1.6108711-2.3905226 1.6108711-3.85745208 0-1.46604976-.5850634-2.83898246-1.6090736-3.85566829-.1951894-.19379323-.1950192-.50782531.0003802-.70141028.1953993-.19358497.512034-.19341614.7072234.00037709 1.2094886 1.20083761 1.901635 2.8250555 1.901635 4.55670148 0 1.73268608-.6929822 3.35779608-1.9037571 4.55880738zm2.1233994 2.1025159c-.195234.193749-.5118687.1938462-.7072235.0002171-.1953548-.1936292-.1954528-.5076613-.0002189-.7014104 1.5832215-1.5711805 2.4881302-3.6939808 2.4881302-5.96012998 0-2.26581266-.9046382-4.3883241-2.487443-5.95944795-.1952117-.19377107-.1950777-.50780316.0002993-.70141031s.5120117-.19347426.7072234.00029682c1.7683321 1.75528196 2.7800854 4.12911258 2.7800854 6.66056144 0 2.53182498-1.0120556 4.90597838-2.7808529 6.66132328zm-14.21898205-3.6854911c-.5523759 0-1.00016505-.4441085-1.00016505-.991944v-3.96777631c0-.54783558.44778915-.99194407 1.00016505-.99194407h2.0003301l5.41965617-3.8393633c.44948677-.31842296 1.07413994-.21516983 1.39520191.23062232.12116339.16823446.18629727.36981184.18629727.57655577v12.01603479c0 .5478356-.44778914.9919441-1.00016505.9919441-.20845738 0-.41170538-.0645985-.58133413-.184766l-5.41965617-3.8393633zm0-.991944h2.32084805l5.68047235 4.0241292v-12.01603479l-5.68047235 4.02412928h-2.32084805z" fill-rule="evenodd"/></symbol><symbol id="icon-block" viewBox="0 0 24 24"><path d="m0 0h24v24h-24z" fill-rule="evenodd"/></symbol><symbol id="icon-book" viewBox="0 0 18 18"><path d="m4 13v-11h1v11h11v-11h-13c-.55228475 0-1 .44771525-1 1v10.2675644c.29417337-.1701701.63571286-.2675644 1-.2675644zm12 1h-13c-.55228475 0-1 .4477153-1 1s.44771525 1 1 1h13zm0 3h-13c-1.1045695 0-2-.8954305-2-2v-12c0-1.1045695.8954305-2 2-2h13c.5522847 0 1 .44771525 1 1v14c0 .5522847-.4477153 1-1 1zm-8.5-13h6c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-6c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm1 2h4c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-4c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-broad" viewBox="0 0 24 24"><path d="m9.18274226 7.81v7.7999954l2.48162734-2.4816273c.3928221-.3928221 1.0219731-.4005617 1.4030652-.0194696.3911301.3911301.3914806 1.0249268-.0001404 1.4165479l-4.17620796 4.1762079c-.39120769.3912077-1.02508144.3916069-1.41671995-.0000316l-4.1763942-4.1763942c-.39122514-.3912251-.39767006-1.0190815-.01657798-1.4001736.39113012-.3911301 1.02337106-.3930364 1.41951349.0031061l2.48183446 2.4818344v-8.7999954c0-.54911294.4426881-.99439484.99778758-.99557515l8.00221246-.00442485c.5522847 0 1 .44771525 1 1s-.4477153 1-1 1z" fill-rule="evenodd" transform="matrix(-1 0 0 -1 20.182742 24.805206)"/></symbol><symbol id="icon-calendar" viewBox="0 0 18 18"><path d="m12.5 0c.2761424 0 .5.21505737.5.49047852v.50952148h2c1.1072288 0 2 .89451376 2 2v12c0 1.1072288-.8945138 2-2 2h-12c-1.1072288 0-2-.8945138-2-2v-12c0-1.1072288.89451376-2 2-2h1v1h-1c-.55393837 0-1 .44579254-1 1v3h14v-3c0-.55393837-.4457925-1-1-1h-2v1.50952148c0 .27088381-.2319336.49047852-.5.49047852-.2761424 0-.5-.21505737-.5-.49047852v-3.01904296c0-.27088381.2319336-.49047852.5-.49047852zm3.5 7h-14v8c0 .5539384.44579254 1 1 1h12c.5539384 0 1-.4457925 1-1zm-11 6v1h-1v-1zm3 0v1h-1v-1zm3 0v1h-1v-1zm-6-2v1h-1v-1zm3 0v1h-1v-1zm6 0v1h-1v-1zm-3 0v1h-1v-1zm-3-2v1h-1v-1zm6 0v1h-1v-1zm-3 0v1h-1v-1zm-5.5-9c.27614237 0 .5.21505737.5.49047852v.50952148h5v1h-5v1.50952148c0 .27088381-.23193359.49047852-.5.49047852-.27614237 0-.5-.21505737-.5-.49047852v-3.01904296c0-.27088381.23193359-.49047852.5-.49047852z" fill-rule="evenodd"/></symbol><symbol id="icon-cart" viewBox="0 0 18 18"><path d="m5 14c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm10 0c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm-10 1c-.55228475 0-1 .4477153-1 1s.44771525 1 1 1 1-.4477153 1-1-.44771525-1-1-1zm10 0c-.5522847 0-1 .4477153-1 1s.4477153 1 1 1 1-.4477153 1-1-.4477153-1-1-1zm-12.82032249-15c.47691417 0 .88746157.33678127.98070211.80449199l.23823144 1.19501025 13.36277974.00045554c.5522847.00001882.9999659.44774934.9999659 1.00004222 0 .07084994-.0075361.14150708-.022474.2107727l-1.2908094 5.98534344c-.1007861.46742419-.5432548.80388386-1.0571651.80388386h-10.24805106c-.59173366 0-1.07142857.4477153-1.07142857 1 0 .5128358.41361449.9355072.94647737.9932723l.1249512.0067277h10.35933776c.2749512 0 .4979349.2228539.4979349.4978051 0 .2749417-.2227336.4978951-.4976753.4980063l-10.35959736.0041886c-1.18346732 0-2.14285714-.8954305-2.14285714-2 0-.6625717.34520317-1.24989198.87690425-1.61383592l-1.63768102-8.19004794c-.01312273-.06561364-.01950005-.131011-.0196107-.19547395l-1.71961253-.00064219c-.27614237 0-.5-.22385762-.5-.5 0-.27614237.22385763-.5.5-.5zm14.53193359 2.99950224h-13.11300004l1.20580469 6.02530174c.11024034-.0163252.22327998-.02480398.33844139-.02480398h10.27064786z"/></symbol><symbol id="icon-chevron-less" viewBox="0 0 10 10"><path d="m5.58578644 4-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" fill-rule="evenodd" transform="matrix(0 -1 -1 0 9 9)"/></symbol><symbol id="icon-chevron-more" viewBox="0 0 10 10"><path d="m5.58578644 6-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4.00000002c-.39052429.3905243-1.02368927.3905243-1.41421356 0s-.39052429-1.02368929 0-1.41421358z" fill-rule="evenodd" transform="matrix(0 1 -1 0 11 1)"/></symbol><symbol id="icon-chevron-right" 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)"/></symbol><symbol id="icon-circle-fill" viewBox="0 0 16 16"><path d="m8 14c-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6 6 2.6862915 6 6-2.6862915 6-6 6z" fill-rule="evenodd"/></symbol><symbol id="icon-circle" viewBox="0 0 16 16"><path d="m8 12c2.209139 0 4-1.790861 4-4s-1.790861-4-4-4-4 1.790861-4 4 1.790861 4 4 4zm0 2c-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6 6 2.6862915 6 6-2.6862915 6-6 6z" fill-rule="evenodd"/></symbol><symbol id="icon-citation" viewBox="0 0 18 18"><path d="m8.63593473 5.99995183c2.20913897 0 3.99999997 1.79084375 3.99999997 3.99996146 0 1.40730761-.7267788 2.64486871-1.8254829 3.35783281 1.6240224.6764218 2.8754442 2.0093871 3.4610603 3.6412466l-1.0763845.000006c-.5310008-1.2078237-1.5108121-2.1940153-2.7691712-2.7181346l-.79002167-.329052v-1.023992l.63016577-.4089232c.8482885-.5504661 1.3698342-1.4895187 1.3698342-2.51898361 0-1.65683828-1.3431457-2.99996146-2.99999997-2.99996146-1.65685425 0-3 1.34312318-3 2.99996146 0 1.02946491.52154569 1.96851751 1.36983419 2.51898361l.63016581.4089232v1.023992l-.79002171.329052c-1.25835905.5241193-2.23817037 1.5103109-2.76917113 2.7181346l-1.07638453-.000006c.58561612-1.6318595 1.8370379-2.9648248 3.46106024-3.6412466-1.09870405-.7129641-1.82548287-1.9505252-1.82548287-3.35783281 0-2.20911771 1.790861-3.99996146 4-3.99996146zm7.36897597-4.99995183c1.1018574 0 1.9950893.89353404 1.9950893 2.00274083v5.994422c0 1.10608317-.8926228 2.00274087-1.9950893 2.00274087l-3.0049107-.0009037v-1l3.0049107.00091329c.5490631 0 .9950893-.44783123.9950893-1.00275046v-5.994422c0-.55646537-.4450595-1.00275046-.9950893-1.00275046h-14.00982141c-.54906309 0-.99508929.44783123-.99508929 1.00275046v5.9971821c0 .66666024.33333333.99999036 1 .99999036l2-.00091329v1l-2 .0009037c-1 0-2-.99999041-2-1.99998077v-5.9971821c0-1.10608322.8926228-2.00274083 1.99508929-2.00274083zm-8.5049107 2.9999711c.27614237 0 .5.22385547.5.5 0 .2761349-.22385763.5-.5.5h-4c-.27614237 0-.5-.2238651-.5-.5 0-.27614453.22385763-.5.5-.5zm3 0c.2761424 0 .5.22385547.5.5 0 .2761349-.2238576.5-.5.5h-1c-.27614237 0-.5-.2238651-.5-.5 0-.27614453.22385763-.5.5-.5zm4 0c.2761424 0 .5.22385547.5.5 0 .2761349-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238651-.5-.5 0-.27614453.2238576-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-close" viewBox="0 0 16 16"><path d="m2.29679575 12.2772478c-.39658757.3965876-.39438847 1.0328109-.00062148 1.4265779.39651227.3965123 1.03246768.3934888 1.42657791-.0006214l4.27724782-4.27724787 4.2772478 4.27724787c.3965876.3965875 1.0328109.3943884 1.4265779.0006214.3965123-.3965122.3934888-1.0324677-.0006214-1.4265779l-4.27724787-4.2772478 4.27724787-4.27724782c.3965875-.39658757.3943884-1.03281091.0006214-1.42657791-.3965122-.39651226-1.0324677-.39348875-1.4265779.00062148l-4.2772478 4.27724782-4.27724782-4.27724782c-.39658757-.39658757-1.03281091-.39438847-1.42657791-.00062148-.39651226.39651227-.39348875 1.03246768.00062148 1.42657791l4.27724782 4.27724782z" fill-rule="evenodd"/></symbol><symbol id="icon-collections" viewBox="0 0 18 18"><path d="m15 4c1.1045695 0 2 .8954305 2 2v9c0 1.1045695-.8954305 2-2 2h-8c-1.1045695 0-2-.8954305-2-2h1c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h8c.5128358 0 .9355072-.3860402.9932723-.8833789l.0067277-.1166211v-9c0-.51283584-.3860402-.93550716-.8833789-.99327227l-.1166211-.00672773h-1v-1zm-4-3c1.1045695 0 2 .8954305 2 2v9c0 1.1045695-.8954305 2-2 2h-8c-1.1045695 0-2-.8954305-2-2v-9c0-1.1045695.8954305-2 2-2zm0 1h-8c-.51283584 0-.93550716.38604019-.99327227.88337887l-.00672773.11662113v9c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h8c.5128358 0 .9355072-.3860402.9932723-.8833789l.0067277-.1166211v-9c0-.51283584-.3860402-.93550716-.8833789-.99327227zm-1.5 7c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm0-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm0-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-compare" viewBox="0 0 18 18"><path d="m12 3c3.3137085 0 6 2.6862915 6 6s-2.6862915 6-6 6c-1.0928452 0-2.11744941-.2921742-2.99996061-.8026704-.88181407.5102749-1.90678042.8026704-3.00003939.8026704-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6c1.09325897 0 2.11822532.29239547 3.00096303.80325037.88158756-.51107621 1.90619177-.80325037 2.99903697-.80325037zm-6 1c-2.76142375 0-5 2.23857625-5 5 0 2.7614237 2.23857625 5 5 5 .74397391 0 1.44999672-.162488 2.08451611-.4539116-1.27652344-1.1000812-2.08451611-2.7287264-2.08451611-4.5460884s.80799267-3.44600721 2.08434391-4.5463015c-.63434719-.29121054-1.34037-.4536985-2.08434391-.4536985zm6 0c-.7439739 0-1.4499967.16248796-2.08451611.45391156 1.27652341 1.10008123 2.08451611 2.72872644 2.08451611 4.54608844s-.8079927 3.4460072-2.08434391 4.5463015c.63434721.2912105 1.34037001.4536985 2.08434391.4536985 2.7614237 0 5-2.2385763 5-5 0-2.76142375-2.2385763-5-5-5zm-1.4162763 7.0005324h-3.16744736c.15614659.3572676.35283837.6927622.58425872 1.0006671h1.99892988c.23142036-.3079049.42811216-.6433995.58425876-1.0006671zm.4162763-2.0005324h-4c0 .34288501.0345146.67770871.10025909 1.0011864h3.79948181c.0657445-.32347769.1002591-.65830139.1002591-1.0011864zm-.4158423-1.99953894h-3.16831543c-.13859957.31730812-.24521946.651783-.31578599.99935097h3.79988742c-.0705665-.34756797-.1771864-.68204285-.315786-.99935097zm-1.58295822-1.999926-.08316107.06199199c-.34550042.27081213-.65446126.58611297-.91825862.93727862h2.00044041c-.28418626-.37830727-.6207872-.71499149-.99902072-.99927061z" fill-rule="evenodd"/></symbol><symbol id="icon-download-file" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm0 1h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v14.00982141c0 .5500396.44491393.9950893.99406028.9950893h12.01187942c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717zm-1.5046024 4c.27614237 0 .5.21637201.5.49209595v6.14827645l1.7462789-1.77990922c.1933927-.1971171.5125222-.19455839.7001689-.0069117.1932998.19329992.1910058.50899492-.0027774.70277812l-2.59089271 2.5908927c-.19483374.1948337-.51177825.1937771-.70556873-.0000133l-2.59099079-2.5909908c-.19484111-.1948411-.19043735-.5151448-.00279066-.70279146.19329987-.19329987.50465175-.19237083.70018565.00692852l1.74638684 1.78001764v-6.14827695c0-.27177709.23193359-.49209595.5-.49209595z" fill-rule="evenodd"/></symbol><symbol id="icon-download" viewBox="0 0 16 16"><path d="m12.9975267 12.999368c.5467123 0 1.0024733.4478567 1.0024733 1.000316 0 .5563109-.4488226 1.000316-1.0024733 1.000316h-9.99505341c-.54671233 0-1.00247329-.4478567-1.00247329-1.000316 0-.5563109.44882258-1.000316 1.00247329-1.000316zm-4.9975267-11.999368c.55228475 0 1 .44497754 1 .99589209v6.80214418l2.4816273-2.48241149c.3928222-.39294628 1.0219732-.4006883 1.4030652-.01947579.3911302.39125371.3914806 1.02525073-.0001404 1.41699553l-4.17620792 4.17752758c-.39120769.3913313-1.02508144.3917306-1.41671995-.0000316l-4.17639421-4.17771394c-.39122513-.39134876-.39767006-1.01940351-.01657797-1.40061601.39113012-.39125372 1.02337105-.3931606 1.41951349.00310701l2.48183446 2.48261871v-6.80214418c0-.55001601.44386482-.99589209 1-.99589209z" fill-rule="evenodd"/></symbol><symbol id="icon-editors" viewBox="0 0 18 18"><path d="m8.72592184 2.54588137c-.48811714-.34391207-1.08343326-.54588137-1.72592184-.54588137-1.65685425 0-3 1.34314575-3 3 0 1.02947485.5215457 1.96853646 1.3698342 2.51900785l.6301658.40892721v1.02400182l-.79002171.32905522c-1.93395773.8055207-3.20997829 2.7024791-3.20997829 4.8180274v.9009805h-1v-.9009805c0-2.5479714 1.54557359-4.79153984 3.82548288-5.7411543-1.09870406-.71297106-1.82548288-1.95054399-1.82548288-3.3578652 0-2.209139 1.790861-4 4-4 1.09079823 0 2.07961816.43662103 2.80122451 1.1446278-.37707584.09278571-.7373238.22835063-1.07530267.40125357zm-2.72592184 14.45411863h-1v-.9009805c0-2.5479714 1.54557359-4.7915398 3.82548288-5.7411543-1.09870406-.71297106-1.82548288-1.95054399-1.82548288-3.3578652 0-2.209139 1.790861-4 4-4s4 1.790861 4 4c0 1.40732121-.7267788 2.64489414-1.8254829 3.3578652 2.2799093.9496145 3.8254829 3.1931829 3.8254829 5.7411543v.9009805h-1v-.9009805c0-2.1155483-1.2760206-4.0125067-3.2099783-4.8180274l-.7900217-.3290552v-1.02400184l.6301658-.40892721c.8482885-.55047139 1.3698342-1.489533 1.3698342-2.51900785 0-1.65685425-1.3431458-3-3-3-1.65685425 0-3 1.34314575-3 3 0 1.02947485.5215457 1.96853646 1.3698342 2.51900785l.6301658.40892721v1.02400184l-.79002171.3290552c-1.93395773.8055207-3.20997829 2.7024791-3.20997829 4.8180274z" fill-rule="evenodd"/></symbol><symbol id="icon-email" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587h-14.00982141c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm0 1h-14.00982141c-.54871518 0-.99508929.44887827-.99508929 1.00585866v9.98828264c0 .5572961.44630695 1.0058587.99508929 1.0058587h14.00982141c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-.0049107 2.55749512v1.44250488l-7 4-7-4v-1.44250488l7 4z" fill-rule="evenodd"/></symbol><symbol id="icon-error" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm2.8630343 4.71100931-2.8630343 2.86303426-2.86303426-2.86303426c-.39658757-.39658757-1.03281091-.39438847-1.4265779-.00062147-.39651227.39651226-.39348876 1.03246767.00062147 1.4265779l2.86303426 2.86303426-2.86303426 2.8630343c-.39658757.3965875-.39438847 1.0328109-.00062147 1.4265779.39651226.3965122 1.03246767.3934887 1.4265779-.0006215l2.86303426-2.8630343 2.8630343 2.8630343c.3965875.3965876 1.0328109.3943885 1.4265779.0006215.3965122-.3965123.3934887-1.0324677-.0006215-1.4265779l-2.8630343-2.8630343 2.8630343-2.86303426c.3965876-.39658757.3943885-1.03281091.0006215-1.4265779-.3965123-.39651227-1.0324677-.39348876-1.4265779.00062147z" fill-rule="evenodd"/></symbol><symbol id="icon-ethics" viewBox="0 0 18 18"><path d="m6.76384967 1.41421356.83301651-.8330165c.77492941-.77492941 2.03133823-.77492941 2.80626762 0l.8330165.8330165c.3750728.37507276.8837806.58578644 1.4142136.58578644h1.3496361c1.1045695 0 2 .8954305 2 2v1.34963611c0 .53043298.2107137 1.03914081.5857864 1.41421356l.8330165.83301651c.7749295.77492941.7749295 2.03133823 0 2.80626762l-.8330165.8330165c-.3750727.3750728-.5857864.8837806-.5857864 1.4142136v1.3496361c0 1.1045695-.8954305 2-2 2h-1.3496361c-.530433 0-1.0391408.2107137-1.4142136.5857864l-.8330165.8330165c-.77492939.7749295-2.03133821.7749295-2.80626762 0l-.83301651-.8330165c-.37507275-.3750727-.88378058-.5857864-1.41421356-.5857864h-1.34963611c-1.1045695 0-2-.8954305-2-2v-1.3496361c0-.530433-.21071368-1.0391408-.58578644-1.4142136l-.8330165-.8330165c-.77492941-.77492939-.77492941-2.03133821 0-2.80626762l.8330165-.83301651c.37507276-.37507275.58578644-.88378058.58578644-1.41421356v-1.34963611c0-1.1045695.8954305-2 2-2h1.34963611c.53043298 0 1.03914081-.21071368 1.41421356-.58578644zm-1.41421356 1.58578644h-1.34963611c-.55228475 0-1 .44771525-1 1v1.34963611c0 .79564947-.31607052 1.55871121-.87867966 2.12132034l-.8330165.83301651c-.38440512.38440512-.38440512 1.00764896 0 1.39205408l.8330165.83301646c.56260914.5626092.87867966 1.3256709.87867966 2.1213204v1.3496361c0 .5522847.44771525 1 1 1h1.34963611c.79564947 0 1.55871121.3160705 2.12132034.8786797l.83301651.8330165c.38440512.3844051 1.00764896.3844051 1.39205408 0l.83301646-.8330165c.5626092-.5626092 1.3256709-.8786797 2.1213204-.8786797h1.3496361c.5522847 0 1-.4477153 1-1v-1.3496361c0-.7956495.3160705-1.5587112.8786797-2.1213204l.8330165-.83301646c.3844051-.38440512.3844051-1.00764896 0-1.39205408l-.8330165-.83301651c-.5626092-.56260913-.8786797-1.32567087-.8786797-2.12132034v-1.34963611c0-.55228475-.4477153-1-1-1h-1.3496361c-.7956495 0-1.5587112-.31607052-2.1213204-.87867966l-.83301646-.8330165c-.38440512-.38440512-1.00764896-.38440512-1.39205408 0l-.83301651.8330165c-.56260913.56260914-1.32567087.87867966-2.12132034.87867966zm3.58698944 11.4960218c-.02081224.002155-.04199226.0030286-.06345763.002542-.98766446-.0223875-1.93408568-.3063547-2.75885125-.8155622-.23496767-.1450683-.30784554-.4531483-.16277726-.688116.14506827-.2349677.45314827-.3078455.68811595-.1627773.67447084.4164161 1.44758575.6483839 2.25617384.6667123.01759529.0003988.03495764.0017019.05204365.0038639.01713363-.0017748.03452416-.0026845.05212715-.0026845 2.4852814 0 4.5-2.0147186 4.5-4.5 0-1.04888973-.3593547-2.04134635-1.0074477-2.83787157-.1742817-.21419731-.1419238-.5291218.0722736-.70340353.2141973-.17428173.5291218-.14192375.7034035.07227357.7919032.97327203 1.2317706 2.18808682 1.2317706 3.46900153 0 3.0375661-2.4624339 5.5-5.5 5.5-.02146768 0-.04261937-.0013529-.06337445-.0039782zm1.57975095-10.78419583c.2654788.07599731.419084.35281842.3430867.61829728-.0759973.26547885-.3528185.419084-.6182973.3430867-.37560116-.10752146-.76586237-.16587951-1.15568824-.17249193-2.5587807-.00064534-4.58547766 2.00216524-4.58547766 4.49928198 0 .62691557.12797645 1.23496.37274865 1.7964426.11035133.2531347-.0053975.5477984-.25853224.6581497-.25313473.1103514-.54779841-.0053975-.65814974-.2585322-.29947131-.6869568-.45606667-1.43097603-.45606667-2.1960601 0-3.05211432 2.47714695-5.50006595 5.59399617-5.49921198.48576182.00815502.96289603.0795037 1.42238033.21103795zm-1.9766658 6.41091303 2.69835-2.94655317c.1788432-.21040373.4943901-.23598862.7047939-.05714545.2104037.17884318.2359886.49439014.0571454.70479387l-3.01637681 3.34277395c-.18039088.1999106-.48669547.2210637-.69285412.0478478l-1.93095347-1.62240047c-.21213845-.17678204-.24080048-.49206439-.06401844-.70420284.17678204-.21213844.49206439-.24080048.70420284-.06401844z" fill-rule="evenodd"/></symbol><symbol id="icon-expand"><path d="M7.498 11.918a.997.997 0 0 0-.003-1.411.995.995 0 0 0-1.412-.003l-4.102 4.102v-3.51A1 1 0 0 0 .98 10.09.992.992 0 0 0 0 11.092V17c0 .554.448 1.002 1.002 1.002h5.907c.554 0 1.002-.45 1.002-1.003 0-.539-.45-.978-1.006-.978h-3.51zm3.005-5.835a.997.997 0 0 0 .003 1.412.995.995 0 0 0 1.411.003l4.103-4.103v3.51a1 1 0 0 0 1.001 1.006A.992.992 0 0 0 18 6.91V1.002A1 1 0 0 0 17 0h-5.907a1.003 1.003 0 0 0-1.002 1.003c0 .539.45.978 1.006.978h3.51z" fill-rule="evenodd"/></symbol><symbol id="icon-explore" viewBox="0 0 18 18"><path d="m9 17c4.418278 0 8-3.581722 8-8s-3.581722-8-8-8-8 3.581722-8 8 3.581722 8 8 8zm0 1c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9zm0-2.5c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5c2.969509 0 5.400504-2.3575119 5.497023-5.31714844.0090007-.27599565.2400359-.49243782.5160315-.48343711.2759957.0090007.4924378.2400359.4834371.51603155-.114093 3.4985237-2.9869632 6.284554-6.4964916 6.284554zm-.29090657-12.99359748c.27587424-.01216621.50937715.20161139.52154336.47748563.01216621.27587423-.20161139.50937715-.47748563.52154336-2.93195733.12930094-5.25315116 2.54886451-5.25315116 5.49456849 0 .27614237-.22385763.5-.5.5s-.5-.22385763-.5-.5c0-3.48142406 2.74307146-6.34074398 6.20909343-6.49359748zm1.13784138 8.04763908-1.2004882-1.20048821c-.19526215-.19526215-.19526215-.51184463 0-.70710678s.51184463-.19526215.70710678 0l1.20048821 1.2004882 1.6006509-4.00162734-4.50670359 1.80268144-1.80268144 4.50670359zm4.10281269-6.50378907-2.6692597 6.67314927c-.1016411.2541026-.3029834.4554449-.557086.557086l-6.67314927 2.6692597 2.66925969-6.67314926c.10164107-.25410266.30298336-.45544495.55708602-.55708602z" fill-rule="evenodd"/></symbol><symbol id="icon-filter" viewBox="0 0 16 16"><path d="m14.9738641 0c.5667192 0 1.0261359.4477136 1.0261359 1 0 .24221858-.0902161.47620768-.2538899.65849851l-5.6938314 6.34147206v5.49997973c0 .3147562-.1520673.6111434-.4104543.7999971l-2.05227171 1.4999945c-.45337535.3313696-1.09655869.2418269-1.4365902-.1999993-.13321514-.1730955-.20522717-.3836284-.20522717-.5999978v-6.99997423l-5.69383133-6.34147206c-.3731872-.41563511-.32996891-1.0473954.09653074-1.41107611.18705584-.15950448.42716133-.2474224.67571519-.2474224zm-5.9218641 8.5h-2.105v6.491l.01238459.0070843.02053271.0015705.01955278-.0070558 2.0532976-1.4990996zm-8.02585008-7.5-.01564945.00240169 5.83249953 6.49759831h2.313l5.836-6.499z"/></symbol><symbol id="icon-home" viewBox="0 0 18 18"><path d="m9 5-6 6v5h4v-4h4v4h4v-5zm7 6.5857864v4.4142136c0 .5522847-.4477153 1-1 1h-5v-4h-2v4h-5c-.55228475 0-1-.4477153-1-1v-4.4142136c-.25592232 0-.51184464-.097631-.70710678-.2928932l-.58578644-.5857864c-.39052429-.3905243-.39052429-1.02368929 0-1.41421358l8.29289322-8.29289322 8.2928932 8.29289322c.3905243.39052429.3905243 1.02368928 0 1.41421358l-.5857864.5857864c-.1952622.1952622-.4511845.2928932-.7071068.2928932zm-7-9.17157284-7.58578644 7.58578644.58578644.5857864 7-6.99999996 7 6.99999996.5857864-.5857864z" fill-rule="evenodd"/></symbol><symbol id="icon-image" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm-3.49645283 10.1752453-3.89407257 6.7495552c.11705545.048464.24538859.0751995.37998328.0751995h10.60290092l-2.4329715-4.2154691-1.57494129 2.7288098zm8.49779013 6.8247547c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v13.98991071l4.50814957-7.81026689 3.08089884 5.33809539 1.57494129-2.7288097 3.5875735 6.2159812zm-3.0059397-11c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm0 1c-.5522847 0-1 .44771525-1 1s.4477153 1 1 1 1-.44771525 1-1-.4477153-1-1-1z" fill-rule="evenodd"/></symbol><symbol id="icon-info" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm0 7h-1.5l-.11662113.00672773c-.49733868.05776511-.88337887.48043643-.88337887.99327227 0 .47338693.32893365.86994729.77070917.97358929l.1126697.01968298.11662113.00672773h.5v3h-.5l-.11662113.0067277c-.42082504.0488782-.76196299.3590206-.85696816.7639815l-.01968298.1126697-.00672773.1166211.00672773.1166211c.04887817.4208251.35902055.761963.76398144.8569682l.1126697.019683.11662113.0067277h3l.1166211-.0067277c.4973387-.0577651.8833789-.4804365.8833789-.9932723 0-.4733869-.3289337-.8699473-.7707092-.9735893l-.1126697-.019683-.1166211-.0067277h-.5v-4l-.00672773-.11662113c-.04887817-.42082504-.35902055-.76196299-.76398144-.85696816l-.1126697-.01968298zm0-3.25c-.69035594 0-1.25.55964406-1.25 1.25s.55964406 1.25 1.25 1.25 1.25-.55964406 1.25-1.25-.55964406-1.25-1.25-1.25z" fill-rule="evenodd"/></symbol><symbol id="icon-institution" viewBox="0 0 18 18"><path d="m7 16.9998189v-2.0003623h4v2.0003623h2v-3.0005434h-8v3.0005434zm-3-10.00181122h-1.52632364c-.27614237 0-.5-.22389817-.5-.50009056 0-.13995446.05863589-.27350497.16166338-.36820841l1.23156713-1.13206327h-2.36690687v12.00217346h3v-2.0003623h-3v-1.0001811h3v-1.0001811h1v-4.00072448h-1zm10 0v2.00036224h-1v4.00072448h1v1.0001811h3v1.0001811h-3v2.0003623h3v-12.00217346h-2.3695309l1.2315671 1.13206327c.2033191.186892.2166633.50325042.0298051.70660631-.0946863.10304615-.2282126.16169266-.3681417.16169266zm3-3.00054336c.5522847 0 1 .44779634 1 1.00018112v13.00235456h-18v-13.00235456c0-.55238478.44771525-1.00018112 1-1.00018112h3.45499992l4.20535144-3.86558216c.19129876-.17584288.48537447-.17584288.67667324 0l4.2053514 3.86558216zm-4 3.00054336h-8v1.00018112h8zm-2 6.00108672h1v-4.00072448h-1zm-1 0v-4.00072448h-2v4.00072448zm-3 0v-4.00072448h-1v4.00072448zm8-4.00072448c.5522847 0 1 .44779634 1 1.00018112v2.00036226h-2v-2.00036226c0-.55238478.4477153-1.00018112 1-1.00018112zm-12 0c.55228475 0 1 .44779634 1 1.00018112v2.00036226h-2v-2.00036226c0-.55238478.44771525-1.00018112 1-1.00018112zm5.99868798-7.81907007-5.24205601 4.81852671h10.48411203zm.00131202 3.81834559c-.55228475 0-1-.44779634-1-1.00018112s.44771525-1.00018112 1-1.00018112 1 .44779634 1 1.00018112-.44771525 1.00018112-1 1.00018112zm-1 11.00199236v1.0001811h2v-1.0001811z" fill-rule="evenodd"/></symbol><symbol id="icon-location" viewBox="0 0 18 18"><path d="m9.39521328 16.2688008c.79596342-.7770119 1.59208152-1.6299956 2.33285652-2.5295081 1.4020032-1.7024324 2.4323601-3.3624519 2.9354918-4.871847.2228715-.66861448.3364384-1.29323246.3364384-1.8674457 0-3.3137085-2.6862915-6-6-6-3.36356866 0-6 2.60156856-6 6 0 .57421324.11356691 1.19883122.3364384 1.8674457.50313169 1.5093951 1.53348863 3.1694146 2.93549184 4.871847.74077492.8995125 1.53689309 1.7524962 2.33285648 2.5295081.13694479.1336842.26895677.2602648.39521328.3793207.12625651-.1190559.25826849-.2456365.39521328-.3793207zm-.39521328 1.7311992s-7-6-7-11c0-4 3.13400675-7 7-7 3.8659932 0 7 3.13400675 7 7 0 5-7 11-7 11zm0-8c-1.65685425 0-3-1.34314575-3-3s1.34314575-3 3-3c1.6568542 0 3 1.34314575 3 3s-1.3431458 3-3 3zm0-1c1.1045695 0 2-.8954305 2-2s-.8954305-2-2-2-2 .8954305-2 2 .8954305 2 2 2z" fill-rule="evenodd"/></symbol><symbol id="icon-minus" viewBox="0 0 16 16"><path d="m2.00087166 7h11.99825664c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-11.99825664c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-newsletter" viewBox="0 0 18 18"><path d="m9 11.8482489 2-1.1428571v-1.7053918h-4v1.7053918zm-3-1.7142857v-2.1339632h6v2.1339632l3-1.71428574v-6.41967746h-12v6.41967746zm10-5.3839632 1.5299989.95624934c.2923814.18273835.4700011.50320827.4700011.8479983v8.44575236c0 1.1045695-.8954305 2-2 2h-14c-1.1045695 0-2-.8954305-2-2v-8.44575236c0-.34479003.1776197-.66525995.47000106-.8479983l1.52999894-.95624934v-2.75c0-.55228475.44771525-1 1-1h12c.5522847 0 1 .44771525 1 1zm0 1.17924764v3.07075236l-7 4-7-4v-3.07075236l-1 .625v8.44575236c0 .5522847.44771525 1 1 1h14c.5522847 0 1-.4477153 1-1v-8.44575236zm-10-1.92924764h6v1h-6zm-1 2h8v1h-8z" fill-rule="evenodd"/></symbol><symbol id="icon-orcid" viewBox="0 0 18 18"><path d="m9 1c4.418278 0 8 3.581722 8 8s-3.581722 8-8 8-8-3.581722-8-8 3.581722-8 8-8zm-2.90107518 5.2732337h-1.41865256v7.1712107h1.41865256zm4.55867178.02508949h-2.99247027v7.14612121h2.91062487c.7673039 0 1.4476365-.1483432 2.0410182-.445034s1.0511995-.7152915 1.3734671-1.2558144c.3222677-.540523.4833991-1.1603247.4833991-1.85942385 0-.68545815-.1602789-1.30270225-.4808414-1.85175082-.3205625-.54904856-.7707074-.97532211-1.3504481-1.27883343-.5797408-.30351132-1.2413173-.45526471-1.9847495-.45526471zm-.1892674 1.07933542c.7877654 0 1.4143875.22336734 1.8798852.67010873.4654977.44674138.698243 1.05546001.698243 1.82617415 0 .74343221-.2310402 1.34447791-.6931277 1.80315511-.4620874.4586773-1.0750688.6880124-1.8389625.6880124h-1.46810075v-4.98745039zm-5.08652545-3.71099194c-.21825533 0-.410525.08444276-.57681478.25333081-.16628977.16888806-.24943341.36245684-.24943341.58071218 0 .22345188.08314364.41961891.24943341.58850696.16628978.16888806.35855945.25333082.57681478.25333082.233845 0 .43390938-.08314364.60019916-.24943342.16628978-.16628977.24943342-.36375592.24943342-.59240436 0-.233845-.08314364-.43131115-.24943342-.59240437s-.36635416-.24163862-.60019916-.24163862z" fill-rule="evenodd"/></symbol><symbol id="icon-plus" viewBox="0 0 16 16"><path d="m2.00087166 7h4.99912834v-4.99912834c0-.55276616.44386482-1.00087166 1-1.00087166.55228475 0 1 .44463086 1 1.00087166v4.99912834h4.9991283c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-4.9991283v4.9991283c0 .5527662-.44386482 1.0008717-1 1.0008717-.55228475 0-1-.4446309-1-1.0008717v-4.9991283h-4.99912834c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-print" viewBox="0 0 18 18"><path d="m16.0049107 5h-14.00982141c-.54941618 0-.99508929.4467783-.99508929.99961498v6.00077002c0 .5570958.44271433.999615.99508929.999615h1.00491071v-3h12v3h1.0049107c.5494162 0 .9950893-.4467783.9950893-.999615v-6.00077002c0-.55709576-.4427143-.99961498-.9950893-.99961498zm-2.0049107-1v-2.00208688c0-.54777062-.4519464-.99791312-1.0085302-.99791312h-7.9829396c-.55661731 0-1.0085302.44910695-1.0085302.99791312v2.00208688zm1 10v2.0018986c0 1.103521-.9019504 1.9981014-2.0085302 1.9981014h-7.9829396c-1.1092806 0-2.0085302-.8867064-2.0085302-1.9981014v-2.0018986h-1.00491071c-1.10185739 0-1.99508929-.8874333-1.99508929-1.999615v-6.00077002c0-1.10435686.8926228-1.99961498 1.99508929-1.99961498h1.00491071v-2.00208688c0-1.10341695.90195036-1.99791312 2.0085302-1.99791312h7.9829396c1.1092806 0 2.0085302.89826062 2.0085302 1.99791312v2.00208688h1.0049107c1.1018574 0 1.9950893.88743329 1.9950893 1.99961498v6.00077002c0 1.1043569-.8926228 1.999615-1.9950893 1.999615zm-1-3h-10v5.0018986c0 .5546075.44702548.9981014 1.0085302.9981014h7.9829396c.5565964 0 1.0085302-.4491701 1.0085302-.9981014zm-9 1h8v1h-8zm0 2h5v1h-5zm9-5c-.5522847 0-1-.44771525-1-1s.4477153-1 1-1 1 .44771525 1 1-.4477153 1-1 1z" fill-rule="evenodd"/></symbol><symbol id="icon-search" viewBox="0 0 22 22"><path d="M21.697 20.261a1.028 1.028 0 01.01 1.448 1.034 1.034 0 01-1.448-.01l-4.267-4.267A9.812 9.811 0 010 9.812a9.812 9.811 0 1117.43 6.182zM9.812 18.222A8.41 8.41 0 109.81 1.403a8.41 8.41 0 000 16.82z" fill-rule="evenodd"/></symbol><symbol id="icon-social-facebook" viewBox="0 0 24 24"><path d="m6.00368507 20c-1.10660471 0-2.00368507-.8945138-2.00368507-1.9940603v-12.01187942c0-1.10128908.89451376-1.99406028 1.99406028-1.99406028h12.01187942c1.1012891 0 1.9940603.89451376 1.9940603 1.99406028v12.01187942c0 1.1012891-.88679 1.9940603-2.0032184 1.9940603h-2.9570132v-6.1960818h2.0797387l.3114113-2.414723h-2.39115v-1.54164807c0-.69911803.1941355-1.1755439 1.1966615-1.1755439l1.2786739-.00055875v-2.15974763l-.2339477-.02492088c-.3441234-.03134957-.9500153-.07025255-1.6293054-.07025255-1.8435726 0-3.1057323 1.12531866-3.1057323 3.19187953v1.78079225h-2.0850778v2.414723h2.0850778v6.1960818z" fill-rule="evenodd"/></symbol><symbol id="icon-social-twitter" viewBox="0 0 24 24"><path d="m18.8767135 6.87445248c.7638174-.46908424 1.351611-1.21167363 1.6250764-2.09636345-.7135248.43394112-1.50406.74870123-2.3464594.91677702-.6695189-.73342162-1.6297913-1.19486605-2.6922204-1.19486605-2.0399895 0-3.6933555 1.69603749-3.6933555 3.78628909 0 .29642457.0314329.58673729.0942985.8617704-3.06469922-.15890802-5.78835241-1.66547825-7.60988389-3.9574208-.3174714.56076194-.49978171 1.21167363-.49978171 1.90536824 0 1.31404706.65223085 2.47224203 1.64236444 3.15218497-.60350999-.0198635-1.17401554-.1925232-1.67222562-.47366811v.04583885c0 1.83355406 1.27302891 3.36609966 2.96411421 3.71294696-.31118484.0886217-.63651445.1329326-.97441718.1329326-.2357461 0-.47149219-.0229194-.69466516-.0672303.47149219 1.5065703 1.83253297 2.6036468 3.44975116 2.632678-1.2651707 1.0160946-2.85724264 1.6196394-4.5891906 1.6196394-.29861172 0-.59093688-.0152796-.88011875-.0504227 1.63450624 1.0726291 3.57548241 1.6990934 5.66104951 1.6990934 6.79263079 0 10.50641749-5.7711113 10.50641749-10.7751859l-.0094298-.48894775c.7229547-.53478659 1.3516109-1.20250585 1.8419628-1.96190282-.6632323.30100846-1.3751855.50422736-2.1217148.59590507z" fill-rule="evenodd"/></symbol><symbol id="icon-social-youtube" viewBox="0 0 24 24"><path d="m10.1415 14.3973208-.0005625-5.19318431 4.863375 2.60554491zm9.963-7.92753362c-.6845625-.73643756-1.4518125-.73990314-1.803375-.7826454-2.518875-.18714178-6.2971875-.18714178-6.2971875-.18714178-.007875 0-3.7861875 0-6.3050625.18714178-.352125.04274226-1.1188125.04620784-1.8039375.7826454-.5394375.56084773-.7149375 1.8344515-.7149375 1.8344515s-.18 1.49597903-.18 2.99138042v1.4024082c0 1.495979.18 2.9913804.18 2.9913804s.1755 1.2736038.7149375 1.8344515c.685125.7364376 1.5845625.7133337 1.9850625.7901542 1.44.1420891 6.12.1859866 6.12.1859866s3.78225-.005776 6.301125-.1929178c.3515625-.0433198 1.1188125-.0467854 1.803375-.783223.5394375-.5608477.7155-1.8344515.7155-1.8344515s.18-1.4954014.18-2.9913804v-1.4024082c0-1.49540139-.18-2.99138042-.18-2.99138042s-.1760625-1.27360377-.7155-1.8344515z" fill-rule="evenodd"/></symbol><symbol id="icon-subject-medicine" viewBox="0 0 18 18"><path d="m12.5 8h-6.5c-1.65685425 0-3 1.34314575-3 3v1c0 1.6568542 1.34314575 3 3 3h1v-2h-.5c-.82842712 0-1.5-.6715729-1.5-1.5s.67157288-1.5 1.5-1.5h1.5 2 1 2c1.6568542 0 3-1.34314575 3-3v-1c0-1.65685425-1.3431458-3-3-3h-2v2h1.5c.8284271 0 1.5.67157288 1.5 1.5s-.6715729 1.5-1.5 1.5zm-5.5-1v-1h-3.5c-1.38071187 0-2.5-1.11928813-2.5-2.5s1.11928813-2.5 2.5-2.5h1.02786405c.46573528 0 .92507448.10843528 1.34164078.31671843l1.13382424.56691212c.06026365-1.05041141.93116291-1.88363055 1.99667093-1.88363055 1.1045695 0 2 .8954305 2 2h2c2.209139 0 4 1.790861 4 4v1c0 2.209139-1.790861 4-4 4h-2v1h2c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2h-2c0 1.1045695-.8954305 2-2 2s-2-.8954305-2-2h-1c-2.209139 0-4-1.790861-4-4v-1c0-2.209139 1.790861-4 4-4zm0-2v-2.05652691c-.14564246-.03538148-.28733393-.08714006-.42229124-.15461871l-1.15541752-.57770876c-.27771087-.13885544-.583937-.21114562-.89442719-.21114562h-1.02786405c-.82842712 0-1.5.67157288-1.5 1.5s.67157288 1.5 1.5 1.5zm4 1v1h1.5c.2761424 0 .5-.22385763.5-.5s-.2238576-.5-.5-.5zm-1 1v-5c0-.55228475-.44771525-1-1-1s-1 .44771525-1 1v5zm-2 4v5c0 .5522847.44771525 1 1 1s1-.4477153 1-1v-5zm3 2v2h2c.5522847 0 1-.4477153 1-1s-.4477153-1-1-1zm-4-1v-1h-.5c-.27614237 0-.5.2238576-.5.5s.22385763.5.5.5zm-3.5-9h1c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-success" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm3.4860198 4.98163161-4.71802968 5.50657859-2.62834168-2.02300024c-.42862421-.36730544-1.06564993-.30775346-1.42283677.13301307-.35718685.44076653-.29927542 1.0958383.12934879 1.46314377l3.40735508 2.7323063c.42215801.3385221 1.03700951.2798252 1.38749189-.1324571l5.38450527-6.33394549c.3613513-.43716226.3096573-1.09278382-.115462-1.46437175-.4251192-.37158792-1.0626796-.31842941-1.4240309.11873285z" fill-rule="evenodd"/></symbol><symbol id="icon-table" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587l-4.0059107-.001.001.001h-1l-.001-.001h-5l.001.001h-1l-.001-.001-3.00391071.001c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm-11.0059107 5h-3.999v6.9941413c0 .5572961.44630695 1.0058587.99508929 1.0058587h3.00391071zm6 0h-5v8h5zm5.0059107-4h-4.0059107v3h5.001v1h-5.001v7.999l4.0059107.001c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-12.5049107 9c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.2238576.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238576-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm-6-2c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.2238576.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238576-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm-6-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.22385763-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm1.499-5h-5v3h5zm-6 0h-3.00391071c-.54871518 0-.99508929.44887827-.99508929 1.00585866v1.99414134h3.999z" fill-rule="evenodd"/></symbol><symbol id="icon-tick-circle" viewBox="0 0 24 24"><path d="m12 2c5.5228475 0 10 4.4771525 10 10s-4.4771525 10-10 10-10-4.4771525-10-10 4.4771525-10 10-10zm0 1c-4.97056275 0-9 4.02943725-9 9 0 4.9705627 4.02943725 9 9 9 4.9705627 0 9-4.0294373 9-9 0-4.97056275-4.0294373-9-9-9zm4.2199868 5.36606669c.3613514-.43716226.9989118-.49032077 1.424031-.11873285s.4768133 1.02720949.115462 1.46437175l-6.093335 6.94397871c-.3622945.4128716-.9897871.4562317-1.4054264.0971157l-3.89719065-3.3672071c-.42862421-.3673054-.48653564-1.0223772-.1293488-1.4631437s.99421256-.5003185 1.42283677-.1330131l3.11097438 2.6987741z" fill-rule="evenodd"/></symbol><symbol id="icon-tick" viewBox="0 0 16 16"><path d="m6.76799012 9.21106946-3.1109744-2.58349728c-.42862421-.35161617-1.06564993-.29460792-1.42283677.12733148s-.29927541 1.04903009.1293488 1.40064626l3.91576307 3.23873978c.41034319.3393961 1.01467563.2976897 1.37450571-.0948578l6.10568327-6.660841c.3613513-.41848908.3096572-1.04610608-.115462-1.4018218-.4251192-.35571573-1.0626796-.30482786-1.424031.11366122z" fill-rule="evenodd"/></symbol><symbol id="icon-update" viewBox="0 0 18 18"><path d="m1 13v1c0 .5522847.44771525 1 1 1h14c.5522847 0 1-.4477153 1-1v-1h-1v-10h-14v10zm16-1h1v2c0 1.1045695-.8954305 2-2 2h-14c-1.1045695 0-2-.8954305-2-2v-2h1v-9c0-.55228475.44771525-1 1-1h14c.5522847 0 1 .44771525 1 1zm-1 0v1h-4.5857864l-1 1h-2.82842716l-1-1h-4.58578644v-1h5l1 1h2l1-1zm-13-8h12v7h-12zm1 1v5h10v-5zm1 1h4v1h-4zm0 2h4v1h-4z" fill-rule="evenodd"/></symbol><symbol id="icon-upload" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm0 1h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v14.00982141c0 .5500396.44491393.9950893.99406028.9950893h12.01187942c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717zm-1.85576936 4.14572769c.19483374-.19483375.51177826-.19377714.70556874.00001334l2.59099082 2.59099079c.1948411.19484112.1904373.51514474.0027906.70279143-.1932998.19329987-.5046517.19237083-.7001856-.00692852l-1.74638687-1.7800176v6.14827687c0 .2717771-.23193359.492096-.5.492096-.27614237 0-.5-.216372-.5-.492096v-6.14827641l-1.74627892 1.77990922c-.1933927.1971171-.51252214.19455839-.70016883.0069117-.19329987-.19329988-.19100584-.50899493.00277731-.70277808z" fill-rule="evenodd"/></symbol><symbol id="icon-video" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587h-14.00982141c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm0 1h-14.00982141c-.54871518 0-.99508929.44887827-.99508929 1.00585866v9.98828264c0 .5572961.44630695 1.0058587.99508929 1.0058587h14.00982141c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-8.30912922 2.24944486 4.60460462 2.73982242c.9365543.55726659.9290753 1.46522435 0 2.01804082l-4.60460462 2.7398224c-.93655425.5572666-1.69578148.1645632-1.69578148-.8937585v-5.71016863c0-1.05087579.76670616-1.446575 1.69578148-.89375851zm-.67492769.96085624v5.5750128c0 .2995102-.10753745.2442517.16578928.0847713l4.58452283-2.67497259c.3050619-.17799716.3051624-.21655446 0-.39461026l-4.58452283-2.67497264c-.26630747-.15538481-.16578928-.20699944-.16578928.08477139z" fill-rule="evenodd"/></symbol><symbol id="icon-warning" viewBox="0 0 18 18"><path d="m9 11.75c.69035594 0 1.25.5596441 1.25 1.25s-.55964406 1.25-1.25 1.25-1.25-.5596441-1.25-1.25.55964406-1.25 1.25-1.25zm.41320045-7.75c.55228475 0 1.00000005.44771525 1.00000005 1l-.0034543.08304548-.3333333 4c-.043191.51829212-.47645714.91695452-.99654578.91695452h-.15973424c-.52008864 0-.95335475-.3986624-.99654576-.91695452l-.33333333-4c-.04586475-.55037702.36312325-1.03372649.91350028-1.07959124l.04148683-.00259031zm-.41320045 14c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-left-bullet" viewBox="0 0 8 16"><path d="M3 8l5 5v3L0 8l8-8v3L3 8z"/></symbol><symbol id="icon-chevron-down" viewBox="0 0 16 16"><path d="m5.58578644 3-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" fill-rule="evenodd" transform="matrix(0 1 -1 0 11 3)"/></symbol><symbol id="icon-download-rounded"><path d="M0 13c0-.556.449-1 1.002-1h9.996a.999.999 0 110 2H1.002A1.006 1.006 0 010 13zM7 1v6.8l2.482-2.482c.392-.392 1.022-.4 1.403-.02a1.001 1.001 0 010 1.417l-4.177 4.177a1.001 1.001 0 01-1.416 0L1.115 6.715a.991.991 0 01-.016-1.4 1 1 0 011.42.003L5 7.8V1c0-.55.444-.996 1-.996.552 0 1 .445 1 .996z"/></symbol><symbol id="icon-ext-link" viewBox="0 0 16 16"><path d="M12.9 16H3.1C1.4 16 0 14.6 0 12.9V3.2C0 1.4 1.4 0 3.1 0h3.7v1H3.1C2 1 1 2 1 3.2v9.7C1 14 2 15 3.1 15h9.7c1.2 0 2.1-1 2.1-2.1V8.7h1v4.2c.1 1.7-1.3 3.1-3 3.1z"/><path d="M12.8 2.5l.7.7-9 8.9-.7-.7 9-8.9z"/><path d="M9.7 0L16 6.2V0z"/></symbol><symbol id="icon-remove" viewBox="-296 388 18 18"><path d="M-291.7 396.1h9v2h-9z"/><path d="M-287 405.5c-4.7 0-8.5-3.8-8.5-8.5s3.8-8.5 8.5-8.5 8.5 3.8 8.5 8.5-3.8 8.5-8.5 8.5zm0-16c-4.1 0-7.5 3.4-7.5 7.5s3.4 7.5 7.5 7.5 7.5-3.4 7.5-7.5-3.4-7.5-7.5-7.5z"/></symbol><symbol id="icon-rss" viewBox="0 0 18 18"><path d="m.97480857 6.01583891.11675372.00378391c5.75903295.51984988 10.34261021 5.10537458 10.85988231 10.86480098.0494035.5500707-.3564674 1.0360406-.906538 1.0854441-.5500707.0494036-1.0360406-.3564673-1.08544412-.906538-.43079083-4.7965248-4.25151132-8.61886853-9.04770289-9.05180573-.55004837-.04965115-.95570047-.53580366-.90604933-1.08585203.04610464-.5107592.46858035-.89701345.96909831-.90983323zm1.52519143 6.95474179c1.38071187 0 2.5 1.1192881 2.5 2.5s-1.11928813 2.5-2.5 2.5-2.5-1.1192881-2.5-2.5 1.11928813-2.5 2.5-2.5zm-1.43253846-12.96884168c9.09581416.53242539 16.37540296 7.8163886 16.90205336 16.91294558.0319214.5513615-.389168 1.0242056-.9405294 1.056127-.5513615.0319214-1.0242057-.389168-1.0561271-.9405294-.4679958-8.08344784-6.93949306-14.55883389-15.02226722-15.03196077-.55134101-.03227286-.97212889-.50538538-.93985602-1.05672639.03227286-.551341.50538538-.97212888 1.05672638-.93985602z" fill-rule="evenodd"/></symbol><symbol id="icon-springer-arrow-left"><path d="M15 7a1 1 0 000-2H3.385l2.482-2.482a.994.994 0 00.02-1.403 1.001 1.001 0 00-1.417 0L.294 5.292a1.001 1.001 0 000 1.416l4.176 4.177a.991.991 0 001.4.016 1 1 0 00-.003-1.42L3.385 7H15z"/></symbol><symbol id="icon-springer-arrow-right"><path d="M1 7a1 1 0 010-2h11.615l-2.482-2.482a.994.994 0 01-.02-1.403 1.001 1.001 0 011.417 0l4.176 4.177a1.001 1.001 0 010 1.416l-4.176 4.177a.991.991 0 01-1.4.016 1 1 0 01.003-1.42L12.615 7H1z"/></symbol><symbol id="icon-springer-collections" viewBox="3 3 32 32"><path fill-rule="evenodd" d="M25.583333,30.1249997 L25.583333,7.1207574 C25.583333,7.10772495 25.579812,7.10416665 25.5859851,7.10416665 L6.10400517,7.10571021 L6.10400517,30.1355179 C6.10400517,31.1064087 6.89406744,31.8958329 7.86448169,31.8958329 L26.057145,31.8958329 C25.7558021,31.374901 25.583333,30.7700915 25.583333,30.1249997 Z M4.33333333,30.1355179 L4.33333333,7.10571021 C4.33333333,6.12070047 5.12497502,5.33333333 6.10151452,5.33333333 L25.5859851,5.33333333 C26.5617372,5.33333333 27.3541664,6.13359035 27.3541664,7.1207574 L27.3541664,12.4166666 L32.6666663,12.4166666 L32.6666663,30.1098941 C32.6666663,32.0694626 31.0857174,33.6666663 29.1355179,33.6666663 L7.86448169,33.6666663 C5.91736809,33.6666663 4.33333333,32.0857174 4.33333333,30.1355179 Z M27.3541664,14.1874999 L27.3541664,30.1249997 C27.3541664,31.1030039 28.1469954,31.8958329 29.1249997,31.8958329 C30.1030039,31.8958329 30.8958329,31.1030039 30.8958329,30.1249997 L30.8958329,14.1874999 L27.3541664,14.1874999 Z M9.64583326,10.6458333 L22.0416665,10.6458333 L22.0416665,17.7291665 L9.64583326,17.7291665 L9.64583326,10.6458333 Z M11.4166666,12.4166666 L11.4166666,15.9583331 L20.2708331,15.9583331 L20.2708331,12.4166666 L11.4166666,12.4166666 Z M9.64583326,19.4999998 L22.0416665,19.4999998 L22.0416665,21.2708331 L9.64583326,21.2708331 L9.64583326,19.4999998 Z M9.64583326,23.0416665 L22.0416665,23.0416665 L22.0416665,24.8124997 L9.64583326,24.8124997 L9.64583326,23.0416665 Z M9.64583326,26.583333 L22.0416665,26.583333 L22.0416665,28.3541664 L9.64583326,28.3541664 L9.64583326,26.583333 Z"/></symbol><symbol id="icon-springer-download" viewBox="-301 390 9 14"><path d="M-301 395.6l4.5 5.1 4.5-5.1h-3V390h-3v5.6h-3zm0 6.5h9v1.9h-9z"/></symbol><symbol id="icon-springer-info" viewBox="0 0 24 24"><!--Generator: Sketch 63.1 (92452) - https://sketch.com--><g id="V&I" stroke="none" stroke-width="1" fill-rule="evenodd"><g id="info" fill-rule="nonzero"><path d="M12,0 C18.627417,0 24,5.372583 24,12 C24,18.627417 18.627417,24 12,24 C5.372583,24 0,18.627417 0,12 C0,5.372583 5.372583,0 12,0 Z M12.5540543,9.1 L11.5540543,9.1 C11.0017696,9.1 10.5540543,9.54771525 10.5540543,10.1 L10.5540543,10.1 L10.5540543,18.1 C10.5540543,18.6522847 11.0017696,19.1 11.5540543,19.1 L11.5540543,19.1 L12.5540543,19.1 C13.1063391,19.1 13.5540543,18.6522847 13.5540543,18.1 L13.5540543,18.1 L13.5540543,10.1 C13.5540543,9.54771525 13.1063391,9.1 12.5540543,9.1 L12.5540543,9.1 Z M12,5 C11.5356863,5 11.1529412,5.14640523 10.8517647,5.43921569 C10.5505882,5.73202614 10.4,6.11546841 10.4,6.58954248 C10.4,7.06361656 10.5505882,7.45054466 10.8517647,7.7503268 C11.1529412,8.05010893 11.5356863,8.2 12,8.2 C12.4768627,8.2 12.8627451,8.05010893 13.1576471,7.7503268 C13.452549,7.45054466 13.6,7.06361656 13.6,6.58954248 C13.6,6.11546841 13.452549,5.73202614 13.1576471,5.43921569 C12.8627451,5.14640523 12.4768627,5 12,5 Z" id="Combined-Shape"/></g></g></symbol><symbol id="icon-springer-tick-circle" viewBox="0 0 24 24"><g id="Page-1" stroke="none" stroke-width="1" fill-rule="evenodd"><g id="springer-tick-circle" fill-rule="nonzero"><path d="M12,24 C5.372583,24 0,18.627417 0,12 C0,5.372583 5.372583,0 12,0 C18.627417,0 24,5.372583 24,12 C24,18.627417 18.627417,24 12,24 Z M7.657,10.79 C7.45285634,10.6137568 7.18569967,10.5283283 6.91717333,10.5534259 C6.648647,10.5785236 6.40194824,10.7119794 6.234,10.923 C5.87705269,11.3666969 5.93445559,12.0131419 6.364,12.387 L10.261,15.754 C10.6765468,16.112859 11.3037113,16.0695601 11.666,15.657 L17.759,8.713 C18.120307,8.27302248 18.0695334,7.62621189 17.644,7.248 C17.4414817,7.06995024 17.1751516,6.9821166 16.9064461,7.00476032 C16.6377406,7.02740404 16.3898655,7.15856958 16.22,7.368 L10.768,13.489 L7.657,10.79 Z" id="path-1"/></g></g></symbol><symbol id="icon-updates" viewBox="0 0 18 18"><g fill-rule="nonzero"><path d="M16.98 3.484h-.48c-2.52-.058-5.04 1.161-7.44 2.903-2.46-1.8-4.74-2.903-8.04-2.903-.3 0-.54.29-.54.58v9.813c0 .29.24.523.54.581 2.76.348 4.86 1.045 7.62 2.903.24.116.54.116.72 0 2.76-1.858 4.86-2.555 7.62-2.903.3-.058.54-.29.54-.58V4.064c0-.29-.24-.523-.54-.581zm-15.3 1.22c2.34 0 4.86 1.509 6.72 2.786v8.478c-2.34-1.394-4.38-2.09-6.72-2.439V4.703zm14.58 8.767c-2.34.348-4.38 1.045-6.72 2.439V7.374C12 5.632 14.1 4.645 16.26 4.645v8.826z"/><path d="M9 .058c-1.56 0-2.76 1.22-2.76 2.671C6.24 4.181 7.5 5.4 9 5.4c1.5 0 2.76-1.22 2.76-2.671 0-1.452-1.2-2.67-2.76-2.67zm0 4.413c-.96 0-1.8-.755-1.8-1.742C7.2 1.8 7.98.987 9 .987s1.8.755 1.8 1.742c0 .93-.84 1.742-1.8 1.742z"/></g></symbol><symbol id="icon-checklist-banner" viewBox="0 0 56.69 56.69"><path style="fill:none" d="M0 0h56.69v56.69H0z"/><clipPath id="b"><use xlink:href="#a" style="overflow:visible"/></clipPath><path d="M21.14 34.46c0-6.77 5.48-12.26 12.24-12.26s12.24 5.49 12.24 12.26-5.48 12.26-12.24 12.26c-6.76-.01-12.24-5.49-12.24-12.26zm19.33 10.66 10.23 9.22s1.21 1.09 2.3-.12l2.09-2.32s1.09-1.21-.12-2.3l-10.23-9.22m-19.29-5.92c0-4.38 3.55-7.94 7.93-7.94s7.93 3.55 7.93 7.94c0 4.38-3.55 7.94-7.93 7.94-4.38-.01-7.93-3.56-7.93-7.94zm17.58 12.99 4.14-4.81" style="clip-path:url(#b);fill:none;stroke:#01324b;stroke-width:2;stroke-linecap:round"/><path d="M8.26 9.75H28.6M8.26 15.98H28.6m-20.34 6.2h12.5m14.42-5.2V4.86s0-2.93-2.93-2.93H4.13s-2.93 0-2.93 2.93v37.57s0 2.93 2.93 2.93h15.01M8.26 9.75H28.6M8.26 15.98H28.6m-20.34 6.2h12.5" style="clip-path:url(#b);fill:none;stroke:#01324b;stroke-width:2;stroke-linecap:round;stroke-linejoin:round"/></symbol><symbol id="icon-submit-closed" viewBox="0 0 18 18"><path d="m15 0c1.1045695 0 2 .8954305 2 2v4.5c0 .27614237-.2238576.5-.5.5s-.5-.22385763-.5-.5v-4.5c0-.51283584-.3860402-.93550716-.8833789-.99327227l-.1166211-.00672773h-9v3c0 1.1045695-.8954305 2-2 2h-3v10c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h4.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-4.5c-1.1045695 0-2-.8954305-2-2v-10.17157288c0-.53043297.21071368-1.0391408.58578644-1.41421356l3.82842712-3.82842712c.37507276-.37507276.88378059-.58578644 1.41421356-.58578644zm-2.5 7c3.0375661 0 5.5 2.46243388 5.5 5.5 0 3.0375661-2.4624339 5.5-5.5 5.5-3.03756612 0-5.5-2.4624339-5.5-5.5 0-3.03756612 2.46243388-5.5 5.5-5.5zm0 1c-2.4852814 0-4.5 2.0147186-4.5 4.5s2.0147186 4.5 4.5 4.5 4.5-2.0147186 4.5-4.5-2.0147186-4.5-4.5-4.5zm2.3087379 2.1912621c.2550161.2550162.2550161.668479 0 .9234952l-1.3859024 1.3845831 1.3859024 1.3859023c.2550161.2550162.2550161.668479 0 .9234952-.2550162.2550161-.668479.2550161-.9234952 0l-1.3859023-1.3859024-1.3845831 1.3859024c-.2550162.2550161-.668479.2550161-.9234952 0-.25501614-.2550162-.25501614-.668479 0-.9234952l1.3845831-1.3859023-1.3845831-1.3845831c-.25501614-.2550162-.25501614-.668479 0-.9234952.2550162-.25501614.668479-.25501614.9234952 0l1.3845831 1.3845831 1.3859023-1.3845831c.2550162-.25501614.668479-.25501614.9234952 0zm-9.8087379-8.7782621-3.587 3.587h2.587c.55228475 0 1-.44771525 1-1z"/></symbol><symbol id="icon-submit-open" viewBox="0 0 18 18"><path d="m15 0c1.1045695 0 2 .8954305 2 2v5.5c0 .27614237-.2238576.5-.5.5s-.5-.22385763-.5-.5v-5.5c0-.51283584-.3860402-.93550716-.8833789-.99327227l-.1166211-.00672773h-9v3c0 1.1045695-.8954305 2-2 2h-3v10c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h7.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-7.5c-1.1045695 0-2-.8954305-2-2v-10.17157288c0-.53043297.21071368-1.0391408.58578644-1.41421356l3.82842712-3.82842712c.37507276-.37507276.88378059-.58578644 1.41421356-.58578644zm-.5442863 8.18867991 3.3545404 3.35454039c.2508994.2508994.2538696.6596433.0035959.909917-.2429543.2429542-.6561449.2462671-.9065387-.0089489l-2.2609825-2.3045251.0010427 7.2231989c0 .3569916-.2898381.6371378-.6473715.6371378-.3470771 0-.6473715-.2852563-.6473715-.6371378l-.0010428-7.2231995-2.2611222 2.3046654c-.2531661.2580415-.6562868.2592444-.9065605.0089707-.24295423-.2429542-.24865597-.6576651.0036132-.9099343l3.3546673-3.35466731c.2509089-.25090888.6612706-.25227691.9135302-.00001728zm-.9557137-3.18867991c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-6c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm-8.5-3.587-3.587 3.587h2.587c.55228475 0 1-.44771525 1-1zm8.5 1.587c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-6c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z"/></symbol><symbol id="icon-submit-upcoming" viewBox="0 0 18 18"><path d="m15 0c1.1045695 0 2 .8954305 2 2v4.5c0 .27614237-.2238576.5-.5.5s-.5-.22385763-.5-.5v-4.5c0-.51283584-.3860402-.93550716-.8833789-.99327227l-.1166211-.00672773h-9v3c0 1.1045695-.8954305 2-2 2h-3v10c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h4.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-4.5c-1.1045695 0-2-.8954305-2-2v-10.17157288c0-.53043297.21071368-1.0391408.58578644-1.41421356l3.82842712-3.82842712c.37507276-.37507276.88378059-.58578644 1.41421356-.58578644zm-2.5 7c3.0375661 0 5.5 2.46243388 5.5 5.5 0 3.0375661-2.4624339 5.5-5.5 5.5-3.03756612 0-5.5-2.4624339-5.5-5.5 0-1.6607442.73606908-3.14957021 1.89976608-4.15803695l-1.51549374.02214397c-.27613212.00263356-.49998143-.22483432-.49998143-.49020681 0-.24299316.17766103-.44509007.40961587-.48700057l.08928713-.00797472h2.66407569c.2449213 0 .4486219.17766776.490865.40963137l.008038.08929051v2.6642143c0 .275547-.2296028.4989219-.4949753.4989219-.24299317 0-.44342617-.1744719-.4830969-.4093269l-.00710993-.0906783.01983146-1.46576707c-.96740882.82538117-1.58082193 2.05345007-1.58082193 3.42478927 0 2.4852814 2.0147186 4.5 4.5 4.5s4.5-2.0147186 4.5-4.5-2.0147186-4.5-4.5-4.5c-.7684937 0-.7684937-1 0-1zm0 2.85c.3263501 0 .5965265.2405082.6429523.5539478l.0070477.0960522v1.731l.8096194.8093806c.2284567.2284567.2513024.5846637.068537.8386705l-.068537.0805683c-.2284567.2284567-.5846637.2513024-.8386705.068537l-.0805683-.068537-.9707107-.9707107c-.1125218-.1125218-.1855975-.257116-.2103268-.412296l-.0093431-.1180341v-1.9585786c0-.3589851.2910149-.65.65-.65zm-7.5-8.437-3.587 3.587h2.587c.55228475 0 1-.44771525 1-1z"/></symbol><symbol id="icon-facebook-bordered" viewBox="463.812 263.868 32 32"><path d="M479.812,263.868c-8.837,0-16,7.163-16,16s7.163,16,16,16s16-7.163,16-16S488.649,263.868,479.812,263.868z M479.812,293.868c-7.732,0-14-6.269-14-14s6.268-14,14-14s14,6.269,14,14S487.545,293.868,479.812,293.868z"/><path d="M483.025,280.48l0.32-2.477h-2.453v-1.582c0-0.715,0.199-1.207,1.227-1.207h1.311v-2.213 c-0.227-0.029-1.003-0.098-1.907-0.098c-1.894,0-3.186,1.154-3.186,3.271v1.826h-2.142v2.477h2.142v6.354h2.557v-6.354 L483.025,280.48L483.025,280.48z"/></symbol><symbol id="icon-twitter-bordered" viewBox="463.812 263.868 32 32"><g><path d="M486.416,276.191c-0.483,0.215-1.007,0.357-1.554,0.429c0.558-0.338,0.991-0.868,1.19-1.502 c-0.521,0.308-1.104,0.536-1.72,0.657c-0.494-0.526-1.2-0.854-1.979-0.854c-1.496,0-2.711,1.213-2.711,2.71 c0,0.212,0.023,0.419,0.069,0.616c-2.252-0.111-4.25-1.19-5.586-2.831c-0.231,0.398-0.365,0.866-0.365,1.361 c0,0.94,0.479,1.772,1.204,2.257c-0.441-0.015-0.861-0.138-1.227-0.339v0.031c0,1.314,0.937,2.41,2.174,2.656 c-0.227,0.062-0.47,0.098-0.718,0.098c-0.171,0-0.343-0.018-0.511-0.049c0.35,1.074,1.347,1.859,2.531,1.883 c-0.928,0.726-2.095,1.16-3.366,1.16c-0.22,0-0.433-0.014-0.644-0.037c1.2,0.768,2.621,1.215,4.155,1.215 c4.983,0,7.71-4.129,7.71-7.711c0-0.115-0.004-0.232-0.006-0.351C485.592,277.212,486.054,276.734,486.416,276.191z"/></g><path d="M479.812,263.868c-8.837,0-16,7.163-16,16s7.163,16,16,16s16-7.163,16-16S488.649,263.868,479.812,263.868z M479.812,293.868c-7.732,0-14-6.269-14-14s6.268-14,14-14s14,6.269,14,14S487.545,293.868,479.812,293.868z"/></symbol><symbol id="icon-weibo-bordered" viewBox="463.812 263.868 32 32"><path d="M479.812,263.868c-8.838,0-16,7.163-16,16s7.162,16,16,16c8.837,0,16-7.163,16-16S488.649,263.868,479.812,263.868z M479.812,293.868c-7.732,0-14-6.269-14-14s6.268-14,14-14c7.731,0,14,6.269,14,14S487.545,293.868,479.812,293.868z"/><g><path d="M478.552,285.348c-2.616,0.261-4.876-0.926-5.044-2.649c-0.167-1.722,1.814-3.33,4.433-3.588 c2.609-0.263,4.871,0.926,5.041,2.647C483.147,283.479,481.164,285.089,478.552,285.348 M483.782,279.63 c-0.226-0.065-0.374-0.109-0.259-0.403c0.25-0.639,0.276-1.188,0.005-1.581c-0.515-0.734-1.915-0.693-3.521-0.021 c0,0-0.508,0.224-0.378-0.181c0.247-0.798,0.209-1.468-0.178-1.852c-0.87-0.878-3.194,0.032-5.183,2.027 c-1.489,1.494-2.357,3.082-2.357,4.453c0,2.619,3.354,4.213,6.631,4.213c4.297,0,7.154-2.504,7.154-4.493 C485.697,280.594,484.689,279.911,483.782,279.63"/><path d="M486.637,274.833c-1.039-1.154-2.57-1.592-3.982-1.291l0,0c-0.325,0.068-0.532,0.391-0.465,0.72 c0.068,0.328,0.391,0.537,0.72,0.466c1.005-0.215,2.092,0.104,2.827,0.92c0.736,0.818,0.938,1.939,0.625,2.918l0,0 c-0.102,0.318,0.068,0.661,0.39,0.762c0.32,0.104,0.658-0.069,0.763-0.391v-0.001C487.953,277.558,487.674,275.985,486.637,274.833 "/><path d="M485.041,276.276c-0.504-0.562-1.25-0.774-1.938-0.63c-0.279,0.06-0.461,0.339-0.396,0.621 c0.062,0.281,0.335,0.461,0.617,0.398l0,0c0.336-0.071,0.702,0.03,0.947,0.307s0.312,0.649,0.207,0.979l0,0 c-0.089,0.271,0.062,0.565,0.336,0.654c0.274,0.09,0.564-0.062,0.657-0.336C485.686,277.604,485.549,276.837,485.041,276.276"/><path d="M478.694,282.227c-0.09,0.156-0.293,0.233-0.451,0.166c-0.151-0.062-0.204-0.235-0.115-0.389 c0.093-0.155,0.284-0.229,0.44-0.168C478.725,281.892,478.782,282.071,478.694,282.227 M477.862,283.301 c-0.253,0.405-0.795,0.58-1.202,0.396c-0.403-0.186-0.521-0.655-0.27-1.051c0.248-0.39,0.771-0.566,1.176-0.393 C477.979,282.423,478.109,282.889,477.862,283.301 M478.812,280.437c-1.244-0.326-2.65,0.294-3.19,1.396 c-0.553,1.119-0.021,2.369,1.236,2.775c1.303,0.42,2.84-0.225,3.374-1.436C480.758,281.989,480.1,280.77,478.812,280.437"/></g></symbol></svg> </div> <div class="u-vh-full"> <a class="c-skip-link" href="#main-content">Skip to main content</a> <div class="u-hide u-show-following-ad"></div> <aside class="adsbox c-ad c-ad--728x90" data-component-mpu> <div class="c-ad__inner"> <p class="c-ad__label">Advertisement</p> <div id="div-gpt-ad-LB1" data-ad-type="LB1" data-test="LB1-ad" data-pa11y-ignore data-gpt data-gpt-unitpath="/270604982/bmc/bmcinfectdis/articles" data-gpt-sizes="728x90,970x90" data-gpt-targeting="pos=LB1;doi=10.1186/s12879-017-2876-9;type=article;kwrd=Plasmodium falciparum malaria-associated anaemia,Artemisinin-based combination treatments,Children,Nigeria;pmc=H33096,B19002,B16003,H61006,H33002;" > <noscript> <a href="//pubads.g.doubleclick.net/gampad/jump?iu=/270604982/bmc/bmcinfectdis/articles&sz=728x90,970x90&pos=LB1&doi=10.1186/s12879-017-2876-9&type=article&kwrd=Plasmodium falciparum malaria-associated anaemia,Artemisinin-based combination treatments,Children,Nigeria&pmc=H33096,B19002,B16003,H61006,H33002&"> <img data-test="gpt-advert-fallback-img" src="//pubads.g.doubleclick.net/gampad/ad?iu=/270604982/bmc/bmcinfectdis/articles&sz=728x90,970x90&pos=LB1&doi=10.1186/s12879-017-2876-9&type=article&kwrd=Plasmodium falciparum malaria-associated anaemia,Artemisinin-based combination treatments,Children,Nigeria&pmc=H33096,B19002,B16003,H61006,H33002&" alt="Advertisement" width="728" height="90"> </a> </noscript> </div> </div> </aside> <div id="membership-message-loader-desktop" class="placeholder" data-placeholder="/placeholder/v1/membership/message"></div> <div id="top" class="u-position-relative"> <header class="c-header" data-test="publisher-header"> <div class="c-header__container"> <div class="c-header__brand u-mr-48" itemscope itemtype="http://schema.org/Organization" data-test="navbar-logo-header"> <div class="c-logo"> <a href="https://www.biomedcentral.com" itemprop="url"> <img alt="BMC" itemprop="logo" width="76" height="18" role="img" src=/static/images/bmc/logos/logo-bmc-white-series-d1f4e4f0a7.svg> <div class="c-logo__strapline"> <img alt="Part of Springer Nature" width="173" height="16" role="img" src=/static/images/bmc/logos/logo-bmc-white-strapline-sn-f224388d67.svg> </div> </a> </div> </div> <div class="c-header__navigation"> <button type="button" class="c-header__link u-button-reset u-mr-24" data-expander data-expander-target="#publisher-header-search" data-expander-autofocus="firstTabbable" data-test="header-search-button" aria-controls="publisher-header-search" aria-expanded="false"> <span class="u-display-flex u-align-items-center"> <span>Search</span> <svg class="u-icon u-flex-static u-ml-8" aria-hidden="true" focusable="false"> <use xlink:href="#icon-search"></use> </svg> </span> </button> <nav> <ul class="c-header__menu" data-enhanced-menu data-test="publisher-navigation"> <li class="c-header__item u-hide-at-lt-lg"> <a class="c-header__link" href="//www.biomedcentral.com/journals"> Explore journals </a> </li> <li class="c-header__item u-hide-at-lt-lg"> <a class="c-header__link" href="//www.biomedcentral.com/getpublished"> Get published </a> </li> <li class="c-header__item u-hide-at-lt-lg"> <a class="c-header__link" href="//www.biomedcentral.com/about"> About BMC </a> </li> <li class="c-header__item"> <a data-enhanced-account class="c-header__link" href="https://www.biomedcentral.com/account" data-test="login-link"> My account </a> </li> </ul> </nav> </div> </div> </header> <div class="c-popup-search u-js-hide" id="publisher-header-search"> <div class="u-container"> <div class="c-popup-search__container"> <div class="ctx-search"> <form role="search" class="c-form-field js-skip-validation" method="GET" action="//www.biomedcentral.com/search" data-track="search" data-track-context="pop out website-wide search in bmc website header" data-track-category="Search and Results" data-track-action="Submit search" data-dynamic-track-label data-track-label="" data-test="global-search"> <label for="publisherSearch" class="c-form-field__label">Search all BMC articles</label> <div class="u-display-flex"> <input id="publisherSearch" class="c-form-field__input" data-search-input autocomplete="off" role="textbox" data-test="search-input" name="query" type="text" value=""/> <div> <button class="u-button" type="submit" data-test="search-submit-button"> <span class="u-visually-hidden">Search</span> <svg class="u-icon u-flex-static" width="16" height="16" aria-hidden="true" focusable="false"> <use xlink:href="#icon-search"></use> </svg> </button> </div> </div> <input type="hidden" name="searchType" value="publisherSearch"/> </form> </div> </div> </div> </div> </div> <header class="c-journal-header c-journal-header--bmc-infectious-diseases ctx-journal-header"> <div class="u-container"> <div class="c-journal-header__inner "> <div class="c-journal-title" id="journalTitle"> <a href="/"> <span class="c-journal-title__text ">BMC Infectious Diseases</span> </a> </div> </div> </div> <div class="c-navbar c-navbar--with-submit-button"> <div class="c-navbar__container"> <div class="c-navbar__content"> <nav class="c-navbar__nav"> <ul class="c-navbar__nav c-navbar__nav--journal" role="menu" data-test="site-navigation"> <li class="c-navbar__item" role="menuitem"> <a class="c-navbar__link" data-track="click" data-track-category="Home" data-track-action="Clicked journal navigation link" href='/'>Home</a> </li> <li class="c-navbar__item" role="menuitem"> <a class="c-navbar__link" data-track="click" data-track-category="About" data-track-action="Clicked journal navigation link" href='/about'>About</a> </li> <li class="c-navbar__item" role="menuitem"> <a class="c-navbar__link c-navbar__link--is-shown" data-track="click" data-track-category="Articles" data-track-action="Clicked journal navigation link" href='/articles'>Articles</a> </li> <li class="c-navbar__item" role="menuitem"> <a class="c-navbar__link" data-track="click" data-track-category="Submission Guidelines" data-track-action="Clicked journal navigation link" href='/submission-guidelines'>Submission Guidelines</a> </li> <li class="c-navbar__item" role="menuitem"> <a class="c-navbar__link" data-track="click" data-track-category="Join the board" data-track-action="Clicked journal navigation link" href='/join-our-editorial-board'>Join the board</a> </li> <li class="c-navbar__item" role="menuitem"> <a class="c-navbar__link" data-track="click" data-track-category="Collections" data-track-action="Clicked journal navigation link" href='/articles/collections'>Collections</a> </li> <li class="c-navbar__item" role="menuitem" data-test="journal-header-submit-button"> <div class=""> <a class="u-button u-button--tertiary u-button--alt-colour-on-mobile" href="https://submission.nature.com/new-submission/12879/3" data-track="click_submit_manuscript" data-track-action="manuscript submission" data-track-category="article" data-track-label="button in journal nav" data-track-context="journal header on article page" data-track-external data-test="submit-manuscript-button">Submit manuscript<svg class="u-ml-8" width="15" height="16" aria-hidden="true" focusable="false"><use xlink:href="#icon-submit-open"></use></svg></a> </div> </li> </ul> </nav> </div> </div> </div> <div class="c-journal-header__identity c-journal-header__identity--default"> </div> </header> <div class="u-container u-mt-32 u-mb-32 u-clearfix" id="main-content" data-component="article-container"> <main class="c-article-main-column u-float-left 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" data-track-context="sticky banner"> <div class="c-context-bar__title"> Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials </div> <div class="c-pdf-container"> <div class="c-pdf-download u-clear-both"> <a href="//bmcinfectdis.biomedcentral.com/counter/pdf/10.1186/s12879-017-2876-9.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="link" 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-download"/></svg> </a> </div> </div> </div> </div> <div class="c-pdf-button__container u-hide-at-lg js-context-bar-sticky-point-mobile"> <div class="c-pdf-container" data-track-context="article body"> <div class="c-pdf-download u-clear-both"> <a href="//bmcinfectdis.biomedcentral.com/counter/pdf/10.1186/s12879-017-2876-9.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="link" 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-download"/></svg> </a> </div> </div> </div> <article lang="en"> <div class="c-article-header"> <ul class="c-article-identifiers" data-test="article-identifier"> <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="2017-12-19">19 December 2017</time></li> </ul> <h1 class="c-article-title c-article-title--long" data-test="article-title" data-article-title="">Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials</h1> <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-Aff3-Aff20" data-author-popup="auth-Akintunde-Sowunmi-Aff1-Aff2-Aff3-Aff20" 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="#Aff3">3</a>,<a href="#Aff20">20</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-Bayo-Fatunmbi-Aff1-Aff4" data-author-popup="auth-Bayo-Fatunmbi-Aff1-Aff4" data-author-search="Fatunmbi, Bayo">Bayo Fatunmbi</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<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-Kazeem-Akano-Aff2" data-author-popup="auth-Kazeem-Akano-Aff2" data-author-search="Akano, Kazeem">Kazeem Akano</a><sup class="u-js-hide"><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-Olubunmi_A_-Wewe-Aff2" data-author-popup="auth-Olubunmi_A_-Wewe-Aff2" data-author-search="Wewe, Olubunmi A.">Olubunmi A. Wewe</a><sup class="u-js-hide"><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-Chimere-Agomo-Aff1-Aff5" data-author-popup="auth-Chimere-Agomo-Aff1-Aff5" data-author-search="Agomo, Chimere">Chimere Agomo</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<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-Finomo-Finomo-Aff1-Aff6" data-author-popup="auth-Finomo-Finomo-Aff1-Aff6" data-author-search="Finomo, Finomo">Finomo Finomo</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<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-Joy-Ebenebe-Aff1-Aff7" data-author-popup="auth-Joy-Ebenebe-Aff1-Aff7" data-author-search="Ebenebe, Joy">Joy Ebenebe</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff7">7</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-Nma-Jiya-Aff1-Aff8" data-author-popup="auth-Nma-Jiya-Aff1-Aff8" data-author-search="Jiya, Nma">Nma Jiya</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff8">8</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-Jose-Ambe-Aff1-Aff9" data-author-popup="auth-Jose-Ambe-Aff1-Aff9" data-author-search="Ambe, Jose">Jose Ambe</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff9">9</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-Robinson-Wammanda-Aff1-Aff10" data-author-popup="auth-Robinson-Wammanda-Aff1-Aff10" data-author-search="Wammanda, Robinson">Robinson Wammanda</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff10">10</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-Aff1-Aff2" data-author-popup="auth-Godwin-Ntadom-Aff1-Aff2" data-author-search="Ntadom, Godwin">Godwin Ntadom</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-Olugbenga-Mokuolu-Aff1-Aff11" data-author-popup="auth-Olugbenga-Mokuolu-Aff1-Aff11" data-author-search="Mokuolu, Olugbenga">Olugbenga Mokuolu</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff11">11</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-George-Emechebe-Aff1-Aff12" data-author-popup="auth-George-Emechebe-Aff1-Aff12" data-author-search="Emechebe, George">George Emechebe</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff12">12</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-Nnenna-Ezeigwe-Aff1" data-author-popup="auth-Nnenna-Ezeigwe-Aff1" data-author-search="Ezeigwe, Nnenna">Nnenna Ezeigwe</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-Aff13" data-author-popup="auth-Adejumoke_I_-Ayede-Aff13" data-author-search="Ayede, Adejumoke I.">Adejumoke I. Ayede</a><sup class="u-js-hide"><a href="#Aff13">13</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-Aff14" data-author-popup="auth-Elsie_O_-Adewoye-Aff14" data-author-search="Adewoye, Elsie O.">Elsie O. Adewoye</a><sup class="u-js-hide"><a href="#Aff14">14</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-Aff2-Aff3-Aff15" data-author-popup="auth-Grace_O_-Gbotosho-Aff2-Aff3-Aff15" data-author-search="Gbotosho, Grace O.">Grace O. Gbotosho</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff15">15</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-Aff16" data-author-popup="auth-Onikepe_A_-Folarin-Aff16" data-author-search="Folarin, Onikepe A.">Onikepe A. Folarin</a><sup class="u-js-hide"><a href="#Aff16">16</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-Christian_T_-Happi-Aff1-Aff16" data-author-popup="auth-Christian_T_-Happi-Aff1-Aff16" data-author-search="Happi, Christian T.">Christian T. Happi</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff16">16</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-Stephen-Oguche-Aff1-Aff17" data-author-popup="auth-Stephen-Oguche-Aff1-Aff17" data-author-search="Oguche, Stephen">Stephen Oguche</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff17">17</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-Wellington_A_-Oyibo-Aff1-Aff18" data-author-popup="auth-Wellington_A_-Oyibo-Aff1-Aff18" data-author-search="Oyibo, Wellington A.">Wellington A. Oyibo</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff18">18</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 22 authors for this article" title="Show all 22 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-Francis-Useh-Aff1-Aff19" data-author-popup="auth-Francis-Useh-Aff1-Aff19" data-author-search="Useh, Francis">Francis Useh</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff19">19</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> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">BMC Infectious Diseases</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 17</b>, Article number: <span data-test="article-number">781</span> (<span data-test="article-publication-year">2017</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">2508 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">10 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">1 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/10.1186/s12879-017-2876-9/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </div> <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>Artemisinin-based combination therapies (ACTs) have remained efficacious treatments of acute falciparum malaria in many endemic areas but there is little evaluation of factors contributing to the anaemia of acute falciparum malaria following long term adoption of ACTs as first-line antimalarials in African children.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Methods</h3><p>Malarious <5 year-olds randomized to artemether-lumefantrine, artesunate-amodiaquine or dihydroartemisinin-piperaquine treatments were followed up clinically for 6 weeks. Anaemia was defined as haematocrit <30%; Malaria-attributable fall in haematocrit (MAFH) as the difference between haematocrit 28–42 days post- and pre-treatment; Total MAFH (TMAFH) as the difference between days 28–42 haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation; Drug-attributable fall in haematocrit (DAFH) as the difference between MAFH and TMAFH; Early appearing anaemia (EAA) as haematocrit <30% occurring within 1 week in children with normal haematocrit pre-treatment. Predictors of anaemia pre-treatment, EAA, MAFH or DAFH >4% were evaluated by stepwise multiple logistic regression models. Survival analysis and kinetics of DAFH were evaluated by Kaplan-Meier estimator and non-compartment model, respectively.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Results</h3><p>Pre-treatment, 355 of 959 children were anaemic. Duration of illness >2 days and parasitaemia ≤10,000 μL<sup>−1</sup> were independent predictors of anaemia pre-treatment. EAA occurred in 301 of 604 children. Predictors of EAA were age ≤ 15 months, history of fever pre-treatment and enrolment haematocrit ≤35%. The probabilities of progression from normal haematocrit to EAA were similar for all treatments. MAFH >4% occurred in 446 of 694 children; its predictors were anaemia pre-treatment, enrolment parasitaemia ≤50,000 μL<sup>−1</sup>, parasitaemia one day post-treatment initiation and gametocytaemia. DAFH >4% occurred in 334 of 719 children; its predictors were history of fever pre-and fever 1 day post-treatment initiation, haematocrit ≥37%, and parasitaemia >100,000 μL<sup>−1</sup>. In 432 children, declines in DAFH deficits were monoexponential with overall estimated half-time of 2.2d (95% CI 1.9–2.6). Area under curve of deficits in DAFH versus time and estimated half-time were significantly higher in non-anaemic children indicating greater loss of haematocrit in these children.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Conclusion</h3><p>After ten years of adoption of ACTs, anaemia is common pre-and early post-treatment, falls in haematocrit attributable to a single infection is high, and DAFH >4% is common and significantly lower in anaemic compared to non-anaemic Nigerian children.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Trial registration</h3><p>Pan African Clinical Trial Registry (PACTR) [<a href="http://www.pactr.org">PACTR201709002064150, 1 March 2017</a>].</p></div></div></section> <p class="c-status-message c-status-message--info c-status-message--boxed u-mb-32"> <svg class="c-status-message__icon" width="24" height="24" aria-hidden="true" focusable="false"><use xlink:href="#icon-eds-i-info-filled-medium"></use></svg> <a href="/articles/10.1186/s12879-017-2876-9/peer-review" data-track="click" data-track-category="article body" data-track-action="open peer review reports" data-track-label="10.1186/s12879-017-2876-9">Peer Review reports</a> </p> <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>Artemisinin-based combination therapies (ACTs) have been adopted as first-line treatments of uncomplicated <i>Plasmodium falciparum</i> malaria by over 80 countries [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Bosman A, Mendis KNA. Major transition in malaria treatment: the adoption and deployment of artemisinin-based combination therapies. Am J Trop Med Hyg. 2007;66(Suppl 6):193–7." href="#ref-CR1" id="ref-link-section-d85324754e1324">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="World Health Organization. World malaria report 2015. Geneva: WHO; 2015. 
 http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/
 
 
 " href="#ref-CR2" id="ref-link-section-d85324754e1324_1">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="World Health Organization. Antimalarial Drug Combination Therapy. Report of a WHO Technical Consultation. Geneva: World Health Organization. 2001. WHO/CDS/RBM/2001.35." href="/articles/10.1186/s12879-017-2876-9#ref-CR3" id="ref-link-section-d85324754e1327">3</a>]. In many of these countries particularly those in southeast Asia, the period of adoption as first-line treatments has exceeded 10 years [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Carrara VI, Zwang J, Ashley EA, Price RN, Stepniewka K, Marion B, Brockman A, Anderson T, McGready R, Phaiphun L, Stephane P, van Vugt M, Hutagalung R, Lwin KM, Phyo AP, Piyanuch P, Imwong M, Pukrittayakamee S, Singhasivanon P, White NJ, Nosten F. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One. 2009;4:e4551." href="/articles/10.1186/s12879-017-2876-9#ref-CR4" id="ref-link-section-d85324754e1330">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Phyo AP, Ashley EA, Anderson TJC, Bozdech Z, Carrara VI, Sriprawat K, Nair S, White MM, Dziekan J, Ling C, Proux S, Konghahong K, Jeeyapant A, Woodrow CJ, Imwong M, McGready R, Lwin KM, Day NPJ, White NJ, Nosten F. Declining efficacy of artemisinin combination therapy against P. falciparum malaria on the Thai-Myanmar border (2003-2013): the role of parasite genetic factors. Clin Infect Dis. 2016;63:784–91." href="/articles/10.1186/s12879-017-2876-9#ref-CR5" id="ref-link-section-d85324754e1333">5</a>]. In Nigeria, artemether-lumefantrine (AL) and artesunate-amodiaquine (AA) were adopted as first-line treatments in 2005 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Federal Ministry of Health. National Antimalaria Treatment Guideline. Abuja, Nigeria: Federal Ministry of Health; 2005." href="/articles/10.1186/s12879-017-2876-9#ref-CR6" id="ref-link-section-d85324754e1337">6</a>].</p><p>Anaemia, a consequence of treated and untreated falciparum malaria, is common before, during or after treatment in up to 40% of African children [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Nkuo-Akenji TK, Chi PC, Cho JF, Ndamukong KK, Sumbele I. Malaria and helminth co-infection in children living in a malaria endemic setting of Mount Cameroon and predictors of anemia. J Parasitol. 2006;92:1191–5." href="#ref-CR7" id="ref-link-section-d85324754e1343">7</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Sowunmi A, Gbotosho GO, Happi CT, Fateye B. Factors contributing to anaemia after uncomplicated Plasmodium falciparum malaria in children. Acta Trop. 2010;113:155–61." href="#ref-CR8" id="ref-link-section-d85324754e1343_1">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Sumbele IUN, Samje M, Nkuo-Akenji TA. Longitudinal study on anaemia in children with Plasmodium falciparum infection in the Mount Cameroon region: prevalence, risk factors and perceptions by caregivers. BioMed Central of Infectious Diseases. 2013;13:123." href="/articles/10.1186/s12879-017-2876-9#ref-CR9" id="ref-link-section-d85324754e1346">9</a>]. It is a major public health problem, and in anaemic patients, has been attributed to repeated infections within a short time frame, bone marrow dyserythropoiesis and increased splenic clearance of infected and non-infected erythrocytes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" 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="#ref-CR10" id="ref-link-section-d85324754e1349">10</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dondorp AM, Angus BJ, Chotivanich K, Silamut K, Ruangveerayuth R, Hardeman MR, Kager PA, Vreeken J, White NJ. Red blood cell deformability as a predictor of anemia in severe falciparum malaria. Am J Trop Med Hyg. 1999;60:733–7." href="#ref-CR11" id="ref-link-section-d85324754e1349_1">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Safeukui I, Correas JM, Brousse V, Hirt D, Deplaine G, Mulé S, Lesurtel M, Goasguen N, Sauvanet A, Couvelard A, Kerneis S, Khun H, Vigan-Womas I, Ottone C, Molina TJ, Tréluyer JM, Mercereau-Puijalon O, Milon G, David PH, Buffet PA. Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen. Blood. 2008;112:2520–8." href="#ref-CR12" id="ref-link-section-d85324754e1349_2">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Buffet PA, Safeukui I, Deplaine G, Brousse V, Prendki V, Thellier M, Turner GD, Mercereau-Puijalon O. The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology. Blood. 2011;117:381–92." href="/articles/10.1186/s12879-017-2876-9#ref-CR13" id="ref-link-section-d85324754e1352">13</a>]. Anaemia can also occur in African children with apparently asymptomatic infections [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Ouédraogo HZ, Zeba A, Dramaix-Wilmet M, Donnen P. Moderate to severe anaemia due to afebrile Plasmodium falciparum infections in children aged 6- 23 months from rural district of Kongoussi, Burkina Faso. J Trop Pediatr. 2008;54:395–400." href="/articles/10.1186/s12879-017-2876-9#ref-CR14" id="ref-link-section-d85324754e1355">14</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Njua-Yafi C, Achidi EA, Anchang-Kimbi JK, Apinjoh TO, Mugri RN, Chi HF, Tata RB, Njumkeng C, Nkock EN, Nkuo-Akenji T. Malaria, helminths, co-infection and anaemia in a cohort of children from Mutengene, south western Cameroon. Malar J. 2016;15:69." href="/articles/10.1186/s12879-017-2876-9#ref-CR15" id="ref-link-section-d85324754e1359">15</a>].</p><p>Despite adoption as first-line treatments in many countries for over a decade, there is little evaluation of the predictors of anaemia before, during or in the 1 week following initiation of treatment in malarious children. In malarious patients, the effects of infections and the drugs used to treat the infections can be evaluated using the following indices: malaria-attributable fall in haematocrit (MAFH), total malaria-attributable fall in haematocrit (TMAFH) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" 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="/articles/10.1186/s12879-017-2876-9#ref-CR10" id="ref-link-section-d85324754e1365">10</a>], or drug-attributable fall in haematocrit (DAFH) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" 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="/articles/10.1186/s12879-017-2876-9#ref-CR16" id="ref-link-section-d85324754e1368">16</a>]. Such evaluations are urgently needed as they can provide useful leads in the diagnosis and management of the anaemia following ACTs, and the extent to which adoption of ACTs as first-line antimalarials has modified the burden of the anaemia associated with malaria infections. From the clinical point of view, worsening of haematocrit levels or falls in haematocrit following ACTs of uncomplicated falciparum malaria in young African children, until proven otherwise, can be considered an adverse event attributable to the drug(s) used [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" 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="/articles/10.1186/s12879-017-2876-9#ref-CR17" id="ref-link-section-d85324754e1371">17</a>] – drug attributable falls in haematocrit [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" 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="/articles/10.1186/s12879-017-2876-9#ref-CR16" id="ref-link-section-d85324754e1374">16</a>]. However, DAFH can be attributed to interaction between the drug, the infection and the host.</p><p>For the reasons indicated above, the aims of present study were: using pre-determined cut-offs (haematocrit <30%, MAFH or DAFH >4%), to evaluate the predictors of the following: anaemia at presentation, progression from normal haematocrit at presentation to anaemia within 1 week of starting treatment (early-appearing anaemia [EAA]), and MAFH or DAFH >4% in a group of under 5 year old malarious children who were treated with AL, AA or dihydroartemisinin-piperaquine (DHP), during an open labelled therapeutic efficacy study. An additional aim was to evaluate the kinetics of the disposition of DAFH in anaemic and non-anaemic children following initiation of treatment.</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 locations</h3><p>The study took place between June 2014 and September 2015. It was part of a programme to monitor antimalarial therapeutic efficacy at eight sentinel sites located in six geographical areas of Nigeria namely, Ogbia, Neni, Ogwa, Numan, Ilorin, Kura, Bodinga and Ibadan in Bayelsa, Anambra, Imo, Adamawa, Kwara, Kano, Sokoto and Oyo States, respectively. In virtually all study locations, malaria is hyperendemic and transmission occurs all year round; however, it is more intense during the rainy season from April to October. The details of the therapeutic efficacy study will be described elsewhere. The dataset presented here have not been previously published elsewhere.</p><h3 class="c-article__sub-heading" id="Sec4">Study procedures</h3><p>Standardized procedures and protocol were used at all sentinel sites. Briefly, patients were eligible to participate in the study if they were: aged 6–59 months, had symptoms compatible with acute uncomplicated malaria and <i>P. falciparum</i> mono-infections between 2000 and 200,000 μL<sup>−1</sup> of blood, no history of antimalarial drug ingestion in the two weeks preceding enrolment, had no evidence of severe malaria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="World Health Organization. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000; 94 Supp1: 1–90." href="/articles/10.1186/s12879-017-2876-9#ref-CR18" id="ref-link-section-d85324754e1405">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="World Health Organization. Severe malaria. Trop Med Int Health. 2014;19(Suppl 1):7–131." href="/articles/10.1186/s12879-017-2876-9#ref-CR19" id="ref-link-section-d85324754e1408">19</a>] and parents or guardians gave written informed consent.</p><p>Enrolled patients were randomized to AL, AA or DHP treatments for 3 days (day 0–2) as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" 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="/articles/10.1186/s12879-017-2876-9#ref-CR20" id="ref-link-section-d85324754e1414">20</a>]. The day of presentation (day of starting treatment) was regarded as day 0. Thick and thin blood films were obtained from each child as soon as they came to the clinic and the slides were carefully labelled with the patients’ codes and air-dried before being Giemsa-stained. Follow-up with clinical and parasitological evaluation was done daily on days 1–3 and 7, and thereafter, weekly for additional 5 weeks. Parasitaemia, asexual or sexual, in thick films was 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 6000 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 21" title="World Health Organization: Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: world health Organization 2003." href="/articles/10.1186/s12879-017-2876-9#ref-CR21" id="ref-link-section-d85324754e1419">21</a>]. A slide was considered asexual parasite negative if no asexual parasite was detected after examination of 200 microscope fields. Parasite reduction ratio was defined as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Sowunmi A, Akano K, Ayede AI, Ntadom G, Adewoye EO, Fatunmbi B, Aderoyeje T. Therapeutic efficacy and effects of artesunate-amodiaquine and artemether-lumefantrine on malaria-associated anaemia in Nigerian children aged two years and under. Infectious Diseases of Poverty. 2016;5:70." href="/articles/10.1186/s12879-017-2876-9#ref-CR22" id="ref-link-section-d85324754e1422">22</a>].</p><h3 class="c-article__sub-heading" id="Sec5">Haematological evaluation</h3><p>Capillary blood obtained from a finger prick was collected before treatment and during follow-up<u>,</u> and was used to measure haematocrit using a microhaematocrit tube and microcentrifuge (Hawksley, Lancing, UK). Anaemia was defined as a haematocrit <30% and was further classified as mild, moderate or severe if haematocrit was 21–29%, 15–20% or <15%, respectively [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Sowunmi A, Gbotosho GO, Happi CT, Fateye B. Factors contributing to anaemia after uncomplicated Plasmodium falciparum malaria in children. Acta Trop. 2010;113:155–61." href="/articles/10.1186/s12879-017-2876-9#ref-CR8" id="ref-link-section-d85324754e1436">8</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" 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="/articles/10.1186/s12879-017-2876-9#ref-CR10" id="ref-link-section-d85324754e1439">10</a>].</p><h3 class="c-article__sub-heading" id="Sec6">Definition of haematological parameters evaluated</h3><p>The following parameters described by Price et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" 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="/articles/10.1186/s12879-017-2876-9#ref-CR10" id="ref-link-section-d85324754e1450">10</a>] and modified by Sowunmi et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" 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="/articles/10.1186/s12879-017-2876-9#ref-CR16" id="ref-link-section-d85324754e1453">16</a>] were used for evaluation (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig1">1</a>):</p><ol class="u-list-style-none"> <li> <span class="u-custom-list-number">(i)</span> <p> <i>Malaria-attributable fall in haematocrit (MAFH)</i> before treatment was defined as the difference between the patient’s maximum haematocrit value measured on days 28–42 and that on day 0 (pre-treatment).</p> </li> <li> <span class="u-custom-list-number">(ii)</span> <p> <i>Total malaria-attributable fall in haematocrit (TMAFH)</i> was defined as the difference between the patient’s maximum haematocrit on days 28–42 and lowest haematocrit value recorded in the first week post-treatment initiation.</p> </li> <li> <span class="u-custom-list-number">(iii)</span> <p> <i>Drug-attributable falls in haematocrit (DAFH)</i> was defined as the difference between MAFH and TMAFH, or as the difference between pre-treatment haematocrit and the lowest haematocrit recorded in the first week post-treatment initiation.</p> </li> <li> <span class="u-custom-list-number">(iv)</span> <p> <i>Early-appearing anaemia (EAA)</i> was defined as haematocrit <30% occurring within 1 week in patients who were non-anaemic pre-treatment.</p> </li> <li> <span class="u-custom-list-number">(v)</span> <p> <i>Anaemia recovery time:</i> Anaemia recovery time (in anaemic children pre-treatment) was defined as time elapsing from initiation of treatment to attainment of haematocrit value ≥30%. In non-anaemic children (pre-treatment) who subsequently progressed to anaemia following initiation of treatment (early-appearing anaemia), anaemia recovery time was defined as the time from the appearance of (onset of anaemia), to recovery from anaemia (until haematocrit rose to ≥30%).</p> </li> </ol> <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="/articles/10.1186/s12879-017-2876-9/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig1_HTML.gif?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_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>Parameters used for estimation of malaria-related falls in haematocrit (adapted from Price et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" 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="/articles/10.1186/s12879-017-2876-9#ref-CR10" id="ref-link-section-d85324754e1542">10</a>] and Sowunmi et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" 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="/articles/10.1186/s12879-017-2876-9#ref-CR16" id="ref-link-section-d85324754e1545">16</a>]</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="/articles/10.1186/s12879-017-2876-9/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="Sec7">Kinetics of the disposition of drug-attributable falls in haematocrit</h3><p>The kinetics of the deposition of the deficits in haematocrit from 30% using the lowest recorded haematocrit in the first week of initiating treatment (DAFH) were evaluated as previously described for the general evaluation of kinetics of the disposition of anaemia in malarious children [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Gbotosho GO, Sowunmi A, Okuboyejo TM, Happi CT, Folarin OO, Michael OS, Adewoye EO. Therapeutic efficacy and effects of artemether-lumefantrine and artesunate amodiaquine co-formulated or co-packaged on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria. Am J Trop Med Hyg. 2011;84:813–9." href="/articles/10.1186/s12879-017-2876-9#ref-CR23" id="ref-link-section-d85324754e1566">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Sowunmi A, Gbotosho GO, Happi CT, Folarin O, Okuboyejo T, Michael O, Fatunmbi B. Use of area under the curve to evaluate the effects of antimalarial drugs on malaria-associated anaemia after treatment. Am J Ther. 2011;18:190–7." href="/articles/10.1186/s12879-017-2876-9#ref-CR24" id="ref-link-section-d85324754e1569">24</a>]. Briefly, in all children, haematocrit values below pre-treatment levels following initiation of treatment and at follow-up were subtracted from pre-treatment haematocrit at each time of measurement until haematocrit rose to or above pre-treatment level and the resulting values plotted against time. The final haematocrit when pre-treatment level was reached was therefore zero in all patients with falls in haematocrit following initiation of treatment. However, the final haematocrit at the time when pre-treatment haematocrit level was reached was assumed to be 0.01% [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Sowunmi A, Gbotosho GO, Happi CT, Folarin O, Okuboyejo T, Michael O, Fatunmbi B. Use of area under the curve to evaluate the effects of antimalarial drugs on malaria-associated anaemia after treatment. Am J Ther. 2011;18:190–7." href="/articles/10.1186/s12879-017-2876-9#ref-CR24" id="ref-link-section-d85324754e1572">24</a>]. The areas under the curve (AUC) of deficit in haematocrit from pre-treatment level versus time were obtained by trapezoidal rule using the computer program <i>Turbo Ken</i> (designed by Clinical Pharmacology Group, University of Southampton, United Kingdom) 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="Gbotosho GO, Sowunmi A, Okuboyejo TM, Happi CT, Folarin OO, Michael OS, Adewoye EO. Therapeutic efficacy and effects of artemether-lumefantrine and artesunate amodiaquine co-formulated or co-packaged on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria. Am J Trop Med Hyg. 2011;84:813–9." href="/articles/10.1186/s12879-017-2876-9#ref-CR23" id="ref-link-section-d85324754e1578">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Sowunmi A, Gbotosho GO, Happi CT, Folarin O, Okuboyejo T, Michael O, Fatunmbi B. Use of area under the curve to evaluate the effects of antimalarial drugs on malaria-associated anaemia after treatment. Am J Ther. 2011;18:190–7." href="/articles/10.1186/s12879-017-2876-9#ref-CR24" id="ref-link-section-d85324754e1582">24</a>]. AUC was also obtained manually by calculating the average haematocrit values between two consecutive time measurements and multiplying it by the time interval between the measurements, and summing up all the values, in a manner similar to that for the numerical estimation of area under a drug concentration-time curve (AUC) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Rowland M, Tozer TN. Clinical pharmacokinetics: concept and application. Philadelphia: PA Lea and Ferbiger; 1980." href="/articles/10.1186/s12879-017-2876-9#ref-CR25" id="ref-link-section-d85324754e1585">25</a>]. The unit of quantification would be %.d, if haematocrit values were used or g/L.d if haemoglobin values were used. Haematocrit values may be converted to haemoglobin values by dividing by 3 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Bain BJ, Bates I. Basic haematological techniques. In: Lewis SM, Bain BJ, Bates I, editors. Practical Haematology. 9th ed. Edinburgh: Churchill Living stone 2001; pg. 19–46." href="/articles/10.1186/s12879-017-2876-9#ref-CR26" id="ref-link-section-d85324754e1588">26</a>]. Semilogarithm plots of deficit in haematocrit from pre-treatment level versus time were plotted. The apparent terminal elimination rate constant (λ) was obtained by least-square regression analysis of the post-peak log-linear part of the plot of deficit in haematocrit from pre-treatment level versus time. The apparent terminal half-time of DAFH (t<sub>1/2(DAFH)</sub>) was calculated from ln 2/λ (that is, λt = 0.693). Only children in whom haematocrit values were measured at least 3 times following a drug-attributable fall in haematocrit post-initiation of treatment were included in this evaluation.</p><h3 class="c-article__sub-heading" id="Sec8">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 27" title="Epi Info Version 6. A Word Processing Data Base and Statistics Program for Public Health on IBM-compatible Microcomputers. Centers for Disease Control and Prevention, Atlanta, GA; 1994." href="/articles/10.1186/s12879-017-2876-9#ref-CR27" id="ref-link-section-d85324754e1601">27</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 28" title="SPSS for Windows Release 20.0 (standard version). SPSS Inc., Chicago IL; 2011." href="/articles/10.1186/s12879-017-2876-9#ref-CR28" id="ref-link-section-d85324754e1604">28</a>]. Variables considered in the analysis were related to the densities of <i>P. falciparum</i> asexual forms, haematocrit status at presentation and the values of DAFH and AUC<sub>(DAFH)</sub>. Proportions were compared by calculating χ<sup>2</sup> using Yates’ correction, Fisher’s exact or Mantel Haenszel tests. Normally distributed, continuous data were compared by Student’s t test and analysis of variance (ANOVA). Kaplan-Meier estimator and pairwise log-rank tests were used to determine cumulative risk of anaemia occurring within 1 week post-treatment initiation with AL, AA or DHP. Stepwise multiple logistic regression models were used to test the association between: anaemia pre-treatment, normal haematocrit pre-treatment progressing to EAA within 1 week post-treatment initiation, malaria-attributable fall in haematocrit (MAFH) in excess of 4%, or drug-attributable fall in haematocrit (DAFH) in excess of 4%, and factors that were significant at univariate analysis. Correlation between the values of DAFH and AUC<sub>(DAFH)</sub> in the same patients was assessed by Pearson’s correlation coefficient. Agreement between the values of DAFH and AUC<sub>(DAFH)</sub> was assessed by Bland-Altman analysis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1:307–10." href="/articles/10.1186/s12879-017-2876-9#ref-CR29" id="ref-link-section-d85324754e1619">29</a>]. 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="Sec9-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec9">Results</h2><div class="c-article-section__content" id="Sec9-content"><h3 class="c-article__sub-heading" id="Sec10">Characteristics of children enrolled in the study and parasite positivity following treatment</h3><p>Nine hundred and ninety two children were enrolled and randomized to AL (<i>n</i> = 324), AA (<i>n</i> = 321) or DHP (<i>n</i> = 347) treatments. Of these children, haematocrit values were measured at presentation in 959 children (<i>n</i> = 315, 307 and 337 in AL, AA and DHP treatments, respectively). Mean weight of 959 children enrolled in the study was 13.2 kg (95% CI 12.9–13.4). The other characteristics of these children at presentation are shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab1">1</a>. Two hundred and fifty six of the 959 children (27%) were aged ≤24 months and 121 (13%) were aged ≤15 months. One hundred and one (11%) had asexual parasitaemia >100,000 μL<sup>−1</sup>. Overall, mean haematocrit at presentation was 30.6% (95% CI 30.3–30.9). At presentation, anaemia was present in 355 of 959 children (37%) and it was mild, moderate or severe in 323 (33.7%), 30 (3.1%) or 2 children (0.2%), respectively (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab1">1</a>). Overall, asexual parasite positivity on day 3 was 29 of 959 children (3%) and it was similar in all treatments groups [11 of 315 children (3%), 12 of 307 children (4%), and 6 of 337 children (2%) in AL-, AA- and DHP-treated children, respectively, <i>P</i> = 0.24].</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 Characteristics of the 959 children enrolled in the study of risk factors for anaemia in uncomplicated falciparum malaria</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="/articles/10.1186/s12879-017-2876-9/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> <h3 class="c-article__sub-heading" id="Sec11">Factors contributing to anaemia at presentation</h3><p>Factors associated with anaemia at presentation are presented in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab2">2</a>. In a univariate analysis, an age ≤ 15 months, duration of illness >2 days, and enrolment asexual parasitaemia ≤10,000 μL<sup>−1</sup> were associated with anaemia at presentation. In a multivariate analysis, duration of illness >2 days and an enrolment asexual parasitaemia ≤10,000 μL<sup>−1</sup> were independent predictors of anaemia at presentation (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab2">2</a>).</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 Predictors of anaemia at presentation in children <5 years with uncomplicated falciparum malaria</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="/articles/10.1186/s12879-017-2876-9/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="Sec12">Recovery from pre-treatment anaemia</h3><p>Data for the evaluation of recovery from pre-treatment anaemia were available in 318 of 355 children. Of these children, 142, 101, 58, 26, 8 and 3 children recovered from their anaemia within 1, 2, 3, 4, 5 and 6 weeks post-treatment initiation, respectively. Overall, mean anaemia recovery time was 11.5 days (95% CI 10.5–12.5, <i>n</i> = 308). Mean anaemia recovery time was significantly longer in DHP-treated children compared with AL- and AA-treated children [13.3 days (95% CI 11.5–15.2, <i>n</i> = 95) versus 11.7 days (95% CI 9.9–13.6, <i>n</i> = 108) versus 9.5 days (95% CI 8–11, <i>n</i> = 105) respectively, <i>P</i> = 0.01]. Ten children did not recover from their pre-treatment anaemia during the entire follow-up period.</p><h3 class="c-article__sub-heading" id="Sec13">Factors contributing to progression from normal haematocrit pre-treatment to anaemia within 1 week post –treatment initiation (early-appearing anaemia)</h3><p>Data for evaluation progression from normal haematocrit pre-treatment to an early-appearing anaemia (EAA) within 1 week post-treatment initiation were available in 604 children. Of these children, 301 children (50%) progressed to anaemia within 1 week post-treatment initiation. The proportions of non-anaemic children who subsequently progressed to anaemia within 1 week of starting treatment were similar with all three treatments (101 of 191 (53%) versus 90 of 187 (48%) versus 110 of 226 children (49%) in AL, AA and DHP treatments, respectively <i>P</i> = 0.59). The probabilities of progression to anaemia 1 week post-treatment initiation were also similar in all three treatments (Log-rank statistic = 1.24; <i>P</i> = 0.54, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig2">2</a>). Factors contributing to progression to anaemia within 1 week are shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab3">3</a>. In a univariate analysis, an age ≤ 15 months, history of fever at presentation, enrolment haematocrit ≤35% and persistent asexual parasitaemia till 1 or 2 days post-treatment initiation were significantly associated with progression to anaemia within 1 week post-initiation of treatment. In a multivariate analysis, an age ≤ 15 months, history of fever at presentation and enrolment haematocrit ≤35% were independent predictors of progression to anaemia within 1 week (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab3">3</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="/articles/10.1186/s12879-017-2876-9/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig2_HTML.gif?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_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>Kaplan-Meier survival estimates of anaemia occurring within 1 week following treatment with artesunate-amodiaquine (AA, blue line), artemether-lumefantrine (AL, green line) or dihydroartemisinin-piperaquine (DHP, yellow line) in children who were non-anaemic pre-treatment. Log-rank statistic = 1.24, <i>P</i> = 0.54. Pooled data from all sentinel sites. The probabilities of progression to anaemia within 1 week post-treatment were similar with all three 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="/articles/10.1186/s12879-017-2876-9/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> <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 Predictors of progression from normal haematocrit pre-treatment to anaemia within one week post-initiation of artemisinin-based combination treatments in <5 year-old children with uncomplicated falciparum malaria</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="/articles/10.1186/s12879-017-2876-9/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="Sec14">Recovery from early-appearing anaemia</h3><p>Data for evaluation of recovery from EAA were available in 275 of 301 children. Of these children, 166, 71, 19, 9, 3 and 2 children recovered at 1, 2, 3, 4, 5 and 6 weeks post-treatment initiation, respectively. Overall, mean anaemia recovery time was 8.4 days (95% CI 7.4–9.3, <i>n</i> = 270). Anaemia recovery times were similar with all three treatments [8.6 days (95% CI 6.8–10.4, <i>n</i> = 91) versus 7.3 days (95% CI 6–8.5, <i>n</i> = 80) versus 9.5 days (95% CI 8–11, <i>n</i> = 99) in AL-, AA- and DHP-treated children, respectively <i>P</i> = 0.14]. Five children did not recover from their anaemia during the entire follow-up period. Anaemia recovery time in children who progressed to EAA was significantly shorter than anaemia recovery time of children who were anaemic at presentation [8.4 days (95% CI 7.4–9.3, <i>n</i> = 270) versus 11.5 days (95% CI 10.5–12.5, <i>n</i> = 308), respectively <i>P</i> < 0.0001].</p><h3 class="c-article__sub-heading" id="Sec15">Time-course of haematocrit following artemisinin-based combination treatments</h3><p>Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig3">3a</a> shows the time-course of haematocrit in children who were non-anaemic at presentation and those who were anaemic at presentation following ACTs. Following treatment, there was little or no fall in haematocrit in anaemic children compared to non-anaemic children indicating little or no drug-attributable falls in the former. Additionally, the rate of rise in haematocrit was rather ‘steep’ in anaemic children following treatment. Following initiation of treatment, overall, mean time to nadir hematocrit was reached 2.2 days (95% CI 2.1–2.4, <i>n</i> = 719) after initiation of treatment and it was significantly shorter in anaemic compared to non-anaemic children at presentation [1.4 days (95% CI 1.3–1.7, <i>n</i> = 213) versus 2.6 days (95% CI 2.5–2.8, <i>n</i> = 506) in anaemic and non-anaemic children, respectively, <i>P</i> < 0.0001]. Compared with pre-treatment haematocrit, falls in haematocrit to nadir levels were significantly lower in anaemic compared to non-anaemic children [3.4% (95% CI 3.1–3.8 <i>n</i> = 213) versus 5.6% (95% CI 5.3–6, <i>n</i> = 506, respectively, <i>P</i> < 0.0001]. When falls to nadir haematocrits were expressed as percentages of pre-treatment haematocrit levels, falls were significantly higher in non-anaemic compared to anaemic children [16.3% (95% CI 15.5–17.2, <i>n</i> = 506) versus 13.1% (95% CI 11.9–14.4, <i>n</i> = 213), respectively <i>P</i> < 0.0001]. The time-course of haematocrit were similar with all three treatments (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig3">3b</a>). Mean time to nadir haematocrit was also similar with all three treatments [2.1 days (95% CI16.8–2.3, <i>n</i> = 234) versus 2.2 days (95% CI 2–2.4, <i>n</i> = 234) versus 2.4 days (95% CI 2.1–2.6, <i>n</i> = 251) in AL-, AA- and DHP-treated children, respectively <i>P</i> = 0.24]. Similarly, when falls to nadir haematocrits were expressed as percentages of pre-treatment haematocrit levels, falls were not significantly different between all three treatments [15.3% (95% CI 14.1–16.6, <i>n</i> = 234) versus 14.8% (95% CI 13.6–16.1, <i>n</i> = 234) versus 16% (95% CI 14.7–17.2, <i>n</i> = 251) in AL-, AA- and DHP-treated children, respectively <i>P</i> = 0.44].</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="/articles/10.1186/s12879-017-2876-9/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig3_HTML.gif?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_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>Time-course of haematocrit in (<b>a</b>) all (black line), anaemic (green line) and non-anaemic (blue line) children following artemisinin-based combination treatments, and (<b>b</b>) in children treated with artemether-lumefantrine (red line), artesunate-amodiaquine (green line) or dihydroartemisinin-piperaquine (blue line). Values represent means of haematocrit and standard error of means. Note little or no fall in haematocrit in anaemic children following treatment</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="/articles/10.1186/s12879-017-2876-9/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> <h3 class="c-article__sub-heading" id="Sec16">Malaria-attributable fall in haematocrit</h3><p>Data for estimation of MAFH were available in 748 children (428 and 320 non-anemic and anaemic children, respectively). In these children, there was no malaria-attributable fall in haematocrit following infection in 54 children (49 and 5 non-anaemic and anaemic children, respectively). The proportion of children with no MAFH following treatment was significantly higher in non-anaemic children compared with anaemic children at presentation (<i>P</i> < 0.0001). Varying degrees of malaria-attributable falls in haematocrit were seen in 694 children (379 and 315 in non-anaemic and anaemic children, respectively). Overall, mean MAFH was 6.8% (95% CI 6.5–7.2, <i>n</i> = 694) and it was significantly lower in non-anemic compared to anaemic children [4.6% (95% CI 4.3–4.9, <i>n</i> = 379) versus 9.5% (95% CI 9–10, <i>n</i> = 315), respectively <i>P</i> < 0.0001)].</p><p>MAFH in excess of 4% occurred in 446 of 694 children (64.3%). The proportion of non-anaemic children with MAFH in excess of 4% was significantly lower compared to anaemic children (170 of 379 children (44.9%) versus 276 of 315 children (87.6%), respectively; <i>P</i> < 0.0001) indicating a greater burden of a single episode of infection was borne by anaemic compared to non-anaemic children. Mean MAFH in non-anaemic children were similar for all three treatments [4.8% (95% CI 4.3–5.3, <i>n</i> = 117) versus 4.8% (95% CI 4.3–5.3, <i>n</i> = 127) versus 4.8% (95% CI 4.3–5.3, <i>n</i> = 135) in AL, AA and DHP- treated children, respectively, <i>P</i> = 0.33]. Similarly, mean MAFH in anaemic children were similar for all three treatments [9.4% (95% CI 8.6–10.2, <i>n</i> = 112) versus 9.8% (95% CI 8.9–10.6, <i>n</i> = 107) versus 9.3% (95% CI 8.3–10.3, <i>n</i> = 96) in AL, AA and DHP -treated children, respectively, <i>P</i> = 0.75]. The proportions of children with MAFH in excess of 4% were also similar for all three treatments in non-anaemic [56 of 117 versus 58 of 127 versus 56 of 135 children in AL. AA and DHP -treated children, respectively, <i>P</i> = 0.58] and anaemic children [98 of 112 versus 97 of 107 versus 81 of 96 children in AL-, AA- and DHP-treated children, respectively, <i>P</i> = 0.4].</p><p>Factors associated with MAFH in excess of 4% are shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab4">4</a>. In a univariate analysis, an age ≤ 38 months, anaemia at presentation, enrolment parasitaemia ≤50,000 μL<sup>−1</sup>, parasitaemia 1 day after start of treatment and gametocytaemia within 1 week were associated with MAFH >4%. In a multivariate analysis, anaemia at presentation, enrolment parasitaemia ≤50,000 μL<sup>−1</sup>, parasitaemia 1 day after start of treatments and gametocytaemia within 1 week were independent predictors of MAFH >4% (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab4">4</a>).</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 Predictors of malaria-attributable fall in haematocrit (MAFH) in excess of 4% in <5 year-old children with uncomplicated falciparum malaria 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="/articles/10.1186/s12879-017-2876-9/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> <h3 class="c-article__sub-heading" id="Sec17">Drug-attributable falls in haematocrit</h3><p>Data for estimation of DAFH were available in 929 children (588 and 341 non-anaemic and anaemic children at presentation, respectively). In these children, there was no DAFH following treatment in 210 children (82 and 128 non-anaemic and anaemic children, respectively). The proportions of children without DAFH were significantly higher in anaemic compared to non-anaemic children (<i>P</i> < 0.0001, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig4">4</a>). Varying degrees of DAFH occurred in 719 children (506 and 213 non-anaemic and anaemic children, respectively; Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig4">4</a>). Overall, lowest falls from pre-treatment levels were seen on day 1, 2 or 3 in 232, 217 or 158 children, respectively. Overall, mean DAFH was 5% (95% CI 4.7–5.2, <i>n</i> = 719) and it was significantly higher in non-anaemic compared to anaemic children [5.6% (95% CI 5.3–5.9, <i>n</i> = 506) versus 3.4% (95% CI 3.1–3.8, <i>n</i> = 213), <i>P</i> < 0.0001; Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig4">4</a>) [see also time-course of changes in haematocrit following treatments above]. DAFH in excess of 4% occurred in 385 of 719 children (53.5%) [279 of 506 (55.1%) and 55 of 213 (25.8%) in non-anaemic and anaemic children, respectively]. The proportion of non-anaemic children with DAFH in excess of 4% was significantly higher than in anaemic children (<i>P</i> < 0.0001) indicating relative lack of conservation in non-anaemic children and relative conservation in anaemic children.</p><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="/articles/10.1186/s12879-017-2876-9/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig4_HTML.gif?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_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>Drug-attributable falls in haematocrit in anaemic <b>(a)</b> and non-anaemic children <b>(b)</b> 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="/articles/10.1186/s12879-017-2876-9/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> <p>DAFH in non-anaemic children were similar for all three treatments [5.7% (95% CI 5.1–6.2, <i>n</i> = 167) versus 5.5% (95% CI 4.9–6.1, <i>n</i> = 155) versus 5.6% (95% CI 5.1–6.2, <i>n</i> = 184) in AL-, AA- and DHP-treated children, respectively, <i>P</i> = 0.93]. Similarly, mean DAFH in anaemic children were similar for all three treatments [3.2% (95% CI 2.7–3.7, <i>n</i> = 67) versus 3.2% (95% CI 2.7–3.8, <i>n</i> = 79) versus 3.9% (95% CI 3.2–4.5, <i>n</i> = 67) in AL-, AA- and-treated children, respectively, <i>P</i> = 0.2]. The proportions of children with DAFH in excess of 4% were also similar for all three treatments in non-anaemic [97 of 167 (58%) versus 82 of 155 (53%) versus 100 of 184 children (54%) in AL-, AA- and DHP-treated children, respectively <i>P</i> = 0.62] and in anaemic children [16 of 67 (24%) versus 19 of 79 (24%) versus 20 of 67 children (30%) in AL-, AA- and DHP-treated children, respectively <i>P</i> = 0.66].</p><p>Factors associated with DAFH in excess of 4% are shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab5">5</a>. In a univariate analysis, enrolment body temperature ≥ 38°C, history of fever at presentation, fever 1 day post-treatment initiation, enrolment haematocrit ≥37%, enrolment parasitaemia >100,000 μL<sup>−1</sup>, no gametocytaemia at presentation and within one week post-treatment initiation were significantly associated with DAFH >4%. In a multivariate analysis, history of fever at presentation, fever 1 day post-treatment initiation, enrolment haematocrit ≥37%, and enrolment parasitaemia >100,000 μL<sup>−1</sup> were independent predictors of DAFH >4% (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#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 Predictors of drug-attributable falls in haematocrit (DAFH) in excess of 4% in <5 year-old children with uncomplicated falciparum malaria 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="/articles/10.1186/s12879-017-2876-9/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> <p>Of the non-anaemic children who subsequently became anaemic 1 week after start of treatment [EAA], 245 of 298 children (82%) had DAFH >4%. At a DAFH of 4%, 84 of 301 non-anaemic children at presentation (28%) progressed to anaemia within 1 week. At a DAFH of 10%, 121 of 301 non-anaemic children at presentation (40%) progressed to anaemia within 1 week.</p><h3 class="c-article__sub-heading" id="Sec18">Kinetics of the disposition of drug-attributable falls in haematocrit</h3><p>The demographic and other characteristics of the 432 children enrolled in kinetics of the disposition of DAFH study (<i>n</i> = 148 for AL, <i>n</i> = 138 for AA and <i>n</i> = 146 for DHP) are shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab6">6</a>. Overall, there was a monoexponential decline of the deficits in DAFH with an estimated mean half-time (t<sub>½el</sub>) of 2.2 days (95% CI 1.9–2.6) (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig5">5a</a>). Estimated t<sub>½el</sub> was significantly higher in children treated with DHP compared to AA and AL [2.8 days (95% CI 2.1–3.5, <i>n</i> = 146) versus 1.6 days (95% CI 1.3–2, <i>n</i> = 138) versus 2.2 days (95% CI 1.7–2.8, <i>n</i> = 148), respectively <i>P</i> = 0.01] but it was similar between AA and AL (<i>P</i> = 0.27). Estimated t<sub>½el</sub> was also significantly higher in children who were non-anaemic compared to anaemic children at presentation [2.7 days (95% CI 2.2–3.1, <i>n</i> = 318) versus 1.1 days (95% CI 0.9–1.2, <i>n</i> = 114) <i>P</i> < 0.0001] (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig5">5b</a>).</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 Demographic and clinical characteristics of <5 years old children with uncomplicated falciparum malaria enrolled in study of the kinetics of the disposition of drug-attributable falls in haematocrit 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="/articles/10.1186/s12879-017-2876-9/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> <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="/articles/10.1186/s12879-017-2876-9/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig5_HTML.gif?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_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>Semilog plots of deficit in haematocrit from baseline versus time (<b>a</b>) in all children (black line), anaemic (green line) and non-anaemic children (blue line) and (<b>b</b>) in children treated with artemether lumefantrine (red line), artesunate-amodiaquine (green line) or dihydroartemisinin-piperaquine (blue line)</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="/articles/10.1186/s12879-017-2876-9/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> <p>Overall, estimated mean estimated AUC<sub>(DAFH)</sub> was 56.3%.day (95% CI 48.5–64.2). Estimated mean AUC<sub>DAFH</sub> was significantly higher in children treated with DHP compared to AA and AL [67%.day (95% CI 57.4–82.6, <i>n</i> = 146) versus 41.7%.day (95% CI 32.5–50.8, <i>n</i> = 138) versus 59.5%.day (95% CI 44.7–74.3, <i>n</i> = 148), respectively <i>P</i> = 0.03] but it was similar between AA and AL (<i>P</i> = 0.16). Estimated mean AUC<sub>DAFH</sub> was also significantly higher in children who were non-anaemic compared to anaemic children at presentation [66.1%.day (95% CI 57–75.2, <i>n</i> = 317) versus 29.3%.day (95% CI 14.5–44.1, <i>n</i> = 114) <i>P</i> < 0.0001].</p><h3 class="c-article__sub-heading" id="Sec19">Relationship between area under curve of the plot of deficit in drug-attributable falls in haematocrit and value of drug-attributable falls in haematocrit</h3><p>The relationship between AUC<sub>(DAFH)</sub> and the value of DAFH was evaluated in 432 children. The mean of the ratio of AUC<sub>(DAFH)</sub>: value of DAFH was 8.8 (95% CI 7.4–10.3). There was a significantly positive correlation between AUC<sub>(DAFH)</sub> and value of DAFH (<i>r</i> = 0.47, <i>P</i> < 0.0001). Bland-Altman plots of AUC<sub>(DAFH)</sub> and multiples of values of DAFH are shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig6">6</a>. The limits of agreement between AUC<sub>(DAFH)</sub> and 9 or 10 multiples of value of DAFH were narrow. At 9 and 10 multiples of value of DAFH, the limits of agreement were −142.1 – 148.6% and −147.4 – 142.1%, respectively. The bias at multiples of 9 or 10 value of DAFH was statistically insignificant (<i>P</i> = 0.36 and 0.46, respectively) indicating that AUC<sub>(DAFH)</sub> and 9 or 10 multiples of value of DAFH can be used interchangeably in the same patient. However, there was a statistically significant bias at 8 multiples of value of DAFH (<i>P</i> = 0.01).</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="/articles/10.1186/s12879-017-2876-9/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_Fig6_HTML.gif?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12879-017-2876-9/MediaObjects/12879_2017_2876_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>Bland-Altman plots of area under curve of drug-attributable fall in haematocrit (AUC<sub>(DAFH)</sub>) and multiples [8 (<b>a</b>), 9 (<b>b</b>) and 10 (<b>c</b>)] of values of drug-attributable falls in haematocrit. Biases were 9.18, 3.27 and −2.63 for plots A, B and C; <i>P</i> = 0.01, 0.36 and 0.46, respectively. The mean values ±1.96 standard deviation (SD) of the differences are shown</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="/articles/10.1186/s12879-017-2876-9/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> </div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec20-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec20">Discussion</h2><div class="c-article-section__content" id="Sec20-content"><p>In this study, we evaluated prospectively in young malarious children, the factors contributing to: anaemia at presentation, anaemia one week after starting treatment in children who were not anaemic at presentation, the burden of anaemia imposed by a single episode of malaria, the falls and the duration of falls in haematocrit attributable to three ACTs. Our results showed: anaemia is common at presentation and in the one week following initiation of treatment; the burden of anaemia after a single episode of infection is high; and drug related falls in haematocrit are significantly more common and more severe in children who were not anaemic at presentation compared with those who were anaemic at presentation.</p><p>Compared with factors contributing to anaemia during the early period of adoption of ACTs as first-line antimalarials in the study areas [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Sowunmi A, Gbotosho GO, Happi CT, Fateye B. Factors contributing to anaemia after uncomplicated Plasmodium falciparum malaria in children. Acta Trop. 2010;113:155–61." href="/articles/10.1186/s12879-017-2876-9#ref-CR8" id="ref-link-section-d85324754e8469">8</a>], the factors contributing to anaemia ten years after adoption as first-line treatments appeared to have been considerably modified as shown in the results of the present study. The significant modifications include: reduction in age band susceptible to malarial anaemia at presentation from children 6–59 months to children 6–15 months and relatively low gametocyte carriage at presentation or following treatment. However, the prevalence of anaemia at presentation and the burden of anaemia following a single episode of infection appeared to have been little affected. The low gametocyte carriage ten years following adoption as first-line antimalarials can be attributable to rapid clearance of asexual parasitaemia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" 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="/articles/10.1186/s12879-017-2876-9#ref-CR17" id="ref-link-section-d85324754e8472">17</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Gbotosho GO, Sowunmi A, Okuboyejo TM, Happi CT, Folarin OO, Michael OS, Adewoye EO. Therapeutic efficacy and effects of artemether-lumefantrine and artesunate amodiaquine co-formulated or co-packaged on malaria-associated anemia in children with uncomplicated Plasmodium falciparum malaria in southwest Nigeria. Am J Trop Med Hyg. 2011;84:813–9." href="/articles/10.1186/s12879-017-2876-9#ref-CR23" id="ref-link-section-d85324754e8475">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Sowunmi A, Akano K, Ayede AI, Adewoye EO, Ntadom G, Fatunmbi B, Gbotosho GO, Folarin OA, Happi CT. Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria. BMC Infect Dis. 2017;17:110." href="/articles/10.1186/s12879-017-2876-9#ref-CR30" id="ref-link-section-d85324754e8478">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Sowunmi A, Akano K, Ntadom G, Ayede AI, Ibironke FO, Aderoyeje T, Adewoye EO, Fatunmbi B, Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Folarin OA, Gbotosho GO, Happi CT. Therapeutic efficacy and effects of artemisinin-based combination treatments on uncomplicated Plasmodium falciparum malaria-associated anaemia in Nigerian children during seven years of adoption as first-line treatments. Infectious Diseases of Poverty. 2017;6:36." href="/articles/10.1186/s12879-017-2876-9#ref-CR31" id="ref-link-section-d85324754e8481">31</a>] and alteration in gametocyte sex ratios [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" 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. Antimicrob Agents Chemother. 2007;51:1694–9." href="/articles/10.1186/s12879-017-2876-9#ref-CR32" id="ref-link-section-d85324754e8485">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" 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 Chemotherapy Control and Elimination. 2012;1 doi:
 10.4303/mcce/235498
 
 ." href="/articles/10.1186/s12879-017-2876-9#ref-CR33" id="ref-link-section-d85324754e8488">33</a>] which can produce a female bias sex ratio that is less infective to mosquitoes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" 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="/articles/10.1186/s12879-017-2876-9#ref-CR34" id="ref-link-section-d85324754e8491">34</a>]. It has also been postulated that ACTs can mobilize immature gametocytes from bone marrow to peripheral blood where they can be rapidly eliminated by components of ACTs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Sowunmi A, Akano K, Ayede AI, Adewoye EO, Ntadom G, Fatunmbi B, Gbotosho GO, Folarin OA, Happi CT. Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria. BMC Infect Dis. 2017;17:110." href="/articles/10.1186/s12879-017-2876-9#ref-CR30" id="ref-link-section-d85324754e8494">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" 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 Chemotherapy Control and Elimination. 2012;1 doi:
 10.4303/mcce/235498
 
 ." href="/articles/10.1186/s12879-017-2876-9#ref-CR33" id="ref-link-section-d85324754e8497">33</a>]. The latter can also prevent development of immature gametocytes which are non-infective to mosquitoes to mature gametocyte which are infective to mosquitoes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Sowunmi A, Akano K, Ayede AI, Adewoye EO, Ntadom G, Fatunmbi B, Gbotosho GO, Folarin OA, Happi CT. Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria. BMC Infect Dis. 2017;17:110." href="/articles/10.1186/s12879-017-2876-9#ref-CR30" id="ref-link-section-d85324754e8500">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" 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 Chemotherapy Control and Elimination. 2012;1 doi:
 10.4303/mcce/235498
 
 ." href="/articles/10.1186/s12879-017-2876-9#ref-CR33" id="ref-link-section-d85324754e8504">33</a>]. This is particularly important because all components of ACTs can kill immature gametocytes. It is not apparent from the results of the present study why a low asexual parasitaemia is a predictor of anaemia at presentation. This finding is paradoxical.</p><p>Progression to anaemia within one week of treatment initiation in a half of the children who were not anaemic at presentation can be clearly attributable to relatively high DAFH values with all three treatments. These children differ significantly from anaemic children at presentation in whom DAFH values were relatively low and who did not have a worsening of their anaemia in the one week following treatment initiation (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig5">5</a>). This finding in anaemic children suggests considerable degree of “haematocrit conservation” [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Sowunmi A, Akano K, Ntadom G, Ayede AI, Ibironke FO, Aderoyeje T, Adewoye EO, Fatunmbi B, Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Folarin OA, Gbotosho GO, Happi CT. Therapeutic efficacy and effects of artemisinin-based combination treatments on uncomplicated Plasmodium falciparum malaria-associated anaemia in Nigerian children during seven years of adoption as first-line treatments. Infectious Diseases of Poverty. 2017;6:36." href="/articles/10.1186/s12879-017-2876-9#ref-CR31" id="ref-link-section-d85324754e8513">31</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Sowunmi A, Akano K, Ntadom G, Ayede A, Oguche S, Agomo C, Okafor H, Watila I, Meremikwu M, Ogala W, Agomo P, Adewoye E, Fatunmbi B, Aderoyeje T, Happi C, Gbotosho G, Folarin O. Anaemia following artemisinin-based combination treatments of uncomplicated Plasmodium falciparum malaria in children: temporal patterns of haematocrit and the use of uncomplicated hyperparasitaemia as a model for evaluating late-appearing anaemia. Chemotherapy. 2017;62:231–8." href="/articles/10.1186/s12879-017-2876-9#ref-CR35" id="ref-link-section-d85324754e8516">35</a>]. Taking together, this would suggest the three ACTs may prevent further falls in haematocrit in anaemic children at presentation and in half of non-anaemic children at presentation.</p><p>The burden of anaemia imposed by a single episode of infection was relatively high and it occurred in two-third of the young malarious children. In these children, repeated attacks of acute infections within a short time frame can be expected to lead to development of anaemia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" 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="/articles/10.1186/s12879-017-2876-9#ref-CR16" id="ref-link-section-d85324754e8522">16</a>]. Expectedly, anaemia and gametocytaemia at presentation predicted MAFH >4%. Indeed the risk of MAFH >4% was approximately nine and a half fold higher in anaemic compared to non-anaemic children at presentation (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab4">4</a>). Taking together with factors predicting anaemia at presentation, it would appear that by reducing the age band susceptible to malaria at presentation from 6 to 59 months to 6–15 months, ACTs have, during the ten years of adoption as first-line treatments, not reduced the burden of anaemia imposed by a single episode of an apparently uncomplicated infection. We have no ready explanation for a presenting parasitaemia ≤50,000 μL<sup>−1</sup> being a predictor of MAFH in excess of 4%.</p><p>The early-appearing anaemia in 50% of non-anaemic children was clearly attributable to DAFH in excess of 4% (see above, paragraph 3). Therefore, all of the predictors of DAFH in excess of 4% were not unexpected (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/s12879-017-2876-9#Tab5">5</a>). However, there is no ready explanation from the results presented for temperature in excess of 37.9°C being a predictor of DAFH in excess of 4%. In this context, there is need to justify the use of DAFH >4% as cut off for predictors of DAFH. Firstly, this cut off has been used in a previous study [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" 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="/articles/10.1186/s12879-017-2876-9#ref-CR16" id="ref-link-section-d85324754e8537">16</a>]. Second, a ≥ 5% (5 units) fall in haematocrit from baseline is unlikely to be a random effect and likely to represent a significant fall from baseline in a manner similar to using 95% confidence interval in a two-way analysis of variance [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Sowunmi A, Akano K, Ayede AI, Adewoye EO, Ntadom G, Fatunmbi B, Gbotosho GO, Folarin OA, Happi CT. Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria. BMC Infect Dis. 2017;17:110." href="/articles/10.1186/s12879-017-2876-9#ref-CR30" id="ref-link-section-d85324754e8540">30</a>].</p><p>An important question arising from the present study is whether there are differences in the recovery from anaemia attributable to infections (pre-treatment anaemia) and the anaemia which follows treatment of the infections in patients who were not previously anaemic at presentation (early-appearing anaemia). Overall, it would appear there are significant differences as evidenced by the significantly longer anaemia recovery time in children with anaemia primarily due to the infections compared to the anaemia following treatment of the infections. Additionally, pre-treatment anaemia is primarily due to interaction(s) between host and the parasites while the anaemia following treatment is due to interaction(s) between host, parasite and the drug. A striking feature of all non-anaemic children pre-treatment who progressed to early-appearing anaemia were: most had pre-treatment haematocrit close to the lower threshold of normal and the critical falls in haematocrit at which all progressed to anemia was a drug-attributable fall in excess of 10% (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/s12879-017-2876-9#Fig4">4</a>). Perhaps determining threshold for progression of all those developing early appearing anaemia should form routine part of the clinical evaluation of drug-attributable falls in haematocrit following different drug regimens. The pre-treatment haematocrit threshold in the cohort of children with normal haematocrit at presentation appears to be a haematocrit of 40%.</p><p>The ratio of the estimated AUC<sub>(DAFH)</sub> to value of DAFH was approximately nine folds. This ratio represents the relationship of a pharmacokinetic estimate to a pharmacodynamic estimate - two methods of measuring DAFH in the same patients employed in the present study. An intriguing feature of the ratio is: it is somewhat similar to the number of half-times required for >99.9% completion of a pharmacokinetic process in a rudimentary one-compartment pharmacokinetic model. A somewhat more intriguing finding is their insignificant agreement when 9 or 10 multiples of value of DAFH and AUC<sub>(DAFH)</sub> were subjected to Bland-Altman analyses. The analyses indicate both measurements can be used interchangeably in the same patients despite the difference in their units of measurement. The difference in units of measurement would suggest some further application of Bland-Altman analysis when applied to establishing agreement between pharmacokinetic and pharmacodynamic processes in clinical drug studies.</p><p>The main limitation of the present study is not quantifying once-infected red blood cells. Quantification of once-infected red blood cells would have enabled the study to distinguish between non-anaemic children at presentation who progressed to early-appearing anaemia from those who did not. Another limitation is that the study did not evaluate the contribution of the background causes of anaemia, to the factors contributing to anaemia pre- and post-treatment initiation.</p></div></div></section><section data-title="Conclusions"><div class="c-article-section" id="Sec21-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec21">Conclusions</h2><div class="c-article-section__content" id="Sec21-content"><p>In conclusion, after ten years of adopting of ACTs as first-line antimalarials in Nigeria, anaemia is common pre-and early post-treatment, anaemia burden of a single infection is relatively high, and drug-attributable falls in haematocrit >4% is common and significantly lower in anaemic compared to non-anaemic malarious children.</p></div></div></section> <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> <sup>o</sup>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>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>AUC<sub>(DAFH)</sub> :</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Area under curve of drug-attributable falls in haematocrit versus time</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>CI:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Confidence interval</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>d:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Day</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>DAFH:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Drug-attributable falls in haematocrit</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>EAA:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Early-appearing anaemia</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>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>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>MAFH:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Malaria-attributable 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>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>t<sub>1/2</sub> :</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Half-time</p> </dd><dt class="c-abbreviation_list__term u-text-bold u-float-left u-pr-16" style="min-width:50px;"><dfn>TMAFH:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Total malaria-attributable 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>μL:</dfn></dt><dd class="c-abbreviation_list__description u-mb-24"> <p>Microliter</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">Bosman A, Mendis KNA. Major transition in malaria treatment: the adoption and deployment of artemisinin-based combination therapies. Am J Trop Med Hyg. 2007;66(Suppl 6):193–7.</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 1" href="http://scholar.google.com/scholar_lookup?&title=Major%20transition%20in%20malaria%20treatment%3A%20the%20adoption%20and%20deployment%20of%20artemisinin-based%20combination%20therapies&journal=Am%20J%20Trop%20Med%20Hyg&volume=66&issue=Suppl%206&pages=193-197&publication_year=2007&author=Bosman%2CA&author=Mendis%2CKNA"> 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">World Health Organization. World malaria report 2015. Geneva: WHO; 2015. <a href="http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/">http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/</a> </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 2" href="http://scholar.google.com/scholar_lookup?&title=World%20malaria%20report%202015&publication_year=2015"> 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">World Health Organization. Antimalarial Drug Combination Therapy. Report of a WHO Technical Consultation. Geneva: World Health Organization. 2001. WHO/CDS/RBM/2001.35.</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">Carrara VI, Zwang J, Ashley EA, Price RN, Stepniewka K, Marion B, Brockman A, Anderson T, McGready R, Phaiphun L, Stephane P, van Vugt M, Hutagalung R, Lwin KM, Phyo AP, Piyanuch P, Imwong M, Pukrittayakamee S, Singhasivanon P, White NJ, Nosten F. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS One. 2009;4:e4551.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1371/journal.pone.0004551" data-track-item_id="10.1371/journal.pone.0004551" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1371%2Fjournal.pone.0004551" aria-label="Article reference 4" data-doi="10.1371/journal.pone.0004551">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=19234601" aria-label="PubMed reference 4">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/PMC2641001" aria-label="PubMed Central reference 4">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 4" href="http://scholar.google.com/scholar_lookup?&title=Changes%20in%20the%20treatment%20responses%20to%20artesunate-mefloquine%20on%20the%20northwestern%20border%20of%20Thailand%20during%2013%20years%20of%20continuous%20deployment&journal=PLoS%20One&doi=10.1371%2Fjournal.pone.0004551&volume=4&publication_year=2009&author=Carrara%2CVI&author=Zwang%2CJ&author=Ashley%2CEA&author=Price%2CRN&author=Stepniewka%2CK&author=Marion%2CB&author=Brockman%2CA&author=Anderson%2CT&author=McGready%2CR&author=Phaiphun%2CL&author=Stephane%2CP&author=van%20Vugt%2CM&author=Hutagalung%2CR&author=Lwin%2CKM&author=Phyo%2CAP&author=Piyanuch%2CP&author=Imwong%2CM&author=Pukrittayakamee%2CS&author=Singhasivanon%2CP&author=White%2CNJ&author=Nosten%2CF"> 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">Phyo AP, Ashley EA, Anderson TJC, Bozdech Z, Carrara VI, Sriprawat K, Nair S, White MM, Dziekan J, Ling C, Proux S, Konghahong K, Jeeyapant A, Woodrow CJ, Imwong M, McGready R, Lwin KM, Day NPJ, White NJ, Nosten F. Declining efficacy of artemisinin combination therapy against <i>P. falciparum</i> malaria on the Thai-Myanmar border (2003-2013): the role of parasite genetic factors. Clin Infect Dis. 2016;63:784–91.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/cid/ciw388" data-track-item_id="10.1093/cid/ciw388" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fcid%2Fciw388" aria-label="Article reference 5" data-doi="10.1093/cid/ciw388">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=27313266" aria-label="PubMed reference 5">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/PMC4996140" aria-label="PubMed Central reference 5">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 5" href="http://scholar.google.com/scholar_lookup?&title=Declining%20efficacy%20of%20artemisinin%20combination%20therapy%20against%20P.%20falciparum%20malaria%20on%20the%20Thai-Myanmar%20border%20%282003-2013%29%3A%20the%20role%20of%20parasite%20genetic%20factors&journal=Clin%20Infect%20Dis&doi=10.1093%2Fcid%2Fciw388&volume=63&pages=784-791&publication_year=2016&author=Phyo%2CAP&author=Ashley%2CEA&author=Anderson%2CTJC&author=Bozdech%2CZ&author=Carrara%2CVI&author=Sriprawat%2CK&author=Nair%2CS&author=White%2CMM&author=Dziekan%2CJ&author=Ling%2CC&author=Proux%2CS&author=Konghahong%2CK&author=Jeeyapant%2CA&author=Woodrow%2CCJ&author=Imwong%2CM&author=McGready%2CR&author=Lwin%2CKM&author=Day%2CNPJ&author=White%2CNJ&author=Nosten%2CF"> 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">Federal Ministry of Health. National Antimalaria Treatment Guideline. Abuja, Nigeria: Federal Ministry of Health; 2005.</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 6" href="http://scholar.google.com/scholar_lookup?&title=National%20Antimalaria%20Treatment%20Guideline&publication_year=2005"> 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">Nkuo-Akenji TK, Chi PC, Cho JF, Ndamukong KK, Sumbele I. Malaria and helminth co-infection in children living in a malaria endemic setting of Mount Cameroon and predictors of anemia. J Parasitol. 2006;92:1191–5.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1645/GE-895R.1" data-track-item_id="10.1645/GE-895R.1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1645%2FGE-895R.1" aria-label="Article reference 7" data-doi="10.1645/GE-895R.1">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=17304793" aria-label="PubMed reference 7">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 7" href="http://scholar.google.com/scholar_lookup?&title=Malaria%20and%20helminth%20co-infection%20in%20children%20living%20in%20a%20malaria%20endemic%20setting%20of%20Mount%20Cameroon%20and%20predictors%20of%20anemia&journal=J%20Parasitol&doi=10.1645%2FGE-895R.1&volume=92&pages=1191-1195&publication_year=2006&author=Nkuo-Akenji%2CTK&author=Chi%2CPC&author=Cho%2CJF&author=Ndamukong%2CKK&author=Sumbele%2CI"> 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">Sowunmi A, Gbotosho GO, Happi CT, Fateye B. Factors contributing to anaemia after uncomplicated <i>Plasmodium falciparum</i> malaria in children. Acta Trop. 2010;113:155–61.</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 8" data-doi="10.1016/j.actatropica.2009.10.011">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=19874795" aria-label="PubMed reference 8">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 8" 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=113&pages=155-161&publication_year=2010&author=Sowunmi%2CA&author=Gbotosho%2CGO&author=Happi%2CCT&author=Fateye%2CB"> 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">Sumbele IUN, Samje M, Nkuo-Akenji TA. Longitudinal study on anaemia in children with <i>Plasmodium falciparum</i> infection in the Mount Cameroon region: prevalence, risk factors and perceptions by caregivers. BioMed Central of Infectious Diseases. 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 9" data-doi="10.1186/1471-2334-13-123">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 9" href="http://scholar.google.com/scholar_lookup?&title=Longitudinal%20study%20on%20anaemia%20in%20children%20with%20Plasmodium%20falciparum%20infection%20in%20the%20Mount%20Cameroon%20region%3A%20prevalence%2C%20risk%20factors%20and%20perceptions%20by%20caregivers&journal=BioMed%20Central%20of%20Infectious%20Diseases&doi=10.1186%2F1471-2334-13-123&volume=13&publication_year=2013&author=Sumbele%2CIUN&author=Samje%2CM&author=Nkuo-Akenji%2CTA"> 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">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="10.4269/ajtmh.2001.65.614" data-track-item_id="10.4269/ajtmh.2001.65.614" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.4269%2Fajtmh.2001.65.614" aria-label="Article reference 10" data-doi="10.4269/ajtmh.2001.65.614">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%2BD3MnntVOmtQ%3D%3D" aria-label="CAS reference 10">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 10">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 10">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 10" href="http://scholar.google.com/scholar_lookup?&title=Factors%20contributing%20to%20anemia%20after%20uncomplicated%20falciparum%20malaria&journal=Am%20J%20Trop%20Med%20Hyg&doi=10.4269%2Fajtmh.2001.65.614&volume=65&pages=614-622&publication_year=2001&author=Price%2CRC&author=Simpson%2CJA&author=Nosten%2CF&author=Luxemberger%2CC&author=Hkirjaroen%2CL&author=ter%20Kuile%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="11."><p class="c-article-references__text" id="ref-CR11">Dondorp AM, Angus BJ, Chotivanich K, Silamut K, Ruangveerayuth R, Hardeman MR, Kager PA, Vreeken J, White NJ. Red blood cell deformability as a predictor of anemia in severe falciparum malaria. Am J Trop Med Hyg. 1999;60:733–7.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.4269/ajtmh.1999.60.733" data-track-item_id="10.4269/ajtmh.1999.60.733" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.4269%2Fajtmh.1999.60.733" aria-label="Article reference 11" data-doi="10.4269/ajtmh.1999.60.733">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:DyaK1M3nsVCnsg%3D%3D" aria-label="CAS reference 11">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=10344643" aria-label="PubMed reference 11">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 11" href="http://scholar.google.com/scholar_lookup?&title=Red%20blood%20cell%20deformability%20as%20a%20predictor%20of%20anemia%20in%20severe%20falciparum%20malaria&journal=Am%20J%20Trop%20Med%20Hyg&doi=10.4269%2Fajtmh.1999.60.733&volume=60&pages=733-737&publication_year=1999&author=Dondorp%2CAM&author=Angus%2CBJ&author=Chotivanich%2CK&author=Silamut%2CK&author=Ruangveerayuth%2CR&author=Hardeman%2CMR&author=Kager%2CPA&author=Vreeken%2CJ&author=White%2CNJ"> 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">Safeukui I, Correas JM, Brousse V, Hirt D, Deplaine G, Mulé S, Lesurtel M, Goasguen N, Sauvanet A, Couvelard A, Kerneis S, Khun H, Vigan-Womas I, Ottone C, Molina TJ, Tréluyer JM, Mercereau-Puijalon O, Milon G, David PH, Buffet PA. Retention of <i>Plasmodium falciparum</i> ring-infected erythrocytes in the slow, open microcirculation of the human spleen. Blood. 2008;112:2520–8.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1182/blood-2008-03-146779" data-track-item_id="10.1182/blood-2008-03-146779" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1182%2Fblood-2008-03-146779" aria-label="Article reference 12" data-doi="10.1182/blood-2008-03-146779">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%2BD1cXhtFCru73M" aria-label="CAS reference 12">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=18579796" aria-label="PubMed reference 12">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 12" href="http://scholar.google.com/scholar_lookup?&title=Retention%20of%20Plasmodium%20falciparum%20ring-infected%20erythrocytes%20in%20the%20slow%2C%20open%20microcirculation%20of%20the%20human%20spleen&journal=Blood&doi=10.1182%2Fblood-2008-03-146779&volume=112&pages=2520-2528&publication_year=2008&author=Safeukui%2CI&author=Correas%2CJM&author=Brousse%2CV&author=Hirt%2CD&author=Deplaine%2CG&author=Mul%C3%A9%2CS&author=Lesurtel%2CM&author=Goasguen%2CN&author=Sauvanet%2CA&author=Couvelard%2CA&author=Kerneis%2CS&author=Khun%2CH&author=Vigan-Womas%2CI&author=Ottone%2CC&author=Molina%2CTJ&author=Tr%C3%A9luyer%2CJM&author=Mercereau-Puijalon%2CO&author=Milon%2CG&author=David%2CPH&author=Buffet%2CPA"> 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">Buffet PA, Safeukui I, Deplaine G, Brousse V, Prendki V, Thellier M, Turner GD, Mercereau-Puijalon O. The pathogenesis of <i>Plasmodium falciparum</i> malaria in humans: insights from splenic physiology. Blood. 2011;117:381–92.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1182/blood-2010-04-202911" data-track-item_id="10.1182/blood-2010-04-202911" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1182%2Fblood-2010-04-202911" aria-label="Article reference 13" data-doi="10.1182/blood-2010-04-202911">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%2BC3MXht1aqsL0%3D" aria-label="CAS reference 13">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=20852127" aria-label="PubMed reference 13">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/PMC3031473" aria-label="PubMed Central reference 13">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 13" href="http://scholar.google.com/scholar_lookup?&title=The%20pathogenesis%20of%20Plasmodium%20falciparum%20malaria%20in%20humans%3A%20insights%20from%20splenic%20physiology&journal=Blood&doi=10.1182%2Fblood-2010-04-202911&volume=117&pages=381-392&publication_year=2011&author=Buffet%2CPA&author=Safeukui%2CI&author=Deplaine%2CG&author=Brousse%2CV&author=Prendki%2CV&author=Thellier%2CM&author=Turner%2CGD&author=Mercereau-Puijalon%2CO"> 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">Ouédraogo HZ, Zeba A, Dramaix-Wilmet M, Donnen P. Moderate to severe anaemia due to afebrile <i>Plasmodium falciparum</i> infections in children aged 6- 23 months from rural district of Kongoussi, Burkina Faso. J Trop Pediatr. 2008;54:395–400.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/tropej/fmn049" data-track-item_id="10.1093/tropej/fmn049" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Ftropej%2Ffmn049" aria-label="Article reference 14" data-doi="10.1093/tropej/fmn049">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=18599531" aria-label="PubMed reference 14">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 14" href="http://scholar.google.com/scholar_lookup?&title=Moderate%20to%20severe%20anaemia%20due%20to%20afebrile%20Plasmodium%20falciparum%20infections%20in%20children%20aged%206-%2023%20months%20from%20rural%20district%20of%20Kongoussi%2C%20Burkina%20Faso&journal=J%20Trop%20Pediatr&doi=10.1093%2Ftropej%2Ffmn049&volume=54&pages=395-400&publication_year=2008&author=Ou%C3%A9draogo%2CHZ&author=Zeba%2CA&author=Dramaix-Wilmet%2CM&author=Donnen%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">Njua-Yafi C, Achidi EA, Anchang-Kimbi JK, Apinjoh TO, Mugri RN, Chi HF, Tata RB, Njumkeng C, Nkock EN, Nkuo-Akenji T. Malaria, helminths, co-infection and anaemia in a cohort of children from Mutengene, south western Cameroon. Malar J. 2016;15:69.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12936-016-1111-2" data-track-item_id="10.1186/s12936-016-1111-2" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12936-016-1111-2" aria-label="Article reference 15" data-doi="10.1186/s12936-016-1111-2">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=26852392" aria-label="PubMed reference 15">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/PMC4744422" aria-label="PubMed Central reference 15">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 15" href="http://scholar.google.com/scholar_lookup?&title=Malaria%2C%20helminths%2C%20co-infection%20and%20anaemia%20in%20a%20cohort%20of%20children%20from%20Mutengene%2C%20south%20western%20Cameroon&journal=Malar%20J&doi=10.1186%2Fs12936-016-1111-2&volume=15&publication_year=2016&author=Njua-Yafi%2CC&author=Achidi%2CEA&author=Anchang-Kimbi%2CJK&author=Apinjoh%2CTO&author=Mugri%2CRN&author=Chi%2CHF&author=Tata%2CRB&author=Njumkeng%2CC&author=Nkock%2CEN&author=Nkuo-Akenji%2CT"> 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, 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 16" 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 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=18992209" 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=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="17."><p class="c-article-references__text" id="ref-CR17">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 17" 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 17">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 17">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 17">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 17" 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=925-935&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="18."><p class="c-article-references__text" id="ref-CR18">World Health Organization. Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 2000; 94 Supp1: 1–90.</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">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 19" 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="20."><p class="c-article-references__text" id="ref-CR20">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 20" 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 20">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 20">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 20" 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="21."><p class="c-article-references__text" id="ref-CR21">World Health Organization: Assessment and monitoring of antimalarial drug efficacy for the treatment of uncomplicated falciparum malaria. Geneva: world health Organization 2003.</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">Sowunmi A, Akano K, Ayede AI, Ntadom G, Adewoye EO, Fatunmbi B, Aderoyeje T. Therapeutic efficacy and effects of artesunate-amodiaquine and artemether-lumefantrine on malaria-associated anaemia in Nigerian children aged two years and under. Infectious Diseases of Poverty. 2016;5:70.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40249-016-0165-2" data-track-item_id="10.1186/s40249-016-0165-2" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40249-016-0165-2" aria-label="Article reference 22" data-doi="10.1186/s40249-016-0165-2">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=27384596" aria-label="PubMed reference 22">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/PMC4933999" aria-label="PubMed Central reference 22">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 22" href="http://scholar.google.com/scholar_lookup?&title=Therapeutic%20efficacy%20and%20effects%20of%20artesunate-amodiaquine%20and%20artemether-lumefantrine%20on%20malaria-associated%20anaemia%20in%20Nigerian%20children%20aged%20two%20years%20and%20under&journal=Infectious%20Diseases%20of%20Poverty&doi=10.1186%2Fs40249-016-0165-2&volume=5&publication_year=2016&author=Sowunmi%2CA&author=Akano%2CK&author=Ayede%2CAI&author=Ntadom%2CG&author=Adewoye%2CEO&author=Fatunmbi%2CB&author=Aderoyeje%2CT"> 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">Gbotosho GO, Sowunmi A, Okuboyejo TM, Happi CT, Folarin OO, Michael OS, Adewoye EO. Therapeutic efficacy and effects of artemether-lumefantrine and artesunate amodiaquine co-formulated or co-packaged on malaria-associated anemia in children with uncomplicated <i>Plasmodium falciparum</i> malaria in southwest Nigeria. Am J Trop Med Hyg. 2011;84:813–9.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.4269/ajtmh.2011.10-0582" data-track-item_id="10.4269/ajtmh.2011.10-0582" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.4269%2Fajtmh.2011.10-0582" aria-label="Article reference 23" data-doi="10.4269/ajtmh.2011.10-0582">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%2BC3MXns1Cisb8%3D" aria-label="CAS reference 23">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=21540395" aria-label="PubMed reference 23">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/PMC3083753" aria-label="PubMed Central reference 23">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 23" href="http://scholar.google.com/scholar_lookup?&title=Therapeutic%20efficacy%20and%20effects%20of%20artemether-lumefantrine%20and%20artesunate%20amodiaquine%20co-formulated%20or%20co-packaged%20on%20malaria-associated%20anemia%20in%20children%20with%20uncomplicated%20Plasmodium%20falciparum%20malaria%20in%20southwest%20Nigeria&journal=Am%20J%20Trop%20Med%20Hyg&doi=10.4269%2Fajtmh.2011.10-0582&volume=84&pages=813-819&publication_year=2011&author=Gbotosho%2CGO&author=Sowunmi%2CA&author=Okuboyejo%2CTM&author=Happi%2CCT&author=Folarin%2COO&author=Michael%2COS&author=Adewoye%2CEO"> 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">Sowunmi A, Gbotosho GO, Happi CT, Folarin O, Okuboyejo T, Michael O, Fatunmbi B. Use of area under the curve to evaluate the effects of antimalarial drugs on malaria-associated anaemia after treatment. Am J Ther. 2011;18:190–7.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1097/MJT.0b013e3181d169c9" data-track-item_id="10.1097/MJT.0b013e3181d169c9" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1097%2FMJT.0b013e3181d169c9" aria-label="Article reference 24" data-doi="10.1097/MJT.0b013e3181d169c9">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=20683244" 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/PMC2974963" 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=Use%20of%20area%20under%20the%20curve%20to%20evaluate%20the%20effects%20of%20antimalarial%20drugs%20on%20malaria-associated%20anaemia%20after%20treatment&journal=Am%20J%20Ther&doi=10.1097%2FMJT.0b013e3181d169c9&volume=18&pages=190-197&publication_year=2011&author=Sowunmi%2CA&author=Gbotosho%2CGO&author=Happi%2CCT&author=Folarin%2CO&author=Okuboyejo%2CT&author=Michael%2CO&author=Fatunmbi%2CB"> 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">Rowland M, Tozer TN. Clinical pharmacokinetics: concept and application. Philadelphia: PA 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 25" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20pharmacokinetics%3A%20concept%20and%20application&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="26."><p class="c-article-references__text" id="ref-CR26">Bain BJ, Bates I. Basic haematological techniques. In: Lewis SM, Bain BJ, Bates I, editors. Practical Haematology. 9th ed. Edinburgh: Churchill Living stone 2001; pg. 19–46.</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">Epi Info Version 6. A Word Processing Data Base and Statistics Program for Public Health on IBM-compatible Microcomputers. Centers for Disease Control and Prevention, Atlanta, GA; 1994.</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">SPSS for Windows Release 20.0 (standard version). SPSS Inc., Chicago IL; 2011.</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">Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1:307–10.</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(86)90837-8" data-track-item_id="10.1016/S0140-6736(86)90837-8" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0140-6736%2886%2990837-8" aria-label="Article reference 29" data-doi="10.1016/S0140-6736(86)90837-8">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:DyaL287hslWqsQ%3D%3D" aria-label="CAS reference 29">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=2868172" aria-label="PubMed reference 29">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 29" href="http://scholar.google.com/scholar_lookup?&title=Statistical%20methods%20for%20assessing%20agreement%20between%20two%20methods%20of%20clinical%20measurement&journal=Lancet&doi=10.1016%2FS0140-6736%2886%2990837-8&volume=1&pages=307-310&publication_year=1986&author=Bland%2CJM&author=Altman%2CDG"> 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">Sowunmi A, Akano K, Ayede AI, Adewoye EO, Ntadom G, Fatunmbi B, Gbotosho GO, Folarin OA, Happi CT. Early rising asexual parasitaemia in Nigerian children following a first dose of artemisinin-based combination treatments of falciparum malaria. BMC Infect Dis. 2017;17:110.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12879-016-2173-z" data-track-item_id="10.1186/s12879-016-2173-z" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12879-016-2173-z" aria-label="Article reference 30" data-doi="10.1186/s12879-016-2173-z">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=28143417" aria-label="PubMed reference 30">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/PMC5286790" aria-label="PubMed Central reference 30">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 30" href="http://scholar.google.com/scholar_lookup?&title=Early%20rising%20asexual%20parasitaemia%20in%20Nigerian%20children%20following%20a%20first%20dose%20of%20artemisinin-based%20combination%20treatments%20of%20falciparum%20malaria&journal=BMC%20Infect%20Dis&doi=10.1186%2Fs12879-016-2173-z&volume=17&publication_year=2017&author=Sowunmi%2CA&author=Akano%2CK&author=Ayede%2CAI&author=Adewoye%2CEO&author=Ntadom%2CG&author=Fatunmbi%2CB&author=Gbotosho%2CGO&author=Folarin%2COA&author=Happi%2CCT"> 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">Sowunmi A, Akano K, Ntadom G, Ayede AI, Ibironke FO, Aderoyeje T, Adewoye EO, Fatunmbi B, Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, Ogala W, Agomo C, Folarin OA, Gbotosho GO, Happi CT. Therapeutic efficacy and effects of artemisinin-based combination treatments on uncomplicated <i>Plasmodium falciparum</i> malaria-associated anaemia in Nigerian children during seven years of adoption as first-line treatments. Infectious Diseases of Poverty. 2017;6:36.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40249-016-0217-7" data-track-item_id="10.1186/s40249-016-0217-7" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40249-016-0217-7" aria-label="Article reference 31" data-doi="10.1186/s40249-016-0217-7">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=28173853" aria-label="PubMed reference 31">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/PMC5294876" aria-label="PubMed Central reference 31">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 31" href="http://scholar.google.com/scholar_lookup?&title=Therapeutic%20efficacy%20and%20effects%20of%20artemisinin-based%20combination%20treatments%20on%20uncomplicated%20Plasmodium%20falciparum%20malaria-associated%20anaemia%20in%20Nigerian%20children%20during%20seven%20years%20of%20adoption%20as%20first-line%20treatments&journal=Infectious%20Diseases%20of%20Poverty&doi=10.1186%2Fs40249-016-0217-7&volume=6&publication_year=2017&author=Sowunmi%2CA&author=Akano%2CK&author=Ntadom%2CG&author=Ayede%2CAI&author=Ibironke%2CFO&author=Aderoyeje%2CT&author=Adewoye%2CEO&author=Fatunmbi%2CB&author=Oguche%2CS&author=Okafor%2CHU&author=Watila%2CI&author=Meremikwu%2CM&author=Agomo%2CP&author=Ogala%2CW&author=Agomo%2CC&author=Folarin%2COA&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="32."><p class="c-article-references__text" id="ref-CR32">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. Antimicrob 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 32" 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 32">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=17325222" aria-label="PubMed reference 32">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/PMC1855566" aria-label="PubMed Central reference 32">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 32" 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=Antimicrob%20Agents%20Chemother&doi=10.1128%2FAAC.00077-07&volume=51&pages=1694-1699&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="33."><p class="c-article-references__text" id="ref-CR33">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 Chemotherapy Control and Elimination. 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="34."><p class="c-article-references__text" id="ref-CR34">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 34" 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 34">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 34">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 34" 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=621-624&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="35."><p class="c-article-references__text" id="ref-CR35">Sowunmi A, Akano K, Ntadom G, Ayede A, Oguche S, Agomo C, Okafor H, Watila I, Meremikwu M, Ogala W, Agomo P, Adewoye E, Fatunmbi B, Aderoyeje T, Happi C, Gbotosho G, Folarin O. Anaemia following artemisinin-based combination treatments of uncomplicated <i>Plasmodium falciparum</i> malaria in children: temporal patterns of haematocrit and the use of uncomplicated hyperparasitaemia as a model for evaluating late-appearing anaemia. Chemotherapy. 2017;62:231–8.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1159/000449366" data-track-item_id="10.1159/000449366" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1159%2F000449366" aria-label="Article reference 35" data-doi="10.1159/000449366">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%2BC2sXpvFOnsbc%3D" aria-label="CAS reference 35">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=28448988" aria-label="PubMed reference 35">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 35" href="http://scholar.google.com/scholar_lookup?&title=Anaemia%20following%20artemisinin-based%20combination%20treatments%20of%20uncomplicated%20Plasmodium%20falciparum%20malaria%20in%20children%3A%20temporal%20patterns%20of%20haematocrit%20and%20the%20use%20of%20uncomplicated%20hyperparasitaemia%20as%20a%20model%20for%20evaluating%20late-appearing%20anaemia&journal=Chemotherapy&doi=10.1159%2F000449366&volume=62&pages=231-238&publication_year=2017&author=Sowunmi%2CA&author=Akano%2CK&author=Ntadom%2CG&author=Ayede%2CA&author=Oguche%2CS&author=Agomo%2CC&author=Okafor%2CH&author=Watila%2CI&author=Meremikwu%2CM&author=Ogala%2CW&author=Agomo%2CP&author=Adewoye%2CE&author=Fatunmbi%2CB&author=Aderoyeje%2CT&author=Happi%2CC&author=Gbotosho%2CG&author=Folarin%2CO"> Google Scholar</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/s12879-017-2876-9?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>The therapeutic efficacy study from which the data were derived received financial support from Global Fund for AIDS, Tuberculosis and Malaria, United States Presidential Malaria Initiative (PMI), and Malaria Consortium Grants to The Federal Ministry of Health, Abuja, through Drug Therapeutic Efficacy Testing in Nigeria. Logistic support was provided by The Government of the States where the sites are located.</p> <h3 class="c-article__sub-heading" id="FPar2">Availability of data and materials</h3> <p>The dataset supporting the findings of this article are available from the corresponding author upon request.</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">Antimalarial Therapeutic Efficacy Monitoring Group, National Malaria Elimination Programme, The Federal Ministry of Health, Abuja, Nigeria</p><p class="c-article-author-affiliation__authors-list">Akintunde Sowunmi, Bayo Fatunmbi, Chimere Agomo, Finomo Finomo, Joy Ebenebe, Nma Jiya, Jose Ambe, Robinson Wammanda, Godwin Ntadom, Olugbenga Mokuolu, George Emechebe, Nnenna Ezeigwe, Christian T. Happi, Stephen Oguche, Wellington A. Oyibo & Francis Useh</p></li><li id="Aff2"><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, Olubunmi A. Wewe, Godwin Ntadom & Grace O. Gbotosho</p></li><li id="Aff3"><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="Aff4"><p class="c-article-author-affiliation__address">World Health Organization, Country Office, Kampala, Uganda</p><p class="c-article-author-affiliation__authors-list">Bayo Fatunmbi</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Department of Medical Laboratory Science, University of Lagos, Lagos, Nigeria</p><p class="c-article-author-affiliation__authors-list">Chimere Agomo</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Department of Paediatrics, Federal Medical Centre, Yenagoa, Nigeria</p><p class="c-article-author-affiliation__authors-list">Finomo Finomo</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Paediatrics, Nnamdi Azikiwe University, Awka, Nigeria</p><p class="c-article-author-affiliation__authors-list">Joy Ebenebe</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">Department of Paediatrics, Uthman Dan Fodio University, Sokoto, Nigeria</p><p class="c-article-author-affiliation__authors-list">Nma Jiya</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Paediatrics, University of Maiduguri, Maiduguri, Nigeria</p><p class="c-article-author-affiliation__authors-list">Jose Ambe</p></li><li id="Aff10"><p class="c-article-author-affiliation__address">Department of Paediatrics, Ahmadu Bello University, Zaria, Nigeria</p><p class="c-article-author-affiliation__authors-list">Robinson Wammanda</p></li><li id="Aff11"><p class="c-article-author-affiliation__address">Department of Paediatrics, University of Ilorin, Ilorin, Nigeria</p><p class="c-article-author-affiliation__authors-list">Olugbenga Mokuolu</p></li><li id="Aff12"><p class="c-article-author-affiliation__address">Department of Paediatrics, Imo State University Teaching Hospital, Orlu, Nigeria</p><p class="c-article-author-affiliation__authors-list">George Emechebe</p></li><li id="Aff13"><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="Aff14"><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="Aff15"><p class="c-article-author-affiliation__address">Department of Pharmacology and Toxicology, University of Ibadan, Ibadan, Nigeria</p><p class="c-article-author-affiliation__authors-list">Grace O. Gbotosho</p></li><li id="Aff16"><p class="c-article-author-affiliation__address">Department of Biological Sciences and African Centre of Excellence for Genomics of Infectious Diseases (ACEGID), Redeemer University, Ede, Nigeria</p><p class="c-article-author-affiliation__authors-list">Onikepe A. Folarin & Christian T. Happi</p></li><li id="Aff17"><p class="c-article-author-affiliation__address">Department of Paediatrics, University of Jos, Jos, Nigeria</p><p class="c-article-author-affiliation__authors-list">Stephen Oguche</p></li><li id="Aff18"><p class="c-article-author-affiliation__address">Department of Medical Microbiology and Parasitology, University of Lagos, Lagos, Nigeria</p><p class="c-article-author-affiliation__authors-list">Wellington A. Oyibo</p></li><li id="Aff19"><p class="c-article-author-affiliation__address">Department of Medical Laboratory Science, University of Calabar, Calabar, Nigeria</p><p class="c-article-author-affiliation__authors-list">Francis Useh</p></li><li id="Aff20"><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-Aff3-Aff20"><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="https://www.biomedcentral.com/search?query=author%23Akintunde%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-Bayo-Fatunmbi-Aff1-Aff4"><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="https://www.biomedcentral.com/search?query=author%23Bayo%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-Kazeem-Akano-Aff2"><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="https://www.biomedcentral.com/search?query=author%23Kazeem%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-Olubunmi_A_-Wewe-Aff2"><span class="c-article-authors-search__title u-h3 js-search-name">Olubunmi A. Wewe</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Olubunmi%20A.%20Wewe" 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=Olubunmi%20A.%20Wewe" 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=%22Olubunmi%20A.%20Wewe%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-Chimere-Agomo-Aff1-Aff5"><span class="c-article-authors-search__title u-h3 js-search-name">Chimere Agomo</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Chimere%20Agomo" 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=Chimere%20Agomo" 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=%22Chimere%20Agomo%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-Finomo-Finomo-Aff1-Aff6"><span class="c-article-authors-search__title u-h3 js-search-name">Finomo Finomo</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Finomo%20Finomo" 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=Finomo%20Finomo" 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=%22Finomo%20Finomo%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-Joy-Ebenebe-Aff1-Aff7"><span class="c-article-authors-search__title u-h3 js-search-name">Joy Ebenebe</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Joy%20Ebenebe" 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=Joy%20Ebenebe" 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=%22Joy%20Ebenebe%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-Nma-Jiya-Aff1-Aff8"><span class="c-article-authors-search__title u-h3 js-search-name">Nma Jiya</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Nma%20Jiya" 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=Nma%20Jiya" 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=%22Nma%20Jiya%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-Jose-Ambe-Aff1-Aff9"><span class="c-article-authors-search__title u-h3 js-search-name">Jose Ambe</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Jose%20Ambe" 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=Jose%20Ambe" 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=%22Jose%20Ambe%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-Robinson-Wammanda-Aff1-Aff10"><span class="c-article-authors-search__title u-h3 js-search-name">Robinson Wammanda</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Robinson%20Wammanda" 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=Robinson%20Wammanda" 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=%22Robinson%20Wammanda%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-Aff1-Aff2"><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="https://www.biomedcentral.com/search?query=author%23Godwin%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-Olugbenga-Mokuolu-Aff1-Aff11"><span class="c-article-authors-search__title u-h3 js-search-name">Olugbenga Mokuolu</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Olugbenga%20Mokuolu" 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=Olugbenga%20Mokuolu" 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=%22Olugbenga%20Mokuolu%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-George-Emechebe-Aff1-Aff12"><span class="c-article-authors-search__title u-h3 js-search-name">George Emechebe</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23George%20Emechebe" 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=George%20Emechebe" 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=%22George%20Emechebe%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-Nnenna-Ezeigwe-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Nnenna Ezeigwe</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Nnenna%20Ezeigwe" 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=Nnenna%20Ezeigwe" 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=%22Nnenna%20Ezeigwe%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-Aff13"><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="https://www.biomedcentral.com/search?query=author%23Adejumoke%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-Aff14"><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="https://www.biomedcentral.com/search?query=author%23Elsie%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-Grace_O_-Gbotosho-Aff2-Aff3-Aff15"><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="https://www.biomedcentral.com/search?query=author%23Grace%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-Aff16"><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="https://www.biomedcentral.com/search?query=author%23Onikepe%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-Aff1-Aff16"><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="https://www.biomedcentral.com/search?query=author%23Christian%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><li id="auth-Stephen-Oguche-Aff1-Aff17"><span class="c-article-authors-search__title u-h3 js-search-name">Stephen Oguche</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Stephen%20Oguche" 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=Stephen%20Oguche" 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=%22Stephen%20Oguche%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-Wellington_A_-Oyibo-Aff1-Aff18"><span class="c-article-authors-search__title u-h3 js-search-name">Wellington A. Oyibo</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Wellington%20A.%20Oyibo" 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=Wellington%20A.%20Oyibo" 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=%22Wellington%20A.%20Oyibo%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-Francis-Useh-Aff1-Aff19"><span class="c-article-authors-search__title u-h3 js-search-name">Francis Useh</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Francis%20Useh" 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=Francis%20Useh" 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=%22Francis%20Useh%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="contributions">Contributions</h3><p>AS led the design, conduct, data analysis and manuscript preparation. BF was involved in data analysis; KA in data collection, analysis and manuscript preparation; OAW in data analysis, CA in data management; FF, JE, NJ, JA, RW, GN, OM, GE, NE, WAO, FU in data collection; AIA, EOA, GOG, OAF, CTH, SO in data analysis. CA, FF, JE, NJ, JA, RW, GN, OM, GE, WAO and FU made substantial contributions to the conception, design and conduct of the study. AS, FF, JE, NJ, JA, RW, OM and GE were Principal Investigators at the sentinel sites. All authors read, contributed and approved the final draft of the manuscript.</p><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="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading" id="FPar3">Ethics approval and consent to participate</h3> <p>The study protocol was approved by National Health Research Ethics Committee, Abuja, Nigeria. NHREC/01/01/2007–28/10/2013 (29 October 2013), NHREC/01/01/2007–22/10/2014 (30 October 2014). Written informed consents were obtained from parents/guardians of the children.</p> <h3 class="c-article__sub-heading" id="FPar4">Consent for publication</h3> <p>Not applicable</p> <h3 class="c-article__sub-heading" id="FPar5">Competing interests</h3> <p>The authors declare they have no competing interests.</p> <h3 class="c-article__sub-heading" id="FPar6">Publisher’s Note</h3> <p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</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=Factors%20contributing%20to%20anaemia%20after%20uncomplicated%20falciparum%20malaria%20in%20under%20five%20year-old%20Nigerian%20children%20ten%20years%20following%20adoption%20of%20artemisinin-based%20combination%20therapies%20as%20first-line%20antimalarials&author=Akintunde%20Sowunmi%20et%20al&contentID=10.1186%2Fs12879-017-2876-9&copyright=The%20Author%28s%29.&publication=1471-2334&publicationDate=2017-12-19&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/s12879-017-2876-9" target="_blank" rel="noopener" href="https://crossmark.crossref.org/dialog/?doi=10.1186/s12879-017-2876-9" 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., Fatunmbi, B., Akano, K. <i>et al.</i> Factors contributing to anaemia after uncomplicated falciparum malaria in under five year-old Nigerian children ten years following adoption of artemisinin-based combination therapies as first-line antimalarials. <i>BMC Infect Dis</i> <b>17</b>, 781 (2017). https://doi.org/10.1186/s12879-017-2876-9</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/s12879-017-2876-9?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="2017-07-04">04 July 2017</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="2017-11-30">30 November 2017</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="2017-12-19">19 December 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/s12879-017-2876-9</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=%0A%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20%20malaria-associated%20anaemia&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link"> <i>Plasmodium falciparum</i> malaria-associated anaemia</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> </article> </main> <div class="c-article-extras u-text-sm u-hide-print" data-container-type="reading-companion" data-track-component="reading companion"> <aside> <div data-test="download-article-link-wrapper" class="js-context-bar-sticky-point-desktop" data-track-context="reading companion"> <div class="c-pdf-download u-clear-both"> <a href="//bmcinfectdis.biomedcentral.com/counter/pdf/10.1186/s12879-017-2876-9.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="link" 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-download"/></svg> </a> </div> </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="js-ad u-lazy-ad-wrapper u-mt-16 u-hide" data-component-mpu> <aside class="adsbox c-ad c-ad--300x250 u-mt-16" data-component-mpu> <div class="c-ad__inner"> <p class="c-ad__label">Advertisement</p> <div id="div-gpt-ad-MPU1" data-ad-type="MPU1" data-test="MPU1-ad" data-pa11y-ignore data-gpt data-gpt-unitpath="/270604982/bmc/bmcinfectdis/articles" data-gpt-sizes="300x250" data-gpt-targeting="pos=MPU1;doi=10.1186/s12879-017-2876-9;type=article;kwrd=Plasmodium falciparum malaria-associated anaemia,Artemisinin-based combination treatments,Children,Nigeria;pmc=H33096,B19002,B16003,H61006,H33002;" > <noscript> <a href="//pubads.g.doubleclick.net/gampad/jump?iu=/270604982/bmc/bmcinfectdis/articles&sz=300x250&pos=MPU1&doi=10.1186/s12879-017-2876-9&type=article&kwrd=Plasmodium falciparum malaria-associated anaemia,Artemisinin-based combination treatments,Children,Nigeria&pmc=H33096,B19002,B16003,H61006,H33002&"> <img data-test="gpt-advert-fallback-img" src="//pubads.g.doubleclick.net/gampad/ad?iu=/270604982/bmc/bmcinfectdis/articles&sz=300x250&pos=MPU1&doi=10.1186/s12879-017-2876-9&type=article&kwrd=Plasmodium falciparum malaria-associated anaemia,Artemisinin-based combination treatments,Children,Nigeria&pmc=H33096,B19002,B16003,H61006,H33002&" alt="Advertisement" width="300" height="250"> </a> </noscript> </div> </div> </aside> </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> <div class="c-journal-footer"> <div class="c-journal-footer__inner"> <div class="c-journal-footer__summary"> <h4 class="c-journal-title c-journal-title--footer"> <span class="c-journal-title__text">BMC Infectious Diseases</span> </h4> <p class="c-journal-footer__issn">ISSN: 1471-2334</p> </div> <div class="c-journal-footer__contact"> <h4 class="c-journal-footer__contact-title ">Contact us</h4> <ul class="c-journal-footer__contact-list"> <li class="c-journal-footer__contact-item">General enquiries: <a href="mailto:journalsubmissions@springernature.com">journalsubmissions@springernature.com</a></li> </ul> </div> </div> </div> <img rel="nofollow" class='tracker' style='display:none' src='/track/article/10.1186/s12879-017-2876-9' alt=""/> <footer> <div class="c-publisher-footer u-color-inherit" data-test="publisher-footer"> <div class="u-container"> <div class="u-display-flex u-flex-wrap u-justify-content-space-between" data-test="publisher-footer-menu"> <div class="u-display-flex"> <ul class="c-list-group c-list-group--sm u-mr-24 u-mb-16"> <li class="c-list-group__item"> <a class="u-gray-link" href="https://blogs.biomedcentral.com/">Read more on our blogs</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="//www.biomedcentral.com/login">Receive BMC newsletters</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="//www.biomedcentral.com/account">Manage article alerts</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="https://authorservices.springernature.com/go/sn/?utm_source=Website&utm_medium=BMC&utm_campaign=SNAS+Referrals+2022&utm_id=ref2022">Language editing for authors</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="https://authorservices.springernature.com/go/sn/?utm_source=Website&utm_medium=BMC&utm_campaign=SNAS+Referrals+2022&utm_id=ref2022">Scientific editing for authors</a> </li> </ul> <ul class="c-list-group c-list-group--sm u-mr-24 u-mb-16"> <li class="c-list-group__item"> <a class="u-gray-link" href="//www.biomedcentral.com/about/policies">Policies</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="//www.biomedcentral.com/accessibility">Accessibility</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="//www.biomedcentral.com/about/press-centre">Press center</a> </li> </ul> <ul class="c-list-group c-list-group--sm u-mr-24 u-mb-16"> <li class="c-list-group__item"> <a class="u-gray-link" href="https://support.biomedcentral.com/support/home">Support and Contact</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="https://biomedcentral.typeform.com/to/VLXboo">Leave feedback</a> </li> <li class="c-list-group__item"> <a class="u-gray-link" href="//www.biomedcentral.com/about/jobs">Careers</a> </li> </ul> </div> <div class="u-mb-24"> <h3 id="social-menu" class="u-text-sm u-reset-margin u-text-normal">Follow BMC</h3> <ul class="u-display-flex u-list-reset" data-test="footer-social-links"> <li class="u-mt-8 u-mr-8"> <a href="https://twitter.com/biomedcentral" data-track="click" data-track-category="Social" data-track-action="Clicked BMC Twitter" class="u-gray-link"> <span class="u-visually-hidden">BMC Twitter page</span> <svg class="u-icon u-text-lg" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-twitter-bordered"></use> </svg> </a> </li> <li class="u-mt-8 u-mr-8"> <a href="https://www.facebook.com/BioMedCentral" data-track="click" data-track-category="Social" data-track-action="Clicked BMC Facebook" class="u-gray-link"> <span class="u-visually-hidden">BMC Facebook page</span> <svg class="u-icon u-text-lg" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-facebook-bordered"></use> </svg> </a> </li> <li class="u-mt-8 u-mr-8"> <a href="http://www.weibo.com/biomedcentral" data-track="click" data-track-category="Social" data-track-action="Clicked BMC Weibo" class="u-gray-link"> <span class="u-visually-hidden">BMC Weibo page</span> <svg class="u-icon u-text-lg" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-weibo-bordered"></use> </svg> </a> </li> </ul> </div> </div> <p class="u-reset-margin"> By using this website, you agree to our <a class="u-gray-link" href="//www.biomedcentral.com/terms-and-conditions">Terms and Conditions</a>, <a class="u-gray-link" href="https://www.springernature.com/ccpa">Your US state privacy rights</a>, <a class="u-gray-link" href="//www.biomedcentral.com/privacy-statement">Privacy statement</a> and <a class="u-gray-link" href="//www.biomedcentral.com/cookies" data-test="cookie-link">Cookies</a> policy. <a class="u-gray-link" data-cc-action="preferences" href="javascript:void(0);">Your privacy choices/Manage cookies</a> we use in the preference centre. </p> </div> </div> <div class="c-corporate-footer"> <div class="u-container"> <img src=/static/images/logo-springernature-acb40b85fb.svg class="c-corporate-footer__logo" alt="Springer Nature" itemprop="logo" role="img"> <p class="c-corporate-footer__legal" data-test="copyright"> © 2024 BioMed Central Ltd unless otherwise stated. Part of <a class="c-corporate-footer__link" href="https://www.springernature.com" itemscope itemtype="http://schema.org/Organization" itemid="#parentOrganization">Springer Nature</a>. </p> </div> </div> </footer> </div> <div class="u-visually-hidden" aria-hidden="true"> <?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"><defs><path id="a" d="M0 .74h56.72v55.24H0z"/></defs><symbol id="icon-access" viewBox="0 0 18 18"><path d="m14 8c.5522847 0 1 .44771525 1 1v7h2.5c.2761424 0 .5.2238576.5.5v1.5h-18v-1.5c0-.2761424.22385763-.5.5-.5h2.5v-7c0-.55228475.44771525-1 1-1s1 .44771525 1 1v6.9996556h8v-6.9996556c0-.55228475.4477153-1 1-1zm-8 0 2 1v5l-2 1zm6 0v7l-2-1v-5zm-2.42653766-7.59857636 7.03554716 4.92488299c.4162533.29137735.5174853.86502537.226108 1.28127873-.1721584.24594054-.4534847.39241464-.7536934.39241464h-14.16284822c-.50810197 0-.92-.41189803-.92-.92 0-.30020869.1464741-.58153499.39241464-.75369337l7.03554714-4.92488299c.34432015-.2410241.80260453-.2410241 1.14692468 0zm-.57346234 2.03988748-3.65526982 2.55868888h7.31053962z" fill-rule="evenodd"/></symbol><symbol id="icon-account" viewBox="0 0 18 18"><path d="m10.2379028 16.9048051c1.3083556-.2032362 2.5118471-.7235183 3.5294683-1.4798399-.8731327-2.5141501-2.0638925-3.935978-3.7673711-4.3188248v-1.27684611c1.1651924-.41183641 2-1.52307546 2-2.82929429 0-1.65685425-1.3431458-3-3-3-1.65685425 0-3 1.34314575-3 3 0 1.30621883.83480763 2.41745788 2 2.82929429v1.27684611c-1.70347856.3828468-2.89423845 1.8046747-3.76737114 4.3188248 1.01762123.7563216 2.22111275 1.2766037 3.52946833 1.4798399.40563808.0629726.81921174.0951949 1.23790281.0951949s.83226473-.0322223 1.2379028-.0951949zm4.3421782-2.1721994c1.4927655-1.4532925 2.419919-3.484675 2.419919-5.7326057 0-4.418278-3.581722-8-8-8s-8 3.581722-8 8c0 2.2479307.92715352 4.2793132 2.41991895 5.7326057.75688473-2.0164459 1.83949951-3.6071894 3.48926591-4.3218837-1.14534283-.70360829-1.90918486-1.96796271-1.90918486-3.410722 0-2.209139 1.790861-4 4-4s4 1.790861 4 4c0 1.44275929-.763842 2.70711371-1.9091849 3.410722 1.6497664.7146943 2.7323812 2.3054378 3.4892659 4.3218837zm-5.580081 3.2673943c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-alert" viewBox="0 0 18 18"><path d="m4 10h2.5c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-3.08578644l-1.12132034 1.1213203c-.18753638.1875364-.29289322.4418903-.29289322.7071068v.1715729h14v-.1715729c0-.2652165-.1053568-.5195704-.2928932-.7071068l-1.7071068-1.7071067v-3.4142136c0-2.76142375-2.2385763-5-5-5-2.76142375 0-5 2.23857625-5 5zm3 4c0 1.1045695.8954305 2 2 2s2-.8954305 2-2zm-5 0c-.55228475 0-1-.4477153-1-1v-.1715729c0-.530433.21071368-1.0391408.58578644-1.4142135l1.41421356-1.4142136v-3c0-3.3137085 2.6862915-6 6-6s6 2.6862915 6 6v3l1.4142136 1.4142136c.3750727.3750727.5857864.8837805.5857864 1.4142135v.1715729c0 .5522847-.4477153 1-1 1h-4c0 1.6568542-1.3431458 3-3 3-1.65685425 0-3-1.3431458-3-3z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-broad" viewBox="0 0 16 16"><path d="m6.10307866 2.97190702v7.69043288l2.44965196-2.44676915c.38776071-.38730439 1.0088052-.39493524 1.38498697-.01919617.38609051.38563612.38643641 1.01053024-.00013864 1.39665039l-4.12239817 4.11754683c-.38616704.3857126-1.01187344.3861062-1.39846576-.0000311l-4.12258206-4.11773056c-.38618426-.38572979-.39254614-1.00476697-.01636437-1.38050605.38609047-.38563611 1.01018509-.38751562 1.4012233.00306241l2.44985644 2.4469734v-8.67638639c0-.54139983.43698413-.98042709.98493125-.98159081l7.89910522-.0043627c.5451687 0 .9871152.44142642.9871152.98595351s-.4419465.98595351-.9871152.98595351z" fill-rule="evenodd" transform="matrix(-1 0 0 -1 14 15)"/></symbol><symbol id="icon-arrow-down" viewBox="0 0 16 16"><path d="m3.28337502 11.5302405 4.03074001 4.176208c.37758093.3912076.98937525.3916069 1.367372-.0000316l4.03091977-4.1763942c.3775978-.3912252.3838182-1.0190815.0160006-1.4001736-.3775061-.39113013-.9877245-.39303641-1.3700683.003106l-2.39538585 2.4818345v-11.6147896l-.00649339-.11662112c-.055753-.49733869-.46370161-.88337888-.95867408-.88337888-.49497246 0-.90292107.38604019-.95867408.88337888l-.00649338.11662112v11.6147896l-2.39518594-2.4816273c-.37913917-.39282218-.98637524-.40056175-1.35419292-.0194697-.37750607.3911302-.37784433 1.0249269.00013556 1.4165479z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-left" viewBox="0 0 16 16"><path d="m4.46975946 3.28337502-4.17620792 4.03074001c-.39120768.37758093-.39160691.98937525.0000316 1.367372l4.1763942 4.03091977c.39122514.3775978 1.01908149.3838182 1.40017357.0160006.39113012-.3775061.3930364-.9877245-.00310603-1.3700683l-2.48183446-2.39538585h11.61478958l.1166211-.00649339c.4973387-.055753.8833789-.46370161.8833789-.95867408 0-.49497246-.3860402-.90292107-.8833789-.95867408l-.1166211-.00649338h-11.61478958l2.4816273-2.39518594c.39282216-.37913917.40056173-.98637524.01946965-1.35419292-.39113012-.37750607-1.02492687-.37784433-1.41654791.00013556z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-right" viewBox="0 0 16 16"><path d="m11.5302405 12.716625 4.176208-4.03074003c.3912076-.37758093.3916069-.98937525-.0000316-1.367372l-4.1763942-4.03091981c-.3912252-.37759778-1.0190815-.38381821-1.4001736-.01600053-.39113013.37750607-.39303641.98772445.003106 1.37006824l2.4818345 2.39538588h-11.6147896l-.11662112.00649339c-.49733869.055753-.88337888.46370161-.88337888.95867408 0 .49497246.38604019.90292107.88337888.95867408l.11662112.00649338h11.6147896l-2.4816273 2.39518592c-.39282218.3791392-.40056175.9863753-.0194697 1.3541929.3911302.3775061 1.0249269.3778444 1.4165479-.0001355z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-sub" viewBox="0 0 16 16"><path d="m7.89692134 4.97190702v7.69043288l-2.44965196-2.4467692c-.38776071-.38730434-1.0088052-.39493519-1.38498697-.0191961-.38609047.3856361-.38643643 1.0105302.00013864 1.3966504l4.12239817 4.1175468c.38616704.3857126 1.01187344.3861062 1.39846576-.0000311l4.12258202-4.1177306c.3861843-.3857298.3925462-1.0047669.0163644-1.380506-.3860905-.38563612-1.0101851-.38751563-1.4012233.0030624l-2.44985643 2.4469734v-8.67638639c0-.54139983-.43698413-.98042709-.98493125-.98159081l-7.89910525-.0043627c-.54516866 0-.98711517.44142642-.98711517.98595351s.44194651.98595351.98711517.98595351z" fill-rule="evenodd"/></symbol><symbol id="icon-arrow-up" viewBox="0 0 16 16"><path d="m12.716625 4.46975946-4.03074003-4.17620792c-.37758093-.39120768-.98937525-.39160691-1.367372.0000316l-4.03091981 4.1763942c-.37759778.39122514-.38381821 1.01908149-.01600053 1.40017357.37750607.39113012.98772445.3930364 1.37006824-.00310603l2.39538588-2.48183446v11.61478958l.00649339.1166211c.055753.4973387.46370161.8833789.95867408.8833789.49497246 0 .90292107-.3860402.95867408-.8833789l.00649338-.1166211v-11.61478958l2.39518592 2.4816273c.3791392.39282216.9863753.40056173 1.3541929.01946965.3775061-.39113012.3778444-1.02492687-.0001355-1.41654791z" fill-rule="evenodd"/></symbol><symbol id="icon-article" viewBox="0 0 18 18"><path d="m13 15v-12.9906311c0-.0073595-.0019884-.0093689.0014977-.0093689l-11.00158888.00087166v13.00506804c0 .5482678.44615281.9940603.99415146.9940603h10.27350412c-.1701701-.2941734-.2675644-.6357129-.2675644-1zm-12 .0059397v-13.00506804c0-.5562408.44704472-1.00087166.99850233-1.00087166h11.00299537c.5510129 0 .9985023.45190985.9985023 1.0093689v2.9906311h3v9.9914698c0 1.1065798-.8927712 2.0085302-1.9940603 2.0085302h-12.01187942c-1.09954652 0-1.99406028-.8927712-1.99406028-1.9940603zm13-9.0059397v9c0 .5522847.4477153 1 1 1s1-.4477153 1-1v-9zm-10-2h7v4h-7zm1 1v2h5v-2zm-1 4h7v1h-7zm0 2h7v1h-7zm0 2h7v1h-7z" fill-rule="evenodd"/></symbol><symbol id="icon-audio" viewBox="0 0 18 18"><path d="m13.0957477 13.5588459c-.195279.1937043-.5119137.193729-.7072234.0000551-.1953098-.193674-.1953346-.5077061-.0000556-.7014104 1.0251004-1.0168342 1.6108711-2.3905226 1.6108711-3.85745208 0-1.46604976-.5850634-2.83898246-1.6090736-3.85566829-.1951894-.19379323-.1950192-.50782531.0003802-.70141028.1953993-.19358497.512034-.19341614.7072234.00037709 1.2094886 1.20083761 1.901635 2.8250555 1.901635 4.55670148 0 1.73268608-.6929822 3.35779608-1.9037571 4.55880738zm2.1233994 2.1025159c-.195234.193749-.5118687.1938462-.7072235.0002171-.1953548-.1936292-.1954528-.5076613-.0002189-.7014104 1.5832215-1.5711805 2.4881302-3.6939808 2.4881302-5.96012998 0-2.26581266-.9046382-4.3883241-2.487443-5.95944795-.1952117-.19377107-.1950777-.50780316.0002993-.70141031s.5120117-.19347426.7072234.00029682c1.7683321 1.75528196 2.7800854 4.12911258 2.7800854 6.66056144 0 2.53182498-1.0120556 4.90597838-2.7808529 6.66132328zm-14.21898205-3.6854911c-.5523759 0-1.00016505-.4441085-1.00016505-.991944v-3.96777631c0-.54783558.44778915-.99194407 1.00016505-.99194407h2.0003301l5.41965617-3.8393633c.44948677-.31842296 1.07413994-.21516983 1.39520191.23062232.12116339.16823446.18629727.36981184.18629727.57655577v12.01603479c0 .5478356-.44778914.9919441-1.00016505.9919441-.20845738 0-.41170538-.0645985-.58133413-.184766l-5.41965617-3.8393633zm0-.991944h2.32084805l5.68047235 4.0241292v-12.01603479l-5.68047235 4.02412928h-2.32084805z" fill-rule="evenodd"/></symbol><symbol id="icon-block" viewBox="0 0 24 24"><path d="m0 0h24v24h-24z" fill-rule="evenodd"/></symbol><symbol id="icon-book" viewBox="0 0 18 18"><path d="m4 13v-11h1v11h11v-11h-13c-.55228475 0-1 .44771525-1 1v10.2675644c.29417337-.1701701.63571286-.2675644 1-.2675644zm12 1h-13c-.55228475 0-1 .4477153-1 1s.44771525 1 1 1h13zm0 3h-13c-1.1045695 0-2-.8954305-2-2v-12c0-1.1045695.8954305-2 2-2h13c.5522847 0 1 .44771525 1 1v14c0 .5522847-.4477153 1-1 1zm-8.5-13h6c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-6c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm1 2h4c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-4c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-broad" viewBox="0 0 24 24"><path d="m9.18274226 7.81v7.7999954l2.48162734-2.4816273c.3928221-.3928221 1.0219731-.4005617 1.4030652-.0194696.3911301.3911301.3914806 1.0249268-.0001404 1.4165479l-4.17620796 4.1762079c-.39120769.3912077-1.02508144.3916069-1.41671995-.0000316l-4.1763942-4.1763942c-.39122514-.3912251-.39767006-1.0190815-.01657798-1.4001736.39113012-.3911301 1.02337106-.3930364 1.41951349.0031061l2.48183446 2.4818344v-8.7999954c0-.54911294.4426881-.99439484.99778758-.99557515l8.00221246-.00442485c.5522847 0 1 .44771525 1 1s-.4477153 1-1 1z" fill-rule="evenodd" transform="matrix(-1 0 0 -1 20.182742 24.805206)"/></symbol><symbol id="icon-calendar" viewBox="0 0 18 18"><path d="m12.5 0c.2761424 0 .5.21505737.5.49047852v.50952148h2c1.1072288 0 2 .89451376 2 2v12c0 1.1072288-.8945138 2-2 2h-12c-1.1072288 0-2-.8945138-2-2v-12c0-1.1072288.89451376-2 2-2h1v1h-1c-.55393837 0-1 .44579254-1 1v3h14v-3c0-.55393837-.4457925-1-1-1h-2v1.50952148c0 .27088381-.2319336.49047852-.5.49047852-.2761424 0-.5-.21505737-.5-.49047852v-3.01904296c0-.27088381.2319336-.49047852.5-.49047852zm3.5 7h-14v8c0 .5539384.44579254 1 1 1h12c.5539384 0 1-.4457925 1-1zm-11 6v1h-1v-1zm3 0v1h-1v-1zm3 0v1h-1v-1zm-6-2v1h-1v-1zm3 0v1h-1v-1zm6 0v1h-1v-1zm-3 0v1h-1v-1zm-3-2v1h-1v-1zm6 0v1h-1v-1zm-3 0v1h-1v-1zm-5.5-9c.27614237 0 .5.21505737.5.49047852v.50952148h5v1h-5v1.50952148c0 .27088381-.23193359.49047852-.5.49047852-.27614237 0-.5-.21505737-.5-.49047852v-3.01904296c0-.27088381.23193359-.49047852.5-.49047852z" fill-rule="evenodd"/></symbol><symbol id="icon-cart" viewBox="0 0 18 18"><path d="m5 14c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm10 0c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm-10 1c-.55228475 0-1 .4477153-1 1s.44771525 1 1 1 1-.4477153 1-1-.44771525-1-1-1zm10 0c-.5522847 0-1 .4477153-1 1s.4477153 1 1 1 1-.4477153 1-1-.4477153-1-1-1zm-12.82032249-15c.47691417 0 .88746157.33678127.98070211.80449199l.23823144 1.19501025 13.36277974.00045554c.5522847.00001882.9999659.44774934.9999659 1.00004222 0 .07084994-.0075361.14150708-.022474.2107727l-1.2908094 5.98534344c-.1007861.46742419-.5432548.80388386-1.0571651.80388386h-10.24805106c-.59173366 0-1.07142857.4477153-1.07142857 1 0 .5128358.41361449.9355072.94647737.9932723l.1249512.0067277h10.35933776c.2749512 0 .4979349.2228539.4979349.4978051 0 .2749417-.2227336.4978951-.4976753.4980063l-10.35959736.0041886c-1.18346732 0-2.14285714-.8954305-2.14285714-2 0-.6625717.34520317-1.24989198.87690425-1.61383592l-1.63768102-8.19004794c-.01312273-.06561364-.01950005-.131011-.0196107-.19547395l-1.71961253-.00064219c-.27614237 0-.5-.22385762-.5-.5 0-.27614237.22385763-.5.5-.5zm14.53193359 2.99950224h-13.11300004l1.20580469 6.02530174c.11024034-.0163252.22327998-.02480398.33844139-.02480398h10.27064786z"/></symbol><symbol id="icon-chevron-less" viewBox="0 0 10 10"><path d="m5.58578644 4-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" fill-rule="evenodd" transform="matrix(0 -1 -1 0 9 9)"/></symbol><symbol id="icon-chevron-more" viewBox="0 0 10 10"><path d="m5.58578644 6-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4.00000002c-.39052429.3905243-1.02368927.3905243-1.41421356 0s-.39052429-1.02368929 0-1.41421358z" fill-rule="evenodd" transform="matrix(0 1 -1 0 11 1)"/></symbol><symbol id="icon-chevron-right" 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)"/></symbol><symbol id="icon-circle-fill" viewBox="0 0 16 16"><path d="m8 14c-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6 6 2.6862915 6 6-2.6862915 6-6 6z" fill-rule="evenodd"/></symbol><symbol id="icon-circle" viewBox="0 0 16 16"><path d="m8 12c2.209139 0 4-1.790861 4-4s-1.790861-4-4-4-4 1.790861-4 4 1.790861 4 4 4zm0 2c-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6 6 2.6862915 6 6-2.6862915 6-6 6z" fill-rule="evenodd"/></symbol><symbol id="icon-citation" viewBox="0 0 18 18"><path d="m8.63593473 5.99995183c2.20913897 0 3.99999997 1.79084375 3.99999997 3.99996146 0 1.40730761-.7267788 2.64486871-1.8254829 3.35783281 1.6240224.6764218 2.8754442 2.0093871 3.4610603 3.6412466l-1.0763845.000006c-.5310008-1.2078237-1.5108121-2.1940153-2.7691712-2.7181346l-.79002167-.329052v-1.023992l.63016577-.4089232c.8482885-.5504661 1.3698342-1.4895187 1.3698342-2.51898361 0-1.65683828-1.3431457-2.99996146-2.99999997-2.99996146-1.65685425 0-3 1.34312318-3 2.99996146 0 1.02946491.52154569 1.96851751 1.36983419 2.51898361l.63016581.4089232v1.023992l-.79002171.329052c-1.25835905.5241193-2.23817037 1.5103109-2.76917113 2.7181346l-1.07638453-.000006c.58561612-1.6318595 1.8370379-2.9648248 3.46106024-3.6412466-1.09870405-.7129641-1.82548287-1.9505252-1.82548287-3.35783281 0-2.20911771 1.790861-3.99996146 4-3.99996146zm7.36897597-4.99995183c1.1018574 0 1.9950893.89353404 1.9950893 2.00274083v5.994422c0 1.10608317-.8926228 2.00274087-1.9950893 2.00274087l-3.0049107-.0009037v-1l3.0049107.00091329c.5490631 0 .9950893-.44783123.9950893-1.00275046v-5.994422c0-.55646537-.4450595-1.00275046-.9950893-1.00275046h-14.00982141c-.54906309 0-.99508929.44783123-.99508929 1.00275046v5.9971821c0 .66666024.33333333.99999036 1 .99999036l2-.00091329v1l-2 .0009037c-1 0-2-.99999041-2-1.99998077v-5.9971821c0-1.10608322.8926228-2.00274083 1.99508929-2.00274083zm-8.5049107 2.9999711c.27614237 0 .5.22385547.5.5 0 .2761349-.22385763.5-.5.5h-4c-.27614237 0-.5-.2238651-.5-.5 0-.27614453.22385763-.5.5-.5zm3 0c.2761424 0 .5.22385547.5.5 0 .2761349-.2238576.5-.5.5h-1c-.27614237 0-.5-.2238651-.5-.5 0-.27614453.22385763-.5.5-.5zm4 0c.2761424 0 .5.22385547.5.5 0 .2761349-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238651-.5-.5 0-.27614453.2238576-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-close" viewBox="0 0 16 16"><path d="m2.29679575 12.2772478c-.39658757.3965876-.39438847 1.0328109-.00062148 1.4265779.39651227.3965123 1.03246768.3934888 1.42657791-.0006214l4.27724782-4.27724787 4.2772478 4.27724787c.3965876.3965875 1.0328109.3943884 1.4265779.0006214.3965123-.3965122.3934888-1.0324677-.0006214-1.4265779l-4.27724787-4.2772478 4.27724787-4.27724782c.3965875-.39658757.3943884-1.03281091.0006214-1.42657791-.3965122-.39651226-1.0324677-.39348875-1.4265779.00062148l-4.2772478 4.27724782-4.27724782-4.27724782c-.39658757-.39658757-1.03281091-.39438847-1.42657791-.00062148-.39651226.39651227-.39348875 1.03246768.00062148 1.42657791l4.27724782 4.27724782z" fill-rule="evenodd"/></symbol><symbol id="icon-collections" viewBox="0 0 18 18"><path d="m15 4c1.1045695 0 2 .8954305 2 2v9c0 1.1045695-.8954305 2-2 2h-8c-1.1045695 0-2-.8954305-2-2h1c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h8c.5128358 0 .9355072-.3860402.9932723-.8833789l.0067277-.1166211v-9c0-.51283584-.3860402-.93550716-.8833789-.99327227l-.1166211-.00672773h-1v-1zm-4-3c1.1045695 0 2 .8954305 2 2v9c0 1.1045695-.8954305 2-2 2h-8c-1.1045695 0-2-.8954305-2-2v-9c0-1.1045695.8954305-2 2-2zm0 1h-8c-.51283584 0-.93550716.38604019-.99327227.88337887l-.00672773.11662113v9c0 .5128358.38604019.9355072.88337887.9932723l.11662113.0067277h8c.5128358 0 .9355072-.3860402.9932723-.8833789l.0067277-.1166211v-9c0-.51283584-.3860402-.93550716-.8833789-.99327227zm-1.5 7c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm0-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm0-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-5c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-compare" viewBox="0 0 18 18"><path d="m12 3c3.3137085 0 6 2.6862915 6 6s-2.6862915 6-6 6c-1.0928452 0-2.11744941-.2921742-2.99996061-.8026704-.88181407.5102749-1.90678042.8026704-3.00003939.8026704-3.3137085 0-6-2.6862915-6-6s2.6862915-6 6-6c1.09325897 0 2.11822532.29239547 3.00096303.80325037.88158756-.51107621 1.90619177-.80325037 2.99903697-.80325037zm-6 1c-2.76142375 0-5 2.23857625-5 5 0 2.7614237 2.23857625 5 5 5 .74397391 0 1.44999672-.162488 2.08451611-.4539116-1.27652344-1.1000812-2.08451611-2.7287264-2.08451611-4.5460884s.80799267-3.44600721 2.08434391-4.5463015c-.63434719-.29121054-1.34037-.4536985-2.08434391-.4536985zm6 0c-.7439739 0-1.4499967.16248796-2.08451611.45391156 1.27652341 1.10008123 2.08451611 2.72872644 2.08451611 4.54608844s-.8079927 3.4460072-2.08434391 4.5463015c.63434721.2912105 1.34037001.4536985 2.08434391.4536985 2.7614237 0 5-2.2385763 5-5 0-2.76142375-2.2385763-5-5-5zm-1.4162763 7.0005324h-3.16744736c.15614659.3572676.35283837.6927622.58425872 1.0006671h1.99892988c.23142036-.3079049.42811216-.6433995.58425876-1.0006671zm.4162763-2.0005324h-4c0 .34288501.0345146.67770871.10025909 1.0011864h3.79948181c.0657445-.32347769.1002591-.65830139.1002591-1.0011864zm-.4158423-1.99953894h-3.16831543c-.13859957.31730812-.24521946.651783-.31578599.99935097h3.79988742c-.0705665-.34756797-.1771864-.68204285-.315786-.99935097zm-1.58295822-1.999926-.08316107.06199199c-.34550042.27081213-.65446126.58611297-.91825862.93727862h2.00044041c-.28418626-.37830727-.6207872-.71499149-.99902072-.99927061z" fill-rule="evenodd"/></symbol><symbol id="icon-download-file" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm0 1h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v14.00982141c0 .5500396.44491393.9950893.99406028.9950893h12.01187942c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717zm-1.5046024 4c.27614237 0 .5.21637201.5.49209595v6.14827645l1.7462789-1.77990922c.1933927-.1971171.5125222-.19455839.7001689-.0069117.1932998.19329992.1910058.50899492-.0027774.70277812l-2.59089271 2.5908927c-.19483374.1948337-.51177825.1937771-.70556873-.0000133l-2.59099079-2.5909908c-.19484111-.1948411-.19043735-.5151448-.00279066-.70279146.19329987-.19329987.50465175-.19237083.70018565.00692852l1.74638684 1.78001764v-6.14827695c0-.27177709.23193359-.49209595.5-.49209595z" fill-rule="evenodd"/></symbol><symbol id="icon-download" viewBox="0 0 16 16"><path d="m12.9975267 12.999368c.5467123 0 1.0024733.4478567 1.0024733 1.000316 0 .5563109-.4488226 1.000316-1.0024733 1.000316h-9.99505341c-.54671233 0-1.00247329-.4478567-1.00247329-1.000316 0-.5563109.44882258-1.000316 1.00247329-1.000316zm-4.9975267-11.999368c.55228475 0 1 .44497754 1 .99589209v6.80214418l2.4816273-2.48241149c.3928222-.39294628 1.0219732-.4006883 1.4030652-.01947579.3911302.39125371.3914806 1.02525073-.0001404 1.41699553l-4.17620792 4.17752758c-.39120769.3913313-1.02508144.3917306-1.41671995-.0000316l-4.17639421-4.17771394c-.39122513-.39134876-.39767006-1.01940351-.01657797-1.40061601.39113012-.39125372 1.02337105-.3931606 1.41951349.00310701l2.48183446 2.48261871v-6.80214418c0-.55001601.44386482-.99589209 1-.99589209z" fill-rule="evenodd"/></symbol><symbol id="icon-editors" viewBox="0 0 18 18"><path d="m8.72592184 2.54588137c-.48811714-.34391207-1.08343326-.54588137-1.72592184-.54588137-1.65685425 0-3 1.34314575-3 3 0 1.02947485.5215457 1.96853646 1.3698342 2.51900785l.6301658.40892721v1.02400182l-.79002171.32905522c-1.93395773.8055207-3.20997829 2.7024791-3.20997829 4.8180274v.9009805h-1v-.9009805c0-2.5479714 1.54557359-4.79153984 3.82548288-5.7411543-1.09870406-.71297106-1.82548288-1.95054399-1.82548288-3.3578652 0-2.209139 1.790861-4 4-4 1.09079823 0 2.07961816.43662103 2.80122451 1.1446278-.37707584.09278571-.7373238.22835063-1.07530267.40125357zm-2.72592184 14.45411863h-1v-.9009805c0-2.5479714 1.54557359-4.7915398 3.82548288-5.7411543-1.09870406-.71297106-1.82548288-1.95054399-1.82548288-3.3578652 0-2.209139 1.790861-4 4-4s4 1.790861 4 4c0 1.40732121-.7267788 2.64489414-1.8254829 3.3578652 2.2799093.9496145 3.8254829 3.1931829 3.8254829 5.7411543v.9009805h-1v-.9009805c0-2.1155483-1.2760206-4.0125067-3.2099783-4.8180274l-.7900217-.3290552v-1.02400184l.6301658-.40892721c.8482885-.55047139 1.3698342-1.489533 1.3698342-2.51900785 0-1.65685425-1.3431458-3-3-3-1.65685425 0-3 1.34314575-3 3 0 1.02947485.5215457 1.96853646 1.3698342 2.51900785l.6301658.40892721v1.02400184l-.79002171.3290552c-1.93395773.8055207-3.20997829 2.7024791-3.20997829 4.8180274z" fill-rule="evenodd"/></symbol><symbol id="icon-email" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587h-14.00982141c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm0 1h-14.00982141c-.54871518 0-.99508929.44887827-.99508929 1.00585866v9.98828264c0 .5572961.44630695 1.0058587.99508929 1.0058587h14.00982141c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-.0049107 2.55749512v1.44250488l-7 4-7-4v-1.44250488l7 4z" fill-rule="evenodd"/></symbol><symbol id="icon-error" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm2.8630343 4.71100931-2.8630343 2.86303426-2.86303426-2.86303426c-.39658757-.39658757-1.03281091-.39438847-1.4265779-.00062147-.39651227.39651226-.39348876 1.03246767.00062147 1.4265779l2.86303426 2.86303426-2.86303426 2.8630343c-.39658757.3965875-.39438847 1.0328109-.00062147 1.4265779.39651226.3965122 1.03246767.3934887 1.4265779-.0006215l2.86303426-2.8630343 2.8630343 2.8630343c.3965875.3965876 1.0328109.3943885 1.4265779.0006215.3965122-.3965123.3934887-1.0324677-.0006215-1.4265779l-2.8630343-2.8630343 2.8630343-2.86303426c.3965876-.39658757.3943885-1.03281091.0006215-1.4265779-.3965123-.39651227-1.0324677-.39348876-1.4265779.00062147z" fill-rule="evenodd"/></symbol><symbol id="icon-ethics" viewBox="0 0 18 18"><path d="m6.76384967 1.41421356.83301651-.8330165c.77492941-.77492941 2.03133823-.77492941 2.80626762 0l.8330165.8330165c.3750728.37507276.8837806.58578644 1.4142136.58578644h1.3496361c1.1045695 0 2 .8954305 2 2v1.34963611c0 .53043298.2107137 1.03914081.5857864 1.41421356l.8330165.83301651c.7749295.77492941.7749295 2.03133823 0 2.80626762l-.8330165.8330165c-.3750727.3750728-.5857864.8837806-.5857864 1.4142136v1.3496361c0 1.1045695-.8954305 2-2 2h-1.3496361c-.530433 0-1.0391408.2107137-1.4142136.5857864l-.8330165.8330165c-.77492939.7749295-2.03133821.7749295-2.80626762 0l-.83301651-.8330165c-.37507275-.3750727-.88378058-.5857864-1.41421356-.5857864h-1.34963611c-1.1045695 0-2-.8954305-2-2v-1.3496361c0-.530433-.21071368-1.0391408-.58578644-1.4142136l-.8330165-.8330165c-.77492941-.77492939-.77492941-2.03133821 0-2.80626762l.8330165-.83301651c.37507276-.37507275.58578644-.88378058.58578644-1.41421356v-1.34963611c0-1.1045695.8954305-2 2-2h1.34963611c.53043298 0 1.03914081-.21071368 1.41421356-.58578644zm-1.41421356 1.58578644h-1.34963611c-.55228475 0-1 .44771525-1 1v1.34963611c0 .79564947-.31607052 1.55871121-.87867966 2.12132034l-.8330165.83301651c-.38440512.38440512-.38440512 1.00764896 0 1.39205408l.8330165.83301646c.56260914.5626092.87867966 1.3256709.87867966 2.1213204v1.3496361c0 .5522847.44771525 1 1 1h1.34963611c.79564947 0 1.55871121.3160705 2.12132034.8786797l.83301651.8330165c.38440512.3844051 1.00764896.3844051 1.39205408 0l.83301646-.8330165c.5626092-.5626092 1.3256709-.8786797 2.1213204-.8786797h1.3496361c.5522847 0 1-.4477153 1-1v-1.3496361c0-.7956495.3160705-1.5587112.8786797-2.1213204l.8330165-.83301646c.3844051-.38440512.3844051-1.00764896 0-1.39205408l-.8330165-.83301651c-.5626092-.56260913-.8786797-1.32567087-.8786797-2.12132034v-1.34963611c0-.55228475-.4477153-1-1-1h-1.3496361c-.7956495 0-1.5587112-.31607052-2.1213204-.87867966l-.83301646-.8330165c-.38440512-.38440512-1.00764896-.38440512-1.39205408 0l-.83301651.8330165c-.56260913.56260914-1.32567087.87867966-2.12132034.87867966zm3.58698944 11.4960218c-.02081224.002155-.04199226.0030286-.06345763.002542-.98766446-.0223875-1.93408568-.3063547-2.75885125-.8155622-.23496767-.1450683-.30784554-.4531483-.16277726-.688116.14506827-.2349677.45314827-.3078455.68811595-.1627773.67447084.4164161 1.44758575.6483839 2.25617384.6667123.01759529.0003988.03495764.0017019.05204365.0038639.01713363-.0017748.03452416-.0026845.05212715-.0026845 2.4852814 0 4.5-2.0147186 4.5-4.5 0-1.04888973-.3593547-2.04134635-1.0074477-2.83787157-.1742817-.21419731-.1419238-.5291218.0722736-.70340353.2141973-.17428173.5291218-.14192375.7034035.07227357.7919032.97327203 1.2317706 2.18808682 1.2317706 3.46900153 0 3.0375661-2.4624339 5.5-5.5 5.5-.02146768 0-.04261937-.0013529-.06337445-.0039782zm1.57975095-10.78419583c.2654788.07599731.419084.35281842.3430867.61829728-.0759973.26547885-.3528185.419084-.6182973.3430867-.37560116-.10752146-.76586237-.16587951-1.15568824-.17249193-2.5587807-.00064534-4.58547766 2.00216524-4.58547766 4.49928198 0 .62691557.12797645 1.23496.37274865 1.7964426.11035133.2531347-.0053975.5477984-.25853224.6581497-.25313473.1103514-.54779841-.0053975-.65814974-.2585322-.29947131-.6869568-.45606667-1.43097603-.45606667-2.1960601 0-3.05211432 2.47714695-5.50006595 5.59399617-5.49921198.48576182.00815502.96289603.0795037 1.42238033.21103795zm-1.9766658 6.41091303 2.69835-2.94655317c.1788432-.21040373.4943901-.23598862.7047939-.05714545.2104037.17884318.2359886.49439014.0571454.70479387l-3.01637681 3.34277395c-.18039088.1999106-.48669547.2210637-.69285412.0478478l-1.93095347-1.62240047c-.21213845-.17678204-.24080048-.49206439-.06401844-.70420284.17678204-.21213844.49206439-.24080048.70420284-.06401844z" fill-rule="evenodd"/></symbol><symbol id="icon-expand"><path d="M7.498 11.918a.997.997 0 0 0-.003-1.411.995.995 0 0 0-1.412-.003l-4.102 4.102v-3.51A1 1 0 0 0 .98 10.09.992.992 0 0 0 0 11.092V17c0 .554.448 1.002 1.002 1.002h5.907c.554 0 1.002-.45 1.002-1.003 0-.539-.45-.978-1.006-.978h-3.51zm3.005-5.835a.997.997 0 0 0 .003 1.412.995.995 0 0 0 1.411.003l4.103-4.103v3.51a1 1 0 0 0 1.001 1.006A.992.992 0 0 0 18 6.91V1.002A1 1 0 0 0 17 0h-5.907a1.003 1.003 0 0 0-1.002 1.003c0 .539.45.978 1.006.978h3.51z" fill-rule="evenodd"/></symbol><symbol id="icon-explore" viewBox="0 0 18 18"><path d="m9 17c4.418278 0 8-3.581722 8-8s-3.581722-8-8-8-8 3.581722-8 8 3.581722 8 8 8zm0 1c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9zm0-2.5c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5c2.969509 0 5.400504-2.3575119 5.497023-5.31714844.0090007-.27599565.2400359-.49243782.5160315-.48343711.2759957.0090007.4924378.2400359.4834371.51603155-.114093 3.4985237-2.9869632 6.284554-6.4964916 6.284554zm-.29090657-12.99359748c.27587424-.01216621.50937715.20161139.52154336.47748563.01216621.27587423-.20161139.50937715-.47748563.52154336-2.93195733.12930094-5.25315116 2.54886451-5.25315116 5.49456849 0 .27614237-.22385763.5-.5.5s-.5-.22385763-.5-.5c0-3.48142406 2.74307146-6.34074398 6.20909343-6.49359748zm1.13784138 8.04763908-1.2004882-1.20048821c-.19526215-.19526215-.19526215-.51184463 0-.70710678s.51184463-.19526215.70710678 0l1.20048821 1.2004882 1.6006509-4.00162734-4.50670359 1.80268144-1.80268144 4.50670359zm4.10281269-6.50378907-2.6692597 6.67314927c-.1016411.2541026-.3029834.4554449-.557086.557086l-6.67314927 2.6692597 2.66925969-6.67314926c.10164107-.25410266.30298336-.45544495.55708602-.55708602z" fill-rule="evenodd"/></symbol><symbol id="icon-filter" viewBox="0 0 16 16"><path d="m14.9738641 0c.5667192 0 1.0261359.4477136 1.0261359 1 0 .24221858-.0902161.47620768-.2538899.65849851l-5.6938314 6.34147206v5.49997973c0 .3147562-.1520673.6111434-.4104543.7999971l-2.05227171 1.4999945c-.45337535.3313696-1.09655869.2418269-1.4365902-.1999993-.13321514-.1730955-.20522717-.3836284-.20522717-.5999978v-6.99997423l-5.69383133-6.34147206c-.3731872-.41563511-.32996891-1.0473954.09653074-1.41107611.18705584-.15950448.42716133-.2474224.67571519-.2474224zm-5.9218641 8.5h-2.105v6.491l.01238459.0070843.02053271.0015705.01955278-.0070558 2.0532976-1.4990996zm-8.02585008-7.5-.01564945.00240169 5.83249953 6.49759831h2.313l5.836-6.499z"/></symbol><symbol id="icon-home" viewBox="0 0 18 18"><path d="m9 5-6 6v5h4v-4h4v4h4v-5zm7 6.5857864v4.4142136c0 .5522847-.4477153 1-1 1h-5v-4h-2v4h-5c-.55228475 0-1-.4477153-1-1v-4.4142136c-.25592232 0-.51184464-.097631-.70710678-.2928932l-.58578644-.5857864c-.39052429-.3905243-.39052429-1.02368929 0-1.41421358l8.29289322-8.29289322 8.2928932 8.29289322c.3905243.39052429.3905243 1.02368928 0 1.41421358l-.5857864.5857864c-.1952622.1952622-.4511845.2928932-.7071068.2928932zm-7-9.17157284-7.58578644 7.58578644.58578644.5857864 7-6.99999996 7 6.99999996.5857864-.5857864z" fill-rule="evenodd"/></symbol><symbol id="icon-image" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm-3.49645283 10.1752453-3.89407257 6.7495552c.11705545.048464.24538859.0751995.37998328.0751995h10.60290092l-2.4329715-4.2154691-1.57494129 2.7288098zm8.49779013 6.8247547c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v13.98991071l4.50814957-7.81026689 3.08089884 5.33809539 1.57494129-2.7288097 3.5875735 6.2159812zm-3.0059397-11c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2-2-.8954305-2-2 .8954305-2 2-2zm0 1c-.5522847 0-1 .44771525-1 1s.4477153 1 1 1 1-.44771525 1-1-.4477153-1-1-1z" fill-rule="evenodd"/></symbol><symbol id="icon-info" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm0 7h-1.5l-.11662113.00672773c-.49733868.05776511-.88337887.48043643-.88337887.99327227 0 .47338693.32893365.86994729.77070917.97358929l.1126697.01968298.11662113.00672773h.5v3h-.5l-.11662113.0067277c-.42082504.0488782-.76196299.3590206-.85696816.7639815l-.01968298.1126697-.00672773.1166211.00672773.1166211c.04887817.4208251.35902055.761963.76398144.8569682l.1126697.019683.11662113.0067277h3l.1166211-.0067277c.4973387-.0577651.8833789-.4804365.8833789-.9932723 0-.4733869-.3289337-.8699473-.7707092-.9735893l-.1126697-.019683-.1166211-.0067277h-.5v-4l-.00672773-.11662113c-.04887817-.42082504-.35902055-.76196299-.76398144-.85696816l-.1126697-.01968298zm0-3.25c-.69035594 0-1.25.55964406-1.25 1.25s.55964406 1.25 1.25 1.25 1.25-.55964406 1.25-1.25-.55964406-1.25-1.25-1.25z" fill-rule="evenodd"/></symbol><symbol id="icon-institution" viewBox="0 0 18 18"><path d="m7 16.9998189v-2.0003623h4v2.0003623h2v-3.0005434h-8v3.0005434zm-3-10.00181122h-1.52632364c-.27614237 0-.5-.22389817-.5-.50009056 0-.13995446.05863589-.27350497.16166338-.36820841l1.23156713-1.13206327h-2.36690687v12.00217346h3v-2.0003623h-3v-1.0001811h3v-1.0001811h1v-4.00072448h-1zm10 0v2.00036224h-1v4.00072448h1v1.0001811h3v1.0001811h-3v2.0003623h3v-12.00217346h-2.3695309l1.2315671 1.13206327c.2033191.186892.2166633.50325042.0298051.70660631-.0946863.10304615-.2282126.16169266-.3681417.16169266zm3-3.00054336c.5522847 0 1 .44779634 1 1.00018112v13.00235456h-18v-13.00235456c0-.55238478.44771525-1.00018112 1-1.00018112h3.45499992l4.20535144-3.86558216c.19129876-.17584288.48537447-.17584288.67667324 0l4.2053514 3.86558216zm-4 3.00054336h-8v1.00018112h8zm-2 6.00108672h1v-4.00072448h-1zm-1 0v-4.00072448h-2v4.00072448zm-3 0v-4.00072448h-1v4.00072448zm8-4.00072448c.5522847 0 1 .44779634 1 1.00018112v2.00036226h-2v-2.00036226c0-.55238478.4477153-1.00018112 1-1.00018112zm-12 0c.55228475 0 1 .44779634 1 1.00018112v2.00036226h-2v-2.00036226c0-.55238478.44771525-1.00018112 1-1.00018112zm5.99868798-7.81907007-5.24205601 4.81852671h10.48411203zm.00131202 3.81834559c-.55228475 0-1-.44779634-1-1.00018112s.44771525-1.00018112 1-1.00018112 1 .44779634 1 1.00018112-.44771525 1.00018112-1 1.00018112zm-1 11.00199236v1.0001811h2v-1.0001811z" fill-rule="evenodd"/></symbol><symbol id="icon-location" viewBox="0 0 18 18"><path d="m9.39521328 16.2688008c.79596342-.7770119 1.59208152-1.6299956 2.33285652-2.5295081 1.4020032-1.7024324 2.4323601-3.3624519 2.9354918-4.871847.2228715-.66861448.3364384-1.29323246.3364384-1.8674457 0-3.3137085-2.6862915-6-6-6-3.36356866 0-6 2.60156856-6 6 0 .57421324.11356691 1.19883122.3364384 1.8674457.50313169 1.5093951 1.53348863 3.1694146 2.93549184 4.871847.74077492.8995125 1.53689309 1.7524962 2.33285648 2.5295081.13694479.1336842.26895677.2602648.39521328.3793207.12625651-.1190559.25826849-.2456365.39521328-.3793207zm-.39521328 1.7311992s-7-6-7-11c0-4 3.13400675-7 7-7 3.8659932 0 7 3.13400675 7 7 0 5-7 11-7 11zm0-8c-1.65685425 0-3-1.34314575-3-3s1.34314575-3 3-3c1.6568542 0 3 1.34314575 3 3s-1.3431458 3-3 3zm0-1c1.1045695 0 2-.8954305 2-2s-.8954305-2-2-2-2 .8954305-2 2 .8954305 2 2 2z" fill-rule="evenodd"/></symbol><symbol id="icon-minus" viewBox="0 0 16 16"><path d="m2.00087166 7h11.99825664c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-11.99825664c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-newsletter" viewBox="0 0 18 18"><path d="m9 11.8482489 2-1.1428571v-1.7053918h-4v1.7053918zm-3-1.7142857v-2.1339632h6v2.1339632l3-1.71428574v-6.41967746h-12v6.41967746zm10-5.3839632 1.5299989.95624934c.2923814.18273835.4700011.50320827.4700011.8479983v8.44575236c0 1.1045695-.8954305 2-2 2h-14c-1.1045695 0-2-.8954305-2-2v-8.44575236c0-.34479003.1776197-.66525995.47000106-.8479983l1.52999894-.95624934v-2.75c0-.55228475.44771525-1 1-1h12c.5522847 0 1 .44771525 1 1zm0 1.17924764v3.07075236l-7 4-7-4v-3.07075236l-1 .625v8.44575236c0 .5522847.44771525 1 1 1h14c.5522847 0 1-.4477153 1-1v-8.44575236zm-10-1.92924764h6v1h-6zm-1 2h8v1h-8z" fill-rule="evenodd"/></symbol><symbol id="icon-orcid" viewBox="0 0 18 18"><path d="m9 1c4.418278 0 8 3.581722 8 8s-3.581722 8-8 8-8-3.581722-8-8 3.581722-8 8-8zm-2.90107518 5.2732337h-1.41865256v7.1712107h1.41865256zm4.55867178.02508949h-2.99247027v7.14612121h2.91062487c.7673039 0 1.4476365-.1483432 2.0410182-.445034s1.0511995-.7152915 1.3734671-1.2558144c.3222677-.540523.4833991-1.1603247.4833991-1.85942385 0-.68545815-.1602789-1.30270225-.4808414-1.85175082-.3205625-.54904856-.7707074-.97532211-1.3504481-1.27883343-.5797408-.30351132-1.2413173-.45526471-1.9847495-.45526471zm-.1892674 1.07933542c.7877654 0 1.4143875.22336734 1.8798852.67010873.4654977.44674138.698243 1.05546001.698243 1.82617415 0 .74343221-.2310402 1.34447791-.6931277 1.80315511-.4620874.4586773-1.0750688.6880124-1.8389625.6880124h-1.46810075v-4.98745039zm-5.08652545-3.71099194c-.21825533 0-.410525.08444276-.57681478.25333081-.16628977.16888806-.24943341.36245684-.24943341.58071218 0 .22345188.08314364.41961891.24943341.58850696.16628978.16888806.35855945.25333082.57681478.25333082.233845 0 .43390938-.08314364.60019916-.24943342.16628978-.16628977.24943342-.36375592.24943342-.59240436 0-.233845-.08314364-.43131115-.24943342-.59240437s-.36635416-.24163862-.60019916-.24163862z" fill-rule="evenodd"/></symbol><symbol id="icon-plus" viewBox="0 0 16 16"><path d="m2.00087166 7h4.99912834v-4.99912834c0-.55276616.44386482-1.00087166 1-1.00087166.55228475 0 1 .44463086 1 1.00087166v4.99912834h4.9991283c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-4.9991283v4.9991283c0 .5527662-.44386482 1.0008717-1 1.0008717-.55228475 0-1-.4446309-1-1.0008717v-4.9991283h-4.99912834c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-print" viewBox="0 0 18 18"><path d="m16.0049107 5h-14.00982141c-.54941618 0-.99508929.4467783-.99508929.99961498v6.00077002c0 .5570958.44271433.999615.99508929.999615h1.00491071v-3h12v3h1.0049107c.5494162 0 .9950893-.4467783.9950893-.999615v-6.00077002c0-.55709576-.4427143-.99961498-.9950893-.99961498zm-2.0049107-1v-2.00208688c0-.54777062-.4519464-.99791312-1.0085302-.99791312h-7.9829396c-.55661731 0-1.0085302.44910695-1.0085302.99791312v2.00208688zm1 10v2.0018986c0 1.103521-.9019504 1.9981014-2.0085302 1.9981014h-7.9829396c-1.1092806 0-2.0085302-.8867064-2.0085302-1.9981014v-2.0018986h-1.00491071c-1.10185739 0-1.99508929-.8874333-1.99508929-1.999615v-6.00077002c0-1.10435686.8926228-1.99961498 1.99508929-1.99961498h1.00491071v-2.00208688c0-1.10341695.90195036-1.99791312 2.0085302-1.99791312h7.9829396c1.1092806 0 2.0085302.89826062 2.0085302 1.99791312v2.00208688h1.0049107c1.1018574 0 1.9950893.88743329 1.9950893 1.99961498v6.00077002c0 1.1043569-.8926228 1.999615-1.9950893 1.999615zm-1-3h-10v5.0018986c0 .5546075.44702548.9981014 1.0085302.9981014h7.9829396c.5565964 0 1.0085302-.4491701 1.0085302-.9981014zm-9 1h8v1h-8zm0 2h5v1h-5zm9-5c-.5522847 0-1-.44771525-1-1s.4477153-1 1-1 1 .44771525 1 1-.4477153 1-1 1z" fill-rule="evenodd"/></symbol><symbol id="icon-search" viewBox="0 0 22 22"><path d="M21.697 20.261a1.028 1.028 0 01.01 1.448 1.034 1.034 0 01-1.448-.01l-4.267-4.267A9.812 9.811 0 010 9.812a9.812 9.811 0 1117.43 6.182zM9.812 18.222A8.41 8.41 0 109.81 1.403a8.41 8.41 0 000 16.82z" fill-rule="evenodd"/></symbol><symbol id="icon-social-facebook" viewBox="0 0 24 24"><path d="m6.00368507 20c-1.10660471 0-2.00368507-.8945138-2.00368507-1.9940603v-12.01187942c0-1.10128908.89451376-1.99406028 1.99406028-1.99406028h12.01187942c1.1012891 0 1.9940603.89451376 1.9940603 1.99406028v12.01187942c0 1.1012891-.88679 1.9940603-2.0032184 1.9940603h-2.9570132v-6.1960818h2.0797387l.3114113-2.414723h-2.39115v-1.54164807c0-.69911803.1941355-1.1755439 1.1966615-1.1755439l1.2786739-.00055875v-2.15974763l-.2339477-.02492088c-.3441234-.03134957-.9500153-.07025255-1.6293054-.07025255-1.8435726 0-3.1057323 1.12531866-3.1057323 3.19187953v1.78079225h-2.0850778v2.414723h2.0850778v6.1960818z" fill-rule="evenodd"/></symbol><symbol id="icon-social-twitter" viewBox="0 0 24 24"><path d="m18.8767135 6.87445248c.7638174-.46908424 1.351611-1.21167363 1.6250764-2.09636345-.7135248.43394112-1.50406.74870123-2.3464594.91677702-.6695189-.73342162-1.6297913-1.19486605-2.6922204-1.19486605-2.0399895 0-3.6933555 1.69603749-3.6933555 3.78628909 0 .29642457.0314329.58673729.0942985.8617704-3.06469922-.15890802-5.78835241-1.66547825-7.60988389-3.9574208-.3174714.56076194-.49978171 1.21167363-.49978171 1.90536824 0 1.31404706.65223085 2.47224203 1.64236444 3.15218497-.60350999-.0198635-1.17401554-.1925232-1.67222562-.47366811v.04583885c0 1.83355406 1.27302891 3.36609966 2.96411421 3.71294696-.31118484.0886217-.63651445.1329326-.97441718.1329326-.2357461 0-.47149219-.0229194-.69466516-.0672303.47149219 1.5065703 1.83253297 2.6036468 3.44975116 2.632678-1.2651707 1.0160946-2.85724264 1.6196394-4.5891906 1.6196394-.29861172 0-.59093688-.0152796-.88011875-.0504227 1.63450624 1.0726291 3.57548241 1.6990934 5.66104951 1.6990934 6.79263079 0 10.50641749-5.7711113 10.50641749-10.7751859l-.0094298-.48894775c.7229547-.53478659 1.3516109-1.20250585 1.8419628-1.96190282-.6632323.30100846-1.3751855.50422736-2.1217148.59590507z" fill-rule="evenodd"/></symbol><symbol id="icon-social-youtube" viewBox="0 0 24 24"><path d="m10.1415 14.3973208-.0005625-5.19318431 4.863375 2.60554491zm9.963-7.92753362c-.6845625-.73643756-1.4518125-.73990314-1.803375-.7826454-2.518875-.18714178-6.2971875-.18714178-6.2971875-.18714178-.007875 0-3.7861875 0-6.3050625.18714178-.352125.04274226-1.1188125.04620784-1.8039375.7826454-.5394375.56084773-.7149375 1.8344515-.7149375 1.8344515s-.18 1.49597903-.18 2.99138042v1.4024082c0 1.495979.18 2.9913804.18 2.9913804s.1755 1.2736038.7149375 1.8344515c.685125.7364376 1.5845625.7133337 1.9850625.7901542 1.44.1420891 6.12.1859866 6.12.1859866s3.78225-.005776 6.301125-.1929178c.3515625-.0433198 1.1188125-.0467854 1.803375-.783223.5394375-.5608477.7155-1.8344515.7155-1.8344515s.18-1.4954014.18-2.9913804v-1.4024082c0-1.49540139-.18-2.99138042-.18-2.99138042s-.1760625-1.27360377-.7155-1.8344515z" fill-rule="evenodd"/></symbol><symbol id="icon-subject-medicine" viewBox="0 0 18 18"><path d="m12.5 8h-6.5c-1.65685425 0-3 1.34314575-3 3v1c0 1.6568542 1.34314575 3 3 3h1v-2h-.5c-.82842712 0-1.5-.6715729-1.5-1.5s.67157288-1.5 1.5-1.5h1.5 2 1 2c1.6568542 0 3-1.34314575 3-3v-1c0-1.65685425-1.3431458-3-3-3h-2v2h1.5c.8284271 0 1.5.67157288 1.5 1.5s-.6715729 1.5-1.5 1.5zm-5.5-1v-1h-3.5c-1.38071187 0-2.5-1.11928813-2.5-2.5s1.11928813-2.5 2.5-2.5h1.02786405c.46573528 0 .92507448.10843528 1.34164078.31671843l1.13382424.56691212c.06026365-1.05041141.93116291-1.88363055 1.99667093-1.88363055 1.1045695 0 2 .8954305 2 2h2c2.209139 0 4 1.790861 4 4v1c0 2.209139-1.790861 4-4 4h-2v1h2c1.1045695 0 2 .8954305 2 2s-.8954305 2-2 2h-2c0 1.1045695-.8954305 2-2 2s-2-.8954305-2-2h-1c-2.209139 0-4-1.790861-4-4v-1c0-2.209139 1.790861-4 4-4zm0-2v-2.05652691c-.14564246-.03538148-.28733393-.08714006-.42229124-.15461871l-1.15541752-.57770876c-.27771087-.13885544-.583937-.21114562-.89442719-.21114562h-1.02786405c-.82842712 0-1.5.67157288-1.5 1.5s.67157288 1.5 1.5 1.5zm4 1v1h1.5c.2761424 0 .5-.22385763.5-.5s-.2238576-.5-.5-.5zm-1 1v-5c0-.55228475-.44771525-1-1-1s-1 .44771525-1 1v5zm-2 4v5c0 .5522847.44771525 1 1 1s1-.4477153 1-1v-5zm3 2v2h2c.5522847 0 1-.4477153 1-1s-.4477153-1-1-1zm-4-1v-1h-.5c-.27614237 0-.5.2238576-.5.5s.22385763.5.5.5zm-3.5-9h1c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5z" fill-rule="evenodd"/></symbol><symbol id="icon-success" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm3.4860198 4.98163161-4.71802968 5.50657859-2.62834168-2.02300024c-.42862421-.36730544-1.06564993-.30775346-1.42283677.13301307-.35718685.44076653-.29927542 1.0958383.12934879 1.46314377l3.40735508 2.7323063c.42215801.3385221 1.03700951.2798252 1.38749189-.1324571l5.38450527-6.33394549c.3613513-.43716226.3096573-1.09278382-.115462-1.46437175-.4251192-.37158792-1.0626796-.31842941-1.4240309.11873285z" fill-rule="evenodd"/></symbol><symbol id="icon-table" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587l-4.0059107-.001.001.001h-1l-.001-.001h-5l.001.001h-1l-.001-.001-3.00391071.001c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm-11.0059107 5h-3.999v6.9941413c0 .5572961.44630695 1.0058587.99508929 1.0058587h3.00391071zm6 0h-5v8h5zm5.0059107-4h-4.0059107v3h5.001v1h-5.001v7.999l4.0059107.001c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-12.5049107 9c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.2238576.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238576-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm-6-2c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.2238576.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.2238576-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.2238576.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.2238576-.5-.5s.22385763-.5.5-.5zm-6-2c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-1c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm12 0c.2761424 0 .5.22385763.5.5s-.2238576.5-.5.5h-2c-.2761424 0-.5-.22385763-.5-.5s.2238576-.5.5-.5zm-6 0c.27614237 0 .5.22385763.5.5s-.22385763.5-.5.5h-2c-.27614237 0-.5-.22385763-.5-.5s.22385763-.5.5-.5zm1.499-5h-5v3h5zm-6 0h-3.00391071c-.54871518 0-.99508929.44887827-.99508929 1.00585866v1.99414134h3.999z" fill-rule="evenodd"/></symbol><symbol id="icon-tick-circle" viewBox="0 0 24 24"><path d="m12 2c5.5228475 0 10 4.4771525 10 10s-4.4771525 10-10 10-10-4.4771525-10-10 4.4771525-10 10-10zm0 1c-4.97056275 0-9 4.02943725-9 9 0 4.9705627 4.02943725 9 9 9 4.9705627 0 9-4.0294373 9-9 0-4.97056275-4.0294373-9-9-9zm4.2199868 5.36606669c.3613514-.43716226.9989118-.49032077 1.424031-.11873285s.4768133 1.02720949.115462 1.46437175l-6.093335 6.94397871c-.3622945.4128716-.9897871.4562317-1.4054264.0971157l-3.89719065-3.3672071c-.42862421-.3673054-.48653564-1.0223772-.1293488-1.4631437s.99421256-.5003185 1.42283677-.1330131l3.11097438 2.6987741z" fill-rule="evenodd"/></symbol><symbol id="icon-tick" viewBox="0 0 16 16"><path d="m6.76799012 9.21106946-3.1109744-2.58349728c-.42862421-.35161617-1.06564993-.29460792-1.42283677.12733148s-.29927541 1.04903009.1293488 1.40064626l3.91576307 3.23873978c.41034319.3393961 1.01467563.2976897 1.37450571-.0948578l6.10568327-6.660841c.3613513-.41848908.3096572-1.04610608-.115462-1.4018218-.4251192-.35571573-1.0626796-.30482786-1.424031.11366122z" fill-rule="evenodd"/></symbol><symbol id="icon-update" viewBox="0 0 18 18"><path d="m1 13v1c0 .5522847.44771525 1 1 1h14c.5522847 0 1-.4477153 1-1v-1h-1v-10h-14v10zm16-1h1v2c0 1.1045695-.8954305 2-2 2h-14c-1.1045695 0-2-.8954305-2-2v-2h1v-9c0-.55228475.44771525-1 1-1h14c.5522847 0 1 .44771525 1 1zm-1 0v1h-4.5857864l-1 1h-2.82842716l-1-1h-4.58578644v-1h5l1 1h2l1-1zm-13-8h12v7h-12zm1 1v5h10v-5zm1 1h4v1h-4zm0 2h4v1h-4z" fill-rule="evenodd"/></symbol><symbol id="icon-upload" viewBox="0 0 18 18"><path d="m10.0046024 0c.5497429 0 1.3179837.32258606 1.707238.71184039l4.5763192 4.57631922c.3931386.39313859.7118404 1.16760135.7118404 1.71431368v8.98899651c0 1.1092806-.8945138 2.0085302-1.9940603 2.0085302h-12.01187942c-1.10128908 0-1.99406028-.8926228-1.99406028-1.9950893v-14.00982141c0-1.10185739.88743329-1.99508929 1.99961498-1.99508929zm0 1h-7.00498742c-.55709576 0-.99961498.44271433-.99961498.99508929v14.00982141c0 .5500396.44491393.9950893.99406028.9950893h12.01187942c.5463747 0 .9940603-.4506622.9940603-1.0085302v-8.98899651c0-.28393444-.2150684-.80332809-.4189472-1.0072069l-4.5763192-4.57631922c-.2038461-.20384606-.718603-.41894717-1.0001312-.41894717zm-1.85576936 4.14572769c.19483374-.19483375.51177826-.19377714.70556874.00001334l2.59099082 2.59099079c.1948411.19484112.1904373.51514474.0027906.70279143-.1932998.19329987-.5046517.19237083-.7001856-.00692852l-1.74638687-1.7800176v6.14827687c0 .2717771-.23193359.492096-.5.492096-.27614237 0-.5-.216372-.5-.492096v-6.14827641l-1.74627892 1.77990922c-.1933927.1971171-.51252214.19455839-.70016883.0069117-.19329987-.19329988-.19100584-.50899493.00277731-.70277808z" fill-rule="evenodd"/></symbol><symbol id="icon-video" viewBox="0 0 18 18"><path d="m16.0049107 2c1.1018574 0 1.9950893.89706013 1.9950893 2.00585866v9.98828264c0 1.1078052-.8926228 2.0058587-1.9950893 2.0058587h-14.00982141c-1.10185739 0-1.99508929-.8970601-1.99508929-2.0058587v-9.98828264c0-1.10780515.8926228-2.00585866 1.99508929-2.00585866zm0 1h-14.00982141c-.54871518 0-.99508929.44887827-.99508929 1.00585866v9.98828264c0 .5572961.44630695 1.0058587.99508929 1.0058587h14.00982141c.5487152 0 .9950893-.4488783.9950893-1.0058587v-9.98828264c0-.55729607-.446307-1.00585866-.9950893-1.00585866zm-8.30912922 2.24944486 4.60460462 2.73982242c.9365543.55726659.9290753 1.46522435 0 2.01804082l-4.60460462 2.7398224c-.93655425.5572666-1.69578148.1645632-1.69578148-.8937585v-5.71016863c0-1.05087579.76670616-1.446575 1.69578148-.89375851zm-.67492769.96085624v5.5750128c0 .2995102-.10753745.2442517.16578928.0847713l4.58452283-2.67497259c.3050619-.17799716.3051624-.21655446 0-.39461026l-4.58452283-2.67497264c-.26630747-.15538481-.16578928-.20699944-.16578928.08477139z" fill-rule="evenodd"/></symbol><symbol id="icon-warning" viewBox="0 0 18 18"><path d="m9 11.75c.69035594 0 1.25.5596441 1.25 1.25s-.55964406 1.25-1.25 1.25-1.25-.5596441-1.25-1.25.55964406-1.25 1.25-1.25zm.41320045-7.75c.55228475 0 1.00000005.44771525 1.00000005 1l-.0034543.08304548-.3333333 4c-.043191.51829212-.47645714.91695452-.99654578.91695452h-.15973424c-.52008864 0-.95335475-.3986624-.99654576-.91695452l-.33333333-4c-.04586475-.55037702.36312325-1.03372649.91350028-1.07959124l.04148683-.00259031zm-.41320045 14c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-checklist-banner" viewBox="0 0 56.69 56.69"><path style="fill:none" d="M0 0h56.69v56.69H0z"/><clipPath id="b"><use xlink:href="#a" style="overflow:visible"/></clipPath><path d="M21.14 34.46c0-6.77 5.48-12.26 12.24-12.26s12.24 5.49 12.24 12.26-5.48 12.26-12.24 12.26c-6.76-.01-12.24-5.49-12.24-12.26zm19.33 10.66 10.23 9.22s1.21 1.09 2.3-.12l2.09-2.32s1.09-1.21-.12-2.3l-10.23-9.22m-19.29-5.92c0-4.38 3.55-7.94 7.93-7.94s7.93 3.55 7.93 7.94c0 4.38-3.55 7.94-7.93 7.94-4.38-.01-7.93-3.56-7.93-7.94zm17.58 12.99 4.14-4.81" style="clip-path:url(#b);fill:none;stroke:#01324b;stroke-width:2;stroke-linecap:round"/><path d="M8.26 9.75H28.6M8.26 15.98H28.6m-20.34 6.2h12.5m14.42-5.2V4.86s0-2.93-2.93-2.93H4.13s-2.93 0-2.93 2.93v37.57s0 2.93 2.93 2.93h15.01M8.26 9.75H28.6M8.26 15.98H28.6m-20.34 6.2h12.5" style="clip-path:url(#b);fill:none;stroke:#01324b;stroke-width:2;stroke-linecap:round;stroke-linejoin:round"/></symbol><symbol id="icon-chevron-down" viewBox="0 0 16 16"><path d="m5.58578644 3-3.29289322-3.29289322c-.39052429-.39052429-.39052429-1.02368927 0-1.41421356s1.02368927-.39052429 1.41421356 0l4 4c.39052429.39052429.39052429 1.02368927 0 1.41421356l-4 4c-.39052429.39052429-1.02368927.39052429-1.41421356 0s-.39052429-1.02368927 0-1.41421356z" fill-rule="evenodd" transform="matrix(0 1 -1 0 11 1)"/></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-chevron-down-medium" viewBox="0 0 16 16"><path d="m2.00087166 7h4.99912834v-4.99912834c0-.55276616.44386482-1.00087166 1-1.00087166.55228475 0 1 .44463086 1 1.00087166v4.99912834h4.9991283c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-4.9991283v4.9991283c0 .5527662-.44386482 1.0008717-1 1.0008717-.55228475 0-1-.4446309-1-1.0008717v-4.9991283h-4.99912834c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></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-right-medium" 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)"/></symbol><symbol id="icon-eds-i-chevron-right-small" 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)"/></symbol><symbol id="icon-eds-i-chevron-up-medium" viewBox="0 0 16 16"><path d="m2.00087166 7h11.99825664c.5527662 0 1.0008717.44386482 1.0008717 1 0 .55228475-.4446309 1-1.0008717 1h-11.99825664c-.55276616 0-1.00087166-.44386482-1.00087166-1 0-.55228475.44463086-1 1.00087166-1z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-close-medium" viewBox="0 0 16 16"><path d="m2.29679575 12.2772478c-.39658757.3965876-.39438847 1.0328109-.00062148 1.4265779.39651227.3965123 1.03246768.3934888 1.42657791-.0006214l4.27724782-4.27724787 4.2772478 4.27724787c.3965876.3965875 1.0328109.3943884 1.4265779.0006214.3965123-.3965122.3934888-1.0324677-.0006214-1.4265779l-4.27724787-4.2772478 4.27724787-4.27724782c.3965875-.39658757.3943884-1.03281091.0006214-1.42657791-.3965122-.39651226-1.0324677-.39348875-1.4265779.00062148l-4.2772478 4.27724782-4.27724782-4.27724782c-.39658757-.39658757-1.03281091-.39438847-1.42657791-.00062148-.39651226.39651227-.39348875 1.03246768.00062148 1.42657791l4.27724782 4.27724782z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-download-medium" viewBox="0 0 16 16"><path d="m12.9975267 12.999368c.5467123 0 1.0024733.4478567 1.0024733 1.000316 0 .5563109-.4488226 1.000316-1.0024733 1.000316h-9.99505341c-.54671233 0-1.00247329-.4478567-1.00247329-1.000316 0-.5563109.44882258-1.000316 1.00247329-1.000316zm-4.9975267-11.999368c.55228475 0 1 .44497754 1 .99589209v6.80214418l2.4816273-2.48241149c.3928222-.39294628 1.0219732-.4006883 1.4030652-.01947579.3911302.39125371.3914806 1.02525073-.0001404 1.41699553l-4.17620792 4.17752758c-.39120769.3913313-1.02508144.3917306-1.41671995-.0000316l-4.17639421-4.17771394c-.39122513-.39134876-.39767006-1.01940351-.01657797-1.40061601.39113012-.39125372 1.02337105-.3931606 1.41951349.00310701l2.48183446 2.48261871v-6.80214418c0-.55001601.44386482-.99589209 1-.99589209z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-info-filled-medium" viewBox="0 0 18 18"><path d="m9 0c4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9zm0 7h-1.5l-.11662113.00672773c-.49733868.05776511-.88337887.48043643-.88337887.99327227 0 .47338693.32893365.86994729.77070917.97358929l.1126697.01968298.11662113.00672773h.5v3h-.5l-.11662113.0067277c-.42082504.0488782-.76196299.3590206-.85696816.7639815l-.01968298.1126697-.00672773.1166211.00672773.1166211c.04887817.4208251.35902055.761963.76398144.8569682l.1126697.019683.11662113.0067277h3l.1166211-.0067277c.4973387-.0577651.8833789-.4804365.8833789-.9932723 0-.4733869-.3289337-.8699473-.7707092-.9735893l-.1126697-.019683-.1166211-.0067277h-.5v-4l-.00672773-.11662113c-.04887817-.42082504-.35902055-.76196299-.76398144-.85696816l-.1126697-.01968298zm0-3.25c-.69035594 0-1.25.55964406-1.25 1.25s.55964406 1.25 1.25 1.25 1.25-.55964406 1.25-1.25-.55964406-1.25-1.25-1.25z" fill-rule="evenodd"/></symbol><symbol id="icon-eds-i-mail-medium" viewBox="0 0 24 24"><path d="m19.462 0c1.413 0 2.538 1.184 2.538 2.619v12.762c0 1.435-1.125 2.619-2.538 2.619h-16.924c-1.413 0-2.538-1.184-2.538-2.619v-12.762c0-1.435 1.125-2.619 2.538-2.619zm.538 5.158-7.378 6.258a2.549 2.549 0 0 1 -3.253-.008l-7.369-6.248v10.222c0 .353.253.619.538.619h16.924c.285 0 .538-.266.538-.619zm-.538-3.158h-16.924c-.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-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-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-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-filled-medium" viewBox="0 0 18 18"><path d="m9 11.75c.69035594 0 1.25.5596441 1.25 1.25s-.55964406 1.25-1.25 1.25-1.25-.5596441-1.25-1.25.55964406-1.25 1.25-1.25zm.41320045-7.75c.55228475 0 1.00000005.44771525 1.00000005 1l-.0034543.08304548-.3333333 4c-.043191.51829212-.47645714.91695452-.99654578.91695452h-.15973424c-.52008864 0-.95335475-.3986624-.99654576-.91695452l-.33333333-4c-.04586475-.55037702.36312325-1.03372649.91350028-1.07959124l.04148683-.00259031zm-.41320045 14c-4.97056275 0-9-4.0294373-9-9 0-4.97056275 4.02943725-9 9-9 4.9705627 0 9 4.02943725 9 9 0 4.9705627-4.0294373 9-9 9z" fill-rule="evenodd"/></symbol><symbol id="icon-expand-image" viewBox="0 0 18 18"><path d="m7.49754099 11.9178212c.38955542-.3895554.38761957-1.0207846-.00290473-1.4113089-.39324695-.3932469-1.02238878-.3918247-1.41130883-.0029047l-4.10273549 4.1027355.00055454-3.5103985c.00008852-.5603185-.44832171-1.006032-1.00155062-1.0059446-.53903074.0000852-.97857527.4487442-.97866268 1.0021075l-.00093318 5.9072465c-.00008751.553948.44841131 1.001882 1.00174994 1.0017946l5.906983-.0009331c.5539233-.0000875 1.00197907-.4486389 1.00206646-1.0018679.00008515-.5390307-.45026621-.9784332-1.00588841-.9783454l-3.51010549.0005545zm3.00571741-5.83449376c-.3895554.38955541-.3876196 1.02078454.0029047 1.41130883.393247.39324696 1.0223888.39182478 1.4113089.00290473l4.1027355-4.10273549-.0005546 3.5103985c-.0000885.56031852.4483217 1.006032 1.0015506 1.00594461.5390308-.00008516.9785753-.44874418.9786627-1.00210749l.0009332-5.9072465c.0000875-.553948-.4484113-1.00188204-1.0017499-1.00179463l-5.906983.00093313c-.5539233.00008751-1.0019791.44863892-1.0020665 1.00186784-.0000852.53903074.4502662.97843325 1.0058884.97834547l3.5101055-.00055449z" fill-rule="evenodd"/></symbol><symbol id="icon-github" viewBox="0 0 100 100"><path fill-rule="evenodd" clip-rule="evenodd" d="M48.854 0C21.839 0 0 22 0 49.217c0 21.756 13.993 40.172 33.405 46.69 2.427.49 3.316-1.059 3.316-2.362 0-1.141-.08-5.052-.08-9.127-13.59 2.934-16.42-5.867-16.42-5.867-2.184-5.704-5.42-7.17-5.42-7.17-4.448-3.015.324-3.015.324-3.015 4.934.326 7.523 5.052 7.523 5.052 4.367 7.496 11.404 5.378 14.235 4.074.404-3.178 1.699-5.378 3.074-6.6-10.839-1.141-22.243-5.378-22.243-24.283 0-5.378 1.94-9.778 5.014-13.2-.485-1.222-2.184-6.275.486-13.038 0 0 4.125-1.304 13.426 5.052a46.97 46.97 0 0 1 12.214-1.63c4.125 0 8.33.571 12.213 1.63 9.302-6.356 13.427-5.052 13.427-5.052 2.67 6.763.97 11.816.485 13.038 3.155 3.422 5.015 7.822 5.015 13.2 0 18.905-11.404 23.06-22.324 24.283 1.78 1.548 3.316 4.481 3.316 9.126 0 6.6-.08 11.897-.08 13.526 0 1.304.89 2.853 3.316 2.364 19.412-6.52 33.405-24.935 33.405-46.691C97.707 22 75.788 0 48.854 0z"/></symbol><symbol id="icon-springer-arrow-left"><path d="M15 7a1 1 0 000-2H3.385l2.482-2.482a.994.994 0 00.02-1.403 1.001 1.001 0 00-1.417 0L.294 5.292a1.001 1.001 0 000 1.416l4.176 4.177a.991.991 0 001.4.016 1 1 0 00-.003-1.42L3.385 7H15z"/></symbol><symbol id="icon-springer-arrow-right"><path d="M1 7a1 1 0 010-2h11.615l-2.482-2.482a.994.994 0 01-.02-1.403 1.001 1.001 0 011.417 0l4.176 4.177a1.001 1.001 0 010 1.416l-4.176 4.177a.991.991 0 01-1.4.016 1 1 0 01.003-1.42L12.615 7H1z"/></symbol><symbol id="icon-submit-open" viewBox="0 0 16 17"><path d="M12 0c1.10457 0 2 .895431 2 2v5c0 .276142-.223858.5-.5.5S13 7.276142 13 7V2c0-.512836-.38604-.935507-.883379-.993272L12 1H6v3c0 1.10457-.89543 2-2 2H1v8c0 .512836.38604.935507.883379.993272L2 15h6.5c.276142 0 .5.223858.5.5s-.223858.5-.5.5H2c-1.104569 0-2-.89543-2-2V5.828427c0-.530433.210714-1.039141.585786-1.414213L4.414214.585786C4.789286.210714 5.297994 0 5.828427 0H12Zm3.41 11.14c.250899.250899.250274.659726 0 .91-.242954.242954-.649606.245216-.9-.01l-1.863671-1.900337.001043 5.869492c0 .356992-.289839.637138-.647372.637138-.347077 0-.647371-.285256-.647371-.637138l-.001043-5.869492L9.5 12.04c-.253166.258042-.649726.260274-.9.01-.242954-.242954-.252269-.657731 0-.91l2.942184-2.951303c.250908-.250909.66127-.252277.91353-.000017L15.41 11.14ZM5 1.413 1.413 5H4c.552285 0 1-.447715 1-1V1.413ZM11 3c.276142 0 .5.223858.5.5s-.223858.5-.5.5H7.5c-.276142 0-.5-.223858-.5-.5s.223858-.5.5-.5H11Zm0 2c.276142 0 .5.223858.5.5s-.223858.5-.5.5H7.5c-.276142 0-.5-.223858-.5-.5s.223858-.5.5-.5H11Z" fill-rule="nonzero"/></symbol></svg> </div> </body> </html>