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  • 1.
    Abdulla, Salim
    et al.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Bassat, Quique
    Univ Barcelona, Ctr Invest Saude Manhica Manhica Mozamb & ISGloba, Barcelona Ctr Int Hlth Res CRESIB, Hosp Clin, Barcelona, Spain..
    Bethell, Delia
    AFRIMS, Dept Immunol & Med, Bangkok, Thailand..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Borrmann, Steffen
    Kenya Govt Med Res Ctr, Wellcome Trust Res Programme, Kilifi, Kenya.;Univ Magdeburg, Sch Med, D-39106 Magdeburg, Germany..
    D'Alessandro, Umberto
    Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium.;MRC Unit, Fajara, Gambia..
    Dahal, Prabin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Day, Nicholas P.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Diakite, Mahamadou
    Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali..
    Djimde, Abdoulaye A.
    Dondorp, Arjen M.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Duong, Socheat
    Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Edstein, Michael D.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA..
    Faiz, M. Abul
    Malaria Res Grp MRG & Dev Care Fdn, Dhaka, Bangladesh..
    Falade, Catherine
    Univ Ibadan, Coll Med, Ibadan, Nigeria..
    Flegg, Jennifer A.
    Monash Univ, Sch Math Sci, Clayton, Vic 3800, Australia..
    Fogg, Carole
    Univ Portsmouth, Portsmouth, Hants, England..
    Gonzalez, Raquel
    Ctr Invest Saude Manhica Manhica Mozamb, Barcelona, Spain.;CRESIB, Barcelona, Spain..
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1, England..
    Guerin, Philippe J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Guthmann, Jean-Paul
    Epicentre, Paris, France..
    Hamed, Kamal
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hien, Tran Tinh
    Htut, Ye
    Dept Med Res, Lower Myanmar, Yangon, Myanmar..
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA.;US & Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Microbiol Cell & Tumour Biol, Dept Publ Hlth Sci, Malaria Res, Stockholm, Sweden..
    Mayxay, Mayfong
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos.;Univ Hlth Sci, Fac Postgrad Studies, Viangchan, Laos..
    Mokuolu, Olugbenga A.
    Univ Ilorin, Dept Paediat & Child Hlth, Ilorin, Nigeria..
    Moreira, Clarissa
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Newton, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahosot Hosp, Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit LOMWRU, Viangchan, Laos..
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria..
    Nosten, Francois
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, US Army Med Res Unit, Kisumu, Kenya..
    Onyamboko, Marie A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Phyo, Aung Pyae
    Mahidol Univ, Shoklo Malaria Res Unit, Mahidol Oxford Trop Med Res Unit, Fac Trop Med, Bangkok 10700, Thailand..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dar Es Salaam, Tanzania..
    Price, Ric N.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.;Charles Darwin Univ, Darwin, NT 0909, Australia..
    Pukrittayakamee, Sasithon
    Mahidol Univ, Fac Trop Med, Bangkok 10700, Thailand..
    Ramharter, Michael
    Med Univ Vienna, Div Infect Dis & Trop Med, Dept Med 1, Vienna, Austria.;Univ Tubingen, Inst Tropenmed, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Sagara, Issaka
    Univ Bamako, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali..
    Se, Youry
    AFRIMS, Phnom Penh, Cambodia..
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia..
    Stepniewska, Kasia
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;WorldWide Antimalarial Resistance Network WWARN, Oxford, England..
    Ward, Stephen A.
    Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    White, Nicholas J.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Mahidol Oxford Trop Med Res Unit MORU, Fac Trop Med, Bangkok 10700, Thailand..
    Winstanley, Peter A.
    Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis2015In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 359Article in journal (Refereed)
    Abstract [en]

    Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.

  • 2. Adjuik, Martin A.
    et al.
    Allan, Richard
    Anvikar, Anupkumar R.
    Ashley, Elizabeth A.
    Ba, Mamadou S.
    Barennes, Hubert
    Barnes, Karen I.
    Bassat, Quique
    Baudin, Elisabeth
    Bjorkman, Anders
    Bompart, Francois
    Bonnet, Maryline
    Borrmann, Steffen
    Brasseur, Philippe
    Bukirwa, Hasifa
    Checchi, Francesco
    Cot, Michel
    Dahal, Prabin
    D'Alessandro, Umberto
    Deloron, Philippe
    Desai, Meghna
    Diap, Graciela
    Djimde, Abdoulaye A.
    Dorsey, Grant
    Doumbo, Ogobara K.
    Espie, Emmanuelle
    Etard, Jean-Francois
    Fanello, Caterina I.
    Faucher, Jean-Francois
    Faye, Babacar
    Flegg, Jennifer A.
    Gaye, Oumar
    Gething, Peter W.
    Gonzalez, Raquel
    Grandesso, Francesco
    Guerin, Philippe J.
    Guthmann, Jean-Paul
    Hamour, Sally
    Hasugian, Armedy Ronny
    Hay, Simon I.
    Humphreys, Georgina S.
    Jullien, Vincent
    Juma, Elizabeth
    Kamya, Moses R.
    Karema, Corine
    Kiechel, Jean R.
    Kremsner, Peter G.
    Krishna, Sanjeev
    Lameyre, Valerie
    Ibrahim, Laminou M.
    Lee, Sue J.
    Lell, Bertrand
    Martensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Massougbodji, Achille
    Menan, Herve
    Menard, Didier
    Menendez, Clara
    Meremikwu, Martin
    Moreira, Clarissa
    Nabasumba, Carolyn
    Nambozi, Michael
    Ndiaye, Jean-Louis
    Nikiema, Frederic
    Nsanzabana, Christian
    Ntoumi, Francine
    Ogutu, Bernhards R.
    Olliaro, Piero
    Osorio, Lyda
    Ouedraogo, Jean-Bosco
    Penali, Louis K.
    Pene, Mbaye
    Pinoges, Loretxu
    Piola, Patrice
    Price, Ric N.
    Roper, Cally
    Rosenthal, Philip J.
    Rwagacondo, Claude Emile
    Same-Ekobo, Albert
    Schramm, Birgit
    Seck, Amadou
    Sharma, Bhawna
    Sibley, Carol Hopkins
    Sinou, Veronique
    Sirima, Sodiomon B.
    Smith, Jeffery J.
    Smithuis, Frank
    Some, Fabrice A.
    Sow, Doudou
    Staedke, Sarah G.
    Stepniewska, Kasia
    Swarthout, Todd D.
    Sylla, Khadime
    Talisuna, Ambrose O.
    Tarning, Joel
    Taylor, Walter R. J.
    Temu, Emmanuel A.
    Thwing, Julie I.
    Tjitra, Emiliana
    Tine, Roger C. K.
    Tinto, Halidou
    Vaillant, Michel T.
    Valecha, Neena
    Van den Broek, Ingrid
    White, Nicholas J.
    Yeka, Adoke
    Zongo, Issaka
    The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data2015In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 13, article id 66Article in journal (Refereed)
    Abstract [en]

    Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

  • 3.
    Amaratunga, Chanaki
    et al.
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Andrianaranjaka, Voahangy Hanitriniaina
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar;Univ Antananarivo, Fac Sci, Antananarivo, Madagascar.
    Ashley, Elizabeth
    MOCRU, Yangon, Myanmar;Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England.
    Bethell, Delia
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Bjorkman, Anders
    Karolinska Inst, Dept Mol Tumor & Cell Biol, Stockholm, Sweden.
    Bonnington, Craig A.
    Shoklo Malaria Res Unit, Mae Sot, Thailand.
    Cooper, Roland A.
    Dominican Univ Calif, Dept Nat Sci & Math, San Rafael, CA USA.
    Dhorda, Mehul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Dondorp, Arjen
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand.
    Erhart, Annette
    ITM Antwerp, Dept Publ Hlth, Antwerp, Belgium;Inst Trop Med, MRC Unit Gambia, Fajara, Gambia;Inst Trop Med, MRC Unit Gambia, Fajara, Gambia.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Faiz, Abul
    Dev Care Fdn, Dhaka, Bangladesh.
    Fanello, Caterina
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Oxford Res Unit, Bangkok, Thailand.
    Fukuda, Mark M.
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Guerin, Philippe
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    van Huijsduijnen, Rob Hooft
    Med Malaria Venture, Geneva, Switzerland.
    Hien, Tran Tinh
    Hong, N. V.
    Natl Inst Malariol Parasitol & Entomol, Hanoi, Vietnam.
    Htut, Ye
    Dept Med Res, Yangon, Myanmar.
    Huang, Fang
    Chinese Ctr Dis Control & Prevent, Natl Inst Parasit Dis, Shanghai, Peoples R China.
    Humphreys, Georgina
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Imwong, Mallika
    Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Kennon, Kalynn
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Lin, Khin
    Dept Med Res, Pyin Oo Lwin Branch, Anesakhan, Myanmar.
    Lon, Chanthap
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mayxay, Mayfong
    Lao Oxford Mahosot Hospital, Wellcome Trust Res Unit, LOMWRU, Viangchan, Laos;Univ Hlth Sci, Minist Hlth, Fac Postgrad Studies, Viangchan, Laos;Churchill Hosp, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England.
    Mokuolu, Olugbenga
    Univ Ilorin, Coll Hlth Sci, Dept Paediat & Child Hlth, Ilorin, Nigeria;Univ Ilorin, Teaching Hosp, Ctr Malaria & Other Trop Dis Care, Ilorin, Nigeria.
    Morris, Ulrika
    Karolinska Inst, Dept Mol Tumor & Cell Biol, Stockholm, Sweden.
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Amambua-Ngwa, Alfred
    Inst Trop Med, MRC Unit Gambia, Fajara, Gambia.
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria.
    Nosten, Francois
    Shoklo Malaria Res Unit, Mae Sot, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Onyamboko, Marie
    Mahidol Oxford Res Unit, Bangkok, Thailand;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO.
    Phyo, Aung Pyae
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Plowe, Christopher V.
    Duke Univ, Duke Global Hlth Inst, Durham, NC USA.
    Pukrittayakamee, Sasithon
    Mahidol Univ, Dept Clin Trop Med, Bangkok, Thailand;Royal Soc Thailand, Bangkok, Thailand.
    Randrianarivelojosia, Milijaona
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar;Univ Toliara, Fac Sci, Toliara, Madagascar.
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA;Univ Calif San Francisco, Div HIV Infect Dis & Global Med, San Francisco, CA 94143 USA.
    Saunders, David L.
    Armed Forces Res Inst Regenerat Med, Bangkok, Thailand;US Army Med Mat Dev Act, Ft Detrick, MD USA.
    Sibley, Carol Hopkins
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Smithuis, Frank
    Myanmar Oxford Clin Res Unit, Yangon, Myanmar.
    Spring, Michele D.
    Armed Forces Res Inst Med Sci, Dept Immunol & Med, Bangkok, Thailand.
    Sondo, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;CRUN, Ouaga, Burkina Faso.
    Sreng, Sokunthea
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia.
    Starzengruber, Peter
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria;Med Univ Vienna, Dept Lab Med, Div Clin Microbiol, Vienna, Austria.
    Stepniewska, Kasia
    Univ Oxford, Ctr Trop Med & Global Hlth, WWARN, Oxford, England.
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia.
    Takala-Harrison, Shannon
    Univ Maryland, Sch Med, Inst Global Hlth, Div Malaria Res, Baltimore, MD 21201 USA.
    Thriemer, Kamala
    Inst Trop Med, Antwerp, Belgium;Menzies Sch Hlth Res, Darwin, NT, Australia.
    Thuy-Nhien, Nguyen
    Tun, Kyaw Myo
    Myanmar Oxford Clin Res Unit, Yangon, Myanmar;Def Serv Med Acad, Yangon, Myanmar.
    White, Nicholas J.
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Woodrow, Charles
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments: a WWARN individual patient data meta-analysis2019In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 17, p. 1-20, article id 1Article in journal (Refereed)
    Abstract [en]

    Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7_1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC1/2) and pfk13 genotype based on a large set of individual patient records from Asia and Africa.

    Methods: A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site.

    Results: Both the pfk13 genotypes and the PC1/2 were available from 3250 (95%) patients (n=3012 from Asia (93%), n=238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC1/2 compared to the PC1/2 of wild type isolates (all p≤0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4-1.6) longer PC1/2. None of the isolates from four countries in Africa showed a significant difference between the PC1/2 of parasites with or without pfk13 propeller region mutations.Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia.

    Conclusion: Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

  • 4.
    Andersson, Maria Eva
    et al.
    Department of Infectious Diseases, University of Gothenburg , Gothenburg , Sweden.
    Elfving, Kristina
    Department of Infectious Diseases, University of Gothenburg , Gothenburg , Sweden.; Univ Gothenburg, Dept Pediat, Gothenburg, Sweden..
    Shakely, Deler
    Department of Medicine, Kungälv Hospital, Sweden.; Karolinska Institutet, Malaria Res, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Nilsson, Staffan
    Chalmers University of Technology, Gothenburg, Sweden.
    Msellem, Mwinyi
    Zanzibar Malaria Elimination Programme, Ministry of Health, Tanzania.
    Trollfors, Birger
    Department of Pediatrics, University of Gothenburg, Gothenburg, Sweden.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Björkman, Anders
    Malaria Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm.
    Lindh, Magnus
    Department of Infectious Diseases, University of Gothenburg , Gothenburg , Sweden.
    Rapid Clearance and Frequent Reinfection With Enteric Pathogens Among Children With Acute Diarrhea in Zanzibar.2017In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 65, no 8, p. 1371-1377Article in journal (Refereed)
    Abstract [en]

    Background: Acute infectious gastroenteritis is an important cause of illness and death among children in low-income countries. In addition to rotavirus vaccination, actions to improve nutrition status, sanitation, and water quality are important to reduce enteric infections, which are frequent also among asymptomatic children. The aim of this study was to investigate if the high prevalence of these infections reflects that they often are not cleared properly by the immune response or rather is due to frequent pathogen exposure.

    Methods: Rectal swabs were collected at time of acute diarrhea and 14 days later from 127 children, aged 2-59 months and living in rural Zanzibar, and were analyzed by real-time polymerase chain reaction targeting multiple pathogens.

    Results: At baseline, detection rates >20% were found for each of enterotoxigenic Escherichia coli, Shigella, Campylobacter, Cryptosporidium, norovirus GII, and adenovirus. At follow-up, a large proportion of the infections had become cleared (34-100%), or the pathogen load reduced, and this was observed also for agents that were presumably unrelated to diarrhea. Still, the detection frequencies at follow-up were for most agents as high as at baseline, because new infections had been acquired. Neither clearance nor reinfection was associated with moderate malnutrition, which was present in 21% of the children.

    Conclusions: Children residing in poor socioeconomic conditions, as in Zanzibar, are heavily exposed to enteric pathogens, but capable of rapidly clearing causative and coinfecting pathogens.

  • 5.
    Andersson, Maria
    et al.
    Univ Gothenburg, Dept Infect Dis, Guldhedsgatan 10B, S-41346 Gothenburg, Sweden.
    Kabayiza, Jean-Claude
    Univ Rwanda, Dept Pediat, Kigali, Rwanda.
    Elfving, Kristina
    Univ Gothenburg, Dept Infect Dis, Guldhedsgatan 10B, S-41346 Gothenburg, Sweden.
    Nilsson, Staffan
    Chalmers Univ Technol, Gothenburg, Sweden.
    Msellem, Mwinyi I.
    Minist Hlth, Zanzibar Malaria Eliminat Programme ZAMEP, Zanzibar, Tanzania.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Malaria Res, Stockholm, Sweden.
    Bergstrom, Tomas
    Univ Gothenburg, Dept Infect Dis, Guldhedsgatan 10B, S-41346 Gothenburg, Sweden.
    Lindh, Magnus
    Univ Gothenburg, Dept Infect Dis, Guldhedsgatan 10B, S-41346 Gothenburg, Sweden.
    Coinfection with Enteric Pathogens in East African Children with Acute Gastroenteritis-Associations and Interpretations2018In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 98, no 6, p. 1566-1570Article in journal (Refereed)
    Abstract [en]

    Enteric coinfections among children in low-income countries are very common, but it is not well known if specific pathogen combinations are associated or have clinical importance. In this analysis, feces samples from children in Rwanda and Zanzibar less than 5 years of age, with (N = 994) or without (N = 324) acute diarrhea, were analyzed by realtime polymerase chain reaction targeting a wide range of pathogens. Associations were investigated by comparing codetection and mono-detection frequencies for all pairwise pathogen combinations. More than one pathogen was detected in 840 samples (65%). A negative association (coinfections being less common than expected from probability) was observed for rotavirus in combination with Shigella, Campylobacter, or norovirus genogroup II, but only in patients, which is statistically expected for agents that independently cause diarrhea. A positive correlation was observed, in both patients and controls, between Ct (threshold cycle) values for certain virulence factor genes in enteropathogenic Escherichia coli (EPEC) (eae and bfpA) and toxin genes in enterotoxigenic E. coli (eltB and estA), allowing estimation of how often these genes were present in the same bacteria. A significant positive association in patients only was observed for Shigella andEPEC-eae, suggesting that this coinfection might interact in a manner that enhances symptoms. Although interaction between pathogens that affect symptoms is rare, this work emphasizes the importance and difference in interpretation of coinfections depending on whether they are positively or negatively associated.

  • 6.
    Aydin-Schmidt, Berit
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden.;Karolinska Univ Hosp, Infect Dis Unit, Stockholm, Sweden..
    Morris, Ulrika
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Ding, Xavier C.
    FIND, Geneva, Switzerland..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Msellem, Mwinyi I.
    Minist Hlth, Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania..
    Bergman, Daniel
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Islam, Atiqul
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Ali, Abdullah S.
    Minist Hlth, Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania..
    Polley, Spencer
    NHS Fdn Trust, Univ Coll London Hosp, Hosp Trop Dis, Dept Clin Parasitol, London, England..
    Gonzalez, Iveth J.
    FIND, Geneva, Switzerland..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Björkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Field Evaluation of a High Throughput Loop Mediated Isothermal Amplification Test for the Detection of Asymptomatic Plasmodium Infections in Zanzibar2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0169037Article in journal (Refereed)
    Abstract [en]

    Background New field applicable diagnostic tools are needed for highly sensitive detection of residual malaria infections in pre-elimination settings. Field performance of a high throughput DNA extraction system for loop mediated isothermal amplification (HTP-LAMP) was therefore evaluated for detecting malaria parasites among asymptomatic individuals in Zanzibar. Methods HTP-LAMP performance was evaluated against real-time PCR on 3008 paired blood samples collected on filter papers in a community-based survey in 2015. Results The PCR and HTP-LAMP determined malaria prevalences were 1.6% (95% CI 1.3-2.4) and 0.7% (95% CI 0.4-1.1), respectively. The sensitivity of HTP-LAMP compared to PCR was 40.8% (CI95% 27.0-55.8) and the specificity was 99.9% (CI95% 99.8-100). For the PCR positive samples, there was no statistically significant difference between the geometric mean parasite densities among the HTP-LAMP positive (2.5 p/mu L, range 0.2-770) and HTP-LAMP negative (1.4 p/mu L, range 0.1-7) samples (p = 0.088). Two lab technicians analysed up to 282 samples per day and the HTP-LAMP method was experienced as user friendly. Conclusions Although field applicable, this high throughput format of LAMP as used here was not sensitive enough to be recommended for detection of asymptomatic low-density infections in areas like Zanzibar, approaching malaria elimination.

  • 7.
    Björkman, A.
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Shakely, D.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden; Univ Gothenburg, Hlth Metr Sahlgrenska Acad, Gothenburg, Sweden.
    Ali, A. S.
    Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania.
    Morris, U.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Mkali, H.
    MEASURE Evaluat, Dar Es Salaam, Tanzania.
    Abbas, A. K.
    Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania.
    Al-Mafazy, A-W
    Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania.
    Haji, K. A.
    Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania.
    Mcha, J.
    Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania.
    Omar, R.
    Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania.
    Cook, J.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden; London Sch Hyg & Trop Med, London, England.
    Elfving, K.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden; Univ Gothenburg, Dept Infect Dis, Gothenburg, Sweden.
    Petzold, M.
    Univ Gothenburg, Ctr Appl Biostat, Gothenburg, Sweden.
    Sachs, M. C.
    Karolinska Inst, Inst Environm Med, Biostat Unit, Stockholm, Sweden.
    Aydin-Schmidt, B.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Drakeley, C.
    London Sch Hyg & Trop Med, London, England.
    Msellem, M.
    Mnazi Mmoja Hosp, Training & Res, Zanzibar, Tanzania.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    From high to low malaria transmission in Zanzibar-challenges and opportunities to achieve elimination2019In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 17, article id 14Article in journal (Refereed)
    Abstract [en]

    Substantial global progress in the control of malaria in recent years has led to increased commitment to its potential elimination. Whether this is possible in high transmission areas of sub-Saharan Africa remains unclear. Zanzibar represents a unique case study of such attempt, where modern tools and strategies for malaria treatment and vector control have been deployed since 2003. We have studied temporal trends of comprehensive malariometric indices in two districts with over 100,000 inhabitants each. The analyses included triangulation of data from annual community-based cross-sectional surveys, health management information systems, vital registry and entomological sentinel surveys. The interventions, with sustained high-community uptake, were temporally associated with a major malaria decline, most pronounced between 2004 and 2007 and followed by a sustained state of low transmission. In 2015, the Plasmodium falciparum community prevalence of 0.43% (95% CI 0.23-0.73) by microscopy or rapid diagnostic test represented 96% reduction compared with that in 2003. The P. falciparum and P. malariae prevalence by PCR was 1.8% (95% CI 1.3-2.3), and the annual P. falciparum incidence was estimated to 8 infections including 2.8 clinical episodes per 1000 inhabitants. The total parasite load decreased over 1000-fold (99.9%) between 2003 and 2015. The incidence of symptomatic malaria at health facilities decreased by 94% with a trend towards relatively higher incidence in age groups > 5 years, a more pronounced seasonality and with reported travel history to/from Tanzania mainland as a higher risk factor. All-cause mortality among children < 5 years decreased by 72% between 2002 and 2007 mainly following the introduction of artemisinin-based combination therapies whereas the main reduction in malaria incidence followed upon the vector control interventions from 2006. Human biting rates decreased by 98% with a major shift towards outdoor biting by Anopheles arabiensis. Zanzibar provides new evidence of the feasibility of reaching uniquely significant and sustainable malaria reduction (pre-elimination) in a previously high endemic region in sub-Saharan Africa. The data highlight constraints of optimistic prognostic modelling studies. New challenges, mainly with outdoor transmission, a large asymptomatic parasite reservoir and imported infections, require novel tools and reoriented strategies to prevent a rebound effect and achieve elimination.

  • 8.
    Björkman, Anders
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17176 Stockholm, Sweden.
    Cook, Jackie
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17176 Stockholm, Sweden; London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, MRC Trop Epidemiol Grp, London, England.
    Sturrock, Hugh
    Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA.
    Msellem, Mwinyi
    Minist Hlth, Zanzibar Malaria Eliminat Programme, Dar Es Salaam, Tanzania.
    Ali, Abdullah
    Minist Hlth, Zanzibar Malaria Eliminat Programme, Dar Es Salaam, Tanzania.
    Xu, Weiping
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, SE-17176 Stockholm, Sweden.
    Molteni, Fabrizio
    Swiss Trop & Publ Hlth Inst, Dar Es Salaam, Tanzania.
    Gosling, Roly
    Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA.
    Drakeley, Chris
    London Sch Hyg & Trop Med, Dept Immunol & Infect, London, England.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Spatial Distribution of Falciparum Malaria Infections in Zanzibar: Implications for Focal Drug Administration Strategies Targeting Asymptomatic Parasite Carriers2017In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 64, no 9, p. 1236-1243Article in journal (Refereed)
    Abstract [en]

    Background: Optimal use of mass/targeted screen-and-treat or mass or focal drug administration as malaria elimination strategies remains unclear. We therefore studied spatial distribution of Plasmodium falciparum infections to compare simulated effects of these strategies on reducing the parasite reservoir in a pre-elimination setting.

    Methods: P. falciparum rapid diagnostic tests (RDTs) and molecular (polymerase chain reaction [PCR]) and serological (enzyme-linked immunosorbent assay) analyses were performed on finger-prick blood samples from a population-based survey in 3 adjacent communities.

    Results: Among 5278 persons screened, 13 (0.2%) were positive by RDT and 123 (2.3%) by PCR. PCR-positive individuals were scattered over the study area, but logistic regression analysis suggested a propensity of these infections to cluster around RDT-positive individuals. The odds ratios for being PCR positive was 7.4 (95% confidence interval, 2.8-19.9) for those living in the household of an RDT-positive individual and 1.64 (1.0-2.8; P = .06) for those living within <300 m, compared with >1000 m. Treating everyone within households of RDT-positive individuals (1% population) would target 13% of those who are PCR positive. Treating all living within a radius of <300 or <1000 m (14% or 58% population) would target 30% or 66% of infections, respectively. Among 4431 serologically screened individuals, 26% were seropositive. Treating everyone within seropositive households (63% population) would target 77% of PCR-positive individuals.

    Conclusions: Presumptive malaria treatment seemed justified within RDT-positive households and potentially worth considering within, for example, a radius of <300 m. Serology was not discriminative enough in identifying ongoing infections for improving focal interventions in this setting but may rather be useful to detect larger transmission foci.

  • 9.
    Bruxvoort, Katia J.
    et al.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Leurent, Baptiste
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Chandler, Clare I. R.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Ansah, Evelyn K.
    Ghana Hlth Serv, Res & Dev, Accra, Greater Accra, Ghana..
    Baiden, Frank
    Ensign Coll Publ Hlth, Epidemiol, Kpong, Ghana..
    Björkman, Anders
    Karolinska Inst, Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Burchett, Helen E. D.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Clarke, Sian E.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Cundill, Bonnie
    Univ Leeds, Leeds Inst Clin Trials Res, Leeds, W Yorkshire, England..
    DiLiberto, Debora D.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Elfving, Kristina
    Univ Gothenburg, Infect Dis, Gothenburg, Sweden..
    Goodman, Catherine
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Hansen, Kristian S.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England.;Univ Copenhagen, Hlth Serv Res, Copenhagen, Denmark..
    Kachur, Patrick
    US Ctr Dis Control & Prevent, Atlanta, GA USA.;CDC, Malaria Branch, Atlanta, GA 30333 USA..
    Lal, Sham
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Lalloo, David G.
    Univ Liverpool Liverpool Sch Trop Med, Clin Sci & Int Publ Hlth, Liverpool, Merseyside, England..
    Leslie, Toby
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Magnussen, Pascal
    Univ Copenhagen, Ctr Med Parasitol, Copenhagen, Denmark.;Copenhagen Univ Hosp, Ctr Med Parasitol, Copenhagen, Denmark.;Univ Copenhagen, Dept Vet & Anim Sci, Copenhagen, Denmark..
    Mangham-Jefferies, Lindsay
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mayan, Ismail
    Hlth Protect Res Org, Clin Trials, Kabul, Afghanistan..
    Mbonye, Anthony K.
    Minist Hlth, Kampala, Uganda.;Makerere Univ, Sch Publ Hlth, Community Hlth & Behav Sci, Kampala, Uganda..
    Msellem, Mwinyi I.
    Zanzibar Minist Hlth, Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania..
    Onwujekwe, Obinna E.
    Univ Nigeria, Dept Pharmacol & Therapeut, Enugu, Nigeria.;Univ Nigeria, Pharmacol & Therapeut, Enugu Campus, Enugu, Nigeria..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Rowland, Mark W.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Shakely, Deler
    Karolinska Inst, Stockholm, Sweden.;Karolinska Inst, Ctr Malaria Res, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Hlth Metr, Gothenburg, Sweden..
    Staedke, Sarah G.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Vestergaard, Lasse S.
    Univ Copenhagen, Ctr Med Parasitol, Copenhagen, Denmark.;Copenhagen Univ Hosp, Copenhagen, Denmark.;Statens Serum Inst, Dept Infect Dis Epidemiol & Prevent, Copenhagen, Denmark..
    Webster, Jayne
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Whitty, Christopher J. M.
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Wiseman, Virginia L.
    London Sch Hyg & Trop Med, 15-17 Tavistock Pl, London WC1H 9SH, England.;Univ New South Wales, Sch Publ Hlth & Community Med, Sydney, NSW, Australia..
    Yeung, Shunmay
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Schellenberg, David
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    Hopkins, Heidi
    London Sch Hyg & Trop Med, Global Hlth & Dev, London, England..
    The Impact of Introducing Malaria Rapid Diagnostic Tests on Fever Case Management: A Synthesis of Ten Studies from the ACT Consortium2017In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 97, no 4, p. 1170-1179Article in journal (Refereed)
    Abstract [en]

    Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers. The ACT Consortium conducted ten linked studies, eight in sub-Saharan Africa and two in Afghanistan, to evaluate the impact of mRDT introduction on case management across settings that vary in malaria endemicity and healthcare provider type. This synthesis includes 562,368 outpatient encounters (study size range 2,400-432,513). mRDTs were associated with significantly lower ACT prescription (range 8-69% versus 20-100%). Prescribing did not always adhere to malaria test results; in several settings, ACTs were prescribed to more than 30% of test-negative patients or to fewer than 80% of test-positive patients. Either an antimalarial or an antibiotic was prescribed for more than 75% of patients across most settings; lower antimalarial prescription for malaria test-negative patients was partly offset by higher antibiotic prescription. Symptomatic management with antipyretics alone was prescribed for fewer than 25% of patients across all scenarios. In community health worker and private retailer settings, mRDTs increased referral of patients to other providers. This synthesis provides an overview of shifts in casemanagement thatmay be expected with mRDT introduction and highlights areas of focus to improve design and implementation of future case management programs.

  • 10.
    Burchett, Helen E. D.
    et al.
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Leurent, Baptiste
    London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England..
    Baiden, Frank
    Ensign Coll Publ Hlth, Epidemiol Unit, Kpong, Ghana..
    Baltzell, Kimberly
    Univ Calif Berkeley, Dept Family Hlth Care Nursing & Global Hlth Sci, Berkeley, CA 94720 USA..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden..
    Bruxvoort, Katia
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Clarke, Sian
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    DiLiberto, Deborah
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Elfving, Kristina
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Gothenburg, Sweden..
    Goodman, Catherine
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Hopkins, Heidi
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    Lal, Sham
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    Liverani, Marco
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Magnussen, Pascal
    Univ Copenhagen, Fac Hlth & Med Sci, Ctr Med Parasitol, Copenhagen, Denmark..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mbacham, Wilfred
    Univ Yaounde, Ctr Biotechnol, Lab Publ Hlth Res Biotechnol, Yaounde, Cameroon..
    Mbonye, Anthony
    Makerere Univ, Sch Publ Hlth, Kampala, Uganda.;Minist Hlth, Commissioner Hlth Serv, Kampala, Uganda..
    Onwujekwe, Obinna
    Univ Nigeria, Dept Therapeut & Pharmacol, Enugu Campus, Enugu, Nigeria..
    Allen, Denise Roth
    Ctr Dis Control & Prevent CDC, Atlanta, GA USA..
    Shakely, Deler
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Kungalv Hosp, Dept Med, Kungalv, Sweden..
    Staedke, Sarah
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Vestergaard, Lasse S.
    Univ Copenhagen, Ctr Med Parasitol, DK-1168 Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark.;Statens Serum Inst, Dept Infect Dis Epidemiol, Copenhagen, Denmark..
    Whitty, Christopher J. M.
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Wiseman, Virginia
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England.;Sch Publ Hlth & Community Med, Kensington, NSW, Australia..
    Chandler, Clare I. R.
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Improving prescribing practices with rapid diagnostic tests (RDTs): synthesis of 10 studies to explore reasons for variation in malaria RDT uptake and adherence2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, article id e012973Article in journal (Refereed)
    Abstract [en]

    Objectives: The overuse of antimalarial drugs is widespread. Effective methods to improve prescribing practice remain unclear. We evaluated the impact of 10 interventions that introduced rapid diagnostic tests for malaria (mRDTs) on the use of tests and adherence to results in different contexts. Design: A comparative case study approach, analysing variation in outcomes across different settings. Setting: Studies from the ACT Consortium evaluating mRDTs with a range of supporting interventions in 6 malaria endemic countries. Providers were governmental or non-governmental healthcare workers, private retail sector workers or community volunteers. Each study arm in a distinct setting was considered a case. Participants: 28 cases from 10 studies were included, representing 148 461 patients seeking care for suspected malaria. Interventions: The interventions included different mRDT training packages, supervision, supplies and community sensitisation. Outcome measures: Analysis explored variation in: (1) uptake of mRDTs (% febrile patients tested); (2) provider adherence to positive mRDTs (% Plasmodium falciparum positive prescribed/given Artemisinin Combination Treatment); (3) provider adherence to negative mRDTs (% P. falciparum negative not prescribed/given antimalarial). Results: Outcomes varied widely across cases: 12-100% mRDT uptake; 44-98% adherence to positive mRDTs; 27-100% adherence to negative mRDTs. Providers appeared more motivated to perform well when mRDTs and intervention characteristics fitted with their own priorities. Goodness of fit of mRDTs with existing consultation and diagnostic practices appeared crucial to maximising the impact of mRDTs on care, as did prior familiarity with malaria testing; adequate human resources and supplies; possible alternative treatments for mRDT-negative patients; a more directive intervention approach and local preferences for ACTs. Conclusions: Basic training and resources are essential but insufficient to maximise the potential of mRDTs in many contexts. Programme design should respond to assessments of provider priorities, expectations and capacities. As mRDTs become established, the intensity of supporting interventions required seems likely to reduce.

  • 11.
    Dahal, Prabin
    et al.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Simpson, Julie Anne
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostatist, Melbourne, Vic, Australia.
    Abdulla, Salim
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.
    Achan, Jane
    MRC Unit, Banjul, Gambia.
    Adam, Ishag
    Univ Khartoum, Fac Med, Khartoum, Sudan.
    Agarwal, Aarti
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Allan, Richard
    Mentor Initiat, Fajara, Gambia.
    Anvikar, Anupkumar R.
    Natl Inst Malaria Res, Sector 8, Dwarka, New Delhi 110077, India.
    Arinaitwe, Emmanuel
    Infect Dis Res Collaborat, Kampala, Uganda.
    Ashley, Elizabeth A.
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Myanmar Oxford Clin Res Unit, Yangon, Myanmar.
    Awab, Ghulam Rahim
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Minist Publ Hlth, Islam Republ Afghanistan, Kabul, Afghanistan.
    Bassat, Quique
    Ctr Investigacao Saude Manhica CISM, Maputo, Mozambique;Univ Barcelona, Hosp Clin, ISGlobal, Barcelona, Spain;ICREA, Pg Lluis Companys 23, Barcelona 08010, Spain.
    Bjorkman, Anders
    Karolinska Inst, Depatment Microbiol Tumour & Cell Biol, Stockholm, Sweden.
    Bompart, Francois
    Sanofi Access Med, Gentilly, France.
    Borrmann, Steffen
    Kenya Med Res Inst Kilifi, Kilifi, Kenya;Wellcome Trust Res Programme, Kilifi, Kenya;Heidelberg Univ, Sch Med, Dept Infect Dis, Heidelberg, Germany.
    Bousema, Teun
    Radboud Inst Hlth Sci, Radboudumc Nijmegen, Nijmegen, Netherlands;Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands.
    Broek, Ingrid
    Centrum Infectieziektebestrijding, Epidemioloog Epidemiol Surveillance RIVM, Bilthoven, Netherlands.
    Bukirwa, Hasifa
    African Field Epidemiol Network, Kampala, Uganda.
    Carrara, Verena I.
    Shoklo Malaria Res Unit, Mae Sot, Bangkok, Thailand;Mahidol Oxford Univ Res Unit, Bangkok, Thailand.
    Corsi, Marco
    Private Consultancy Drug Dev Trop Dis, Sigma Tau SpA Ind Farmaceutiche Riunite, Pomezia, Rome, Italy.
    Cot, Michel
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    D'Alessandro, Umberto
    MRC Unit, Fajara, Gambia;London Sch Hyg & Trop Med, London, England.
    Davis, Timothy M. E.
    Univ Western Australia, Sch Med & Pharmacol, Crawley, WA, Australia.
    de Wit, Marit
    Med Sans Frontieres Operat Ctr Amsterdam, Geneva, Switzerland.
    Deloron, Philippe
    Univ Paris 05, Sorbonne Paris Cite, MERIT, IRD, F-75006 Paris, France.
    Desai, Meghna
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.
    Dimbu, Pedro Rafael
    Natl Malaria Control Program, Luanda, Angola.
    Djalle, Djibrine
    Inst Pasteur, BP 923, Bangui, Cent Afr Republ.
    Djimde, Abdoulaye
    Univ Sci Techn & Technol Bamako, Fac Pharm, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Bamako, Mali.
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Doumbo, Ogobara K.
    Univ Sci Techn & Technol Bamako, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Fac Med & Odonto Stomatol, Bamako, Mali.
    Drakeley, Chris J.
    London Sch Hyg & Trop Med, Dept Infect & Immun, London, England.
    Duparc, Stephan
    Med Malaria Venture, Geneva, Switzerland.
    Edstein, Michael D.
    Australian Army Malaria Inst, Brisbane, Qld, Australia.
    Espie, Emmanuelle
    R&D Ctr, GSK Vaccines, Clin & Epidemiol Dept, Epicentre, Ave Fleming 20,1300 Wavre,8 Rue St Sabin, F-75011 Paris, France.
    Faiz, Abul
    Malaria Res Grp, Chittagong, Bangladesh;Dev Care Fdn, Dhaka, Bangladesh.
    Falade, Catherine
    Univ Ibadan, Coll Med, Dept Pharmacol & Therapeut, Ibadan, Nigeria.
    Fanello, Caterina
    Univ Oxford, Nuffield Dept Med, Ctr Global Hlth, Oxford, England.
    Faucher, Jean-Francois
    Besancon Univ Med Ctr, Dept Infect Dis, Mother & Child Hlth Trop Res Unit, Inst Rech Dev IRD, Besancon, France.
    Faye, Babacar
    Univ Cheikh Anta Diop, Fac Med, Dept Med Parasitol, Dakar, Senegal.
    Fortes, Filomeno de Jesus
    Natl Malaria Control Program, Luanda, Angola.
    Gadalla, Nahla B.
    Sudanese Amer Med Assoc, Fairfax, VA USA.
    Gaye, Oumar
    Univ Cheikh Anta Diop, Dept Med Parasitol, Fac Med, Dakar, Senegal.
    Gil, J. Pedro
    Karolinska Inst, Div Pharmacogenet, Dept Physiol & Pharmacol, Drug Resistance Unit, Stockholm, Sweden;Univ Lisbon, Ctr Biodivers Funct & Integrat Gen, Fac Ciencias, Lisbon, Portugal.
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England.
    Grivoyannis, Anastasia
    Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA.
    Hamed, Kamal
    Basilea Pharmaceut Int Ltd, Basel, Switzerland;Novartis Pharmaceut, E Hanover, NJ USA.
    Hien, Tran Tinh
    Oxford Univ Clin Res Unit OUCRU, Ctr Trop Med, Wellcome Trust Major Overseas Program MOP, Oxford, England.
    Hughes, David
    Novartis Int AG, Basel, Switzerland.
    Humphreys, Georgina
    Wellcome Trust Res Labs, London, England;World Wide Antimalarial Resistance Network WWARN, London, England.
    Hwang, Jimee
    US Centers Dis Control & Prevent, Div Parasit Dis & Malaria, US Presidents Malaria Initiat Malaria Branch, Atlanta, GA USA;Univ Calif San Francisco, San Francisco, CA 94143 USA;Global Hlth Grp, San Francisco, CA 94143 USA.
    Ibrahim, Maman Laminou
    Ctr Rech Med & Saniataire CERMES, Niamey, Niger.
    Janssens, Bart
    Medecins Sans Frontieres, Phnom Penh, Belgium.
    Jullien, Vincent
    Univ Paris 05, Assistance Publique Hop Paris, Serv Pharmacol Clin, Paris, France;Grp Hosp Cochin Saint Vincent Paul, Inserm U663, WWARN, Paris, France.
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya.
    Kamugisha, Erasmus
    Weill Bugando Univ Coll Hlth Sci, Mwanza, Tanzania.
    Karema, Corine
    Minist Hlth, Natl Malaria Control Program TRAC Plus, Kigali, Rwanda.
    Karunajeewa, Harin A.
    Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia.
    Kiechel, Jean R.
    Drugs Neglected Dis initiat, Geneva, Switzerland.
    Kironde, Fred
    Islam Univ Uganda, Habib Med Sch, Kampala, Uganda.
    Kofoed, Poul-Erik
    Bandim Hlth Project, Indepth Network, Apartado 861, Bissau, Guinea Bissau;Lillebaelt Hosp, Hlth Serv Res Unit, Vejle, Denmark;IRS Univ Southern Denmark, Vejle, Denmark;Kolding Cty Hosp, Dept Paediat, Kolding, Denmark.
    Kremsner, Peter G.
    Univ Tubingen, Inst Trop Med, Tubingen, Germany;Ctr Recherches Medic Lambarene, Lambarene, Gabon.
    Lameyre, Valerie
    Sanofi Access Med, Gentilly, France.
    Lee, Sue J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand;Churchill Hosp, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Marsh, Kevin
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Wellcome Trust Res Programme, Kilifi, Kenya;Kenya Govt Med Res Ctr, Kilifi, Kenya.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Mayxay, Mayfong
    Mahosot Hosp, Lao Oxford Mahosot Hospital, Wellcome Trust Res Unit, Microbiol Lab, Viangchan, Laos.
    Menan, Herve
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire;Univ Hlth Sci, Minist Hlth, Fac Postgraduate Studies, Viangchan, Laos.
    Mens, Petra
    Acad Med Ctr, Med Microbiol Parasitol, Amsterdam, Netherlands.
    Mutabingwa, Theonest K.
    Hubert Kairuki Mem Univ, Dar Es Salaam, Tanzania;London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London, England.
    Ndiaye, Jean-Louis
    Univ Cheikh Anta Diop, Fac Med, Parasitol & Mycol Lab, Dakar, Senegal.
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden.
    Noedl, Harald
    Med Univ Vienna, Vienna, Austria.
    Nosten, Francois
    Univ Oxford, Nuffield Dept Med Res Bldg, Ctr Trop Med & Global Hlth, Old Rd Campus, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Shoklo Malaria Res Unit, Mae Sot, Thailand.
    Offianan, Andre Toure
    Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire.
    Oguike, Mary
    London Sch Hyg & Trop Med, Dept Immunol & Infect, London, England.
    Ogutu, Bernhards R.
    Kenya Govt Med Res Ctr, Kisumu, Kenya;US Army Med Res Unit, Kisumu, Kenya.
    Olliaro, Piero
    UNICEF, UNDP, World Bank, WHO TDR, Geneva, Switzerland.
    Ouedraogo, Jean Bosco
    Inst Rech Sci Sante, Direct Regionale Ouest, Bobo Dioulasso, Burkina Faso;Ctr Muraz Bobo Dioulasso, Non Transmissible Dis Dept, Bobo Dioulasso, Burkina Faso.
    Piola, Patrice
    Inst Pasteur Cambodge, Phnom Penh, Cambodia.
    Plowe, Christopher V.
    Duke Univ, Duke Global Hlth Inst, Durham, NC USA.
    Plucinski, Mateusz M.
    US Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, US Presidents Malaria Initiat, Atlanta, GA USA;Ctr Dis Control & Prevent, Epidem Intelligence Serv, Atlanta, GA USA.
    Pratt, Oliver James
    Minist Hlth & Social Welf, Natl Malaria Control Program, Monrovia, Liberia.
    Premji, Zulfikarali
    Muhimbili Univ Coll Hlth Sci, Dar Es Salaam, Tanzania.
    Ramharter, Michael
    Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Bernhard Nocht Inst Trop Med, Dept Trop Med, Hamburg, Germany.
    Rogier, Christophe
    Div Expertise & Def Hlth strategy, Cent Directorate, French Mil Hlth Serv, Paris, France;IRBA, Bretigny Sur Orge, France;URMITE, UMR 6236, Marseille, France.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Sawa, Patrick
    Human Hlth Div, Int Ctr Insect Physiol & Ecol, Mbita, Kenya.
    Schramm, Birgit
    Epicentre, Paris, France.
    Sibley, Carol
    WWARN, Oxford, England;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Sinou, Veronique
    Aix Marseille Univ, INSERM, SSA, IRBA,MCT, Marseille, France.
    Sirima, Sodiomon
    GRAS, 06 BP 10248, Ouagadougou 06, Burkina Faso.
    Smithuis, Frank
    Myanmar Oxford Clin Res Unit, Oxford, England.
    Staedke, Sarah G.
    Infect Dis Res Collaborat, Kampala, Uganda;London Sch Hyg & Trop Med, Dept Clin Res, London, England.
    Sutanto, Inge
    Univ Indonesia, Dept Parasitol, Fac Med, 6 Salemba Raya, Jakarta 10430, Indonesia.
    Talisuna, Ambrose Otau
    WHO, Reg Off Afr, Brazzaville, Rep Congo;Univ Oxford, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England.
    Tarning, Joel
    WorldWide Antimalarial Resistance Network, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Taylor, Walter R. J.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand.
    Temu, Emmanuel
    MENTOR Initiat, Crawley, England.
    Thriemer, Kamala L.
    Charles Darwin Univ, Menzies Sch Hlth Res, Global & Trop Hlth Div, Darwin, NT, Australia.
    Thuy, Nhien Nguyen
    Oxford Univ Clin Res Unit OUCRU, Wellcome Trust Major Overseas Program MOP, Ctr Trop Med, Oxford, England.
    Udhayakumar, Venkatachalam
    Ctr Dis Control & Prevent, Ctr Global Hlth, Div Parasit Dis & Malaria, Malaria Branch & Presidents Malaria Initiat, Atlanta, GA USA.
    Ursing, Johan
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC C1, Solna, Sweden;Danderyd Hosp, Dept Infect Dis, Danderyd, Sweden.
    van Herp, Michel
    Operat Ctr Brussels, Med Sans Frontieres, Brussels, Belgium;Univ Amsterdam, Acad Med Ctr, Div Infect Dis, Ctr Trop Med & Travel Med, Amsterdam, Netherlands.
    van Vugt, Michele
    Whitty, Christopher
    London Sch Hyg & Trop Med, Dept Infect & Trop Dis, Malaria Partnership, London, England.
    William, Yavo
    Univ Cocody, Dept Parasitol, Fac Pharm, Abidjan, Cote Ivoire.
    Winnips, Cornelis
    NovartisInternat AG, Basel, Switzerland.
    Zongo, Issaka
    Inst Rech Sci Sante, Direct Regionale lOuest, Bobo Dioulasso, Burkina Faso.
    Guerin, Philippe
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Price, Ric N.
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Menzies Sch Hlth Res Charles Darwin Univ, Darwin, NT, Australia;Churchill Hosp, Ctr Clin Vaccinol & Trop Med, Oxford, England.
    Stepniewska, Kasia
    World Wide Antimalarial Resistance Network WWARN, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, WorldWide Antimalarial Resistance Network WWARN, Oxford, England.
    Competing risk events in antimalarial drug trials in uncomplicated Plasmodium falciparum malaria: a WorldWide Antimalarial Resistance Network individual participant data meta-analysis2019In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 18, article id 225Article in journal (Refereed)
    Abstract [en]

    Background: Therapeutic efficacy studies in uncomplicated Plasmodium falciparum malaria are confounded by new infections, which constitute competing risk events since they can potentially preclude/pre-empt the detection of subsequent recrudescence of persistent, sub-microscopic primary infections.

    Methods: Antimalarial studies typically report the risk of recrudescence derived using the Kaplan-Meier (K-M) method, which considers new infections acquired during the follow-up period as censored. Cumulative Incidence Function (CIF) provides an alternative approach for handling new infections, which accounts for them as a competing risk event. The complement of the estimate derived using the K-M method (1 minus K-M), and the CIF were used to derive the risk of recrudescence at the end of the follow-up period using data from studies collated in the WorldWide Antimalarial Resistance Network data repository. Absolute differences in the failure estimates derived using these two methods were quantified. In comparative studies, the equality of two K-M curves was assessed using the log-rank test, and the equality of CIFs using Gray's k-sample test (both at 5% level of significance). Two different regression modelling strategies for recrudescence were considered: cause-specific Cox model and Fine and Gray's sub-distributional hazard model.

    Results: Data were available from 92 studies (233 treatment arms, 31,379 patients) conducted between 1996 and 2014. At the end of follow-up, the median absolute overestimation in the estimated risk of cumulative recrudescence by using 1 minus K-M approach was 0.04% (interquartile range (IQR): 0.00-0.27%, Range: 0.00-3.60%). The overestimation was correlated positively with the proportion of patients with recrudescence [Pearson's correlation coefficient (rho): 0.38, 95% Confidence Interval (CI) 0.30-0.46] or new infection [rho: 0.43; 95% CI 0.35-0.54]. In three study arms, the point estimates of failure were greater than 10% (the WHO threshold for withdrawing antimalarials) when the K-M method was used, but remained below 10% when using the CIF approach, but the 95% confidence interval included this threshold.

    Conclusions: The 1 minus K-M method resulted in a marginal overestimation of recrudescence that became increasingly pronounced as antimalarial efficacy declined, particularly when the observed proportion of new infection was high. The CIF approach provides an alternative approach for derivation of failure estimates in antimalarial trials, particularly in high transmission settings.

  • 12.
    Elfving, Kristina
    et al.
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Shakely, Deler
    Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Maria
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Baltzell, Kimberly
    Department of Family Health Care Nursing, University of California San Francisco, USA.
    Ali, Abdullah S
    Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
    Bachelard, Marc
    Department of Paediatrics, University of Gothenburg, Sweden.
    Falk, Kerstin I
    Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Ljung, Annika
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Msellem, Mwinyi I
    Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
    Omar, Rahila S
    Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
    Parola, Philippe
    Aix Marseille University, UM63, WHO collaborative centre for rickettsioses and other arthropod borne bacterial diseases, Faculté de Médecine, Marseille, France.
    Xu, Weiping
    Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Petzold, Max
    Akademistatistik, Centre for Applied Biostatistics, Occupational and Environmental Medicine, University of Gothenburg, Sweden.
    Trollfors, Birger
    Department of Paediatrics, University of Gothenburg, Sweden.
    Björkman, Anders
    Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Lindh, Magnus
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Acute Uncomplicated Febrile Illness in Children Aged 2-59 months in Zanzibar: Aetiologies, Antibiotic Treatment and Outcome2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0146054Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite the fact that a large proportion of children with fever in Africa present at primary health care facilities, few studies have been designed to specifically study the causes of uncomplicated childhood febrile illness at this level of care, especially in areas like Zanzibar that has recently undergone a dramatic change from high to low malaria transmission.

    METHODS: We prospectively studied the aetiology of febrile illness in 677 children aged 2-59 months with acute uncomplicated fever managed by IMCI (Integrated Management of Childhood Illness) guidelines in Zanzibar, using point-of-care tests, urine culture, blood-PCR, chest X-ray (CXR) of IMCI-pneumonia classified patients, and multiple quantitative (q)PCR investigations of nasopharyngeal (NPH) (all patients) and rectal (GE) swabs (diarrhoea patients). For comparison, we also performed NPH and GE qPCR analyses in 167 healthy community controls. Final fever diagnoses were retrospectively established based on all clinical and laboratory data. Clinical outcome was assessed during a 14-day follow-up. The utility of IMCI for identifying infections presumed to require antibiotics was evaluated.

    FINDINGS: NPH-qPCR and GE-qPCR detected ≥1 pathogen in 657/672 (98%) and 153/164 (93%) of patients and 158/166 (95%) and 144/165 (87%) of controls, respectively. Overall, 57% (387/677) had IMCI-pneumonia, but only 12% (42/342) had CXR-confirmed pneumonia. Two patients were positive for Plasmodium falciparum. Respiratory syncytial virus (24.5%), influenza A/B (22.3%), rhinovirus (10.5%) and group-A streptococci (6.4%), CXR-confirmed pneumonia (6.2%), Shigella (4.3%) were the most common viral and bacterial fever diagnoses, respectively. Blood-PCR conducted in a sub-group of patients (n = 83) without defined fever diagnosis was negative for rickettsiae, chikungunya, dengue, Rift Valley fever and West Nile viruses. Antibiotics were prescribed to 500 (74%) patients, but only 152 (22%) had an infection retrospectively considered to require antibiotics. Clinical outcome was generally good. However, two children died. Only 68 (11%) patients remained febrile on day 3 and three of them had verified fever on day 14. An additional 29 (4.5%) children had fever relapse on day 14. Regression analysis determined C-reactive Protein (CRP) as the only independent variable significantly associated with CXR-confirmed pneumonia.

    CONCLUSIONS: This is the first study on uncomplicated febrile illness in African children that both applied a comprehensive laboratory panel and a healthy control group. A majority of patients had viral respiratory tract infection. Pathogens were frequently detected by qPCR also in asymptomatic children, demonstrating the importance of incorporating controls in fever aetiology studies. The precision of IMCI for identifying infections requiring antibiotics was low.

  • 13. Elfving, Kristina
    et al.
    Shakely, Deler
    Andersson, Maria
    Baltzell, Kimberly
    Msellem, Mwinyi I
    Björkman, Anders
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Petzold, Max
    Trollfors, Birger
    Lindh, Magnus
    Pathogen Clearance and New Respiratory Tract Infections Among Febrile Children in Zanzibar Investigated With Multitargeting Real-Time Polymerase Chain Reaction on Paired Nasopharyngeal Swab Samples2018In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 37, no 7, p. 643-648Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: New molecular methods have revealed frequent and often polymicrobial respiratory infections in children in low-income settings. It is not known whether presence of multiple pathogens is due to prolonged infections or to frequent exposure. The aim of this study was to analyze short-term pathogen clearance from nasopharynx and the rate of new respiratory tract infections in febrile preschool children.

    METHODS: Children (n = 207) with uncomplicated acute febrile illness 2-59 months of age presenting to a health center in Zanzibar, Tanzania, April-July 2011, were included. Paired nasopharyngeal swab samples, collected at enrolment and after 14 days, were analyzed by multiple real-time polymerase chain reaction for Adenovirus, bocavirus, Bordetella pertussis, Chlamydophila pneumoniae, Coronaviruses, Enterovirus, influenza A and B virus, metapneumovirus, measles virus, Mycoplasma pneumoniae, parainfluenza virus, Parechovirus, respiratory syncytial virus and Rhinovirus. An age-matched and geographically matched healthy control group (n = 166) underwent nasopharyngeal sampling on 1 occasion.

    RESULTS: At baseline, 157/207 (76%) patients had at least 1 pathogen detected, in total 199 infections. At follow-up (day 14), 162/199 (81%) of these infections were not detected, including >95% of the previously detected infections with Enterovirus, influenza A virus, influenza B virus, metapneumovirus or parainfluenza virus. Still 115 (56%) children were positive for at least 1 pathogen at follow-up, of which 95/115 (83%) were not found at baseline. Detection of influenza B on day 14 was significantly associated with fever during follow-up.

    CONCLUSION: The results suggest that children with acute febrile illness in Zanzibar rapidly clear respiratory tract infections but frequently acquire new infections within 14 days.

  • 14.
    Ghindilis, Andrey L.
    et al.
    TORCATECH LLC, 5210,104th St SW, Mukilteo, WA 98275 USA.
    Chesnokov, Olga
    Florida Atlantic Univ, Charles E Schmidt Coll Med, Dept Biomed Sci, 777 Glades Rd, Boca Raton, FL 33428 USA.
    Ngasala, Billy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Smith, Maria W.
    TORCATECH LLC, 5210,104th St SW, Mukilteo, WA 98275 USA.
    Smith, Kenneth
    TORCATECH LLC, 5210,104th St SW, Mukilteo, WA 98275 USA.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Oleinikov, Andrew V.
    Florida Atlantic Univ, Charles E Schmidt Coll Med, Dept Biomed Sci, 777 Glades Rd, Boca Raton, FL 33428 USA.
    Detection of sub-microscopic blood levels of Plasmodium falciparum using Tandem Oligonucleotide Repeat Cascade Amplification (TORCA) assay with an attomolar detection limit2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2901Article in journal (Refereed)
    Abstract [en]

    Tandem Oligonucleotide Repeat Cascade Amplification (TORCA) based on signal rather than target amplification under isothermal conditions was developed for nucleic acid assays. The initial signal was generated by hybridization of single stranded DNA targets to immobilized recognition probes followed by hybrid cleavage with specific restriction endonuclease (REase), and release of trigger oligonucleotides (Tr1). The signal amplification chamber contained two bead types carrying single-stranded amplification probes and two amplification REases. The probes consisted of multiple tandem repeats of either Tr1 or another trigger Tr2, with the tandem-Tr1 anchored to the beads through the antisense Tr2 linker and vice versa. Addition of the recognition reaction solution and Tr1 hybridization to the anti-Tr1 linkers started cleavage and release of additional Tr1 and Tr2, resulting in exponential signal amplification. The cleavage cascade also released horseradish peroxidase (HRP) pre-attached to the amplification probes, and the resultant signal was measured colorimetrically. A TORCA assay was developed for detection of Plasmodium falciparum parasites in blood. It had the detection limit in the attomolar concentration range, successfully detecting sub-microscopic P. falciparum infections at less than 0.75 infected erythrocytes per microliter. Further TORCA optimization will likely produce the quantitative isothermal alternative to PCR at a fraction of its cost.

  • 15.
    Holmström, Oscar
    et al.
    Univ Helsinki, Inst Mol Med Finland FIMM, POB 20, FI-00014 Helsinki, Finland.
    Linder, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Univ Helsinki, Inst Mol Med Finland FIMM, POB 20, FI-00014 Helsinki, Finland.
    Ngasala, Billy
    Muhimbili Univ Hlth & Allied Sci, Sch Publ Hlth, Dept Med Entomol & Parasitol, Dar Es Salaam, Tanzania.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Linder, Ewert
    Univ Oulu, Ctr Microscopy & Nanotechnol, Oulu, Finland.
    Lundin, Mikael
    Univ Helsinki, Inst Mol Med Finland FIMM, POB 20, FI-00014 Helsinki, Finland.
    Moilanen, Hannu
    Univ Oulu, Ctr Microscopy & Nanotechnol, Oulu, Finland.
    Suutala, Antti
    Univ Helsinki, Inst Mol Med Finland FIMM, POB 20, FI-00014 Helsinki, Finland.
    Diwan, Vinod
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Lundin, Johan
    Univ Helsinki, Inst Mol Med Finland FIMM, POB 20, FI-00014 Helsinki, Finland.; Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Point-of-care mobile digital microscopy and deep learning for the detection of soil-transmitted helminths and Schistosoma haematobium2017In: Global Health Action, ISSN 1654-9716, E-ISSN 1654-9880, Vol. 10, no sup3, article id 1337325Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Microscopy remains the gold standard in the diagnosis of neglected tropical diseases. As resource limited, rural areas often lack laboratory equipment and trained personnel, new diagnostic techniques are needed. Low-cost, point-of-care imaging devices show potential in the diagnosis of these diseases. Novel, digital image analysis algorithms can be utilized to automate sample analysis.

    OBJECTIVE: Evaluation of the imaging performance of a miniature digital microscopy scanner for the diagnosis of soil-transmitted helminths and Schistosoma haematobium, and training of a deep learning-based image analysis algorithm for automated detection of soil-transmitted helminths in the captured images.

    METHODS: A total of 13 iodine-stained stool samples containing Ascaris lumbricoides, Trichuris trichiura and hookworm eggs and 4 urine samples containing Schistosoma haematobium were digitized using a reference whole slide-scanner and the mobile microscopy scanner. Parasites in the images were identified by visual examination and by analysis with a deep learning-based image analysis algorithm in the stool samples. Results were compared between the digital and visual analysis of the images showing helminth eggs.

    RESULTS: Parasite identification by visual analysis of digital slides captured with the mobile microscope was feasible for all analyzed parasites. Although the spatial resolution of the reference slide-scanner is higher, the resolution of the mobile microscope is sufficient for reliable identification and classification of all parasites studied. Digital image analysis of stool sample images captured with the mobile microscope showed high sensitivity for detection of all helminths studied (range of sensitivity = 83.3-100%) in the test set (n = 217) of manually labeled helminth eggs.

    CONCLUSIONS: In this proof-of-concept study, the imaging performance of a mobile, digital microscope was sufficient for visual detection of soil-transmitted helminths and Schistosoma haematobium. Furthermore, we show that deep learning-based image analysis can be utilized for the automated detection and classification of helminths in the captured images.

  • 16.
    Hopkins, Heidi
    et al.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Bruxvoort, Katia J.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Cairns, Matthew E.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Chandler, Clare I. R.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Leurent, Baptiste
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Ansah, Evelyn K.
    Ghana Hlth Serv, Accra, Ghana..
    Baiden, Frank
    Ensign Coll Publ Hlth, Kpong, Ghana..
    Baltzell, Kimberly A.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Bjorkman, Anders
    Karolinska Inst, S-17176 Stockholm, Sweden..
    Burchett, Helen E. D.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Clarke, Sian E.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    DiLiberto, Deborah D.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Elfving, Kristina
    Univ Gothenburg, Gothenburg, Sweden..
    Goodman, Catherine
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Hansen, Kristian S.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England.;Univ Copenhagen, DK-1014 Copenhagen, Denmark..
    Kachur, S. Patrick
    US Ctr Dis Control & Prevent, Atlanta, GA USA..
    Lal, Sham
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Lalloo, David G.
    Univ Liverpool Liverpool Sch Trop Med, Liverpool, Merseyside, England..
    Leslie, Toby
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England.;Hlth Protect Res Org, Kabul, Afghanistan..
    Magnussen, Pascal
    Univ Copenhagen, Ctr Med Parasitol, Copenhagen, Denmark.;Univ Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark.;Univ Copenhagen, Dept Vet Dis Biol, Copenhagen, Denmark..
    Jefferies, Lindsay Mangham
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mayan, Ismail
    Hlth Protect Res Org, Kabul, Afghanistan..
    Mbonye, Anthony K.
    Minist Hlth, Kampala, Uganda.;Makerere Univ, Sch Publ Hlth, Kampala, Uganda..
    Msellem, Mwinyi I.
    Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania..
    Onwujekwe, Obinna E.
    Univ Nigeria, Dept Pharmacol & Therapeut, Enugu, Nigeria..
    Owusu-Agyei, Seth
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England.;Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Reyburn, Hugh
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Rowland, Mark W.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Shakely, Deler
    Karolinska Inst, Ctr Malaria Res, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Hlth Metr, Gothenburg, Sweden..
    Vestergaard, Lasse S.
    Statens Serum Inst, Dept Infect Dis Epidemiol, Copenhagen, Denmark..
    Webster, Jayne
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Wiseman, Virginia L.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England.;Univ New South Wales, Sch Publ Hlth & Community Med, Sydney, NSW, Australia..
    Yeung, Shunmay
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Schellenberg, David
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Staedke, Sarah G.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Whitty, Christopher J. M.
    Univ London London Sch Hyg & Trop Med, London WC1E 7HT, England..
    Impact of introduction of rapid diagnostic tests for malaria on antibiotic prescribing: analysis of observational and randomised studies in public and private healthcare settings2017In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 356, article id j1054Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES To examine the impact of use of rapid diagnostic tests for malaria on prescribing of antimicrobials, specifically antibiotics, for acute febrile illness in Africa and Asia. DESIGN Analysis of nine preselected linked and codesigned observational and randomised studies (eight cluster or individually randomised trials and one observational study). SETTING Public and private healthcare settings, 2007-13, in Afghanistan, Cameroon, Ghana, Nigeria, Tanzania, and Uganda. PARTICIPANTS 522 480 children and adults with acute febrile illness. INTERVENTIONS Rapid diagnostic tests for malaria. MAIN OUTCOME MEASURES Proportions of patients for whom an antibiotic was prescribed in trial groups who had undergone rapid diagnostic testing compared with controls and in patients with negative test results compared with patients with positive results. A secondary aim compared classes of antibiotics prescribed in different settings. RESULTS Antibiotics were prescribed to 127 052/238 797 (53%) patients in control groups and 167 714/283 683 (59%) patients in intervention groups. Antibiotics were prescribed to 40% (35 505/89 719) of patients with a positive test result for malaria and to 69% (39 400/57 080) of those with a negative result. All but one study showed a trend toward more antibiotic prescribing in groups who underwent rapid diagnostic tests. Random effects meta-analysis of the trials showed that the overall risk of antibiotic prescription was 21% higher (95% confidence interval 7% to 36%) in intervention settings. In most intervention settings, patients with negative test results received more antibiotic prescriptions than patients with positive results for all the most commonly used classes: penicillins, trimethoprim-sulfamethoxazole (one exception), tetracyclines, and metronidazole. CONCLUSIONS Introduction of rapid diagnostic tests for malaria to reduce unnecessary use of antimalarials-a beneficial public health outcome-could drive up untargeted use of antibiotics. That 69% of patients were prescribed antibiotics when test results were negative probably represents overprescription. This included antibiotics from several classes, including those like metronidazole that are seldom appropriate for febrile illness, across varied clinical, health system, and epidemiological settings. It is often assumed that better disease specific diagnostics will reduce antimicrobial overuse, but they might simply shift it from one antimicrobial class to another. Current global implementation of malaria testing might increase untargeted antibiotic use and must be examined.

  • 17.
    Inoue, Juliana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Jovel, Irina
    Morris, Ulrika
    Aydin-Schmidt, Berit
    Islam, Atiqul
    Segurado, Aluisio Cotrim
    Björkman, Anders
    Di Santi, Silvia
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Absence of Plasmodium falciparum K13 Propeller Domain Polymorphisms among Field Isolates Collected from the Brazilian Amazon Basin between 1984 and 20112018In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 99, no 6, p. 1504-1507Article in journal (Refereed)
    Abstract [en]

    Artemisinin resistance, presently confined to Southeast Asia and associated with mutations in the Plasmodium falciparum K13 (PfK13) propeller domain, represents a serious threat to global malaria control. This study aimed to provide baseline information for future artemisinin resistance surveillance, by analyzing the PfK13 propeller domain in P. falciparum field isolates collected from the Brazilian Amazon Basin between 1984 and 2011. A total of 152 P. falciparum mono-infections were assessed, of which 118 (78%) were collected before and 34 (22%) after the introduction of artemisinin-based combination therapy (ACT) in 2006. An 849-base pair fragment encoding the PfK13 propeller was amplified by nested PCR and sequenced in both directions. The sequences were compared with the reference sequence of P. falciparum 3D7. All samples showed wild-type sequences, thus, no mutations were observed. The results are in agreement with other recent reports and do not provide evidence for presence of PfK13 propeller domain polymorphisms associated with artemisinin resistance among P. falciparum field isolates in the Brazilian Amazon Basin neither before nor after the implementation of ACT.

  • 18.
    Inoue, Juliana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Silva, Miguel
    Fofana, Bakary
    Sanogo, Kassim
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Sagara, Issaka
    Björkman, Anders
    Veiga, Maria Isabel
    Ferreira, Pedro Eduardo
    Djimde, Abdoulaye
    Gil, José Pedro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Plasmodium falciparum Plasmepsin 2 Duplications, West Africa2018In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 24, no 8, p. 1591-1593Article in journal (Refereed)
    Abstract [en]

    Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as antimalaria drug in Africa. We report the detection in Mali of Plasmodium falciparum infections carrying plasmepsin 2 duplications (associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.

  • 19.
    Jovel, Irina T.
    et al.
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Björkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden..
    Roper, Cally
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London, England..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Ursing, Johan
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res, Stockholm, Sweden.;Danderyd Hosp, Dept Infect Dis, Stockholm, Sweden..
    Unexpected selections of Plasmodium falciparum polymorphisms in previously treatment-naive areas after monthly presumptive administration of three different anti-malarial drugs in Liberia 1976-782017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 113Article in journal (Refereed)
    Abstract [en]

    Background: To assess the effect on malaria prevalence, village specific monthly administrations of pyrimethamine, chlorproguanil, chloroquine or placebo were given to children in four previously treatment-naive Liberian villages, 1976-78. Plasmodium falciparum in vivo resistance developed to pyrimethamine only. Selection of molecular markers of P.falciparum resistance after 2 years of treatment are reported. Methods: Blood samples were collected from 191 study children in a survey in 1978. Polymorphisms in pfcrt, pfmdr1, pfdhfr, pfdhps, pfmrp1 and pfnhe1 genes were determined using PCR-based methods. Results: Pfcrt 72-76 CVIET was found in one chloroquine village sample, all remaining samples had pfcrt CVMNK. Pfmdr1 N86 prevalence was 100%. A pfmdr1 T1069(ACT -> ACG) synonymous polymorphism was found in 30% of chloroquine village samples and 3% of other samples (P = 0.008). Variations in pfnhe1 block I were found in all except the chloroquine treated village (P < 0.001). Resistance associated pfdhfr 108N prevalence was 2% in the pyrimethamine village compared to 45-65% elsewhere, including the placebo village (P = 0.001). Conclusions: Chloroquine treatment possibly resulted in the development of pfcrt 72-76 CVIET. Selection of pfmdr1 T1069(ACG) and a pfnhe1 block 1 genotypes indicates that chloroquine treatment exerted a selective pressure on P. falciparum. Pyrimethamine resistance associated pfdhfr 108N was present prior to the introduction of any drug. Decreased pfdhfr 108N frequency concurrent with development of pyrimethamine resistance suggests a non-pfdhfr polymorphisms mediated resistance mechanism.

  • 20. Juliano, Jonathan J
    et al.
    Parobek, Christian M
    Brazeau, Nicholas F
    Ngasala, Billy
    Randrianarivelojosia, Milijaona
    Lon, Chanthap
    Mwandagalirwa, Kashamuka
    Tshefu, Antoinette
    Dhar, Ravi
    Das, Bidyut K
    Hoffman, Irving
    Martinson, Francis
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Saunders, David L
    Kumar, Nirbhay
    Meshnick, Steven R
    Pooled Amplicon Deep Sequencing of Candidate Plasmodium falciparum Transmission-Blocking Vaccine Antigens2016In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 94, no 1, p. 143-146Article in journal (Refereed)
    Abstract [en]

    Polymorphisms within Plasmodium falciparum vaccine candidate antigens have the potential to compromise vaccine efficacy. Understanding the allele frequencies of polymorphisms in critical binding regions of antigens can help in the designing of strain-transcendent vaccines. Here, we adopt a pooled deep-sequencing approach, originally designed to study P. falciparum drug resistance mutations, to study the diversity of two leading transmission-blocking vaccine candidates, Pfs25 and Pfs48/45. We sequenced 329 P. falciparum field isolates from six different geographic regions. Pfs25 showed little diversity, with only one known polymorphism identified in the region associated with binding of transmission-blocking antibodies among our isolates. However, we identified four new mutations among eight non-synonymous mutations within the presumed antibody-binding region of Pfs48/45. Pooled deep sequencing provides a scalable and cost-effective approach for the targeted study of allele frequencies of P. falciparum candidate vaccine antigens.

  • 21.
    Kitutu, Freddy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Martensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Wamani, Henry
    Makerere University School of Public Health.
    Ekholm Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Kalyango, Joan
    Makerere University College of Health Sciences, Department of Pharmacy.
    Perceived quality of paediatric fever care from private drug shops and care-seeking choice in South Western Uganda: data from household surveys.In: Article in journal (Refereed)
    Abstract [en]

    Background

    Child mortality is influenced by interventions beyond the health sector such as adequate access to education, quality water and sanitation, transport and general socio-economic wellbeing. Child mortality due to febrile illnesses remains unevenly distributed within countries. The role of context and variables that act at a higher level such as a geographical location has been largely under-examined. Factors that act at group level are commonly described in literature as neighbourhood factors. The aim of the study was to investigate whether contextual differences in choice of childhood fever care-seeking in South Western Uganda remain after relevant individual and household characteristics have been taken into account, for three outcome variables, namely, choice of care-seeking in private versus government health facilities, choice of care-seeking in private health facilities versus community level and perceived quality of childhood fever care at drug shops, among households in Mbarara and Bushenyi districts.

    Methods

    Two household surveys were conducted at different time periods in Bushenyi and Mbarara districts. The first survey of 2261 households was conducted from July to October 2013 before implementation of an adapted integrated Community Case Management (iCCM) intervention for paediatric febrile illness in drug shops in Mbarara district. The second survey of 3073 households was done from April to May 2015 after the intervention. These data were analysed for effect of contextual factors, the iCCM intervention and other predictors on choice of care-seeking and perceived quality of care among the households in Mbarara and Bushenyi.

     

    Results:

    In the pre-intervention survey , more households in both Mbarara and Bushenyi reported time required to travel to either a private clinic (31%) or drug shop (43%) of 15 minutes or less as compared to a government health facility (12%). The crude second level (neighbourhood) variance of the odds ratio for care-seeking in private versus government health facility was 0.446 (SE, 0.089). The intra-neighbourhood correlation and median odds ratio were 11.9% and 1.89, respectively, for the crude model. After adjusting for covariates that were kept in the prediction model, the estimates of neighbourhood variance, intra-neighbourhood correlation and mean odds ratio decreased to 0.241 (0.069), 6.8% and 1.6, respectively.

     

    Conclusion:         

    In addition to individual factors, contextual characteristics of the neighbourhoods predict the choice of care-seeking from private versus government health facilities, private health facilities versus in the community and perceived quality of pediatric fever care at drug shops.

  • 22.
    Kitutu, Freddy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Makerere Univ, Coll Hlth Sci, Pharm Dept, Kampala, Uganda.
    Wamani, Henry
    Makerere University School of Public Health.
    Ekholm Selling, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Katabazi, Fred
    Makerere University College of Health Sciences, Department of Medical Microbiology.
    Kuteesa, Ronald
    Makerere University College of Health Sciences, Infectious Disease Institute.
    Peterson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Makerere Univ, Coll Hlth Sci, Pharm Dept, Kampala, Uganda; Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda.
    Kalyango, Joan
    Makerere University College of Health Sciences, Department of Pharmacy.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Can malaria rapid diagnostic tests by drug sellers under feld conditions classify children 5 years old or less with or without Plasmodium falciparum malaria?: Comparison with nested PCR analysis2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 365Article in journal (Refereed)
    Abstract [en]

    Background

    Malaria rapid diagnostic tests (RDTs) available as dipsticks or strips, are simple to perform, easily interpretable and do not require electricity nor infrastructural investment. Correct interpretation of and compliance with the malaria RDT results is a challenge to drug sellers. Thus, drug seller interpretation of malaria RDT strips was compared with laboratory scientist re-reading, and PCR analysis of Plasmodium DNA extracted from malaria RDT nitrocellulose strips and Fast Transient Analysis (FTA) cards. Malaria RDT cassettes are also assessed as potential source of Plasmodium DNA.

    Methods

    A total of 212 children aged between 2 and 60 months, 199 of whom had complete records at two study drug shops in south west Uganda participated in the study. Duplicate 5μL samples of capillary blood were picked from the 212 children, dispensed onto the sample well of the CareStartTM Pf-HRP2 RDT cassette and a fast transient analysis (FTA), WhatmanTM 3MM filter paper in parallel. The malaria RDT strip was interpreted by the drug seller within 15 to 20 minutes, visually re-read centrally by laboratory scientist and from it; Plasmodium DNA was recovered and detected by PCR, and compared with FTA recovered P. falciparum DNA PCR detection.

    Results

    Malaria positive samples were 62/199 (31.2% 95% CI 24.9 - 38.3) by drug seller interpretation of malaria RDT strip, 59/212 (27.8% 95% CI 22.2 – 34.3) by laboratory scientist, 55/212 (25.9% 95% CI 20.0 – 32.6) by RDT nitrocellulose strip PCR and 64/212 (30.2% 95% CI 24.4 – 37.7). The overall agreement between the drug seller interpretation and laboratory scientist re-reading of the malaria RDT strip was 93% with kappa value of 0.8 (95 % CI 0.7, 0.9). The drug seller compliance with the reported malaria RDT results and kappa value were 92.5% and 0.8 (95% CI 0.7, 0.9), respectively. The performance of the three diagnostic strategies compared with FTA PCR as the gold standard had sensitivity between 76.6% and 86.9%, specificity above 90%, positive predictive value ranging from 79% to 89.8% and negative predictive value above 90%.

    Conclusion:

    Drug sellers can use of malaria RDTs in field conditions and achieve acceptable accuracy for malaria diagnosis, and they comply with the malaria RDT results. Plasmodium DNA can be recovered from malaria RDT nitrocellulose strips even in the context of drug shops. Future malaria surveillance and diagnostic quality control studies with malaria RDT cassette as a source of Plasmodium DNA are recommended.

  • 23. Kloprogge, Frank
    et al.
    Workman, Lesley
    Borrmann, Steffen
    Tékété, Mamadou
    Lefèvre, Gilbert
    Hamed, Kamal
    Piola, Patrice
    Ursing, Johan
    Kofoed, Poul Erik
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Ngasala, Billy
    Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
    Björkman, Anders
    Ashton, Michael
    Friberg Hietala, Sofia
    Aweeka, Francesca
    Parikh, Sunil
    Mwai, Leah
    Davis, Timothy M. E.
    Karunajeewa, Harin
    Salman, Sam
    Checchi, Francesco
    Fogg, Carole
    Newton, Paul N.
    Mayxay, Mayfong
    Deloron, Philippe
    Faucher, Jean François
    Nosten, François
    Ashley, Elizabeth A.
    McGready, Rose
    van Vugt, Michele
    Proux, Stephane
    Price, Ric N.
    Karbwang, Juntra
    Ezzet, Farkad
    Bakshi, Rajesh
    Stepniewska, Kasia
    White, Nicholas J.
    Guerin, Philippe J.
    Barnes, Karen I.
    Tarning, Joel
    Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis2018In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 15, no 6, article id e1002579Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.

    METHODS AND FINDINGS: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.

    CONCLUSIONS: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.

  • 24.
    Mideo, Nicole
    et al.
    Department of Ecology and Evolutionary Biology, University of Toronto, ON, Canada.
    Bailey, Jeffrey A
    Division of Transfusion Medicine, Department of Medicine, University of Massachusetts, Worcester, MA, USA.
    Hathaway, Nicholas J
    Program in Bioinformatics and Integrative Biology, University of Massachusetts, Worcester, MA, USA.
    Ngasala, Billy
    Department of Parasitology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
    Saunders, David L
    Division of Immunology and Medicine, USAMC Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
    Lon, Chanthap
    US Army Medical Component, Armed Forces Research Institute of Medical Sciences, Phnom Penh, Cambodia.
    Kharabora, Oksana
    Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
    Jamnik, Andrew
    Department of Ecology and Evolutionary Biology, University of Toronto, ON, Canada.
    Balasubramanian, Sujata
    Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
    Björkman, Anders
    Malaria Research, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Meshnick, Steven R
    Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
    Read, Andrew F
    Center for Infectious Disease Dynamics, Department of Biology and Entomology, the Pennsylvania State University, University Park, PA, USA.
    Juliano, Jonathan J
    Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
    A deep sequencing tool for partitioning clearance rates following antimalarial treatment in polyclonal infections2016In: Evolution, medicine, and public health, ISSN 2050-6201, Vol. 2016, no 1, p. 21-36Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES

    Current tools struggle to detect drug-resistant malaria parasites when infections contain multiple parasite clones, which is the norm in high transmission settings in Africa. Our aim was to develop and apply an approach for detecting resistance that overcomes the challenges of polyclonal infections without requiring a genetic marker for resistance.

    METHODOLOGY

    Clinical samples from patients treated with artemisinin combination therapy were collected from Tanzania and Cambodia. By deeply sequencing a hypervariable locus, we quantified the relative abundance of parasite subpopulations (defined by haplotypes of that locus) within infections and revealed evolutionary dynamics during treatment. Slow clearance is a phenotypic, clinical marker of artemisinin resistance; we analyzed variation in clearance rates within infections by fitting parasite clearance curves to subpopulation data.

    RESULTS

    In Tanzania, we found substantial variation in clearance rates within individual patients. Some parasite subpopulations cleared as slowly as resistant parasites observed in Cambodia. We evaluated possible explanations for these data, including resistance to drugs. Assuming slow clearance was a stable phenotype of subpopulations, simulations predicted that modest increases in their frequency could substantially increase time to cure.

    CONCLUSIONS AND IMPLICATIONS

    By characterizing parasite subpopulations within patients, our method can detect rare, slow clearing parasites in vivo whose phenotypic effects would otherwise be masked. Since our approach can be applied to polyclonal infections even when the genetics underlying resistance are unknown, it could aid in monitoring the emergence of artemisinin resistance. Our application to Tanzanian samples uncovers rare subpopulations with worrying phenotypes for closer examination.

  • 25. Morris, Ulrika
    et al.
    Msellem, Mwinyi I
    Mkali, Humphrey
    Islam, Atiqul
    Aydin-Schmidt, Berit
    Jovel, Irina
    Shija, Shija Joseph
    Khamis, Mwinyi
    Ali, Safia Mohammed
    Hodzic, Lamija
    Magnusson, Ellinor
    Poirot, Eugenie
    Bennett, Adam
    Sachs, Michael C
    Tarning, Joel
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Ali, Abdullah S
    Björkman, Anders
    A cluster randomised controlled trial of two rounds of mass drug administration in Zanzibar, a malaria pre-elimination setting-high coverage and safety, but no significant impact on transmission.2018In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 16, no 1, article id 215Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Mass drug administration (MDA) has the potential to interrupt malaria transmission and has been suggested as a tool for malaria elimination in low-endemic settings. This study aimed to determine the effectiveness and safety of two rounds of MDA in Zanzibar, a pre-elimination setting.

    METHODS: A cluster randomised controlled trial was conducted in 16 areas considered as malaria hotspots, with an annual parasite index of > 0.8%. The areas were randomised to eight intervention and eight control clusters. The intervention included two rounds of MDA with dihydroartemisinin-piperaquine and single low-dose primaquine 4 weeks apart in May-June 2016. Primary and secondary outcomes were cumulative confirmed malaria case incidences 6 months post-MDA and parasite prevalences determined by PCR 3 months post-MDA. Additional outcomes included intervention coverage, treatment adherence, occurrence of adverse events, and cumulative incidences 3, 12, and 16 months post-MDA.

    RESULTS: Intervention coverage was 91.0% (9959/10944) and 87.7% (9355/10666) in the first and second rounds, respectively; self-reported adherence was 82.0% (881/1136) and 93.7% (985/1196). Adverse events were reported in 11.6% (147/1268) and 3.2% (37/1143) of post-MDA survey respondents after both rounds respectively. No serious adverse event was reported. No difference in cumulative malaria case incidence was observed between the control and intervention arms 6 months post-MDA (4.2 and 3.9 per 1000 population; p = 0.94). Neither was there a difference in PCR-determined parasite prevalences 3 months post-MDA (1.4% and 1.7%; OR = 1.0, p = 0.94), although having received at least the first MDA was associated with reduced odds of malaria infection (aOR = 0.35; p = 0.02). Among confirmed malaria cases at health facilities, 26.0% and 26.3% reported recent travel outside Zanzibar in the intervention and control shehias (aOR ≥ 85; p ≤ 0.001).

    CONCLUSIONS: MDA was implemented with high coverage, adherence, and tolerability. Despite this, no significant impact on transmission was observed. The findings suggest that two rounds of MDA in a single year may not be sufficient for a sustained impact on transmission in a pre-elimination setting, especially when the MDA impact is restricted by imported malaria. Importantly, this study adds to the limited evidence for the use of MDA in low transmission settings in sub-Saharan Africa.

    TRIAL REGISTRATION: ClinicalTrials.gov, NCT02721186 (registration date: March 29, 2016).

  • 26.
    Mwaiswelo, Richard
    et al.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Gosling, Roland
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Premji, Zul
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Poirot, Eugenie
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Mmbando, Bruno P.
    Tanga Ctr, Natl Inst Med Res, Tanga, Tanzania..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Safety of a single low-dose of primaquine in addition to standard artemether-lumefantrine regimen for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania2016In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 316Article in journal (Refereed)
    Abstract [en]

    Background: This study assessed the safety of the new World Health Organization (WHO) recommendation of adding a single low-dose of primaquine (PQ) to standard artemisinin-based combination therapy (ACT), regardless of individual glucose-6-phosphate dehydrogenase (G6PD) status, for treatment of acute uncomplicated Plasmodium falciparum malaria in Tanzania. Methods: Men and non-pregnant, non-lactating women aged >= 1 year with uncomplicated P. falciparum malaria were enrolled and randomized to either standard artemether-lumefantrine (AL) regimen alone or with a 0.25 mg/kg single-dose of PQ. PQ was administered concomitantly with the first AL dose. All drug doses were supervised. Safety was evaluated between days 0 and 28. G6PD status was assessed using rapid test (CareStart (TM)) and molecular genotyping. The primary endpoint was mean percentage relative reduction in haemoglobin (Hb) concentration (g/dL) between days 0 and 7 by genotypic G6PD status and treatment arm. Results: Overall, 220 patients, 110 per treatment arm, were enrolled, of whom 33/217 (15.2 %) were phenotypically G6PD deficient, whereas 15/110 (13.6 %) were genotypically hemizygous males, 5/110 (4.5 %) homozygous females and 22/110 (20 %) heterozygous females. Compared to genotypically G6PD wild-type/normal [ 6.8, 95 % confidence interval (CI) 4.67-8.96], only heterozygous patients in AL arm had significant reduction in day-7 mean relative Hb concentration (14.3, 95 % CI 7.02-21.55, p=0.045), however, none fulfilled the pre-defined haemolytic threshold value of >= 25 % Hb reduction. After adjustment for baseline parasitaemia, Hb, age and sex the mean relative Hb reduction was not statistically significant in both heterozygous and hemizygous/homozygous patients in both arms. A majority of the adverse events (AEs) were mild and unrelated to the study drugs. However, six (4.4 %) episodes, three per treatment arm, of acute haemolytic anaemia occurred between days 0 and 7. Three occurred in phenotypically G6PD deficient patients, two in AL and one in AL + PQ arm, but none in genotypically hemizygous/homozygous patients. All patients with acute haemolytic anaemia recovered without medical intervention. Conclusion: The findings support that the WHO recommendation of adding a single low-dose of PQ to standard AL regimen is safe for the treatment of acute uncomplicated P. falciparum malaria regardless of G6PD status in Tanzania.

  • 27.
    Mwaiswelo, Richard
    et al.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, POB 65011, Dar Es Salaam, Tanzania..
    Ngasala, Billy
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, POB 65011, Dar Es Salaam, Tanzania..
    Gil, J. Pedro
    Karolinska Inst, Div Pharmacogenet, Dept Physiol & Pharmacol, Drug Resistance Unit, Stockholm, Sweden..
    Malmberg, Maja
    Swedish Univ Agr Sci, Virol Sect, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Xu, Weiping
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, POB 65011, Dar Es Salaam, Tanzania..
    Mmbando, Bruno P.
    Natl Inst Med Res, Tanga Ctr, Tanga, Tanzania.;Natl Inst Med Res, Tanga Ctr, Dept Stat & Epidemiol, Tanga, Tanzania..
    Björkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Sustained High Cure Rate of Artemether-Lumefantrine against Uncomplicated Plasmodium falciparum Malaria after 8 Years of Its Wide-Scale Use in Bagamoyo District, Tanzania2017In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 97, no 2, p. 526-532Article in journal (Refereed)
    Abstract [en]

    We assessed the temporal trend of artemether-lumefantrine (AL) cure rate after 8 years of its wide-scale use for treatment of uncomplicated Plasmodium falciparum malaria from 2006 to 2014 in Bagamoyo district, Tanzania. Trend analysis was performed for four studies conducted in 2006, 2007-2008, 2012-2013, and 2014. Patients with acute uncomplicated P. falciparum malaria were enrolled, treated with standard AL regimen and followed-up for 3 (2006), 28 (2014), 42 (2012-2013), or 56 (2007-2008) days for clinical and laboratory evaluation. Primary outcome was day 28 polymerase chain reaction (PCR)-adjusted cure rate across years from 2007 to 2014. Parasite clearance was slower for the 2006 and 2007-2008 cohorts with less than 50% of patients cleared of parasitemia on day 1, but was rapid for the 2012-2013 and 2014 cohorts. Day 28 PCR-adjusted cure rate was 168/170 (98.8%) (95% confidence interval [CI], 97.2-100), 122/127 (96.1%) (95% CI, 92.6-99.5), and 206/207 (99.5%) (95% CI, 98.6-100) in 2007-2008, 2012-2013, and 2014, respectively. There was no significant change in the trend of cure rate between 2007 and 2014 (chi(2)(trend) test = 0.06, P = 0.90). Pretreatment P. falciparum multidrug-resistant gene 1 (Pfmdr1) N86 prevalence increased significantly across years from 13/48 (27.1%) in 2006 to 183/213 (85.9%) in 2014 (P < 0.001), and P. falciparum chloroquine resistance transporter gene (Pfcrt) K76 prevalence increased significantly from 24/47 (51.1%) in 2006 to 198/205 (96.6%) in 2014 (P < 0.001). The AL cure rate remained high after 8 years of its wide-scale use in Bagamoyo district for the treatment of uncomplicated P. falciparum malaria despite an increase in prevalence of pretreatment Pfmdr1 N86 and Pfcrt K76 between 2006 and 2014.

  • 28. Mwaiswelo, Richard
    et al.
    Ngasala, Billy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Jovel, Irina
    Xu, Weiping
    Larsson, Erik
    Malmberg, Maja
    Gil, Jose Pedro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Premji, Zul
    Mmbando, Bruno P
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Prevalence of and Risk Factors Associated with Polymerase Chain Reaction-Determined Plasmodium falciparum Positivity on Day 3 after Initiation of Artemether-Lumefantrine Treatment for Uncomplicated Malaria in Bagamoyo District, Tanzania.2019In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 100, no 5, p. 1179-1186Article in journal (Refereed)
    Abstract [en]

    Prevalence of and risk factors associated with polymerase chain reaction (PCR)-determined Plasmodium falciparum positivity were assessed on day 3 after initiation of treatment, pre-implementation and up to 8 years post-deployment of artemether-lumefantrine as first-line treatment for uncomplicated malaria in Bagamoyo district, Tanzania. Samples originated from previously reported trials conducted between 2006 and 2014. Cytochrome b-nested PCR was used to detect malaria parasites from blood samples collected on a filter paper on day 3. Chi-square and McNemar chi-squared tests, logistic regression models, and analysis of variance were used as appropriate. Primary outcome was based on the proportion of patients with day 3 PCR-determined P. falciparum positivity. Overall, 256/584 (43.8%) of screened patients had day 3 PCR-determined positivity, whereas only 2/584 (0.3%) had microscopy-determined asexual parasitemia. Day 3 PCR-determined positivity increased from 28.0% (14/50) in 2006 to 74.2% (132/178) in 2007-2008 and declined, thereafter, to 36.0% (50/139) in 2012-2013 and 27.6% (60/217) in 2014. When data were pooled, pretreatment microscopy-determined asexual parasitemia ≥ 100,000/µL, hemoglobin < 10 g/dL, age < 5 years, temperature ≥ 37.5°C, and year of study 2007-2008 and 2012-2013 were significantly associated with PCR-determined positivity on day 3. Significant increases in P. falciparum multidrug resistance gene 1 N86 and P. falciparum chloroquine resistant transporter K76 across years were not associated with PCR-determined positivity on day 3. No statistically significant association was observed between day 3 PCR-determined positivity and PCR-adjusted recrudescence. Day 3 PCR-determined P. falciparum positivity remained common in patients treated before and after implementation of artemether-lumefantrine in Bagamoyo district, Tanzania. However, its presence was associated with pretreatment characteristics. Trials registration numbers: NCT00336375, ISRCTN69189899, NCT01998295, and NCT02090036.

  • 29.
    Ngasala, Billy
    et al.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Mwaiswelo, Richard
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Sustained High Cure Rate Of Artemether Lumefantrine In Tanzania2017In: American Journal of Tropical Medicine and Hygiene, ISSN 0002-9637, E-ISSN 1476-1645, Vol. 97, no 5, p. 84-84Article in journal (Other academic)
  • 30.
    Rasti, Reza
    et al.
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.;South Gen Hosp, Sachs Children & Youth Hosp, Stockholm, Sweden..
    Nanjebe, Deborah
    Mbarara Res Ctr, Epictr, Mbarara, Uganda..
    Karlstrom, Jonas
    UNICEF, Hlth Sect, New York, NY USA..
    Muchunguzi, Charles
    Mbarara Univ Sci & Technol, Mbarara, Uganda..
    Mwanga-Amumpaire, Juliet
    Mbarara Res Ctr, Epictr, Mbarara, Uganda.;Mbarara Univ Sci & Technol, Mbarara, Uganda..
    Gantelius, Jesper
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.;KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Rivas, Lourdes
    KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden..
    Galban, Francesc
    KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden..
    Reutersward, Philippa
    KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden..
    Svahn, Helene Andersson
    KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden..
    Alvesson, Helle M.
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden..
    Boum, Yap, II
    Mbarara Res Ctr, Epictr, Mbarara, Uganda.;Mbarara Univ Sci & Technol, Mbarara, Uganda..
    Alfven, Tobias
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.;South Gen Hosp, Sachs Children & Youth Hosp, Stockholm, Sweden..
    Health care workers' perceptions of point-of-care testing in a low-income country-A qualitative study in Southwestern Uganda2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 7, article id e0182005Article in journal (Refereed)
    Abstract [en]

    Background Point-of-care (POC) tests have become increasingly available and more widely used in recent years. They have been of particular importance to low-income settings, enabling them with clinical capacities that had previously been limited. POC testing programs hold a great potential for significant improvement in low-income health systems. However, as most POC tests are developed in high-income countries, disengagement between developers and end-users inhibit their full potential. This study explores perceptions of POC test end-users in a low-income setting, aiming to support the development of novel POC tests for low-income countries. Methods A qualitative study was conducted in Mbarara District, Southwestern Uganda, in October 2014. Fifty health care workers were included in seven focus groups, comprising midwives, laboratory technicians, clinical and medical officers, junior and senior nurses, and medical doctors. Discussions were audio-recorded and transcribed verbatim. Transcripts were coded through a data-driven approach for qualitative content analysis. Results Nineteen different POC tests were identified as currently being in use. While participants displayed being widely accustomed to and appreciative of the use of POC tests, they also assessed the use and characteristics of current tests as imperfect. An ideal POC test was characterized as being adapted to local conditions, thoughtfully implemented in the specific health system, and capable of improving the care of patients. Tests for specific medical conditions were requested. Opinions differed with regard to the ideal distribution of POC tests in the local health system. Conclusion POC tests are commonly used and greatly appreciated in this study setting. However, there are dissatisfactions with current POC tests and their use. To maximize benefit, stakeholders need to include end-user perspectives in the development and implementation of POC tests. Insights from this study will influence our ongoing efforts to develop POC tests that will be particularly usable in low-income settings.

  • 31.
    Rhedin, Samuel Arthur
    et al.
    South Gen Hosp, Sachs Children & Youth Hosp, Hjalmar Cederstroms Gata 14, S-11861 Stockholm, Sweden;Karolinska Insitutet, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Eklundh, Annika
    South Gen Hosp, Sachs Children & Youth Hosp, Hjalmar Cederstroms Gata 14, S-11861 Stockholm, Sweden.
    Ryd-Rinder, Malin
    Astrid Lindgren Childrens Hosp, Stockholm, Sweden.
    Naucler, Pontus
    Karolinska Inst, Dept Med, Div Infect Dis, Stockholm, Sweden;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Gantelius, Jesper
    KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden.
    Zenk, Ingela
    South Gen Hosp, Sachs Children & Youth Hosp, Hjalmar Cederstroms Gata 14, S-11861 Stockholm, Sweden.
    Andersson-Svahn, Helene
    KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden.
    Nybond, Susanna
    KTH Royal Inst Technol, Div Prote & Nanobiotechnol, Sci Life Lab, Stockholm, Sweden.
    Rasti, Reza
    South Gen Hosp, Sachs Children & Youth Hosp, Hjalmar Cederstroms Gata 14, S-11861 Stockholm, Sweden;Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Lindh, Magnus
    Univ Gothenburg, Dept Infect Dis, Gothenburg, Sweden.
    Andersson, Maria
    Univ Gothenburg, Dept Infect Dis, Gothenburg, Sweden.
    Peltola, Ville
    Turku Univ Hosp, Dept Paediat & Adolescent Med, Turku, Finland;Univ Turku, Turku, Finland.
    Waris, Matti
    Turku Univ Hosp, Dept Paediat & Adolescent Med, Turku, Finland;Univ Turku, Turku, Finland.
    Alfven, Tobias
    South Gen Hosp, Sachs Children & Youth Hosp, Hjalmar Cederstroms Gata 14, S-11861 Stockholm, Sweden;Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Introducing a New Algorithm for Classification of Etiology in Studies on Pediatric Pneumonia: Protocol for the Trial of Respiratory Infections in Children for Enhanced Diagnostics Study2019In: JMIR Research Protocols, ISSN 1929-0748, E-ISSN 1929-0748, Vol. 8, no 4, article id e12705Article in journal (Refereed)
    Abstract [en]

    Background: There is a need to better distinguish viral infections from antibiotic-requiring bacterial infections in children presenting with clinical community-acquired pneumonia (CAP) to assist health care workers in decision making and to improve the rational use of antibiotics.

    Objective: The overall aim of the Trial of Respiratory infections in children for ENhanced Diagnostics (TREND) study is to improve the differential diagnosis of bacterial and viral etiologies in children aged below 5 years with clinical CAP, by evaluating myxovims resistance protein A (MxA) as a biomarker for viral CAP and by evaluating an existing (multianalyte point-of-care antigen detection test system [mariPOC respi] ArcDia International Oy Ltd.) and a potential future point-of-care test for respiratory pathogens.

    Methods: Children aged 1 to 59 months with clinical CAP as well as healthy, hospital-based, asymptomatic controls will be included at a pediatric emergency hospital in Stockholm, Sweden. Blood (analyzed for MxA and C-reactive protein) and nasopharyngeal samples (analyzed with real-time polymerase chain reaction as the gold standard and antigen-based mariPOC respi test as well as saved for future analyses of a novel recombinase polymerase amplification-based point-of-care test for respiratory pathogens) will be collected. A newly developed algorithm for the classification of CAP etiology will be used as the reference standard.

    Results: A pilot study was performed from June to August 2017. The enrollment of study subjects started in November 2017. Results are expected by the end of 2019.

    Conclusions: The findings from the TREND study can be an important step to improve the management of children with clinical CAP.

  • 32.
    Rivas, Lourdes
    et al.
    KTH Royal Inst Technol, Sci Life Lab, Div Prote & Nanobiotechnol, Stockholm, Sweden.
    Reuterswärd, Philippa
    KTH Royal Inst Technol, Sci Life Lab, Div Prote & Nanobiotechnol, Stockholm, Sweden.
    Rasti, Reza
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden;South Gen Hosp, Sachs Children & Youth Hosp, Stockholm, Sweden.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Alfven, Tobias
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden;South Gen Hosp, Sachs Children & Youth Hosp, Stockholm, Sweden.
    Gantelius, Jesper
    KTH Royal Inst Technol, Sci Life Lab, Div Prote & Nanobiotechnol, Stockholm, Sweden;Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Andersson-Svahn, Helene
    KTH Royal Inst Technol, Sci Life Lab, Div Prote & Nanobiotechnol, Stockholm, Sweden.
    A vertical flow paper-microarray assay with isothermal DNA amplification for detection of Neisseria meningitidis2018In: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 183, p. 192-200Article in journal (Refereed)
    Abstract [en]

    Paper-based biosensors offer a promising technology to be used at the point of care, enabled by good performance, convenience and low-cost. In this article, we describe a colorimetric vertical-flow DNA microarray (DNAVFM) that takes advantage of the screening capability of DNA microarrays in a paper format together with isothermal amplification by means of Recombinase Polymerase Amplification (RPA). Different assay parameters such as hybridization buffer, flow rate, printing buffer and capture probe concentration were optimized. A limit of detection (LOD) of 4.4 nM was achieved as determined by tabletop scanning. The DNA-VFM was applied as a proof of concept for detection of Neisseria meningitidis, a primary cause of bacterial meningitis. The LOD was determined to be between 38 and 2.1 x 10(6) copies/VFMassay, depending on the choice of DNA capture probes. The presented approach provides multiplex capabilities of DNA microarrays in a paper-based format for future point-of-care applications.

  • 33. Silva, M
    et al.
    Ferreira, P E
    Otienoburu, S D
    Calçada, C
    Ngasala, Billy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
    Björkman, A
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Gil, José Pedro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Division of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;Center for Biodiversity, Functional & Integrative Genomics, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal.
    Veiga, M I
    Plasmodium falciparum K13 expression associated with parasite clearance during artemisinin-based combination therapy2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 7, p. 1890-1893Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Delayed parasite clearance and, consequently, reduced efficacy of artemisinin-based combination therapies have been linked with Plasmodium falciparum K13 gene SNPs in Southeast Asia. In Africa, significantly prolonged clearance has not yet been observed and the presently restricted variation in parasite clearance cannot be explained by K13 polymorphisms.

    OBJECTIVES: Our aim was to study the in vivo pfK13 transcriptional response in patients treated with artemether-lumefantrine and explore whether the pfk13 transcripts can explain the patients' parasite clearance outcomes.

    PATIENTS AND METHODS: A total of 47 Tanzanian children with microscopically confirmed uncomplicated P. falciparum malaria were hospitalized and received artemether-lumefantrine treatment (clinical trial ID: NCT00336375). RNA was extracted from venous blood samples collected before treatment initiation and at five more timepoints after treatment. cDNA was synthesized and pfk13 transcripts measured by real-time PCR.

    RESULTS: A wide range of pfk13 transcript variation was observed throughout all timepoints after artemether-lumefantrine treatment. Taking parasite clearance data together with the pfk13 transcripts profile, we observed a negative correlation inferring that pfk13 down-regulation is associated with longer parasite clearance time.

    CONCLUSIONS: The findings suggest that a reduced PfK13 transcriptional response may represent a first step towards artemisinin tolerance/resistance.

  • 34.
    Vos, Karin
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Div Pharmacogenet, Drug Resistance Unit, Stockholm, Sweden..
    Lo Sciuto, Carlotta
    Karolinska Inst, Dept Physiol & Pharmacol, Div Pharmacogenet, Drug Resistance Unit, Stockholm, Sweden..
    Piedade, Rita
    Karolinska Inst, Dept Physiol & Pharmacol, Div Pharmacogenet, Drug Resistance Unit, Stockholm, Sweden..
    Ashton, Michael
    Univ Gothenburg, Sahlgrenska Acad, Dept Pharmacol, Unit Pharmacokinet & Drug Metab, Gothenburg, Sweden..
    Björkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Malaria Res Unit, Gothenburg, Sweden..
    Ngasala, Billy
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Gil, Jose Pedro
    Karolinska Inst, Dept Physiol & Pharmacol, Div Pharmacogenet, Drug Resistance Unit, Stockholm, Sweden.;Univ Lisbon, Fac Ciencias, Ctr Biodivers Funct & Integrat Genom, Lisbon, Portugal..
    MRP2/ABCC2 C1515Y polymorphism modulates exposure to lumefantrine during artemether-lumefantrine antimalarial therapy2017In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 18, no 10, p. 981-985Article in journal (Refereed)
    Abstract [en]

    Aim: To investigate the potential involvement of the hepatic ATP-binding cassette transporters MRP2 and MDR1 in the disposition of lumefantrine (LUM) among patients with uncomplicated Plasmodium falciparum malaria.

    Materials & methods: The tag SNPs MDR1/ABCB1 C3435T and MRP2/ABCC2 C1515Y were determined in two artemether-LUM clinical trials, including a pharmacokinetic/pharmacodynamic study focused on the treatment phase (72 h), and an efficacy trial where day 7 (D-7) LUM levels were measured.

    Results: The 1515YY genotype was significantly associated with higher (p < 0.01) LUM D-7 concentrations (median 1.42 mu M), compared with 0.77 mu M for 1515CY and 0.59 mu M for 1515CC. No significant influence of the MDR1/ABCB1 C3435T was found.

    Conclusion: LUM body disposition may be influenced by MRP2/ABCC2 genotype.

  • 35.
    Wass, Linda
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Grankvist, Anna
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gustafsson, Helena
    Gavle Cent Hosp, Dept Hematol, Gavle, Sweden.
    Krogfelt, Karen
    Statens Serum Inst, Dept Bacteria Parasites & Fungi, Copenhagen, Denmark.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Quarsten, Hanne
    Sorlandet Hosp Hlth Enterprise, Dept Med Microbiol, Kristiansand, Norway.
    Henningsson, Anna J.
    Cty Hosp Ryhov, Dept Clin Microbiol, Jonkoping, Sweden.
    Wennerås, Christine
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Clin Microbiol, Guldhedsgatan 10, S-41346 Gothenburg, Sweden.
    Serological reactivity to Anaplasma phagocytophilum in neoehrlichiosis patients2018In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 37, no 9, p. 1673-1678Article in journal (Refereed)
    Abstract [en]

    The tick-borne bacterium Candidatus (Ca.) Neoehrlichia (N.) mikurensis is a cause of "fever of unknown origin" because this strict intracellular pathogen escapes detection by routine blood cultures. Case reports suggest that neoehrlichiosis patients may display serological reactivity to Anaplasma (A.) phagocytophilum. Since Anaplasma serology is part of the diagnostic work-up of undetermined fever in European tick-exposed patients, we wanted to investigate (1) the prevalence of A. phagocytophilum seropositivity among neoehrlichiosis patients, (2) the frequency of misdiagnosed neoehrlichiosis patients among A. phagocytophilum seropositive patients, and (3) the frequency of A. phagocytophilum and Ca. N. mikurensis co-infections. Neoehrlichiosis patients (n = 18) were analyzed for A. phagocytophilum IgM and IgG serum antibodies by indirect immunofluorescence assay. Serum samples from suspected anaplasmosis patients (n = 101) were analyzed for bacterial DNA contents by singleplex PCR specific for A. phagocytophilum and Ca. N. mikurensis, respectively. One fifth of the neoehrlichiosis patients (4/18) were seropositive for IgM and/or IgG to A. phagocytophilum at the time of diagnosis. Among the patients with suspected anaplasmosis, 2% (2/101) were positive for Ca. N. mikurensis by PCR whereas none (0/101) had detectable A. phagocytophilum DNA in the serum. To conclude, patients with suspected anaplasmosis may in fact have neoehrlichiosis. We found no evidence of A. phagocytophilum and Ca. N. mikurensis co-infections in humans with suspected anaplasmosis or confirmed neoehrlichiosis.

  • 36. Zwang, Julien
    et al.
    D'Alessandro, Umberto
    MRC Unit, Banjul, Gambia;London Sch Hyg & Trop Med, London, England;Inst Trop Med, Antwerp, Belgium.
    Ndiaye, Jean-Louis
    Cheikh Anta Diop Univ, Dept Parasitol, Fac Med, Dakar, Senegal.
    Djimde, Abdoulaye A.
    Univ Sci Tech & Technol Bamako, Fac Pharm, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali.
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA USA.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition. Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Karema, Corine
    Swiss Trop & Publ Hlth Inst, Basel, Switzerland;Univ Basel, Basel, Switzerland.
    Olliaro, Piero L.
    Special Programme Res & Training Trop Dis WHO TDR, 20 Ave Appia, CH-1211 Geneva, Switzerland;Univ Oxford, Churchill Hosp, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford OX3 7LJ, England;Univ Basel, Basel, Switzerland.
    Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa2017In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 17, article id 443Article in journal (Refereed)
    Abstract [en]

    Background: Anaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity. Methods: Individual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models. Results: Eight thousand eight hundred ninety-seven patients (77.0% < 5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5' s had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 mu l) than older subjects (2784 mu l). Baseline anaemia increased the risk of parasitological recurrence. Hb began to fall after treatment start. In under 5' s the estimated nadir was similar to 35 h (range 29-48), with a drop of -12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15's, the mean Hb decline between day 0-3 was -4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach + 13.8% compared to baseline. Severe anaemia (< 5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28. There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia. Conclusion: On presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1-2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment.

  • 37.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Gametocyte carriage in uncomplicated Plasmodium falciparum malaria following treatment with artemisinin combination therapy: a systematic review and meta-analysis of individual patient data.2016In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 14, article id 79Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP).

    METHODS: Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data.

    RESULTS: The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7.

    CONCLUSIONS: AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.

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