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  • 1.
    Abdulla, Salim
    et al.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania..
    Adam, Ishag
    Univ Khartoum, Fac Med, Khartoum, Sudan..
    Adjei, George O.
    Univ Ghana, Sch Med, Ctr Trop Clin Pharmacol & Therapeut, Accra, Ghana..
    Adjuik, Martin A.
    INDEPTH Network Secretariat, Accra, Ghana..
    Alemayehu, Bereket
    Int Ctr AIDS Care & Treatment Programs, Addis Ababa, Ethiopia..
    Allan, Richard
    MENTOR Initiat, Crawley, England..
    Arinaitwe, Emmanuel
    Infect Dis Res Collaborat, Kampala, Uganda..
    Ashley, Elizabeth A.
    Epictr, Paris, France..
    Ba, Mamadou S.
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Barennes, Hubert
    Ctr Muraz, Bobo Dioulasso, Burkina Faso.;French Foreign Affairs, Biarritz, France..
    Barnes, Karen I.
    WorldWide Antimalarial Resistance Network WWARN, Cape Town, South Africa.;Univ Cape Town, Dept Med, Div Clin Pharmacol, ZA-7925 Cape Town, South Africa..
    Bassat, Quique
    Ctr Invest Saude Manhica, Manhica, Mozambique.;Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain..
    Baudin, Elisabeth
    MENTOR Initiat, Crawley, England..
    Berens-Riha, Nicole
    Univ Munich LMU, Med Ctr, Div Infect Dis & Trop Med, Munich, Germany.;LMU, German Ctr Infect Res DZIF, Munich, Germany..
    Bjoerkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden..
    Bompart, Francois
    Sanofi Aventis, Direct Acces Med Access Med, Gentilly, France..
    Bonnet, Maryline
    Epictr, Geneva, Switzerland..
    Borrmann, Steffen
    Wellcome Trust Res Programme, Kenya Med Res Inst, Kilifi, Kenya.;Univ Tubingen, Inst Trop Med, Tubingen, Germany.;German Ctr Infect Res, Tubingen, Germany..
    Bousema, Teun
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England.;Radboud Univ Nijmegen, Med Ctr, Dept Med Microbiol, Njimegen, Netherlands..
    Brasseur, Philippe
    IRD, Dakar, Senegal..
    Bukirwa, Hasifa
    Uganda Malaria Surveillance Project, Kampala, Uganda..
    Checchi, Francesco
    Epictr, Paris, France..
    Dahal, Prabin
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    D'Alessandro, Umberto
    Inst Trop Med, Unit Malariol, B-2000 Antwerp, Belgium.;MRC Unit, Fajara, Gambia.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Dis Control, London WC1, England..
    Desai, Meghna
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA..
    Dicko, Alassane
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali.;Univ Bamako, Fac Med Pharm & Dent, Dept Publ Hlth, Bamako, Mali..
    Djimde, Abdoulaye A.
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Dorsey, Grant
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA..
    Doumbo, Ogobara K.
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Drakeley, Chris J.
    German Ctr Infect Res, Tubingen, Germany..
    Duparc, Stephan
    Med Malaria Venture, Geneva, Switzerland..
    Eshetu, Teferi
    Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain.;Jimma Univ, Dept Med Lab Sci & Pathol, Jimma, Ethiopia..
    Espie, Emmanuelle
    Epictr, Paris, France..
    Etard, Jean-Francois
    Epictr, Paris, France.;IRD, Montpellier, France..
    Faiz, Abul M.
    Mahidol Univ, Fac Trop Med, Bangkok, Thailand..
    Falade, Catherine O.
    Univ Ibadan, Coll Med, Dept Pharmacol & Therapeut, Ibadan, Nigeria..
    Fanello, Caterina I.
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand..
    Faucher, Jean-Francois
    IRD, Mother & Child Hlth Trop Res Unit, Paris, France.;Univ Paris 05, PRES Sorbonne Paris Cite, Paris, France.;Univ Besancon, Med Ctr, Dept Infect Dis, F-25030 Besancon, France..
    Faye, Babacar
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Faye, Oumar
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Filler, Scott
    Global Fund Fight AIDS TB & Malaria, Geneva, Switzerland..
    Flegg, Jennifer A.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Monash Univ, Sch Math Sci, Melbourne, Vic 3004, Australia.;Monash Univ, Monash Acad Cross & Interdisciplinary Math Applic, Melbourne, Vic 3004, Australia..
    Fofana, Bakary
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Fogg, Carole
    Univ Portsmouth, Portsmouth Hosp NHS Trust, Portsmouth, Hants, England..
    Gadalla, Nahla B.
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England.;Natl Res Ctr, Res Inst Trop Med, Dept Epidemiol, Khartoum, Sudan.;NIAID, Rockville, MD USA..
    Gaye, Oumar
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Genton, Blaise
    Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.;Univ Lausanne Hosp, Div Infect Dis, Lausanne, Switzerland.;Univ Lausanne Hosp, Dept Ambulatory Care & Community Med, Lausanne, Switzerland..
    Gething, Peter W.
    Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England..
    Gil, Jose P.
    Karolinska Inst, Pharmacogenet Sect, Drug Resistance Unit, Dept Physiol & Pharmacol, Stockholm, Sweden.;Univ Lisbon, Fac Sci, Biosyst & Integrat Sci Inst BioISI, P-1699 Lisbon, Portugal.;SUNY Binghamton, Harpur Coll Arts & Sci, Binghamton, NY USA..
    Gonzalez, Raquel
    Ctr Invest Saude Manhica, Manhica, Mozambique.;Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain..
    Grandesso, Francesco
    Epictr, Paris, France..
    Greenhouse, Bryan
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA..
    Greenwood, Brian
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Dis Control, London WC1, England..
    Grivoyannis, Anastasia
    Univ Washington, Div Emergency Med, Seattle, WA 98195 USA..
    Guerin, Philippe J.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Guthmann, Jean-Paul
    Inst Veille Sanit, Dept Malad Infect, St Maurice, France..
    Hamed, Kamal
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hamour, Sally
    Royal Free Hosp, UCL Ctr Nephrol, London NW3 2QG, England..
    Hay, Simon I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA.;NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA..
    Hodel, Eva Maria
    Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.;Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    Humphreys, Georgina S.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Hwang, Jimee
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA.;Univ Calif San Francisco, Global Hlth Grp, San Francisco, CA 94143 USA..
    Ibrahim, Maman L.
    Ctr Rech Med & Sanit, Niamey, Niger..
    Jima, Daddi
    Fed Minist Hlth, Addis Ababa, Ethiopia..
    Jones, Joel J.
    Minist Hlth & Social Welf, Natl Malaria Control Programme, Monrovia, Liberia..
    Jullien, Vincent
    Univ Paris 05, AP HP, Paris, France..
    Juma, Elizabeth
    Kenya Govt Med Res Ctr, Nairobi, Kenya..
    Kachur, Patrick S.
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA..
    Kager, Piet A.
    Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Div Infect Dis Trop Med & AIDS, NL-1105 AZ Amsterdam, Netherlands..
    Kamugisha, Erasmus
    Catholic Univ Hlth & Allied Sci, Mwanza, Tanzania..
    Kamya, Moses R.
    Makerere Univ, Coll Hlth Sci, Kampala, Uganda..
    Karema, Corine
    Minist Hlth, Malaria & Other Parasit Dis Div RBC, Kigali, Rwanda..
    Kayentao, Kassoum
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Kiechel, Jean-Rene
    Drugs Neglected Dis initiat, Geneva, Switzerland..
    Kironde, Fred
    Makerere Univ, Dept Biochem, Kampala, Uganda..
    Kofoed, Poul-Erik
    Projecto Saude Bandim, Bissau, Guinea Bissau.;Kolding Cty Hosp, Dept Paediat, Kolding, Denmark..
    Kremsner, Peter G.
    Univ Tubingen, Inst Trop Med, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Krishna, Sanjeev
    Univ London, Inst Infect & Immun, London, England. Operat Ctr Barcelona Athens, Med Sans Frontieres, Barcelona, Spain..
    Lameyre, Valerie
    Sanofi Aventis, Direct Acces Med Access Med, Gentilly, France..
    Lell, Bertrand
    Univ Tubingen, Inst Trop Med, Tubingen, Germany.;Ctr Rech Med Lambarene, Lambarene, Gabon..
    Lima, Angeles
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Makanga, Michael
    European & Dev Countries Clin Trials Partnership, Cape Town, South Africa..
    Malik, ElFatih M.
    Fed Minist Hlth, Khartoum, Sudan..
    Marsh, Kevin
    Wellcome Trust Res Programme, Kenya Med Res Inst, Kilifi, Kenya.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden..
    Massougbodji, Achille
    Univ Abomey Calavi, FSS, CERPAGE, Cotonou, Benin..
    Menan, Herve
    Univ Cocody, Fac Pharm, Dept Parasitol, Abidjan, Cote Ivoire..
    Menard, Didier
    Inst Pasteur Cambodia, Malaria Mol Epidemiol Unit, Phnom Penh, Cambodia..
    Menendez, Clara
    Ctr Invest Saude Manhica, Manhica, Mozambique.;Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Hosp Clin, Barcelona, Spain..
    Mens, Petra F.
    Univ Amsterdam, Acad Med Ctr, Ctr Infect & Immun Amsterdam CINIMA, Div Infect Dis Trop Med & AIDS, NL-1105 AZ Amsterdam, Netherlands.;KIT Biomed Res, Royal Trop Inst, Amsterdam, Netherlands..
    Meremikwu, Martin
    Univ Calabar, Dept Paediat, Calabar, Nigeria.;Inst Trop Dis Res & Prevent, Calabar, Nigeria..
    Moreira, Clarissa
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Nabasumba, Carolyn
    Epictr, Paris, France.;Mbarara Univ Sci & Technol, Fac Med, Mbarara, Uganda..
    Nambozi, Michael
    Trop Dis Res Ctr, Ndola, Zambia..
    Ndiaye, Jean-Louis
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, 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..
    Nikiema, Frederic
    Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Nsanzabana, Christian
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Ntoumi, Francine
    Univ Tubingen, Inst Trop Med, Tubingen, Germany.;Univ Marien Ngouabi, FCRM, Fac Sci Sante, Brazzaville, Congo..
    Oguike, Mary
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England..
    Ogutu, Bernhards R.
    United States Army Med Res Unit, Kenya Med Res Inst, Kisumu, Kenya..
    Olliaro, Piero
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;UNICEF UNDP World Bank WHO Special Programme Res, Geneva, Switzerland..
    Omar, Sabah A.
    Kenya Govt Med Res Ctr, Ctr Biotechnol Res & Dev, Nairobi, Kenya..
    Ouedraogo, Jean-Bosco
    Ctr Muraz, Bobo Dioulasso, Burkina Faso.;Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Owusu-Agyei, Seth
    Kintampo Hlth Res Ctr, Kintampo, Ghana..
    Penali, Louis K.
    WorldWide Antimalarial Resistance Network WWARN W, Dakar, Senegal..
    Pene, Mbaye
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Peshu, Judy
    Wellcome Trust Res Programme, Kenya Med Res Inst, Kilifi, Kenya..
    Piola, Patrice
    Inst Pasteur Madagascar, Epidemiol Unit, Antananarivo, Madagascar..
    Plowe, Christopher V.
    Univ Maryland, Sch Med, Howard Hughes Med Inst, Ctr Vaccine Dev, Baltimore, MD 21201 USA..
    Premji, Zul
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol, Dar Es Salaam, Tanzania..
    Price, Ric N.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England.;Menzies Sch Hlth Res, Darwin, NT, Australia.;Charles Darwin Univ, Darwin, NT 0909, Australia..
    Randrianarivelojosia, Milijaona
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar..
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Karolinska Inst, Karolinska Univ Hosp, Infect Dis Unit, Malaria Res Lab,Dept Med, Stockholm, Sweden.;Malarsjukhuset, Dept Infect Dis, S-63188 Eskilstuna, Sweden..
    Roper, Cally
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Pathogen Mol Biol, London WC1, England..
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA..
    Sagara, Issaka
    Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali..
    Same-Ekobo, Albert
    Ctr Hosp Univ Yaounde, Fac Med & Sci Biomed, Yaounde, Cameroon..
    Sawa, Patrick
    Int Ctr Insect Physiol & Ecol, Human Hlth Div, Mbita, Kenya..
    Schallig, Henk D. F. H.
    KIT Biomed Res, Royal Trop Inst, Amsterdam, Netherlands..
    Schramm, Birgit
    Epictr, Paris, France..
    Seck, Amadou
    WorldWide Antimalarial Resistance Network WWARN W, Dakar, Senegal..
    Shekalaghe, Seif A.
    Ifakara Hlth Inst, Dar Es Salaam, Tanzania.;Kilimanjaro Christian Med Ctr, Kilimanjaro Clin Med Res Inst, Moshi, Tanzania..
    Sibley, Carol H.
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA..
    Sinou, Vronique
    Aix Marseille Univ, Fac Pharm, UMR MD3, Marseille, France..
    Sirima, Sodiomon B.
    CNRFP, Ouagadougou, Burkina Faso..
    Som, Fabrice A.
    Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Sow, Doudou
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Staedke, Sarah G.
    Infect Dis Res Collaborat, Kampala, Uganda.;London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Clin Res, London WC1, England..
    Stepniewska, Kasia
    WorldWide Antimalarial Resistance Network WWARN, Oxford, England.;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med & Global Hlth, Oxford, England..
    Sutherland, Colin J.
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Dept Infect & Immun, London WC1, England..
    Swarthout, Todd D.
    Med Sans Frontieres, London, England..
    Sylla, Khadime
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Talisuna, Ambrose O.
    East Africa Reg Ctr, WorldWide Antimalarial Resistance Network WWARN, Nairobi, Kenya.;Univ Oxford, KEMRI, Wellcome Trust Res Programme, Nairobi, Kenya..
    Taylor, Walter R. J.
    UNICEF UNDP World Bank WHO Special Programme Res, Geneva, Switzerland.;Hop Cantonal Univ Geneva, Serv Med Int & Humanitaire, Geneva, Switzerland..
    Temu, Emmanuel A.
    MENTOR Initiat, Crawley, England.;Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland.;Univ Basel, Basel, Switzerland..
    Thwing, Julie I.
    Ctr Dis Control & Prevent, Div Parasit Dis & Malaria, Malaria Branch, Atlanta, GA USA..
    Tine, Roger C. K.
    Univ Cheikh Anta Diop, Dept Parasitol & Mycol, Fac Med, Dakar, Senegal..
    Tinto, Halidou
    Ctr Muraz, Bobo Dioulasso, Burkina Faso.;Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Tommasini, Silva
    Sigma Tau Ind Farmaceut Riunite SpA, Rome, Italy..
    Toure, Offianan A.
    Inst Pasteur Cote Ivoire, Malariol Dept, Abidjan, Cote Ivoire..
    Ursing, Johan
    Projecto Saude Bandim, Bissau, Guinea Bissau.;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Malaria Res, Stockholm, Sweden..
    Vaillant, Michel T.
    CRP Sante, Ctr Hlth Studies, Methodol & Stat Unit, Luxembourg, Luxembourg.;Univ Bordeaux 2, Unite Bases Therapeut Inflammat & Infect 3677, F-33076 Bordeaux, France..
    Valentini, Giovanni
    Sigma Tau Ind Farmaceut Riunite SpA, Rome, Italy..
    Van den Broek, Ingrid
    Med Sans Frontieres, London, England.;Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, NL-3720 BA Bilthoven, Netherlands..
    Van Vugt, Michele
    Univ Amsterdam, Acad Med Ctr, Ctr Trop Med & Travel Med, Div Infect Dis, NL-1012 WX Amsterdam, Netherlands..
    Ward, Stephen A.
    Univ Liverpool, Liverpool Sch Trop Med, Dept Parasitol, Liverpool L3 5QA, Merseyside, England..
    Winstanley, Peter A.
    Univ Warwick, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England..
    Yavo, William
    Univ Cocody, Fac Pharmaceut & Biol Sci, Dept Parasitol & Mycol, Abidjan, Cote Ivoire.;Natl Inst Publ Hlth, Malaria Res & Control Ctr, Abidjan, Cote Ivoire..
    Yeka, Adoke
    Uganda Malaria Surveillance Project, Kampala, Uganda..
    Zolia, Yah M.
    Minist Hlth & Social Welf, Natl Malaria Control Programme, Monrovia, Liberia..
    Zongo, Issaka
    Inst Rech Sci Sante, Bobo Dioulasso, Burkina Faso..
    Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data2015In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 13, 212Article, review/survey (Refereed)
    Abstract [en]

    Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5-64.9) on day 1 to 6.7 % (95 % CI: 4.8-8.7) on day 2 and 0.9 % (95 % CI: 0.5-1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08-1.25); per 2-fold increase in parasite density, P <0.001); fever (>37.5 degrees C) (AOR = 1.50 (95 % CI: 1.06-2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21-3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38-5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14-4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

  • 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, 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.
    Alpkvist, Helena
    et al.
    Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.;Karolinska Inst, Dept Med Huddinge, Infect Dis Unit, Stockholm, Sweden..
    Athlin, Simon
    Univ Orebro, Dept Infect Dis, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Naucler, Pontus
    Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Stockholm, Sweden..
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Abdeldaim, Guma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Benghazi Univ, Dept Med Microbiol & Parasitol, Fac Med, Benghazi, Libya..
    Slotved, Hans-Christian
    Statens Serum Inst, Dept Microbiol & Infect Control, DK-2300 Copenhagen, Denmark..
    Hedlund, Jonas
    Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.;Karolinska Inst, Dept Med Solna, Infect Dis Unit, Stockholm, Sweden..
    Stralin, Kristoffer
    Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.;Karolinska Inst, Dept Med Huddinge, Infect Dis Unit, Stockholm, Sweden.;Univ Orebro, Dept Infect Dis, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Clinical and Microbiological Factors Associated with High Nasopharyngeal Pneumococcal Density in Patients with Pneumococcal Pneumonia2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, e0140112Article in journal (Refereed)
    Abstract [en]

    Background We aimed to study if certain clinical and/or microbiological factors are associated with a high nasopharyngeal (NP) density of Streptococcus pneumoniae in pneumococcal pneumonia. In addition, we aimed to study if a high NP pneumococcal density could be useful to detect severe pneumococcal pneumonia. Methods Adult patients hospitalized for radiologically confirmed community-acquired pneumonia were included in a prospective study. NP aspirates were collected at admission and were subjected to quantitative PCR for pneumococcal DNA (Spn9802 DNA). Patients were considered to have pneumococcal etiology if S. pneumoniae was detected in blood culture and/ or culture of respiratory secretions and/or urinary antigen test. Results Of 166 included patients, 68 patients had pneumococcal DNA detected in NP aspirate. Pneumococcal etiology was noted in 57 patients (84%) with positive and 8 patients (8.2%) with negative test for pneumococcal DNA (p<0.0001). The median NP pneumococcal density of DNA positive patients with pneumococcal etiology was 6.83 log(10) DNA copies/mL (range 1.79-9.50). In a multivariate analysis of patients with pneumococcal etiology, a high pneumococcal density was independently associated with severe pneumonia (Pneumonia Severity Index risk class IV-V), symptom duration >= 2 days prior to admission, and a medium/high serum immunoglobulin titer against the patient's own pneumococcal serotype. NP pneumococcal density was not associated with sex, age, smoking, co-morbidity, viral co-infection, pneumococcal serotype, or bacteremia. Severe pneumococcal pneumonia was noted in 28 study patients. When we studied the performance of PCR with different DNA cut-off levels for detection of severe pneumococcal pneumonia, we found sensitivities of 54-82% and positive predictive values of 37-56%, indicating suboptimal performance. Conclusions Pneumonia severity, symptom duration similar to 2 days, and a medium/high serum immunoglobulin titer against the patient's own serotype were independently associated with a high NP pneumococcal density. NP pneumococcal density has limited value for detection of severe pneumococcal pneumonia.

  • 4.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Beillevaire, Didier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mahmoud, Elgaali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hammar, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mard, Per-Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Froman, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Binding of Galanthus nivalis lectin to Chlamydia trachomatis and inhibition of in vitro infection1995In: APMIS: Acta pathologica, microbiologica et immunologica Scandinavica. Supplementum, ISSN 0903-465X, E-ISSN 1600-5503, ISSN 0903-4641, Vol. 103, no 10, 714-720 p., 8534430Article in journal (Refereed)
  • 5.
    Anagandula, Mahesh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Richardson, Sarah J.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Oberste, M. Steven
    Centers for Disease Control and Prevention, Atlanta, Georgia.
    Sioofy-Khojine, Amir-Babak
    School of Medicine, University of Tampere, Tampere, Finland.
    Hyoty, Heikki
    School of Medicine, University of Tampere, Tampere, Finland ,Fimlab Ltd, Pirkanmaa Hospital District, Finland.
    Morgan, Noel G.
    University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, UK.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Infection of Human Islets of Langerhans With Two Strains of Coxsackie B Virus Serotype 1: Assessment of Virus Replication, Degree of Cell Death and Induction of Genes Involved in the Innate Immunity Pathway2014In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, no 8, 1402-1411 p.Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes mellitus is believed to be triggered, in part, by one or more environmental factors and human enteroviruses (HEVs) are among the candidates. Therefore, this study has examined whether two strains of HEV may differentially affect the induction of genes involved in pathways leading to the synthesis of islet hormones, chemokines and cytokines in isolated, highly purified, human islets. Isolated, purified human pancreatic islets were infected with strains of Coxsackievirus B1. Viral replication and the degree of CPE/islet dissociation were monitored. The expression of insulin, glucagon, CXCL10, TLR3, IF1H1, CCL5, OAS-1, IFN beta, and DDX58 was analyzed. Both strains replicated in islets but only one of strain caused rapid islet dissociation/CPE. Expression of the insulin gene was reduced during infection of islets with either viral strain but the gene encoding glucagon was unaffected. All genes analyzed which are involved in viral sensing and the development of innate immunity were induced by Coxsackie B viruses, with the notable exception of TLR3. There was no qualitative difference in the expression pattern between each strain but the magnitude of the response varied between donors. The lack of virus induced expression of TLR3, together with the differential regulation of IF1H1, OAS1 and IFN beta, (each of which has polymorphic variants influence the predisposition to type 1 diabetes), that might result in defective clearance of virus from islet cells. The reduced expression of the insulin gene and the unaffected expression of the gene encoding glucagon by Coxsackie B1 infection is consistent with the preferential beta-cell tropism of the virus.

  • 6.
    Andersson, Madelen
    et al.
    Blekinge Hosp, Dept Infect Dis, Karlskrona, Sweden..
    Resman, Fredrik
    Lund Univ, Dept Translat Med Med Microbiol, Malmo, Sweden..
    Eitrem, Rickard
    Dept Communicable Dis Control Cty Blekinge, Karlskrona, Sweden..
    Drobni, Peter
    Dept Clin Microbiol Cty Kronoberg, Vaxjo Karlskrona, Sweden..
    Riesbeck, Kristian
    Lund Univ, Dept Translat Med Med Microbiol, Malmo, Sweden..
    Kahlmeter, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Dept Clin Microbiol Cty Kronoberg, Vaxjo Karlskrona, Sweden..
    Sundqvist, Martin
    Dept Clin Microbiol Cty Kronoberg, Vaxjo Karlskrona, Sweden.;Univ Orebro, Fac Med & Hlth, Dept Lab Med Clin Microbiol, SE-70182 Orebro, Sweden..
    Outbreak of a beta-lactam resistant non-typeable Haemophilus influenzae sequence type 14 associated with severe clinical outcomes2015In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 15, 581Article in journal (Refereed)
    Abstract [en]

    Background: During October 2011 several residents and staff members at a long-term care facility (LTCF) for elderly fell ill with respiratory symptoms. Several of the residents required hospitalization and one died. Non-typeable Haemophilus influenzae (NTHi) was identified as the causative pathogen. Methods: A descriptive analysis of the outbreak and countermeasures was performed. For each identified bacterial isolate implied in the outbreak, standard laboratory resistance testing was performed, as well as molecular typing and phylogenetic analysis. Results: The identified H. influenzae was beta-lactamase negative but had strikingly high MIC-values of ampicillin, cefuroxime and cefotaxime. All isolates displayed the same mutation in the ftsI gene encoding penicillin-binding protein (PBP) 3, and all but one were identified as sequence type 14 by Multilocus Sequence Typing (MLST). In total 15 individuals in connection to the LTCF; 8 residents, 6 staff members and one partner to a staff member were colonized with the strain. Conclusion: This report illustrates the existence of non-typeable H. influenzae with high virulence, and furthermore emphasizes the importance of continuous surveillance of possible outbreaks in health care facilities and prompt measures when outbreaks occur.

  • 7.
    Anna, Olsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Evaluation of the molecular epidemiology of ESBL-producing Escherichia coli associated with blood stream infections in China2017Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The increasing number of Extended Spectrum Beta-Lactamase (ESBL) producing Escherichia coli (E. coli) associated with sepsis in China is the reason for designing the current study. During 2014-2016, thirty hospitals representing 10 different provinces in China was involved in collecting E. coli isolates causing blood stream infections. Early treatment with suitable antibiotics have been found to be of lifesaving importance in the case of care for septic patients. Thorough understanding of the pathogens involved is therefore crucial. Using antimicrobial susceptibility testing, PCR and Multi Locus Sequence Typing (MLST), the molecular characteristics of ESBL producing E. coli isolates could be determined. This study can report that the most common ESBL producing genes found were CTX-M-14 (51 isolates, 45,5%), CTX-M-55 (23 isolates, 20,5%) CTX-M-15 (22 isolates, 19,6%). In addition, 2 isolates (1,8%) were found to be SHV-11 positive which is another ESBL producing gene. As a side finding, 5 isolates harbored Metallo-beta-lactamase (MBL) encoding genes such as NDM-5 and NDM-1 which were found to coexist with CTX-M-55 and CTX-M-14 respectively. An MLST analysis resulted in the finding of 25 different and 17 previously unknown (16,2 %) sequence types. The most common sequence types were ST131 (18 isolates, 17,1 %) as reported previously.  No significant differences in antimicrobial susceptibility were identified whether ESBL producing genes such as SHV and CTX-M was present or not. This study indicates that there could be novel resistance mechanisms present among those isolates not encoding the genes of interest. However, this finding requires further research before it can be confirmed.

  • 8.
    Ansell, Brendan R. E.
    et al.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    McConville, Malcolm J.
    Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic 3052, Australia..
    Baker, Louise
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Korhonen, Pasi K.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Young, Neil D.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Hall, Ross S.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Rojas, Cristian A. A.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Svärd, Staffan G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Gasser, Robin B.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Jex, Aaron R.
    Univ Melbourne, Fac Vet & Agr Sci, Parkville, Vic 3052, Australia..
    Time-Dependent Transcriptional Changes in Axenic Giardia duodenalis Trophozoites2015In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 9, no 12, e0004261Article in journal (Refereed)
    Abstract [en]

    Giardia duodenalis is the most common gastrointestinal protozoan parasite of humans and a significant contributor to the global burden of both diarrheal disease and post-infectious chronic disorders. Although G. duodenalis can be cultured axenically, significant gaps exist in our understanding of the molecular biology and metabolism of this pathogen. The present study employed RNA sequencing to characterize the mRNA transcriptome of G. duodenalis trophozoites in axenic culture, at log (48 h of growth), stationary (60 h), and declining (96 h) growth phases. Using similar to 400-times coverage of the transcriptome, we identified 754 differentially transcribed genes (DTGs), mainly representing two large DTG groups: 438 that were down-regulated in the declining phase relative to log and stationary phases, and 281 that were up-regulated. Differential transcription of prominent antioxidant and glycolytic enzymes implicated oxygen tension as a key factor influencing the transcriptional program of axenic trophozoites. Systematic bioinformatic characterization of numerous DTGs encoding hypothetical proteins of unknown function was achieved using structural homology searching. This powerful approach greatly informed the differential transcription analysis and revealed putative novel antioxidant-coding genes, and the presence of a nearcomplete two-component-like signaling system that may link cytosolic redox or metabolite sensing to the observed transcriptional changes. Motif searching applied to promoter regions of the two large DTG groups identified different putative transcription factor-binding motifs that may underpin global transcriptional regulation. This study provides new insights into the drivers and potential mediators of transcriptional variation in axenic G. duodenalis and provides context for static transcriptional studies.

  • 9. Artursson, Karin
    et al.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berg, Charlotte
    Varför är det så svårt att förstå betydelsen av One Health?2014In: Svensk veterinärtidning, ISSN 0346-2250, Vol. Feb, no 2, 35-39 p.Article in journal (Refereed)
  • 10.
    Askling, Helena H.
    et al.
    Karolinska Inst, Dept Med Solna, Infect Dis Unit, SE-17176 Stockholm, Sweden; Dept Communicable Dis Control & Prevent, SE-11891 Stockholm, Sweden.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Med Solna, Infect Dis Unit, SE-17176 Stockholm, Sweden.
    van Vollenhoven, Ronald
    Karolinska Inst, Unit Clin Therapy Res Inflammatory Dis ClinTRID, SE-17176 Stockholm, Sweden.
    Hallén, Ingemar
    Karlstad Cty Hosp, Dept Infect Dis, SE-65185 Karlstad, Sweden.
    Thörner, Åke
    Malar Hosp, Dept Rheumatol, SE-63188 Eskilstuna, Sweden.
    Nordin, Margareta
    Karolinska Univ Hosp, Dept Clin Microbiol, SE-17176 Stockholm, Sweden.
    Herzog, Christian
    Swiss Trop & Publ Hlth Inst, CH-4051 Basel, Switzerland.
    Kantele, Anu
    Univ Helsinki, Cent Hosp, Dept Med, Div Infect Dis, FI-00029 Huch Helsinki, Finland; Univ Helsinki, Dept Med, FI-00014 Helsinki, Finland.
    Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis: a prospective, open-label, multi-centre study2014In: Travel Medicine and Infectious Disease, ISSN 1477-8939, E-ISSN 1873-0442, Vol. 12, no 2, 134-42 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hepatitis A vaccine is the most frequently used travel vaccine, yet data are scarce about its ability to induce protection in patients with concurrent immunosuppressive treatment. We assessed the immunogenicity of this vaccine in rheumatoid arthritis (RA) patients treated with tumour necrosis factor-inhibitors (TNFi) and/or methotrexate (MTX).

    METHODS: Hepatitis A vaccine was administered to non-immune RA patients at 0 and 6 months. Hepatitis A virus (HAV) antibodies were assessed at 0, 1, 6, 7, 12, and 24 months with a quantitative Chemiluminescent Microparticle Immuno Assay (CMIA) for HAV-IgG. Samples from month 1, 6, and 7 were, in addition, analysed with a microparticle EIA (MEIA) for anti-HAV IgM + IgG.

    RESULTS: The final study population consisted of 53 patients treated with TNFi (n = 15), TNFi + MTX (n = 21) or MTX (n = 17). One and six months after the first dose, 10% and 33% of the patients had attained seroprotection. One and six months after the second dose 83% and 72% were seroprotected. At month 24, 86% of the vaccinees showed protective levels.

    CONCLUSIONS: Two doses of hepatitis A vaccine at a 6-month interval provided protection for most immunosuppressed RA patients. A single dose does not seem to afford sufficient protection to this group of patients.

  • 11.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ramey, Andrew M.
    Gustafsson Hall, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Järhult, Josef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Börjesson, Stefan
    Bonnedahl, Jonas
    Increased prevalence of antibiotic resistant E. coli in gulls sampled in Southcentral Alaska is associated with urban environments2016In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 6, no 1, 32334Article in journal (Refereed)
    Abstract [en]

    Background : Antibiotic-resistant bacteria pose challenges to healthcare delivery systems globally; however, limited information is available regarding the prevalence and spread of such bacteria in the environment. The aim of this study was to compare the prevalence of antibiotic-resistant bacteria in large-bodied gulls ( Larus spp.) at urban and remote locations in Southcentral Alaska to gain inference into the association between antibiotic resistance in wildlife and anthropogenically influenced habitats. Methods : Escherichia coli was cultured ( n 115 isolates) from fecal samples of gulls (n 160) collected from a remote location, Middleton Island, and a more urban setting on the Kenai Peninsula. Results : Screening of E. coli from fecal samples collected from glaucous-winged gulls ( Larus glaucescens )at Middleton Island revealed 8% of isolates were resistant to one or more antibiotics and 2% of the isolates were resistant to three or more antibiotics. In contrast, 55% of E. coli isolates derived from fecal samples collected from large-bodied gulls (i.e. glaucous, herring [ Larus argentatus ], and potentially hybrid gulls) on the Kenai Peninsula were resistant to one or more antibiotics and 22% were resistant to three or more antibiotics. In addition, total of 16% of the gull samples from locations on the Kenai Peninsula harbored extended-spectrum cephalosporin-resistant E. coli isolates (extended-spectrum beta-lactamases [ESBL] and plasmid-encoded AmpC [pAmpC]), in contrast to Middleton Island where no ESBL- or pAmpC-producing isolates were detected. Conclusion : Our findings indicate that increased prevalence of antibiotic resistance is associated with urban environments in Southcentral Alaska and presumably influenced by anthropogenic impacts. Further investigation is warranted to assess how migratory birds may maintain and spread antimicrobial-resistant bacteria of relevance to human and animal health.

  • 12.
    Avril, Alexis
    et al.
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden..
    Grosbois, Vladimir
    CIRAD, Campus Int Baillarguet, F-34398 Montpellier, France..
    Latorre-Margalef, Neus
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden.;Univ Georgia, Southeeastern Cooperat Wildlife Dis Study, Coll Vet Med, Dept Populat Hlth, Athens, GA 30602 USA..
    Gaidet, Nicolas
    CIRAD, Campus Int Baillarguet, F-34398 Montpellier, France..
    Tolf, Conny
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden..
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst EEMiS, SE-39182 Kalmar, Sweden..
    Capturing individual-level parameters of influenza A virus dynamics in wild ducks using multistate models2016In: Journal of Applied Ecology, ISSN 0021-8901, E-ISSN 1365-2664, Vol. 53, no 4, 1289-1297 p.Article in journal (Refereed)
    Abstract [en]

    Disease prevalence in wildlife is governed by epidemiological parameters (infection and recovery rates) and response to infection, both of which vary within and among individual hosts. Studies quantifying these individual-scale parameters and documenting their source of variation in wild hosts are fundamental for predicting disease dynamics. Such studies do not exist for the influenza A virus (IAV), despite its strong impact on the global economy and public health. Using capture-recaptures of 3500 individual mallards Anas platyrhynchos during seven migration seasons at a stopover site in southern Sweden, we provide the first empirical description of the individual-based mechanisms of IAV dynamics in a wild reservoir host. For most years, prevalence and risk of IAV infection peaked at a single time during the autumn migration season, but the timing, shape and intensity of the infection curve showed strong annual heterogeneity. In contrast, the seasonal pattern of recovery rate only varied in intensity across years. Adults and juveniles displayed similar seasonal patterns of infection and recovery each year. However, compared to adults, juveniles experienced twice the risk of becoming infected, whereas recovery rates were similar across age categories. Finally, we did not find evidence that infection influenced the timing of emigration.Synthesis and applications. Our study provides robust empirical estimates of epidemiological parameters for predicting influenza A virus (IAV) dynamics. However, the strong annual variation in infection curves makes forecasting difficult. Prevalence data can provide reliable surveillance indicators as long as they catch the variation in infection risk. However, individual-based monitoring of infection is required to verify this assumption in areas where surveillance occurs. In this context, monitoring of captive sentinel birds kept in close contact with wild birds is useful. The fact that infection does not impact the timing of migration underpins the potential for mallards to spread viruses rapidly over large geographical scales. Hence, we strongly encourage IAV surveillance with a multistate capture-recapture approach along the entire migratory flyway of mallards.

  • 13. Axelsson-Olsson, Diana
    et al.
    Olofsson, Jenny
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ellström, Patrik
    Waldenström, Jonas
    Olsen, Björn
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    A simple method for long-term storage of Acanthamoeba species2009In: Parasitology Reseach, ISSN 0932-0113, Vol. 104, no 4, 935-7 p.Article in journal (Refereed)
    Abstract [en]

    We present a novel and simple technique for storing live Acanthamoeba for long periods of time. The amoebae are maintained at refrigerator temperatures in a peptone-yeast extract-glucose (PYG) medium normally used for cultivation. Using this method, we obtained survival rates of at least 4 years for Acanthamoeba polyphaga and 3 years for Acanthamoeba castellanii and Acanthamoeba rhysodes. Advantages of this storage method are: (1) it is quick and simple, (2) inexpensive, (3) does not require encystment before storage, (4) resuscitation of cysts can be achieved within a week of culture in PYG medium at 27 degrees C, and does not require co-culture with bacteria or any special equipment.

  • 14.
    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, 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.

  • 15. Bengtsson, Daniel
    et al.
    Avril, Alexis
    Gunnarsson, Gunnar
    Elmberg, Johan
    Soderquist, Par
    Norevik, Gabriel
    Tolf, Conny
    Safi, Kamran
    Fiedler, Wolfgang
    Wikelski, Martin
    Olsén, Bjorn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Waldenström, Jonas
    Movements, Home-Range Size and Habitat Selection of Mallards during Autumn Migration2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, e100764- p.Article in journal (Refereed)
    Abstract [en]

    The mallard (Anas platyrhynchos) is a focal species in game management, epidemiology and ornithology, but comparably little research has focused on the ecology of the migration seasons. We studied habitat use, time-budgets, home-range sizes, habitat selection, and movements based on spatial data collected with GPS devices attached to wild mallards trapped at an autumn stopover site in the Northwest European flyway. Sixteen individuals (13 males, 3 females) were followed for 15-38 days in October to December 2010. Forty-nine percent (SD = 8.4%) of the ducks' total time, and 85% of the day-time (SD = 28.3%), was spent at sheltered reefs and bays on the coast. Two ducks used ponds, rather than coast, as day-roosts instead. Mallards spent most of the night (76% of total time, SD = 15.8%) on wetlands, mainly on alvar steppe, or in various flooded areas (e.g. coastal meadows). Crop fields with maize were also selectively utilized. Movements between roosting and foraging areas mainly took place at dawn and dusk, and the home-ranges observed in our study are among the largest ever documented for mallards (mean = 6,859 ha; SD = 5,872 ha). This study provides insights into relatively unknown aspects of mallard ecology. The fact that autumn-staging migratory mallards have a well-developed diel activity pattern tightly linked to the use of specific habitats has implications for wetland management, hunting and conservation, as well as for the epidemiology of diseases shared between wildlife and domestic animals.

  • 16. Bengtsson, Daniel
    et al.
    Safi, Kamran
    Avril, Alexis
    Fiedler, Wolfgang
    Wikelski, Martin
    Gunnarsson, Gunnar
    Elmberg, Johan
    Tolf, Conny
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Waldenström, Jonas
    Does influenza A virus infection affect movement behaviour during stopover in its wild reservoir host?2016In: The Royal Society, ISSN 2054-5703, Vol. 3, no 2, UNSP 150633Article in journal (Refereed)
    Abstract [en]

    The last decade has seen a surge in research on avian influenza A viruses (IAVs), in part fuelled by the emergence, spread and potential zoonotic importance of highly pathogenic virus subtypes. The mallard (Anas platyrhynchos) is the most numerous and widespread dabbling duck in the world, and one of the most important natural hosts for studying IAV transmission dynamics. In order to predict the likelihood of IAV transmission between individual ducks and to other hosts, as well as between geographical regions, it is important to understand how IAV infection affects the host. In this study, we analysed the movements of 40 mallards equipped with GPS transmitters and three-dimensional accelerometers, of which 20 were naturally infected with low pathogenic avian influenza virus (LPAIV), at a major stopover site in the Northwest European flyway. Movements differed substantially between day and night, as well as between mallards returning to the capture site and those feeding in natural habitats. However, movement patterns did not differ between LPAIV infected and uninfected birds. Hence, LPAIV infection probably does not affect mallard movements during stopover, with high possibility of virus spread along the migration route as a consequence.

  • 17. Bengtsson, S.
    et al.
    Bjelkenbrant, C.
    Kahlmeter, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Validation of EUCAST zone diameter breakpoints against reference broth microdilution2014In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 6, O353-O360 p.Article in journal (Refereed)
    Abstract [en]

    The European Committee on Antimicrobial Susceptibility Testing (EUCAST) began harmonizing clinical breakpoints in Europe 2002. In 2009, work to develop a disc diffusion method began and the first disc diffusion breakpoints calibrated to EUCAST clinical MIC breakpoints were published in December 2009. In this study we validated EUCAST clinical zone diameter breakpoints against the International Standard Organization (ISO) reference broth microdilution. A collection of 544 isolates (238 Gram-negative and 306 Gram-positive) were tested against a panel of antimicrobial agents. Antimicrobial susceptibility testing was performed with broth microdilution as described by ISO and disc diffusion in accordance with EUCAST methodology. Inhibition zone diameters and MIC values were interpreted and categorized (S, I and R) according to EUCAST clinical breakpoint table version 2.0. Categorical agreement (CA) as well as minor (mD), major (MD) and very major (VMD) discrepancies were determined. There was in general good correlation between susceptibility test results obtained with disc diffusion and broth microdilution. Overall CA was 97.3% for all combinations of organisms and antimicrobial agents (n = 5231) and the overall discrepancy rates were 110 (2.1%) mD, 24 (0.5%) MD and 7 (0.1%) VMD. The overall CA for Gram-positive and Gram-negative organisms were 98.7% (2346 tests) and 96.2% (2942 tests), respectively. Seven VMD were observed, five for Gram-positive organisms (coagulase negative staphylococci (n = 2) and Staphylococcus aureus (n = 3)) and two for Gram-negative organisms (Pseudomonas aeruginosa). Minor discrepancies were mainly observed in Gram-negatives and were related to different antimicrobial agents and species.

  • 18.
    Bergfors, Assar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Leenheer, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology. Univ Tsukuba, PhD Program Human Biol, Sch Integrat & Global Majors, Tsukuba, Ibaraki 3058577, Japan..
    Bergqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Analysis of hepatitis C NS5A resistance associated polymorphisms using ultra deep single molecule real time (SMRT) sequencing2016In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 126, 81-89 p.Article in journal (Refereed)
    Abstract [en]

    Development of Hepatitis C virus (HCV) resistance against direct-acting antivirals (DAAs), including NS5A inhibitors, is an obstacle to successful treatment of HCV when DAAs are used in sub-optimal combinations. Furthermore, it has been shown that baseline (pre-existing) resistance against DAAs is present in treatment naive-patients and this will potentially complicate future treatment strategies in different HCV genotypes (GTs). Thus the aim was to detect low levels of NS5A resistant associated variants (RAVs) in a limited sample set of treatment-naive patients of HCV GT1a and 3a, since such polymorphisms can display in vitro resistance as high as 60000 fold. Ultra-deep single molecule real time (SMRT) sequencing with the Pacific Biosciences (PacBio) RSII instrument was used to detect these RAVs. The SMRT sequencing was conducted on ten samples; three of them positive with Sanger sequencing (GT1a Q30H and Y93N, and GT3a Y93H), five GT1a samples, and two GT3a non-positive samples. The same methods were applied to the HCV GT1a H77-plasmid in a dilution series, in order to determine the error rates of replication, which in turn was used to determine the limit of detection (LOD), as defined by mean + 3SD, of minority variants down to 0.24%. We found important baseline NS5A RAVs at levels between 0.24 and 0.5%, which could potentially have clinical relevance. This new method with low level detection of baseline RAVs could be useful in predicting the most cost-efficient combination of DAA treatment, and reduce the treatment duration for an HCV infected individual.

  • 19.
    Bergquist, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Jirholt, Pernilla
    Nurkkala, Merja
    Rylander, Christian
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lindholm, Catharina
    Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock2014In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 69, no 2, 113-122 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: It remains unclear whether glucocorticoid treatment can improve the outcome of sepsis. The aim of the present study was to investigate if glucocorticoid receptor (GR) expression and function is impaired in lipopolysaccharide (LPS) induced shock, and whether the time point for start of glucocorticoid treatment affects the outcome.

    METHODS: Male C57BL/6J mice were administered LPS i.p. and GR expression and binding ability in blood and spleen leukocytes were analysed by flow cytometry. GR translocation was analysed using Image Stream technique. The effect of dexamethasone treatment started 2 h before or 2, 12 or 36 h after LPS administration on survival was studied.

    RESULTS: Despite increased GR expression in neutrophils after LPS administration, the GR binding capacity was reduced. In addition, GR translocation was decreased in neutrophils and T lymphocytes from endotoxic mice at 12 h compared to control animals. Dexamethasone treatment improved survival only when started early (2 h) after LPS administration.

    CONCLUSION: The decreased glucocorticoid responsiveness displayed by neutrophils, in combination with their increased numbers, may explain why survival is increased only when dexamethasone treatment is given early during LPS induced shock.

  • 20. Bonnedahl, Jonas
    et al.
    Hernandez, Jorge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Stedt, Johan
    Waldenstrom, Jonas
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Drobni, Mirva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Extended-Spectrum beta-Lactamases in Escherichia coli and Klebsiella pneumoniae in Gulls, Alaska, USA2014In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 20, no 5, 897-899 p.Article in journal (Refereed)
  • 21. Bonnedahl, Jonas
    et al.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Antibiotic resistance in wild birds2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, 113-116 p.Article, review/survey (Refereed)
    Abstract [en]

    Wild birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance. Antibiotic-resistant bacteria have been isolated from a multitude of wild bird species. Several studies strongly indicate transmission of resistant bacteria from human rest products to wild birds. There is evidence suggesting that wild birds can spread resistant bacteria through migration and that resistant bacteria can be transmitted from birds to humans and vice versa. Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, we can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance.

  • 22.
    Brandis, Gerrit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pietsch, Franziska
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alemayehu, Rahel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Comprehensive phenotypic characterization of rifampicin resistance mutations in Salmonella provides insight into the evolution of resistance in Mycobacterium tuberculosis2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 3, 680-685 p.Article in journal (Refereed)
    Abstract [en]

    Objectives: Mutations in the beta-subunit of RNA polymerase (RNAP), encoded by rpoB, are responsible for rifampicin resistance (Rif(R)). Although many mutations in rpoB can reduce susceptibility, only a few are frequent amongst Rif(R) clinical Mycobacterium tuberculosis (MTB) isolates. It has been suggested that there is a negative correlation between the fitness costs of Rif(R) mutations and their respective clinical frequency, but so far comparable fitness cost measurements have only been conducted for a very limited number of Rif(R) mutations. We tested this hypothesis using Salmonella and Mycobacterium smegmatis as model organisms. Methods: We constructed 122 different Rif(R) mutations in Salmonella. MICs and relative fitness costs in the presence and absence of rifampicin were determined for each mutant, including for a smaller number of Rif(R) M. smegmatis strains. Results were compared with available mutation frequency data from clinical MTB isolates. Results: (i) Rif(R) mutations frequently found in MTB isolates have a fitness cost in Salmonella Typhimurium and M. smegmatis. (ii) Clinically frequent Rif(R) mutations have a high rifampicin MIC. (iii) There is a strong correlation between the magnitude of the fitness cost of a Rif(R) mutation in Salmonella Typhimurium or M. smegmatis and the frequency with which that mutation is associated with secondary (putative compensatory) mutations in RNAP of clinical MTB isolates. Conclusions: This suggests that the success of Rif(R) mutations in clinical MTB isolates may be dependent not only on a low initial fitness cost, but rather the results of three factors: (i) a high rifampicin MIC; (ii) a relatively low initial fitness cost; and (iii) the ability to additionally acquire compensatory mutations selected to further reduce fitness cost.

  • 23.
    Brolund, Alma
    et al.
    Karolinska Univ Hosp, Div Clin Microbiol, Dept Lab Med LABMED, Stockholm, Sweden..
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Characterization of ESBL disseminating plasmids2016In: INFECTIOUS DISEASES, ISSN 2374-4235, Vol. 48, no 1, 18-25 p.Article, review/survey (Refereed)
    Abstract [en]

    Bacteria producing extended-spectrum -lactamases (ESBLs) constitute a globally increasing problem that contributes to treatment complications and elevated death rates. The extremely successful dissemination by ESBL-producing Enterobacteriaceae during the latest decades is a result of the combination of mobilization, evolution and horizontal spread of -lactamase genes on plasmids. In parallel, spread of these plasmids to particularly well-adapted bacterial clones (outbreak clones) has expanded. In this review we describe ESBL-producing bacteria and the genetic mechanisms for dissemination of ESBL resistance. We describe available methodology for studying plasmids and the importance of including plasmids in epidemiological typing as natural parts of the organisms. Plasmids play a fundamental role in how resistance arises and disseminates.

  • 24.
    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, 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.

  • 25.
    Cars, Otto
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Hur kan Norden klara antibiotikaresistenshotet?1996In: Nordisk Medicin, ISSN 0029-1420, Vol. 111, no 4, 102- p.Article in journal (Refereed)
  • 26.
    Castegren, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Modulating Organ Dysfunction in Experimental Septic Shock: Effects of Aminoglycosides, Antiendotoxin Measures and Endotoxin Tolerance2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Sepsis is a common diagnose in the intensive care population, burdened with a high mortality. The systemic inflammatory reaction underlying the development of septic organ dysfunction can be modeled using Gram-negative bacterial lipopolysaccharide, endotoxin. This thesis used a porcine endotoxemic experimental sepsis model to address clinical questions difficult to answer in clinical trials; furthermore a model of secondary sepsis was developed.

    No additional effect on the development of renal dysfunction by tobramycin was found, indicating that a single dose of tobramycin does not further compromise renal function in inflammatory-induced acute kidney injury.

    Antiendotoxin treatment had no measurable effect on TNF-α-mediated toxicity once the inflammatory cascade was activated. There was an effect on the leukocyte response that was associated with improvements in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure.

    The lungs stood out compared to the other organ systems as having a threshold endotoxin dose for the protective effect of endotoxin tolerance. As to the development of circulatory and renal dysfunction, tolerance to endotoxin was evident regardless of the endotoxin pre-exposure and challenge dose.

    There was a temporal variation of endotoxin tolerance that did not follow changes in plasma TNF-α concentrations and maximal tolerance was seen very early in the course. More pronounced endotoxin tolerance at the time of maximum tolerance was associated with a more marked hyperdynamic circulation, reduced oxygen consumption and thrombocytopenia eighteen hours later.

    It might be of interest to use the experimental model of long-term endotoxemia followed by a second hit, which has been designed to resemble an intensive care setting, for the study of treatment effects of immunomodulating therapies in secondary sepsis.

    List of papers
    1. Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model
    Open this publication in new window or tab >>Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model
    Show others...
    2009 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 10, 2782-2790 p.Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:

    To evaluate whether the addition of tobramycin further compromises renal function in inflammatory response-induced acute kidney injury. Effective antibiotic treatment in septic shock is crucial for the outcome. The combination of aminoglycosides with different beta-lactam antibiotics offers a broad antimicrobial coverage, rapid bacterial killing, synergistic effects, and low antibiotic-induced endotoxin release. However, aminoglycosides have nephrotoxic effects that may aggravate sepsis-induced acute kidney injury.

    DESIGN:

    Prospective, randomized, placebo-controlled experimental study.

    SETTING:

    University research unit.

    SUBJECTS:

    Twenty-four healthy pigs.

    INTERVENTIONS:

    The animals were anesthetized and randomized to four groups. Groups I (n = 8) and II (n = 8) received endotoxin infusion for 6 hrs, whereas groups III (n = 4) and IV (n = 4) received saline. Groups I and III received 7 mg/kg of tobramycin 20 mins after the initiation of the protocol, whereas groups II and IV received saline.

    MEASUREMENTS AND MAIN RESULTS:

    The renal elimination rate of a bolus dose of cefuroxime was chosen as the primary end point. Renal function was also evaluated by urine output, creatinine clearance, plasma cystatin C, plasma urea, and urine NAG (N-acetyl-beta-D-glucoaminidase). After 3 hrs, there were significantly lower cefuroxime elimination rates in the two endotoxin groups than in the nonendotoxin groups. No difference in cefuroxime elimination rates between groups I and II could be detected at any time point. Similarly, there were changes indicating acute kidney injury in urine output, creatinine clearance, and plasma cystatin C in the endotoxin groups with no differences between groups I and II. Plasma urea and urine NAG did not differ between any of the groups.

    CONCLUSIONS:

    The result of this study does not lend any support to the hypothesis that a single dose of tobramycin enhances the risk of acute renal failure in cases with systemic inflammatory response-induced acute kidney injury.

    Keyword
    animal model, aminoglycosides, kidney failure, sepsis, endotoxic shock, swine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-114023 (URN)10.1097/CCM.0b013e3181a988f8 (DOI)000270234700015 ()19707126 (PubMedID)
    Available from: 2010-02-08 Created: 2010-02-08 Last updated: 2013-08-02Bibliographically approved
    2. Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination
    Open this publication in new window or tab >>Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination
    Show others...
    2009 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 3, 1031-e4 p.Article in journal (Refereed) Published
    Abstract [en]

    Objective:

    To study whether a reduction of the endotoxin load, once a generalized inflammatory state has been established, reduces the inflammatory response and endotoxin-induced effects on circulation, hypoperfusion, and organ dysfunction.

    Design:

    Prospective parallel-grouped placebo-controlled randomized interventional experimental study.

    Setting:

    University research unit.

    Subjects:

    Healthy pigs.

    Interventions:

    The animals were subjected to a continuous endotoxin infusion rate of either 4.0 or 0.063 µg endotoxin × kg-1 × h-1 for 1, 2, or 6 hours. The 1- and 2-hour infusion groups represented the applied therapy by a reduction of the endotoxin load of 5/6 and 2/3, respectively.

    Measurements and Main Results:

    During a 6-hour experiment, laboratory and physiologic parameters were recorded hourly in 26 anesthetized and mechanically ventilated pigs. Primary end point was to detect differences in tumor necrosis factor-[alpha] (TNF-[alpha]) concentration during the last 3 hours of the experiment. Despite the early reduction of the endotoxin load, no effect on TNF-[alpha] concentration was observed. Similarly, in circulatory parameters, such as mean arterial pressure and oxygen delivery, and in platelet count and renal function, no effects were noted. However, there was some improvement in pulmonary compliance and function as determined by Pao2, Paco2, and pH. These changes were associated with slight improvements in leukocyte response and capillary leakage.

    Conclusions:

    Termination of the endotoxin infusion represents an incontestable model of endotoxin concentration reduction. Endotoxin elimination strategies applied at the TNF-[alpha] peak or later will have very little or no effect on TNF-[alpha]–mediated toxicity. Nevertheless, there was an effect on the leukocyte response that was associated with an improvement in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-114020 (URN)10.1097/CCM.0b013e31819b5683 (DOI)000263779300033 ()19237914 (PubMedID)
    Available from: 2010-02-08 Created: 2010-02-08 Last updated: 2013-08-02Bibliographically approved
    3. Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin
    Open this publication in new window or tab >>Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin
    Show others...
    2012 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 5, 501-510 p.Article in journal (Refereed) Published
    Abstract [en]

    Endotoxin tolerance is a well-studied phenomenon associated with a reduced inflammatory response. In the switch from an inflammatory to an anti-inflammatory response in clinical sepsis the concept of endotoxin tolerance is of obvious interest. However, only limited data exist regarding the effect of endotoxin tolerance on organ dysfunction and, therefore, this was investigated in a porcine intensive care sepsis model. Twenty-seven healthy pigs, including nine control animals, were included in the study. Twelve pigs pre-exposed to 24 h of intravenous endotoxin infusion and intensive care and six unexposed pigs were given either a high- or low-dose endotoxin challenge for 6 h. Inflammatory, circulatory, hypoperfusion and organ dysfunction parameters were followed. The inflammatory responses as well as parameters representing circulation, hypoperfusion, cardiac and renal function were all markedly attenuated in animals pre-exposed to endotoxin and intensive care as compared with animals not pre-exposed. In animals pre-exposed to endotoxin and given the high-dose of endotoxin challenge, deterioration in pulmonary function was equal to or even worse than in animals not pre-exposed.In contrast to the overall protective effect of endotoxin tolerance observed in other organ systems, the lungs of endotoxin tolerant animals demonstrated an increased responsiveness to high-dose endotoxin challenge.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-168692 (URN)10.1097/SHK.0b013e318249bb0d (DOI)000303010000009 ()22266970 (PubMedID)
    Note

    Previous title as submitted: "Compartmentalization of organ endotoxin tolerance in a porcine model of secondary sepsis"

    Available from: 2012-02-15 Created: 2012-02-15 Last updated: 2017-12-07Bibliographically approved
    4. Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction
    Open this publication in new window or tab >>Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, e53221- p.Article in journal (Refereed) Published
    Abstract [en]

    Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-149277 (URN)10.1371/journal.pone.0053221 (DOI)000313552400016 ()
    Available from: 2011-03-16 Created: 2011-03-16 Last updated: 2017-12-11Bibliographically approved
  • 27.
    Chandran, Salesh P.
    et al.
    Karolinska Inst, Dept Publ Hlth Sci Global Hlth Hlth Syst & Policy, Stockholm, Sweden.;St Johns Res Inst, Div Infect Dis, Bangalore, Karnataka, India.;RD Gardi Med Coll, Dept Microbiol, Agar Rd, Ujjain 456006, Madhya Pradesh, India..
    Sarkar, Samarpita
    St Johns Res Inst, Div Infect Dis, Bangalore, Karnataka, India..
    Diwan, Vishal
    Karolinska Inst, Dept Publ Hlth Sci Global Hlth Hlth Syst & Policy, Stockholm, Sweden.;RD Gardi Med Coll, Dept Publ Hlth & Environm, Ujjain, Madhya Pradesh, India..
    Pathak, Ashish
    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). Karolinska Inst, Dept Publ Hlth Sci Global Hlth Hlth Syst & Policy, Stockholm, Sweden.;RD Gardi Med Coll, Dept Pediat, Ujjain, Madhya Pradesh, India..
    Shah, Harshada
    RD Gardi Med Coll, Dept Microbiol, Agar Rd, Ujjain 456006, Madhya Pradesh, India..
    Tamhankar, Ashok J.
    Karolinska Inst, Dept Publ Hlth Sci Global Hlth Hlth Syst & Policy, Stockholm, Sweden.;RD Gardi Med Coll, Indian Initiat Management Antibiot Resistance, Dept Environm Med, Ujjain, Madhya Pradesh, India..
    Macaden, Ragini
    St Johns Res Inst, Div Infect Dis, Bangalore, Karnataka, India..
    Stalsby-Lundborg, Cecilia
    Karolinska Inst, Dept Publ Hlth Sci Global Hlth Hlth Syst & Policy, Stockholm, Sweden..
    Detection of virulence genes in ESBL producing, quinolone resistant commensal Escherichia coli from rural Indian children2017In: Journal of Infection in Developing Countries, ISSN 2036-6590, E-ISSN 1972-2680, Vol. 11, no 5, 387-392 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Extended-spectrum beta-lactamase producing commensal Escherichia coli are considered as a reservoir of antibiotic resistance genes that may be transmitted in the community. This study aimed to determine the genes coding for ESBLs, plasmid mediated quinolone resistance and virulence markers in commensal E. coli isolated from healthy school children. Methodology: ESBL producing E. coli isolates (n = 47) were obtained from 529 fecal samples of healthy school children from a rural area in central India. Multiplex PCR was used to detect the genes coding for cephalosporin and quinolone resistance, for virulence fluA, fluB, stx1, stx2, eae, bfp, lt, stII, virF, ipaH, daaE, aafII and phylogenetic groups. Results: Of the 47 ESBL producing E. coli, 41 were positive for CTXM-15, 23 for TEM-1, 8 for OXA-1and a single for SHV-12. For plasmid-mediated quinolone resistance, all the 47 isolates carried the aac(6')-ib-cr gene, and amongst them18 were qnrS positive. Virulence gene, fluA was detected in 32, whereas eae in 14, daaE in 7 and fluB in 1. In 10 isolates, fluA and eae and in 7, fluA and daaE co-existed. Of the 47 E. coli isolates, 18 were grouped into the phylogenetic group B2, 17 in D and 12 in A. The proportion of isolates positive for fluA gene in the phylogenetic group B2 (18/18), was significantly higher than in group A (7/12) and D (6/17). Conclusion: Commensal E. coli in healthy children in rural India may serve as reservoirs of resistance towards cephalosporins and fluoroquinolones and virulence coding genes for urinary tract and diarrheal infections.

  • 28. Chapman, Joanne R
    et al.
    Helin, Anu S
    Wille, Michelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Atterby, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Fridlund, Jimmy S
    Waldenström, Jonas
    A Panel of Stably Expressed Reference Genes for Real-Time qPCR Gene Expression Studies of Mallards (Anas platyrhynchos)2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, e0149454Article in journal (Refereed)
    Abstract [en]

    Determining which reference genes have the highest stability, and are therefore appropriate for normalising data, is a crucial step in the design of real-time quantitative PCR (qPCR) gene expression studies. This is particularly warranted in non-model and ecologically important species for which appropriate reference genes are lacking, such as the mallard-a key reservoir of many diseases with relevance for human and livestock health. Previous studies assessing gene expression changes as a consequence of infection in mallards have nearly universally used β-actin and/or GAPDH as reference genes without confirming their suitability as normalisers. The use of reference genes at random, without regard for stability of expression across treatment groups, can result in erroneous interpretation of data. Here, eleven putative reference genes for use in gene expression studies of the mallard were evaluated, across six different tissues, using a low pathogenic avian influenza A virus infection model. Tissue type influenced the selection of reference genes, whereby different genes were stable in blood, spleen, lung, gastrointestinal tract and colon. β-actin and GAPDH generally displayed low stability and are therefore inappropriate reference genes in many cases. The use of different algorithms (GeNorm and NormFinder) affected stability rankings, but for both algorithms it was possible to find a combination of two stable reference genes with which to normalise qPCR data in mallards. These results highlight the importance of validating the choice of normalising reference genes before conducting gene expression studies in ducks. The fact that nearly all previous studies of the influence of pathogen infection on mallard gene expression have used a single, non-validated reference gene is problematic. The toolkit of putative reference genes provided here offers a solid foundation for future studies of gene expression in mallards and other waterfowl.

  • 29.
    Cholleti, Harindranath
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Paidikondala, Maruthibabu
    Unit for Virology, Department of Virology, Immunobiology and Parasitology of the National Veterinary Institute (SVA).
    Munir, M.
    Hakhverdyan, M.
    Baule, C.
    Equine arteritis virus induced cell death is associated with activation of the intrinsic apoptotic signalling pathway2013In: Virus Research, ISSN 0168-1702, E-ISSN 1872-7492, Vol. 171, no 1, 222-226 p.Article in journal (Refereed)
    Abstract [en]

    Equine arteritis virus (EAV) causes a respiratory and reproductive disease in horses, equine viral arteritis. Though cell death in infection with EAV is considered to occur by apoptosis, the underlying molecular mechanism has not been extensively elucidated. We investigated the expression of mRNA of pro-apoptotic and caspase genes during EAV infection in BHK21 cells, a well-established cell type for EAV replication. Using a SYBR Green real-time PCR, mRNA of p53, Bax, caspase 3 and caspase 9 were found up-regulated in a time dependent manner in EAV infected cells. Western blot analysis for caspase 3 and caspase 9 showed expression of cleaved forms of these proteins during EAV infection. In addition, a luminescence-based cell assay for caspase 3/7 activation as a hallmark in apoptosis confirmed apoptotic cell death. The findings demonstrate that cell death in EAV infected BHK21 cells results from apoptosis mediated through the intrinsic signalling pathway.

  • 30.
    Clement, Jan
    et al.
    Univ Hosp Leuven, Rega Inst Med Res, Natl Reference Ctr Hantavirus Infect, Lab Clin & Epidemiol Virol, Leuven, Belgium..
    Maes, Piet
    Univ Hosp Leuven, Rega Inst Med Res, Natl Reference Ctr Hantavirus Infect, Lab Clin & Epidemiol Virol, Leuven, Belgium..
    Saegeman, Veroniek
    Univ Hosp Leuven, Lab Med, Leuven, Belgium.;Univ Hosp Leuven, Dept Microbiol & Immunol, Leuven, Belgium..
    Lagrou, Katrien
    Univ Hosp Leuven, Lab Med, Leuven, Belgium.;Univ Hosp Leuven, Dept Microbiol & Immunol, Leuven, Belgium..
    Van Ranst, Marc
    Univ Hosp Leuven, Rega Inst Med Res, Natl Reference Ctr Hantavirus Infect, Lab Clin & Epidemiol Virol, Leuven, Belgium.;Univ Hosp Leuven, Lab Med, Leuven, Belgium.;Univ Hosp Leuven, Dept Microbiol & Immunol, Leuven, Belgium..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Uppsala Hosp, Lab Clin Microbiol, Uppsala, Sweden..
    Comment on "A Cluster of Three Cases of Hantavirus Pulmonary Syndrome among Canadian Military Personnel"2016In: CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY, ISSN 1712-9532, 7458409Article in journal (Refereed)
  • 31.
    Clewe, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aulin, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hu, Yanmin
    Coates, Anthony R M
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 4, 964-974 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states.

    METHODS: The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships.

    RESULTS: The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively.

    CONCLUSIONS: The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.

  • 32.
    Danielsson, Axel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Palanisamy, Navaneethan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Golbob, Sultan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Yin, Hong
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Hedlund, Johan
    Sylvan, Staffan
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Transmission of hepatitis C virus among intravenous drug users in the Uppsala region of Sweden2014In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 4, 22251Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epidemiology and transmission patterns of hepatitis C virus (HCV) are important subjects as we enter a new era of treatment with directly acting antivirals (DAAs). The highest prevalence of HCV in developed countries is found among intravenous drug users (IDUs), where unsafe needle sharing practices provide the main route of infection. Efforts to prohibit the continuous spread of HCV among these groups have been initiated by the community services and health care providers. Our goal was to understand how HCV was transmitted among IDUs within a limited population group. We provide a retrospective study (2005-2007) of the HCV transmission patterns in a population of IDUs in the Uppsala region of Sweden.

    METHOD: Eighty-two serum samples were collected from IDUs in Uppsala County. Our reverse transcription nested polymerase chain reaction (RT-nested PCR) and sequencing method enabled a comprehensive genetic analysis for a broad spectrum of genotypes of two relatively conserved regions, NS5B and NS3, that encodes for the viral polymerase and protease, respectively. HCV RNA in serum samples was amplified and sequenced with in-house primers. Sequence similarities between individuals and subgroups were analyzed with maximum likelihood (ML) phylogenetic trees. Published HCV reference sequences from other geographic regions and countries were also included for clarity.

    RESULTS: Phylogenetic analysis was possible for 59 NS5B (72%) and 29 NS3 (35%) sequences from Uppsala patients. Additionally, we also included 15 NS3 sequences from Örebro patients, making a total of 44 NS3 sequences for the analysis. By analyzing the NS3 sequences, two transmission sets were found between the IDUs (>98% sequence identity), with one set consisting of two individuals and another set consisting of three individuals. In addition, the phylogenetic analysis done with our serum samples displayed clusters that distinguished them from the reference sequences.

    CONCLUSION: Our method seems to enable us to trace the HCV transmission between IDUs. Furthermore, the method is fairly independent of the time of infection because the method uses relatively conserved HCV sequence regions (i.e. NS5B and NS3).

  • 33. Darkahi, Bahman
    et al.
    Sandblom, Gabriel
    Liljeholm, Hakan
    Videhult, Per
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Rasmussen, Ib Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Biliary Microflora in Patients Undergoing Cholecystectomy2014In: Surgical Infections, ISSN 1096-2964, E-ISSN 1557-8674, Vol. 15, no 3, 262-265 p.Article in journal (Refereed)
    Abstract [en]

    Background: The management of acute cholecystitis requires a sound knowledge of the biliary microflora. Methods: Bile samples were taken for culture according to a standard routine during all cholecystectomies performed from April 2007 to February 2009 in the Department of Surgery at Enkoping Hospital. The use of antibiotics within the 3-mo period before surgery, indication for surgery, prophylactic antibiotics, and post-operative complications were recorded prospectively. Results: Altogether, 246 procedures were performed during the study period, of which 149 (62%) were done on women. The mean (SD) age of the study subjects was 49 +/- 16y. Bacterial growth was seen in cultures from 34 (14%) of the subjects. The mean age of subjects with positive cultures was 64y and that of subjects with negative cultures was 47y (p<0.001). Positive culture was seen in 16 (31%) of the 51 patients who underwent operations for acute cholecystitis, whereas positive cultures were obtained in 18 of 195 patients without acute cholecystitis (9%) (p<0.001). Resistance to ampicillin was recorded in three of 34 (9%) of the cultures with bacterial growth, to co-trimoxazole in one of the 34 (3%) cultures, to fluoroquinolones in one of the 34 (3%) cultures, and to cephalosporins in one of the 34 (3%) cultures. Resistance to piperacillin-tazobactam was not observed in any of the cultures. In multivariable logistic regression analysis, a positive culture was the only factor significantly associated with risk for post-operative infectious complications (p<0.05). Discussion: Bacterial growth in the bile is observed more often in patients undergoing surgery for acute cholecystitis. The microflora of the bile is probably important for the outcome of surgery, but further studies are required for assessing the effectiveness of measures for preventing infectious post-operative complications.

  • 34. Denamur, Erick
    et al.
    Bonacorsi, Stéphane
    Giraud, Antoine
    Duriez, Patrick
    Hilali, Farida
    Amorin, Christine
    Bingen, Edouard
    Andremont, Antoine
    Picard, Bertrand
    Taddei, François
    Matic, Ivan
    High frequency of mutator strains among human uropathogenic Escherichia coli isolates.2002In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 184, no 2, 605-9 p.Article in journal (Refereed)
    Abstract [en]

    By using a panel of 603 commensal and pathogenic Escherichia coli and Shigella isolates, we showed that mutation rates of strains vary considerably among different ecotypes. Uropathogenic strains had the highest frequency of mutators, while strains from patients with bacteremia had the lowest mutation rates. No correlation between the mutation rates and antibiotic resistance was observed among the studied strains.

  • 35.
    Dittrich, Sabine
    et al.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland..
    Tadesse, Birkneh Tilahun
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland.;WHO, Special Programme Res & Training Trop Dis TDR, Ave Appia 20, CH-1211 Geneva 27, Switzerland.;Hawassa Univ, Dept Pediat, Coll Med & Hlth Sci, Hawassa, Ethiopia..
    Moussy, Francis
    WHO, 20 Ave Appia, CH-1211 Geneva 27, Switzerland..
    Chua, Arlene
    Tan Took Seng Hosp, Inst Infect Dis & Epidemiol, Singapore, Singapore..
    Zorzet, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dolinger, David L.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland.;WHO, 20 Ave Appia, CH-1211 Geneva 27, Switzerland.;Tan Took Seng Hosp, Inst Infect Dis & Epidemiol, Singapore, Singapore..
    Page, Anne-Laure
    Epicentre, Epidemiol & Populat Hlth, Paris, France..
    Crump, John A.
    Univ Otago, Ctr Int Hlth, POB 56, Dunedin 9054, New Zealand.;Duke Univ, Duke Global Hlth Inst, Box 90519, Durham, NC 27708 USA.;Duke Univ, Med Ctr, Div Infect Dis & Int Hlth, Box 102359, Durham, NC 27710 USA..
    D'Acremont, Valerie
    Swiss Trop & Publ Hlth Inst, CH-4002 Basel, Switzerland.;Univ Lausanne, Dept Ambulatory Care & Community Med, Bugnon 44, CH-1011 Lausanne, Switzerland..
    Bassat, Quique
    Hosp Clin Univ Barcelona, Barcelona Ctr Int Hlth Res CRESIB, ISGlobal, Barcelona, Spain.;CISM, Maputo, Mozambique..
    Lubell, Yoel
    Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England.;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand..
    Newton, Paul N.
    Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England.;Lao Oxford Mahosot Hosp, Wellcome Trust Res Unit, Viangchan, Laos..
    Heinrich, Norbert
    Univ Munich LMU, Med Ctr, Div Infect Dis & Trop Med, Munich, Germany.;German Ctr Infect Res, Munich Partner Site,Leopoldstr 5, D-80802 Munich, Germany..
    Rodwell, Timothy J.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland..
    Gonzalez, Iveth J.
    FIND, 9 Chemin Mines, CH-1202 Geneva, Switzerland..
    Target Product Profile for a Diagnostic Assay to Differentiate between Bacterial and Non-Bacterial Infections and Reduce Antimicrobial Overuse in Resource-Limited Settings: An Expert Consensus2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, e0161721Article in journal (Refereed)
    Abstract [en]

    Acute fever is one of the most common presenting symptoms globally. In order to reduce the empiric use of antimicrobial drugs and improve outcomes, it is essential to improve diagnostic capabilities. In the absence of microbiology facilities in low-income settings, an assay to distinguish bacterial from non-bacterial causes would be a critical first step. To ensure that patient and market needs are met, the requirements of such a test should be specified in a target product profile (TPP). To identify minimal/optimal characteristics for a bacterial vs. non-bacterial fever test, experts from academia and international organizations with expertise in infectious diseases, diagnostic test development, laboratory medicine, global health, and health economics were convened. Proposed TPPs were reviewed by this working group, and consensus characteristics were defined. The working group defined non-severely ill, non-malaria infected children as the target population for the desired assay. To provide access to the most patients, the test should be deployable to community health centers and informal health settings, and staff should require <2 days of training to perform the assay. Further, given that the aim is to reduce inappropriate antimicrobial use as well as to deliver appropriate treatment for patients with bacterial infections, the group agreed on minimal diagnostic performance requirements of >90% and >80% for sensitivity and specificity, respectively. Other key characteristics, to account for the challenging environment at which the test is targeted, included: i) time-to-result <10 min (but maximally <2 hrs); ii) storage conditions at 0-40 degrees C, <= 90% non-condensing humidity with a minimal shelf life of 12 months; iii) operational conditions of 5-40 degrees C, <= 90% non-condensing humidity; and iv) minimal sample collection needs (50-100 mu L, capillary blood). This expert approach to define assay requirements for a bacterial vs. non-bacterial assay should guide product development, and enable targeted and timely efforts by industry partners and academic institutions.

  • 36.
    Dorlo, Thomas P. C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands..
    Ostyn, Bart A.
    Inst Trop Med, B-2000 Antwerp, Belgium..
    Uranw, Surendra
    BP Koirala Inst Hlth Sci, Dharan, Nepal..
    Dujardin, Jean-Claude
    Inst Trop Med, B-2000 Antwerp, Belgium..
    Boelaert, Marleen
    Inst Trop Med, B-2000 Antwerp, Belgium..
    Treatment of visceral leishmaniasis: pitfalls and stewardship2016In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 16, no 7, 777-778 p.Article in journal (Refereed)
  • 37.
    Dyrdak, R.
    et al.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Grabbe, M.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Hammas, B.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Ekwall, J.
    Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Hansson, K. E.
    Soder Sjukhuset, Dept Infect Dis, Stockholm, Sweden..
    Luthander, J.
    Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Pediat Infect Dis Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Naucler, P.
    Karolinska Inst, Dept Med Solna, Infect Dis Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden..
    Reinius, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Rotzen-Ostlund, M.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Albert, J.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Outbreak of enterovirus D68 of the new B3 lineage in Stockholm, Sweden, August to September 20162016In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 21, no 46, 5-10 p.Article in journal (Refereed)
    Abstract [en]

    We report an enterovirus D68 ( EV-D68) outbreak in Stockholm Sweden in 2016. Between 22 August and 25 September EV-D68 was detected in 74/ 495 respiratory samples analysed at the Karolinska University Hospital. During the peak week, 30/ 91 ( 33%) samples were EV-D68 positive. Viral protein ( VP) P4/ VP2 sequencing revealed that cases were caused by B3 lineage strains. Forty-four ( 59%) EV-D68-positive patients were children aged = 5 years. Ten patients had severe respiratory or neurological symptoms and one died. We report an outbreak of enterovirus D68 ( EV-D68) infections in Stockholm, Sweden in late August and September of 2016 caused by the newly described B3 lineage [1].

  • 38. Earnshaw, Sarah
    et al.
    Monnet, D. L.
    Duncan, B.
    O'Toole, J.
    Ekdahl, K.
    Goossens, H.
    European Antibiotic Awareness Day Technical Advisory Committe; European Antibiotic Awareness Day Collaborative Group.,
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    European Antibiotic Awareness Day, 2008 - the first Europe-wide public information campaign on prudent antibiotic use: methods and survey of activities in participating countries2009In: Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin, ISSN 1025-496X, Vol. 14, no 30, 19280- p.Article in journal (Refereed)
    Abstract [en]

    Antibiotic resistance is a major European and global public health problem and is, for a large part, driven by misuse of antibiotics. Hence, reducing unnecessary antibiotic use, particularly for the treatment of certain respiratory tract infections where they are not needed, is a public health priority. The success of national awareness campaigns to educate the public and primary care prescribers about appropriate antibiotic use in Belgium and France stimulated a European initiative coordinated by the European Centre for Disease Prevention and Control (ECDC), and named European Antibiotic Awareness Day (EAAD), to take place each year on 18 November. Specific campaign materials, including key messages, logos, slogans and a media toolkit, were developed and made available for use in European countries. The focus of the first EAAD campaign was about not taking antibiotics for viral infections such as colds and flu. A post-campaign survey was conducted in January 2009. Thirty-two European countries participated in the first EAAD, producing information materials and implementing activities to mark EAAD. Media coverage peaked on 18 and 19 November. At EU level, EAAD was launched at a scientific meeting in the European Parliament, Strasbourg. The event received EU political engagement through support from the EU Commissioner for Health, the Slovenian and French EU Presidencies, and Members of the European Parliament. Critical factors that led to the success of the first EAAD were good cooperation and process for building the campaign, strong political and stakeholder support and development of campaign materials based on scientific evidence. Countries indicated wide support for another EAAD in 2009. For this purpose, ECDC is developing several TV spots as well as a second set of EAAD campaign materials targeting primary care prescribers.

  • 39.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    No evidence of Chlamydophila spp. or other intracellular bacteria in mitral valves.2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 164, no 2, 249-250 p.Article in journal (Refereed)
  • 40.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tallkvist, Jonas
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, S-75007 Uppsala, Sweden..
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Natl Food Agcy, Risk Benefit Assessment Dept, S-75126 Uppsala, Sweden..
    Cholesterol uptake in the mouse aorta increases during Chlamydia pneumoniae infection2017In: Pathogens and Disease, E-ISSN 2049-632X, Vol. 75, no 1, ftx004Article in journal (Refereed)
    Abstract [en]

    Chlamydia pneumoniae has been suggested as a stimulator of the atherosclerotic process. Mice fed a normal diet were infected intranasally with C. pneumoniae and given one intraperitoneal injection of C-14-cholesterol tracer per day for 12 days. Bacteria were demonstrated in the aorta in the early phase of infection and in lungs and liver throughout the study period of 20 days. C-14-cholesterol was not affected in the heart but increased in the blood, liver and aorta on day 4 when the infection was clinically most severe. Furthermore, on day 20 C-14-cholesterol tended to be increased in the aorta. Accordingly, copper-and zinc levels and expressions of the infection biomarkers Cxcl2 and Ifng increased in the liver on day 4 with a tendency of increased of copper, zinc and Ifng on day 20. In mice where bacteria could be cultivated from the lungs, expressions of cholesterol transporters Abca1 and Idol were both increased in the liver on day 4. The increased levels of C-14-cholesterol in blood and aorta together with increased Abca1 and Idol in the liver during C. pneumoniae infection in mice fed a normal diet suggest that this pathogen may have a role in the initiation of the atherosclerotic process.

  • 41.
    Edvinsson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tallkvist, Jonas
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Nyström-Rosander, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ilbäck, Nils-Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Natl Food Agcy, Risk Benefit Assessment Dept, Uppsala, Sweden..
    Iron Homeostasis in Tissues Is Affected during Persistent Chlamydia pneumoniae Infection in Mice2017In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, 3642301Article in journal (Refereed)
    Abstract [en]

    Chlamydia pneumoniae (C. pneumoniae) may be a mediator in the pathogenesis of atherosclerosis. For its growth C. pneumoniae depends on iron (Fe), but how Fe changes in tissues during persistent infection or affects bacterial replication in tissues is unknown. C. pneumoniae-infected C57BL/6J mice were sacrificed on days 4, 8, 20, and 40. Mice had bacteria in the lungs and liver on all days. Inflammatory markers, chemokine Cxcl2 and interferon-gamma, were not affected in the liver on day 40. The copper (Cu)/zinc (Zn) ratio in serum, another marker of infection/inflammation, increased on day 4 and tended to increase again on day 40. The Fe markers, transferrin receptor (TfR), Hepcidin (Hamp1), and ferroportin 1 (Fpn1), increased in the liver on day 4 and then normalized except for TfR that tended to decrease. TfR responses were similar to Fe in serum that increased on day 4 but tended to decrease thereafter. In the liver, Fe was increased on day 4 and also on day 40. The reappearing increases in Cu/Zn on day 40 concomitant with the increase in liver Fe on day 40, even though TfR tended to decrease, and the fact that viable C. pneumoniae was present in the lungs and liver may indicate the early phase of activation of recurrent infection.

  • 42.
    Ehrenborg, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Hagberg, Svante
    Alden, Jakob
    Makitalo, Signar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Myrdal, Gunnar
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hjelm, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Friman, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    First known case of Bartonella quintana endocarditis in Sweden2009In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, Vol. 41, no 1, 73-75 p.Article in journal (Refereed)
    Abstract [en]

    In this report, we present the first known case of Bartonella endocarditis in Sweden. IgG antibody titres to Bartonella spp. were elevated but blood cultures remained negative. Sequencing of a gltA fragment from DNA extracted from heart valve tissue specimens revealed sequence homology with B. quintana.

  • 43.
    Elfving, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Center of Clinical Research, Dalarna, Falun, Sweden..
    Malmsten, Jonas
    Swedish Univ Agr Sci, Dept Clin Sci, Div Reprod, Uppsala, Sweden.;Natl Vet Inst, Dept Pathol & Wildlife Dis, S-75007 Uppsala, Sweden..
    Dalin, Anne-Marie
    Natl Vet Inst, Dept Pathol & Wildlife Dis, S-75007 Uppsala, Sweden..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Dalarna, Clin Res Ctr, Falun, Sweden..
    Serologic and Molecular Prevalence of Rickettsia helvetica and Anaplasma phagocytophilum in Wild Cervids and Domestic Mammals in the Central Parts of Sweden2015In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 15, no 9, 529-534 p.Article in journal (Refereed)
    Abstract [en]

    Both Rickettsia helvetica and Anaplasma phagocytophilum are common in Ixodes ricinus ticks in Sweden. Knowledge is limited regarding different animal species' competence to act as reservoirs for these organism. For this reason, blood samples were collected from wild cervids (roe deer, moose) and domestic mammals (horse, cat, dog) in central Sweden, and sera were tested using immunofluorescence assay to detect antibodies against spotted fever rickettsiae using Rickettsia helvetica as antigen. Sera with a titer >= 1:64 were considered as positive, and 23.1% (104/450) of the animals scored positive. The prevalence of seropositivity was 21.5% (23/107) in roe deer, 23.3% (21/90) in moose, 36.5% (23/63) in horses, 22.1% (19/90) in cats, and 17.0% (17/100) in dogs. PCR analysis of 113 spleen samples from moose and sheep from the corresponding areas were all negative for rickettsial DNA. In roe deer, 85% (91/107) also tested seropositive for A. phagocytophilum with a titer cutoff of 1:128. The findings indicate that the surveyed animal species are commonly exposed to rickettsiae and roe deer also to A. phagocytophilum.

  • 44.
    Ellström, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Feodoroff, B.
    Hanninen, M. -L
    Rautelin, Hilpi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Lipooligosaccharide locus class of Campylobacter jejuni: sialylation is not needed for invasive infection2014In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 20, no 6, 524-529 p.Article in journal (Refereed)
    Abstract [en]

    Campylobacter jejuni is a highly diverse enteropathogen that is commonly detected worldwide. It can sometimes cause bacteraemia, but the bacterial characteristics facilitating bloodstream infection are not known. A total of 73 C. jejuni isolates, consecutively collected from blood-borne infections during a 10-year period all over Finland and for which detailed clinical information of the patients were available, were included. We screened the isolates by PCR for the lipooligosaccharide (LOS) locus class and for the presence of the putative virulence genes ceuE, ciaB, fucP, and virB11. The isolates were also tested for gamma-glutamyl transpeptidase production. The results were analysed with respect to the clinical characteristics of the patients, and the multilocus sequence types (MLSTs) and serum resistance of the isolates. LOS locus classes A, B, and C, which carry genes for sialylation of LOS, were detected in only 23% of the isolates. These isolates were not more resistant to human serum than those with the genes of non-sialylated LOS locus classes, but were significantly more prevalent among patients with underlying diseases (p 0.02). The fucose permease gene fucP was quite uncommon, but was associated with the isolates with the potential to sialylate LOS (p <0.0001). LOS locus classes and some of the putative virulence factors were associated with MLST clonal complexes. Although some of the bacterial characteristics studied here have been suggested to be important for the invasiveness of C. jejuni, they did not explain why the clinical isolates in the present study were able to cause bacteraemia.

  • 45.
    Engström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Res Ctr Borstel, Mol Mycobacteriol, Borstel, Germany..
    Fighting an old disease with modern tools: characteristics and molecular detection methods of drug-resistant Mycobacterium tuberculosis2016In: INFECTIOUS DISEASES, ISSN 2374-4235, Vol. 48, no 1, 1-17 p.Article, review/survey (Refereed)
    Abstract [en]

    Tuberculosis (TB) is an ancient disease, but not a disease of the past. The increasing prevalence of drug-resistant strains of Mycobacterium tuberculosis, the causative agent of TB, demands new measures to combat the situation. Rapid and accurate detection of the pathogen, and its drug susceptibility pattern, is essential for timely initiation of treatment, and ultimately, control of the disease. Molecular-based methods offer a great chance to improve detection of drug-resistant TB; however, their development and usage should be accompanied with a profound understanding of drug resistance mechanisms and circulating M. tuberculosis strains in specific settings, as otherwise, the usefulness of such tests may be limited. This review gives an overview of the history of TB treatment and drug resistance, drug resistance mechanisms for the most commonly used drugs and molecular methods designed to detect drug-resistant strains.

  • 46.
    Eriksson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Karawajczyk, Malgorzata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Garwicz, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Neutrophil CD64 expression - comparison of two different flow cytometry protocols on EPICs MCL and the Leuko64 (TM) assay on a Celldyn Sapphire haematology analyser2015In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 75, no 5, 428-433 p.Article in journal (Refereed)
    Abstract [en]

    Objective. To evaluate the Trillium Diagnostics Leuko64 (TM) assay on Abbott Celldyn Sapphire haematology analyser compared to two flow cytometry protocols on Beckman Coulter EPICS MCL flow cytometer. Materials and methods. CD64 expression on neutrophils was determined by two flow cytometry protocols and by a commercial assay on an automatic haematology analyser. The inclusion of study subjects was based on elevated procalcitonin (PCT) values, identifying patients where a systemic infection was suspected. Healthy blood donors were used as a reference group. Results. Statistically significant correlations between the Trillium Diagnostics Leuko64 (TM) assay and the flow cytometry methods were found when measuring neutrophil CD64 expression. Conclusions. The good correlation between a reference method and an automated haematology analyser method for CD64 expression on neutrophils supports introduction of the latter assay for routine use as an independent biomarker of bacterial infection and inflammation.

  • 47. Estrada-Pena, Agustín
    et al.
    Farkas, Robert
    Jaenson, Thomas G.T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Madder, Maxime
    Pascucci, Ilaria
    Tarrés-Call, Jordi
    European Food Safety Authority (EFSA), Parma, Italy.
    Scientific opinion on the Role of Tick Vectors in the Epidemiology of Crimean-Congo Hemorrhagic Fever and African Swine Fever in Eurasia: EFSA Panel on Animal Health and Welfare2010In: EFSA Journal, ISSN 1831-4732, Vol. 8, no 8, 1-156 p., 1703Article in journal (Refereed)
    Abstract [en]

    The report provides an update on the role of the tick vectors in the epidemiology of African swine fever (ASF) and Crimean and Congo haemorrhagic fever (CCHF) in Eurasia, specifically to review of the geographical distribution of the relevant ticks with presentation of maps of their occurrence in Europe and Mediterranean basin; a description of the factors that define the relevant tick population dynamics and identify possible high risk areas in the EU; an update on the role of tick vectors associated with CCHF and ASF in Eurasia; and reviews available methods for the control of the relevant tick vectors. Data were collected through systematic literature review in a database from which maps of geographic distribution of ticks, CCHF virus and ASF virus were issued. The main vectors for CCHF are Hyalomma spp, Increase in the number of fragmented areas and the degradation of agricultural lands to bush lands are the two main factors in the creation of new foci of CCHF in endemic areas. Movement of livestock and wildlife species, which may carry infected ticks, contributes to the spread of the infection. The Middle East and Balkan countries are the most likely sources of introduction of CCHFV into other European countries. All the Ornithodoros species investigated so far can become infective with ASF virus and are perhaps biological vectors. These ticks are important in maintaining the local foci of the ASFV, but do not play an active role in the geographical spread of the virus. Wild boars have never been found infested by Ornithodoros spp. because wild boars normally do not rest inside protected burrows, but above the ground. There is no single ideal solution to the control of ticks relevant for CCHF or ASF. The integrated control approach is probably the most effective.

  • 48. Estrada-Peña, Agustín
    et al.
    Farkas, Robert
    Jaenson, Thomas G. T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Madder, Maxime
    Pascucci, Ilaria
    Salman, Mo
    Tarrés-Call, Jordi
    European Food Safety (EFSA), Parma, Italy.
    Scientific opinion on geographic distribution of tick-borne infections and their vectors in Europe and the other regions of the Mediterranean Basin: EFSA Panel on Animal Health and Welfare (AHAW)2010In: EFSA Journal, Vol. 8, no 9, 1723 [280 pp.]- p.Article, review/survey (Refereed)
    Abstract [en]

    This report is the second of a series of two technical assessments of the role of ticks in transmission of animal diseases and zoonoses in Eurasia. A previous published scientific opinion (EFSA 2010a) focused on two diseases- Crimean-Congo haemorrhagic fever and African swine fever in Eurasia. The aim of this report is to provide a general overview of the geographic distribution of tick species which have proven involvement in the transmission of pathogens causing animal diseases and zoonoses in Eurasia.The report provides a review of the geographic distribution of the relevant tick species and TBDs in Eurasia by producing maps of the region that display the occurrences of ticks and tick borne pathogens. Systematic literature review of available publications for the last 10 years and other available literature from the experts were used in the retrieval of the geographical reported cases for the presence of ticks and tick borne pathogens. The report includes a description of the factors that influence the dynamics of the relevant tick species and identify possible high-risk areas in the EU for introduction considering the biological and ecological characteristics of the ticks and their ability to adapt to new areas. Surveillance tools and control measures for ticks were discussed.Findings from this review have provided evidence of the extent of ticks and TBDs in geographical ranges and the existing risk areas that should be considered as baseline information to assess potential risk of these diseases. The report indicates the validity of using available literature to support the presence of ticks and TBDs without further predication using weather and other environmental factors associated with the survival of the ticks. Surveillance tools for the detection of the ticks and their control measures are discussed in this report. The report concluded that animal and human movement play a significant impact on the spread of the ticks and TBDs. Climate changes and flight pattern of migratory birds can influence the presence and spread of the ticks and TBDs, These two factors acting by themselves have not been determined be responsible for the widespread distribution of ticks.

  • 49.
    Farzana, R.
    et al.
    Khwaja Yunus Ali Med Coll, Sirajgonj, Bangladesh..
    Mozumder, T.
    ZH Sikder Med Coll, Dhaka, Bangladesh..
    Hasan, Badrul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Molecular epidemiology and spread dynamics of multi-drug resistant in A. baumannii isolated from patients and hospital environment in Bangladesh2016In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 45, 89-89 p.Article in journal (Other academic)
  • 50.
    Forsman, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The impact of the HIV drug efavirenz on the pharmacokinetic disposition of the antimalarial dihydroartemisinin-piperaquine in pregnant women residing in Tororo, Uganda2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction. Pregnant women are one of the major risk groups to get infected with malaria, which can infect the placenta. The parasite causes 10,000 maternal- and 200,000 infant deaths per year. HIV increases the risk of malaria infection. An effective intermittent preventive treatment during pregnancy (IPTp) is necessary to decrease the risk of placental malaria. There are concerns for the current IPTp, sulfadoxine-pyrimethamine, due to resistance.  Dihydroartemisinin-piperaquine (DP) is an effective and safe treatment, but more information is needed on how to optimize its dosing in this important population.

    Aim. Evaluate the pharmacokinetic (PK) exposure of DP in HIV positive pregnant women (BC2) treated with efavirenz and HIV negative pregnant women (BC1).

    Methods. 31 BC1 and 27 BC2-women received DP monthly or bimonthly as IPTp in Tororo, Uganda. BC2-women used efavirenz-based combination antiretroviral therapy (cART). Intensive PK sampling was done and the area under the concentration-time curve (AUC) was used when comparing DP exposure between BC1 and BC2 women.

    Results.  A significant change in exposure was seen between BC1 and BC2 for both dihydroartemisinin (DHA) and piperaquine (PQ). The biggest difference was seen for PQ, where the exposure changed significantly when comparing BC2 monthly to BC1 monthly alone, or the BC1 bimonthly plus monthly. DHA only showed a significant change in exposure when comparing BC1 bimonthly plus monthly vs. BC2.

    Conclusion. This study showed that there is a significant interaction between efavirenz and the anti-malarial combination dihydroartemisinin-piperaquine in pregnant women.

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