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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, article id 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, article id 66Article in journal (Refereed)
    Abstract [en]

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

  • 3.
    Advani, Jayshree
    et al.
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Manipal Acad Higher Educ, Manipal, Karnataka, India.
    Verma, Renu
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India.
    Chatterjee, Oishi
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India;Amrita Vishwa Vidyapeetham, Sch Biotechnol, Kollam, India.
    Balaya, Rex Devasahayam Arokia
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Najar, Mohd Altaf
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Ravishankara, Namitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. MS Ramaiah Inst Technol, Dept Biotechnol, Bangalore, Karnataka, India.
    Suresh, Sneha
    MS Ramaiah Inst Technol, Dept Biotechnol, Bangalore, Karnataka, India;Univ Massachusetts Lowell, Dept Biol Sci, Lowell, MA USA.
    Pachori, Praveen Kumar
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Gupta, Umesh D.
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Pinto, Sneha M.
    Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Chauhan, Devendra S.
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India.
    Tripathy, Srikanth Prasad
    ICMR Natl JALMA Inst Leprosy & Other Mycobacteria, Dept Microbiol & Mol Biol, Agra, Uttar Pradesh, India;Natl Inst Res TB, Madras, Tamil Nadu, India.
    Gowda, Harsha
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India.
    Prasad, T. S. Keshava
    Inst Bioinformat, Int Technol Pk, Bangalore, Karnataka, India;Yenepoya, Yenepoya Res Ctr, Ctr Syst Biol & Mol Med, Univ Rd, Mangalore 575018, India.
    Rise of Clinical Microbial Proteogenomics: A Multiomics Approach to Nontuberculous Mycobacterium-The Case of Mycobacterium abscessus UC222018In: Omics, ISSN 1536-2310, E-ISSN 1557-8100Article in journal (Refereed)
    Abstract [en]

    Nontuberculous mycobacterial (NTM) species present a major challenge for global health with serious clinical manifestations ranging from pulmonary to skin infections. Multiomics research and its applications toward clinical microbial proteogenomics offer veritable potentials in this context. For example, the Mycobacterium abscessus, a highly pathogenic NTM, causes bronchopulmonary infection and chronic pulmonary disease. The rough variant of the M. abscessus UC22 strain is extremely virulent and causes lung upper lobe fibrocavitary disease. Although several whole-genome next-generation sequencing studies have characterized the genes in the smooth variant of M. abscessus, a reference genome sequence for the rough variant was generated only recently and calls for further clinical applications. We carried out whole-genome sequencing and proteomic analysis for a clinical isolate of M. abscessus UC22 strain obtained from a pulmonary tuberculosis patient. We identified 5506 single-nucleotide variations (SNVs), 63 insertions, and 76 deletions compared with the reference genome. Using a high-resolution LC-MS/MS-based approach (liquid chromatography tandem mass spectrometry), we obtained protein coding evidence for 3601 proteins, representing 71% of the total predicted genes in this genome. Application of proteogenomic approach further revealed seven novel protein-coding genes and enabled refinement of six computationally derived gene models. We also identified 30 variant peptides corresponding to 16 SNVs known to be associated with drug resistance. These new observations offer promise for clinical applications of microbial proteogenomics and next-generation sequencing, and provide a resource for future global health applications for NTM species.

  • 4.
    Albinsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital, Uppsala.
    Vene, Sirkka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. The Public Health Agency of Sweden, Solna.
    Rombo, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Department of Infectious diseases, Eskilstuna.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rönnberg, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Laboratory of Clinical Microbiology, Uppsala University Hospital .
    Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 20172018In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 23, no 3, p. 2-7, article id 17-00838Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is an important European vaccine-preventable pathogen. Discrimination of vaccine-induced antibodies from those elicited by infection is important. We studied anti-TBEV IgM/IgG responses, including avidity and neutralisation, by multiplex serology in 50 TBEV patients and 50 TBEV vaccinees. Infection induced antibodies reactive to both whole virus (WV) and non-structural protein 1 (NS1) in 48 clinical cases, whereas 47 TBEV vaccinees had WV, but not NS1 antibodies, enabling efficient discrimination of infection/vaccination.

  • 5.
    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, article id 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.

  • 6.
    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, p. 714-720, article id 8534430Article in journal (Refereed)
  • 7.
    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, p. 1402-1411Article 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.

  • 8.
    Andersen, Maria Goul
    et al.
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark.
    Thorsted, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Storgaard, Merete
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark.
    Kristoffersson, Anders N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Öbrink-Hansen, Kristina
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark.
    Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?2018In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 5, article id e02306Article in journal (Refereed)
    Abstract [en]

    Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% fTMIC) and 0.125 mg/liter (100% fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

  • 9.
    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, article id 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.

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

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

  • 11.
    Ankarklev, Johan
    et al.
    Stockholm Univ, Dept Mol Biosci, SE-10691 Stockholm, Sweden.
    Lebbad, Marianne
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Einarsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Franzen, Oscar
    Karolinska Inst, Integrated Cardio Metab Ctr, Novum, Box 285, SE-14157 Stockholm, Sweden.
    Ahola, Harri
    Natl Vet Inst, Dept Microbiol, SE-75189 Uppsala, Sweden.
    Troell, Karin
    Natl Vet Inst, Dept Microbiol, SE-75189 Uppsala, Sweden.
    Svärd, Staffan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    A novel high-resolution multilocus sequence typing of Giardia intestinalis Assemblage A isolates reveals zoonotic transmission, clonal outbreaks and recombination2018In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 60, p. 7-16Article in journal (Refereed)
    Abstract [en]

    Molecular epidemiology and genotyping studies of the parasitic protozoan Giardia intestinalis have proven difficult due to multiple factors, such as low discriminatory power in the commonly used genotyping loci, which has hampered molecular analyses of outbreak sources, zoonotic transmission and virulence types. Here we have focused on assemblage A Giardia and developed a high-resolution assemblage-specific multilocus sequence typing (MLST) method. Analyses of sequenced G. intestinalis assemblage A genomes from different sub-assemblages identified a set of six genetic loci with high genetic variability. DNA samples from both humans (n = 44) and animals (n = 18) that harbored Giardia assemblage A infections, were PCR amplified (557-700 bp products) and sequenced at the six novel genetic loci. Bioinformatic analyses showed five to ten-fold higher levels of polymorphic sites than what was previously found among assemblage A samples using the classic genotyping loci. Phylogenetically, a division of two major clusters in assemblage A became apparent, separating samples of human and animal origin. A subset of human samples (n = 9) from a documented Giardia outbreak in a Swedish day-care center, showed full complementarity at nine genetic loci (the six new and the standard BG, TPI and GDH loci), strongly suggesting one source of infection. Furthermore, three samples of human origin displayed MLST profiles that were phylogenetically more closely related to MLST profiles from animal derived samples, suggesting zoonotic transmission. These new genotyping loci enabled us to detect events of recombination between different assemblage A isolates but also between assemblage A and E isolates. In summary, we present a novel and expanded MLST strategy with significantly improved sensitivity for molecular analyses of virulence types, zoonotic potential and source tracking for assemblage A Giardia.

  • 12.
    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.

  • 13.
    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, article id 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.

  • 14. 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, p. 35-39Article in journal (Refereed)
  • 15.
    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, p. 134-42Article 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.

  • 16.
    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, article id 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.

  • 17.
    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, p. 1289-1297Article 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.

  • 18. 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 Research, ISSN 0932-0113, E-ISSN 1432-1955, Vol. 104, no 4, p. 935-7Article 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.

  • 19.
    Aydin-Schmidt, Berit
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden.;Karolinska Univ Hosp, Infect Dis Unit, Stockholm, Sweden..
    Morris, Ulrika
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Ding, Xavier C.
    FIND, Geneva, Switzerland..
    Jovel, Irina
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Msellem, Mwinyi I.
    Minist Hlth, Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania..
    Bergman, Daniel
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Islam, Atiqul
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Ali, Abdullah S.
    Minist Hlth, Zanzibar Malaria Eliminat Programme, Zanzibar, Tanzania..
    Polley, Spencer
    NHS Fdn Trust, Univ Coll London Hosp, Hosp Trop Dis, Dept Clin Parasitol, London, England..
    Gonzalez, Iveth J.
    FIND, Geneva, Switzerland..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Björkman, Anders
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Ctr Malaria Res, Stockholm, Sweden..
    Field Evaluation of a High Throughput Loop Mediated Isothermal Amplification Test for the Detection of Asymptomatic Plasmodium Infections in Zanzibar2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0169037Article in journal (Refereed)
    Abstract [en]

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

  • 20.
    Backman, Kesia
    et al.
    Örebro Univ, Sch Med Sci, Örebro, Sweden.
    Skogman, Barbro H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Occurrence of erythema migrans in children with Lyme neuroborreliosis and the association with clinical characteristics and outcome - a prospective cohort study2018In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 18, article id 189Article in journal (Refereed)
    Abstract [en]

    Background: Erythema migrans (EM) is the most common manifestation of Lyme borreliosis (LB), caused by the spirochete Borrelia burgdorferi sensu lato. The infection can disseminate into the nervous system and cause Lyme neuroborreliosis (LNB), the second most frequent LB manifestation in children. The aim of this prospective cohort study is to describe the occurrence of EM among children with LNB and to evaluate possible differences in clinical characteristics or outcome between LNB patients with and without EM. Method: Children being evaluated for LNB in southeast Sweden during the period 2010-2014 underwent a clinical examination, laboratory testing and filled out a questionnaire regarding duration and nature of symptoms, EM and the child's health. Children were classified according to European guidelines for LNB. Clinical recovery was evaluated at a 2-month follow-up. Results: The occurrence of EM among children with LNB was 37 out of 103 (36%). Gender, age, observed tick bite, clinical features, duration of neurological symptoms or clinical outcome did not differ significantly between LNB patients with or without EM. However, facial nerve palsy was significantly more common among children with EM in the head and neck area. Conclusion: EM occurred in 36% of children with LNB and the location on the head and neck was more common among children with facial nerve palsy. EM was not associated with other specific clinical characteristics or outcome. Thus, the occurrence of EM in children with LNB cannot be useful as a prognostic factor for clinical outcome. This aspect has not previously been highlighted but seems to be relevant for the paediatrician in a clinical setting.

  • 21. 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, p. e100764-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.

  • 22. 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, article id 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.

  • 23. 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, p. O353-O360Article 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.

  • 24.
    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, p. 81-89Article 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.

  • 25.
    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, p. 113-122Article 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.

  • 26. 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, p. 897-899Article in journal (Refereed)
  • 27. 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, p. 113-116Article, 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.

  • 28.
    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, p. 680-685Article 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.

  • 29.
    Brill, Margreke J. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kristoffersson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zhao, Chenyan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations2018In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 24, no 7, p. 697-706Article, review/survey (Refereed)
    Abstract [en]

    Background: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. Aims: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. Sources: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. Content: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.

  • 30.
    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, p. 18-25Article, 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.

  • 31.
    Brynildsrud, Ola B.
    et al.
    Norwegian Inst Publ Hlth, Div Infect Dis & Environm Hlth, Lovisenberggata 8, N-0456 Oslo, Norway.
    Pepperell, Caitlin S.
    Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Div Infect Dis, Madison, WI 53726 USA;Univ Wisconsin, Sch Med & Publ Hlth, Dept Med Microbiol & Immunol, Madison, WI 53726 USA.
    Suffys, Philip
    Oswaldo Cruz Inst, Lab Mol Biol Appl Mycobacteria, Ave Brasil 4365,CP 926, BR-21040360 Manguinho, RJ, Brazil.
    Grandjean, Louis
    Imperial Coll London, Dept Paediat Infect Dis, London W2 1NY, England.
    Monteserin, Johana
    ANLIS Carlos Malbran, Inst Nacl Enfermedades Infecciosas, Buenos Aires, DF, Argentina;Consejo Nacl Invest Cient & Tecn, Buenos Aires, DF, Argentina.
    Debech, Nadia
    Norwegian Inst Publ Hlth, Div Infect Dis & Environm Hlth, Lovisenberggata 8, N-0456 Oslo, Norway.
    Bohlin, Jon
    Norwegian Inst Publ Hlth, Div Infect Dis & Environm Hlth, Lovisenberggata 8, N-0456 Oslo, Norway.
    Alfsnes, Kristian
    Norwegian Inst Publ Hlth, Div Infect Dis & Environm Hlth, Lovisenberggata 8, N-0456 Oslo, Norway.
    Pettersson, John
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Norwegian Inst Publ Hlth, Div Infect Dis & Environm Hlth, Lovisenberggata 8, N-0456 Oslo, Norway; Univ Sydney, Charles Perkins Ctr Sch Life & Environm Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia;Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia;Publ Hlth Agcy Sweden, Nobels Vg 18, SE-17182 Solna, Sweden.
    Kirkeleite, Ingerid
    Norwegian Inst Publ Hlth, Div Infect Dis & Environm Hlth, Lovisenberggata 8, N-0456 Oslo, Norway.
    Fandinho, Fatima
    Ctr Referincia Prof Helio Fraga Jacarepagu, Lab Bacteriol Tuberculose, Estr Curic 2000, Rio De Janeiro, RJ, Brazil.
    da Silva, Marcia Aparecida
    Ctr Referincia Prof Helio Fraga Jacarepagu, Lab Bacteriol Tuberculose, Estr Curic 2000, Rio De Janeiro, RJ, Brazil.
    Perdigao, Joao
    Univ Lisbon, Fac Farm, Inst Invest Med, Lisbon, Portugal.
    Portugal, Isabel
    Univ Lisbon, Fac Farm, Inst Invest Med, Lisbon, Portugal.
    Viveiros, Miguel
    Univ Nova Lisboa, Inst Higiene & Med Trop, Unidade Microbiol Med Global Hlth & Trop Med, Lisbon, Portugal.
    Clark, Taane
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1E 7HT, England;London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1E 7HT, England.
    Caws, Maxine
    Univ Liverpool Liverpool Sch Trop Med, Dept Clin Sci, Liverpool, Merseyside, England;Birat Nepal Med Trust, Kathmandu, Nepal.
    Dunstan, Sarah
    Univ Melbourne, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia.
    Thai, Phan Vuong Khac
    Lopez, Beatriz
    ANLIS Carlos Malbran, Inst Nacl Enfermedades Infecciosas, Buenos Aires, DF, Argentina.
    Ritacco, Viviana
    ANLIS Carlos Malbran, Inst Nacl Enfermedades Infecciosas, Buenos Aires, DF, Argentina;Consejo Nacl Invest Cient & Tecn, Buenos Aires, DF, Argentina.
    Kitchen, Andrew
    Univ Iowa, Dept Anthropol, Iowa City, IA 52242 USA.
    Brown, Tyler S.
    Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA.
    van Soolingen, Dick
    Natl Inst Publ Hlth & Environm, Ctr Infect Dis Res Diagnost & Perinatal Screening, POB 1, NL-3720 BA Bilthoven, Netherlands.
    O'Neill, Mary B.
    Univ Wisconsin, Sch Med & Publ Hlth, Dept Med Microbiol & Immunol, Madison, WI 53726 USA;Univ Wisconsin, Lab Genet, Madison, WI 53706 USA;Inst Pasteur, Unit Human Evolutionary Genet, F-75015 Paris, France.
    Holt, Kathryn E.
    London Sch Hyg & Trop Med, Fac Infect & Trop Dis, London WC1E 7HT, England;Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic, Australia;Univ Melbourne, Inst Bio21, Melbourne, Vic, Australia.
    Feil, Edward J.
    Univ Bath, Milner Ctr Evolut, Dept Biol & Biochem, Bath BA2 7AY, Avon, England.
    Mathema, Barun
    Columbia Univ, Mailman Sch Publ Hlth, 722 West 168th St, New York, NY 10032 USA.
    Balloux, Francois
    UCL, UCL Genet Inst, London WC1E 6BT, England.
    Eldholm, Vegard
    Norwegian Inst Publ Hlth, Div Infect Dis & Environm Hlth, Lovisenberggata 8, N-0456 Oslo, Norway.
    Global expansion of Mycobacterium tuberculosis lineage 4 shaped by colonial migration and local adaptation2018In: Science Advances, E-ISSN 2375-2548, Vol. 4, no 10, article id eaat5869Article in journal (Refereed)
    Abstract [en]

    On the basis of population genomic and phylogeographic analyses of 1669 Mycobacterium tuberculosis lineage 4 (L4) genomes, we find that dispersal of L4 has been completely dominated by historical migrations out of Europe. We demonstrate an intimate temporal relationship between European colonial expansion into Africa and the Americas and the spread of L4 tuberculosis (TB). Markedly, in the age of antibiotics, mutations conferring antimicrobial resistance overwhelmingly emerged locally (at the level of nations), with minimal cross-border transmission of resistance. The latter finding was found to reflect the relatively recent emergence of these mutations, as a similar degree of local restriction was observed for susceptible variants emerging on comparable time scales. The restricted international transmission of drug-resistant TB suggests that containment efforts at the level of individual countries could be successful.

  • 32.
    Burchett, Helen E. D.
    et al.
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Leurent, Baptiste
    London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England..
    Baiden, Frank
    Ensign Coll Publ Hlth, Epidemiol Unit, Kpong, Ghana..
    Baltzell, Kimberly
    Univ Calif Berkeley, Dept Family Hlth Care Nursing & Global Hlth Sci, Berkeley, CA 94720 USA..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden..
    Bruxvoort, Katia
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Clarke, Sian
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    DiLiberto, Deborah
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Elfving, Kristina
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Gothenburg, Sweden..
    Goodman, Catherine
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Hopkins, Heidi
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    Lal, Sham
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    Liverani, Marco
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Magnussen, Pascal
    Univ Copenhagen, Fac Hlth & Med Sci, Ctr Med Parasitol, Copenhagen, Denmark..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mbacham, Wilfred
    Univ Yaounde, Ctr Biotechnol, Lab Publ Hlth Res Biotechnol, Yaounde, Cameroon..
    Mbonye, Anthony
    Makerere Univ, Sch Publ Hlth, Kampala, Uganda.;Minist Hlth, Commissioner Hlth Serv, Kampala, Uganda..
    Onwujekwe, Obinna
    Univ Nigeria, Dept Therapeut & Pharmacol, Enugu Campus, Enugu, Nigeria..
    Allen, Denise Roth
    Ctr Dis Control & Prevent CDC, Atlanta, GA USA..
    Shakely, Deler
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Kungalv Hosp, Dept Med, Kungalv, Sweden..
    Staedke, Sarah
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Vestergaard, Lasse S.
    Univ Copenhagen, Ctr Med Parasitol, DK-1168 Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark.;Statens Serum Inst, Dept Infect Dis Epidemiol, Copenhagen, Denmark..
    Whitty, Christopher J. M.
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Wiseman, Virginia
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England.;Sch Publ Hlth & Community Med, Kensington, NSW, Australia..
    Chandler, Clare I. R.
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Improving prescribing practices with rapid diagnostic tests (RDTs): synthesis of 10 studies to explore reasons for variation in malaria RDT uptake and adherence2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, article id e012973Article in journal (Refereed)
    Abstract [en]

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

  • 33.
    Carlander, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Karolinska Inst, Dept Med Huddinge, Unit Infect Dis, SE-17177 Stockholm, Sweden.
    Wagner, Philippe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    van Beirs, Astrid
    Linkoping Univ, Fac Med & Hlth Sci, Linkoping, Sweden.
    Yilmaz, Aylin
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, Gothenburg, Sweden.
    Elfgren, Kristina
    Karolinska Univ Hosp Huddinge, Dept Obstet & Gynaecol, CLINTEC, Stockholm, Sweden.
    Dillner, Joakim
    Karolinska Inst, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden.
    Sönnerborg, Anders
    Karolinska Inst, Dept Med Huddinge, Unit Infect Dis, SE-17177 Stockholm, Sweden.
    Sparen, Pär
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Suppressive antiretroviral therapy associates with effective treatment of high-grade cervical intraepithelial neoplasia2018In: AIDS (London), ISSN 0269-9370, E-ISSN 1473-5571, Vol. 32, no 11, p. 1475-1484Article in journal (Refereed)
    Abstract [en]

    Objectives: To assess if women living with HIV (WLWH) have poorer outcome after treatment of cervical intraepithelial neoplasia grade 2, grade 3, adenocarcinoma in situ or cervical cancer (CIN2+) than HIV-negative women (HNW) and to identify predictors of CIN2+ treatment failure and recurrence in WLWH. Design: Population-based cohort study with follow-up between 1983 and 2015. Methods: The Swedish National HIV Registry, the Swedish Population Registry and the Swedish National Cervical Screening Registry were linked to identify all women in Stockholm and Gothenburg counties (Sweden) living with HIV and diagnosed with CIN2+ (n = 179) sometime between 1983 and 2014. For each WLWH, two HNW resident in the same counties and matched for country of birth, diagnosed with CIN2+, were chosen as controls. Treatment failure was defined as the presence of CIN2+ at initial follow-up. Recurrence was defined as the presence of CIN1+ subsequent to an initial normal follow-up. Results: WLWH were three times more likely to have treatment failure (odds ratio (OR) 3.7 [95% confidence interval (CI) 2.0-6.8]) and five times more likely to recur (hazard ratio 5.0 [95% CI 2.1-11.6]) than HNW. Suppressive antiretroviral therapy (ART) at time of treatment of CIN2+ was associated with reduced OR of treatment failure (OR 0.3 [95% CI 0.1-0.8]). Immunosuppression (CD4(+) cell count < 200 cells/mu l) associated strongly with treatment failure (OR compared with CD4 (+) cell count >= 500: 8.5 [95% CI 2.3-30.7]). Conclusion: Suppressive ART is associated with effective treatment of CIN2+. Early HIV diagnosis and ART are essential for successful CIN2+ treatment.

  • 34.
    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, p. 102-Article in journal (Refereed)
  • 35.
    Casmo, Veronica
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Inst Nacl Saude, Maputo, Mozambique.
    Lebbad, Marianne
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Maungate, Salomao
    Inst Nacl Saude, Maputo, Mozambique.
    Lindh, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Occurrence of Cryptosporidium spp. and Cystoisospora belli among adult patients with diarrhoea in Maputo, Mozambique2018In: HELIYON, ISSN 2405-8440, Vol. 4, no 9, article id e00769Article in journal (Refereed)
    Abstract [en]

    Infections with Cryptosporidium spp. and Cystoisospora belli are important causes of diarrhoea in HIV patients. Nevertheless, information concerning these two parasites is scarce in many African countries, including Mozambique. In this study occurrence of Cryptosporidium spp. and C. belli was investigated by microscopy of stool specimens from 108 adult diarrhoeal patients, most with a confirmed HIV diagnosis. The Cryptosporidium isolates were further characterized by molecular methods. Cryptosporidium and C. belli oocysts were found in 8.3% (9/108), and 25.0% (27/108) of the study participants, respectively. Species identification was possible for all Cryptosporidium isolates with available DNA. The following Cryptosporidium species were detected (number of cases within parentheses): C. parvum (3), C. hominis (3), C. felis (1), and C. hominis/C. parvum (1). Subtyping targeting the gp60 gene revealed two C. hominis isolates with subtype IaA23R3, one C. parvum isolate with IIcA5G3d, and one with IIeAl2G1. In summary the occurrence of C. hominis and anthroponotic subtypes of C. parvum indicates that the main route of Cryptosporidium transmission in the present study population was human to human (direct or via food and water). The high prevalence of C. belli highlights the need for early diagnosis of this parasite, for which a treatment exists.

  • 36.
    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
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    2009 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 10, p. 2782-2790Article 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.

    Keywords
    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: 2017-12-12Bibliographically 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, p. 1031-e4Article 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: 2017-12-12Bibliographically 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
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    2012 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 5, p. 501-510Article 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
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    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53221-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
  • 37.
    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, p. 387-392Article 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.

  • 38. 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, article id 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.

  • 39.
    Chauhan, Abhimanyu Singh
    et al.
    Publ Hlth Fdn India, Plot 47,Sect 44, Gurgaon 122002, Haryana, India;Univ Liege, Fac Med, Dept Publ Hlth Sci, Hosp Dist, Hippocrates Ave 13,Bldg 234000, Liege, Belgium.
    George, Mathew Sunil
    Indian Inst Publ Hlth, Gurgaon 122002, Haryana, India;Univ Canberra, Ctr Res & Act Publ Hlth CeRAPH, Bldg 22,Floor B,Univ Dr, Bruce, ACT 2617, Australia.
    Chatterjee, Pranab
    Publ Hlth Fdn India, Plot 47,Sect 44, Gurgaon 122002, Haryana, India;Natl Inst Cholera & Enter Dis, Indian Council Med Res, Div Epidemiol, Kolkata 700010, India.
    Lindahl, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Int Livestock Res Inst, Nairobi, Kenya and Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden.
    Grace, Delia
    Int Livestock Res Inst, Nairobi 3070900100, Kenya.
    Kakkar, Manish
    Publ Hlth Fdn India, Plot 47,Sect 44, Gurgaon 122002, Haryana, India.
    The social biography of antibiotic use in smallholder dairy farms in India2018In: Antimicrobial Resistance and Infection Control, ISSN 2047-2994, E-ISSN 2047-2994, Vol. 7, article id 60Article in journal (Refereed)
    Abstract [en]

    Background: Antimicrobial resistance (AMR) has been identified as one of the major threats to global health, food security and development today. While there has been considerable attention about the use and misuse of antibiotics amongst human populations in both research and policy environments, there is no definitive estimate of the extent of misuse of antibiotics in the veterinary sector and its contribution to AMR in humans. In this study, we explored the drivers of irrational usage of verterinary antibiotics in the dairy farming sector in peri-urban India.

    Methods and materials: The study was conducted in the peri-urban belts of Ludhiana, Guwahati and Bangalore. A total of 54 interviews (formal and non-formal) were carried out across these three sites. Theme guides were developed to explore different drivers of veterinary antimicrobial use. Data was audio recorded and transcribed. Analysis of the coded data set was carried out using AtlasTi. Version 7. Themes emerged inductively from the set of codes.

    Results: Findings were presented based on concept of 'levels of analyses'. Emergent themes were categorised as individual, health systems, and policy level drivers. Low level of knowledge related to antibiotics among farmers, active informal service providers, direct marketing of drugs to the farmers and easily available antibiotics, dispensed without appropriate prescriptions contributed to easy access to antibiotics, and were identified to be the possible drivers contributing to the non-prescribed and self-administered use of antibiotics in the dairy farms.

    Conclusions: Smallholding dairy farmers operated within very small margins of profits. The paucity of formal veterinary services at the community level, coupled with easy availability of antibiotics and the need to ensure profits and minimise losses, promoted non-prescribed antibiotic consumption. It is essential that these local drivers of irrational antibiotic use are understood in order to develop interventions and policies that seek to reduce antibiotic misuse.

  • 40.
    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, p. 222-226Article 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.

  • 41.
    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, article id 7458409Article in journal (Refereed)
  • 42.
    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, p. 964-974Article 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.

  • 43.
    Cunningham, Anthony L.
    et al.
    Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
    Heineman, Thomas C.
    GSK, King Of Prussia, PA USA;Genocea Biosci, Cambridge, MA USA.
    Lal, Himal
    GSK, King Of Prussia, PA USA;Pfizer Inc, Collegeville, PA USA.
    Godeaux, Olivier
    GSK, Wavre, Belgium;Janssen Vaccines & Prevent, Leiden, Netherlands.
    Chlibek, Roman
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic.
    Hwang, Shinn-Jang
    Taipei Vet Gen Hosp, Dept Family Med, Taipei, Taiwan;Natl Yang Ming Univ, Sch Med, Taipei, Taiwan.
    McElhaney, Janet E.
    Hlth Sci North Res Inst, Sudbury, ON, Canada.
    Vesikari, Timo
    Univ Tampere, Vaccine Res Ctr, Tampere, Finland.
    Andrews, Charles
    Diagnost Res Grp, San Antonio, TX USA.
    Choi, Won Suk
    Korea Univ, Coll Med, Dept Internal Med, Div Infect Dis, Seoul, South Korea.
    Esen, Meral
    Univ Clin Tuebingen, Inst Trop Med, Tubingen, Germany.
    Ikematsu, Hideyuki
    Japan Phys Assoc, Chiyoda Ku, Tokyo, Japan.
    Choma, Martina Kovac
    GSK, Rockville, MD USA.
    Pauksen, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ravault, Stephanie
    GSK, Rixensart, Belgium.
    Salaun, Bruno
    GSK, Rixensart, Belgium.
    Schwarz, Tino F.
    Standort Juliusspital, Klinikum Wurzburg Mitte, Cent Lab & Vaccinat Ctr, Wurzburg, Germany.
    Smetana, Jan
    Univ Def, Fac Mil Hlth Sci, Hradec Kralove, Czech Republic.
    Vanden Abeele, Carline
    GSK, Wavre, Belgium.
    Van den Steen, Peter
    GSK, Wavre, Belgium.
    Vastiau, Ilse
    GSK, Wavre, Belgium.
    Weckx, Lily Yin
    Univ Fed Sao Paulo, Sao Paulo, Brazil.
    Levin, Myron J.
    Univ Colorado, Dept Pediat, Anschutz Med Campus, Aurora, CO USA;Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO USA.
    Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older2018In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 217, no 11, p. 1750-1760Article in journal (Refereed)
    Abstract [en]

    Background. The herpes zoster subunit vaccine (HZ/su), consisting of varicella-zoster virus glycoprotein E (gE) and AS01(B) Adjuvant System, was highly efficacious in preventing herpes zoster in the ZOE-50 and ZOE-70 trials. We present immunogenicity results from those trials. Methods. Participants (ZOE-50: >= 50; ZOE-70: >= 70 years of age) received 2 doses of HZ/su or placebo, 2 months apart. Serum anti-gE antibodies and CD4 T cells expressing >= 2 of 4 activation markers assessed (CD4(2+)) after stimulation with gE-peptides were measured in subcohorts for humoral (n = 3293) and cell-mediated (n = 466) immunogenicity. Results. After vaccination, 97.8% of HZ/su and 2.0% of placebo recipients showed a humoral response. Geometric mean anti-gE antibody concentrations increased 39.1-fold and 8.3-fold over baseline in HZ/su recipients at 1 and 36 months post-dose 2, respectively. A gE-specific CD4(2+) T-cell response was shown in 93.3% of HZ/su and 0% of placebo recipients. Median CD42+ T-cell frequencies increased 24.6-fold (1 month) and 7.9-fold (36 months) over baseline in HZ/su recipients and remained >= 5.6-fold above baseline in all age groups at 36 months. The proportion of CD4 T cells expressing all 4 activation markers increased over time in all age groups. Conclusions. Most HZ/su recipients developed robust immune responses persisting for 3 years following vaccination.

  • 44.
    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, article id 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).

  • 45. 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, p. 262-265Article 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.

  • 46.
    de Glanville, William A.
    et al.
    Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland;Int Livestock Res Inst, Nairobi, Kenya;Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Glasgow, Lanark, Scotland.
    Conde-Alvarez, Raquel
    Univ Navarra, Inst Trop Hlth, Navarra Inst Sanitary Res, Pamplona, Spain;Univ Navarra, Med Sch, Dept Microbiol & Parasitol, Pamplona, Spain.
    Moriyon, Ignacio
    Univ Navarra, Inst Trop Hlth, Navarra Inst Sanitary Res, Pamplona, Spain;Univ Navarra, Med Sch, Dept Microbiol & Parasitol, Pamplona, Spain.
    Njeru, John
    Friedrich Loeffler Inst, Inst Bacterial Infect & Zoonoses, Berlin, Germany;Kenya Govt Med Res Ctr, Ctr Microbiol Res, Nairobi, Kenya.
    Diaz, Ramon
    Univ Navarra, Inst Trop Hlth, Navarra Inst Sanitary Res, Pamplona, Spain;Univ Navarra, Med Sch, Dept Microbiol & Parasitol, Pamplona, Spain.
    Cook, Elizabeth A. J.
    Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland;Int Livestock Res Inst, Nairobi, Kenya.
    Morin, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bronsvoort, Barend M. de C.
    Univ Edinburgh, Roslin Inst, Epidemiol Econ & Risk Assessment Grp, Edinburgh, Midlothian, Scotland.
    Thomas, Lian F.
    Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Ctr Immun Infect & Evolut, Edinburgh, Midlothian, Scotland;Int Livestock Res Inst, Nairobi, Kenya.
    Kariuki, Samuel
    Kenya Govt Med Res Ctr, Ctr Microbiol Res, Nairobi, Kenya.
    Fevre, Eric M.
    Univ Liverpool, Inst Infect & Global Hlth, Liverpool, Merseyside, England;Int Livestock Res Inst, Nairobi, Kenya.
    Poor performance of the rapid test for human brucellosis in health facilities in Kenya2017In: PLoS Neglected Tropical Diseases, ISSN 1935-2727, E-ISSN 1935-2735, Vol. 11, no 4, article id e0005508Article in journal (Refereed)
    Abstract [en]

    Human brucellosis is considered to be an important but typically under-diagnosed cause of febrile illness in many low and middle-income countries. In Kenya, and throughout East Africa, laboratory diagnosis for the disease is based primarily on the febrile antigen Brucella agglutination test (FBAT), yet few studies of the diagnostic accuracy of this test exist. Assessment of the performance of the FBAT is essential for its appropriate clinical use, as well as for evaluating surveillance data reported by public health systems. To assess FBAT performance, we collected sera from people with symptoms compatible with brucellosis attending two health facilities in Busia County, Kenya. Sera were tested using the FBAT and results compared with those from the Rose Bengal Test (RBT), an assay with well-known performance characteristics. Positives on either test were confirmed using the classical serum agglutination test (SAT)-Coombs test combination and a rapid IgM/IgG lateral flow immunochromatography assay (LFA). A questionnaire focussing on known risk factors for exposure to Brucella spp. was also conducted, and relationships with FBAT positivity examined using logistic regression. Out of 825 recruited individuals, 162 (19.6%) were classified as positive using the FBAT. In contrast, only eight (1.0%) were positive using the RBT. Of the 162 FBAT positives, one (0.62%) had an atypical agglutination in SAT and three (1.9%) showed low Coombs titres. Out of 148 FBAT positive individuals tested using the LFA, five (3.4%) were IgM positive and none were IgG positive. Poor or no correlation was observed between FBAT results and most established risk factors for Brucella infection. We observed substantial disagreement between the FBAT and a number of well-known serological tests, with the majority of reactive FBAT results appearing to be false positives. Poor FBAT specificity, combined with a lack of confirmatory testing, strongly suggests overdiagnosis of brucellosis is common in this low prevalence setting. This is expected to have important economic impacts on affected patients subjected to the long and likely unnecessary courses of multiple antibiotics required for treatment of the disease.

  • 47. 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, p. 605-9Article 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.

  • 48.
    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, article id 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.

  • 49.
    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, p. 777-778Article in journal (Refereed)
  • 50.
    Drobin, Kimi
    et al.
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Assadi, Ghazaleh
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Hong, Mun-Gwan
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Andersson, Eni
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Fredolini, Claudia
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Forsström, Björn
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    Reznichenko, Anna
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Akhter, Tahmina
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Ek, Weronica E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
    Bonfiglio, Ferdinando
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden;Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, San Sebastián, Spain.
    Berner Hansen, Mark
    AstraZeneca R&D Mölndal, Innovative and Global Medicines, Mölndal, Sweden;Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
    Sandberg, Kristian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Greco, Dario
    Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
    Repsilber, Dirk
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Schwenk, Jochen M.
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH, Royal Institute of Technology, Stockholm, Sweden.
    D’Amato, Mauro
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden;BioDonostia Health Research Institute, San Sebastian, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
    Halfvarson, Jonas
    Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Targeted Analysis of Serum Proteins Encoded at Known Inflammatory Bowel Disease Risk Loci2018In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844Article in journal (Refereed)
    Abstract [en]

    Background: Few studies have investigated the blood proteome of inflammatory bowel disease (IBD). We characterized the serum abundance of proteins encoded at 163 known IBD risk loci and tested these proteins for their biomarker discovery potential.

    Methods: Based on the Human Protein Atlas (HPA) antibody availability, 218 proteins from genes mapping at 163 IBD risk loci were selected. Targeted serum protein profiles from 49 Crohn’s disease (CD) patients, 51 ulcerative colitis (UC) patients, and 50 sex- and age-matched healthy individuals were obtained using multiplexed antibody suspension bead array assays. Differences in relative serum abundance levels between disease groups and controls were examined. Replication was attempted for CD-UC comparisons (including disease subtypes) by including 64 additional patients (33 CD and 31 UC). Antibodies targeting a potentially novel risk protein were validated by paired antibodies, Western blot, immuno-capture mass spectrometry, and epitope mapping.

    Results: By univariate analysis, 13 proteins mostly related to neutrophil, T-cell, and B-cell activation and function were differentially expressed in IBD patients vs healthy controls, 3 in CD patients vs healthy controls and 2 in UC patients vs healthy controls (q < 0.01). Multivariate analyses further differentiated disease groups from healthy controls and CD subtypes from UC (P < 0.05). Extended characterization of an antibody targeting a novel, discriminative serum marker, the laccase (multicopper oxidoreductase) domain containing 1 (LACC1) protein, provided evidence for antibody on-target specificity.

    Conclusions: Using affinity proteomics, we identified a set of IBD-associated serum proteins encoded at IBD risk loci. These candidate proteins hold the potential to be exploited as diagnostic biomarkers of IBD.

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