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  • 1. Aalto, Mikko
    et al.
    Kukka, Antti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, SWEDESD - Sustainability Learning and Research Centre. Gävle sjukhus, Region Gävleborg.
    Elmi, Hassan Abdirahman
    Yared, Solomon
    Viskeraalinen leishmaniaasi tunnistamattomana tappavana tautina: [Visceral leishmaniasis as an unrecognized deadly disease]2023In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 139, no 11, p. 885-891Article in journal (Refereed)
    Abstract [en]

    Visceral leishmaniasis is a disease caused by Leishmania parasites and transmitted by Phlebotomine sandflies. It affects primarily children and is fatal without treatment but curable with early treatment. Its clinical features are prolonged fever, wasting, hepatosplenomegaly and pancytopenia. Doctors have limited knowledge about its diagnostics. This leads to incorrect diagnoses and deaths, and the disease remains unrecognized. To break this vicious circle, active search of the disease is needed also where environmental factors are conductive to its presence, but it has never been reported. We describe discovering new foci of visceral leishmaniasis in Northern Somalia, Somaliland and Tanzania. 

  • 2.
    Abdalla Omer, Hemn
    et al.
    Department of Microbiology/Immunology, College of Medicine, University of Suleimani, Sulaymaniyah, Iraq.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Amin, Kawa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Department of Microbiology/Immunology, College of Medicine, University of Suleimani, Sulaymaniyah, Iraq.
    The role of inflammatory and remodelling biomarkers in patients with non-small cell lung cancer2023In: Central European Journal of Immunology, ISSN 1426-3912, E-ISSN 1644-4124, Vol. 48, no 4, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Introduction:

    Biomarkers play a crucial role in evaluating the prognosis, diagnosis, and monitoringof non-small cell lung cancer (NSCLC). The aim of this study was to compare the levels of inflammatoryand remodelling biomarkers among patients with NSCLC and healthy controls (HCs) and to investigatethe correlation between these biomarkers.

    Material and methods:

    Blood samples were taken from 93 NSCLC and 84 HCs. Each sample wasanalysed for the inflammatory biomarkers transforming growth factor β1 (TGF-β1), mothers againstdecapentaplegic homolog 2 (SMAD2) and the remodelling biomarkers Wingless-related integration site(Wnt3a) and β-catenin (CTNN-β1).

    Results:

    The patients with NSCLC had significantly higher levels of all the measured biomarkers.In the NSCLC patients, TGF-β1 correlated significantly with SMAD2 (r = 0.34, p = 0.0008), Wnt3a(r = 0.328, p = 0.0013), and CTNN-β1 levels (r = 0.30, p = 0.004). SMAD2 correlated significantlywith CTNN-β1 (r = 0.546, p = 0.0001) and Wnt3a (r = 0.598, p = 0.0001). CTNN-β1 level also correlated with the level of Wnt3a (r = 0.61, p = 0.0001). No correlation was found between biomarkersand symptom scores.

    Discussion:

    In this study, patients with NSCLC had higher inflammatory and remodelling biomarker levels than HCs. In the NSCLC, there were significant associations between inflammatory andremodelling biomarkers. This indicates that measuring biomarkers could be valuable in the workupof NSCLC patients.

    Conclusions:

    Our investigation showed that inflammatory and remodelling biomarkers might playa role in future immunologic response and pharmacologically targeted NSCLC therapy.

    Download full text (pdf)
    Lung Cancer
  • 3.
    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, 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.

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  • 4. 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, 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.

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  • 5.
    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 1557-8100, Vol. 23, no 1, p. 1-16Article 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.

  • 6.
    Aganovic, A.
    et al.
    Arctic Univ Norway, Dept Automat & Proc Engn, Klokkargardsbakken 35, N-9019 Tromso, Norway.
    Cao, G.
    Norwegian Univ Sci & Technol NTNU, Dept Energy & Proc Engn, Trondheim, Norway.
    Fecer, T.
    Brno Univ Technol, Dept Comp Aided Engn & Comp Sci, Fac Civil Engn, Brno, Czech Republic.
    Ljungqvist, B.
    Chalmers Univ Technol, Dept Civil & Environm Engn, Gothenburg, Sweden.
    Lytsy, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Radtke, A.
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
    Reinmüller, B.
    Chalmers Univ Technol, Dept Civil & Environm Engn, Gothenburg, Sweden.
    Traversari, R.
    Netherlands Org Appl Sci Res, The Hague, Netherlands.
    Ventilation design conditions associated with airborne bacteria levels within the wound area during surgical procedures: a systematic review2021In: Journal of Hospital Infection, ISSN 0195-6701, E-ISSN 1532-2939, Vol. 113, p. 85-95Article, review/survey (Refereed)
    Abstract [en]

    Without confirmation of the ventilation design conditions (typology and airflow rate), the common practice of identifying unidirectional airflow (UDAF) systems as equivalent to ultra-clean air ventilation systems may be misleading, but also any claims about the ineffectiveness of UDAF systems should be doubted. The aim of this review was to assess and compare ventilation system design conditions for which ultra-clean air (mean <10 cfu/m3) within 50 cm from the wound has been reported. Six medical databases were systematically searched to identify and select studies reporting intraoperative airborne levels expressed as cfu/m3 close to the wound site, and ventilation system design conditions. Available data on confounding factors such as the number of persons present in the operating room, number of door openings, and clothing material were also included. Predictors for achieving mean airborne bacteria levels within <10 cfu/m3 were identified using a penalized multivariate logistic regression model. Twelve studies met the eligibility criteria and were included for analysis. UDAF systems considered had significantly higher air volume flows compared with turbulent ventilation (TV) systems considered. Ultra-clean environments were reported in all UDAF-ventilated (N = 7) rooms compared with four of 11 operating rooms equipped with TV. On multivariate analysis, the total number of air exchange rates (P=0.019; odds ratio (OR) 95% confidence interval (CI): 0.66–0.96) and type of clothing material (P=0.031; OR 95% CI: 0.01–0.71) were significantly associated with achieving mean levels of airborne bacteria <10 cfu/m3. High-volume UDAF systems complying with DIN 1946-4:2008 standards for the airflow rate and ceiling diffuser size unconditionally achieve ultra-clean air close to the wound site. In conclusion, the studied articles demonstrate that high-volume UDAF systems perform as ultra-clean air systems and are superior to TV systems in reducing airborne bacteria levels close to the wound site.

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  • 7.
    Ahlinder, J.
    et al.
    FOI, Swedish Def Res Agcy, CBRN Def & Secur, Umeå, Sweden..
    Svedberg, A-L
    Reg Norrbotten, Dept Infect Control, Luleå, Sweden..
    Nystedt, A.
    Reg Norrbotten, Dept Infect Control, Luleå, Sweden..
    Dryselius, R.
    Natl Food Agcy, Dept Biol, Uppsala, Sweden..
    Jacobsson, K.
    Natl Food Agcy, Dept Biol, Uppsala, Sweden..
    Hägglund, M.
    Clin Genom Facil, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Brindefalk, B.
    FOI, Swedish Def Res Agcy, CBRN Def & Secur, Umeå, Sweden..
    Forsman, M.
    FOI, Swedish Def Res Agcy, CBRN Def & Secur, Umeå, Sweden..
    Ottoson, J.
    Natl Food Agcy, Dept Risk & Benefit Assessment, Uppsala, Sweden..
    Troell, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Vet Inst, Dept Microbiol, Uppsala, Sweden..
    Use of metagenomic microbial source tracking to investigate the source of a foodborne outbreak of cryptosporidiosis2022In: FOOD AND WATERBORNE PARASITOLOGY, ISSN 2405-6766, Vol. 26, article id e00142Article in journal (Refereed)
    Abstract [en]

    Cryptosporidium is a protozoan parasite of global public health importance that causes gastroenteritis in a variety of vertebrate hosts, with many human outbreaks reported yearly, often from ingestion of contaminated water or food. Despite the major public health implications, little is typically known about sources of contamination of disease outbreaks caused by Cryptosporidium. Here, we study a national foodborne outbreak resulted from infection with Cryptosporidium parvum via romaine lettuce, with the main goal to trace the source of the parasite. To do so, we combined traditional outbreak investigation methods with molecular detection and characterization methods (i.e. PCR based typing, amplicon and shotgun sequencing) of romaine lettuce samples collected at the same farm from which the contaminated food was produced. Using 18S rRNA typing, we detected C. parvum in two out of three lettuce samples, which was supported by detections in the metagenome analysis. Microbial source tracking analysis of the lettuce samples suggested sewage water as a likely source of the contamination, albeit with some uncertainty. In addition, the high degree of overlap in bacterial species content with a public human gut microbial database corroborated the source tracking results. The combination of traditional and molecular based methods applied here is a promising tool for future source tracking investigations of food- and waterborne outbreaks of Cryptosporidium spp. and can help to control and mitigate contamination risks.

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  • 8.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Bonnedahl, Jonas
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Kalmar Cty Council, Dept Infect Dis, Kalmar, Sweden.
    Woksepp, Hanna
    Kalmar Cty Hosp, Res Sect, Dept Dev & Publ Hlth, Kalmar, Sweden.
    Hernandez, Jorge
    Kalmar Cty Hosp, Dept Clin Microbiol, Kalmar, Sweden.
    Reed, John A.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Tibbitts, Lee
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Douglas, David C.
    US Geol Survey, Alaska Sci Ctr, Juneau, AK USA.
    Ramey, Andrew M.
    US Geol Survey, Alaska Sci Ctr, Anchorage, AK 99508 USA.
    Satellite tracking of gulls and genomic characterization of faecal bacteria reveals environmentally mediated acquisition and dispersal of antimicrobial-resistant Escherichia coli on the Kenai Peninsula, Alaska2019In: Molecular Ecology, ISSN 0962-1083, E-ISSN 1365-294X, Vol. 28, no 10, p. 2531-2545Article in journal (Refereed)
    Abstract [en]

    Gulls (Larus spp.) have frequently been reported to carry Escherichia coli exhibiting antimicrobial resistance (AMR E. coli); however, the pathways governing the acquisition and dispersal of such bacteria are not well described. We equipped 17 landfill-foraging gulls with satellite transmitters and collected gull faecal samples longitudinally from four locations on the Kenai Peninsula, Alaska to assess: (a) gull attendance and transitions between sites, (b) spatiotemporal prevalence of faecally shed AMR E. coli, and (c) genomic relatedness of AMR E. coli isolates among sites. We also sampled Pacific salmon (Oncorhynchus spp.) harvested as part of personal-use dipnet fisheries at two sites to assess potential contamination with AMR E. coli. Among our study sites, marked gulls most commonly occupied the lower Kenai River (61% of site locations) followed by the Soldotna landfill (11%), lower Kasilof River (5%) and upper Kenai River (<1%). Gulls primarily moved between the Soldotna landfill and the lower Kenai River (94% of transitions among sites), which were also the two locations with the highest prevalence of AMR E. coli. There was relatively high spatial and temporal variability in AMR E. coli prevalence in gull faeces and there was no evidence of contamination on salmon harvested in personal-use fisheries. We identified E. coli sequence types and AMR genes of clinical importance, with some isolates possessing genes associated with resistance to as many as eight antibiotic classes. Our findings suggest that gulls acquire AMR E. coli at habitats with anthropogenic inputs and subsequent movements may represent pathways through which AMR is dispersed.

  • 9.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, Alaska Sci Ctr, 4210 Univ Dr, Anchorage, AK 99508 USA..
    Woksepp, Hanna
    Kalmar Cty Hosp, Dept Dev & Publ Hlth, S-39185 Kalmar, Sweden.;Linnaeus Univ, Dept Med & Optometry, S-39185 Kalmar, Sweden..
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mohsin, Mashkoor
    Univ Agr Faisalabad, Inst Microbiol, Faisalabad 38040, Pakistan..
    Hasan, Badrul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Anim Bacteriol Sect, Anim Bacteriol Sect Microbial Sci Pests & Dis, Bundoora, Vic, Australia..
    Muzyka, Denys
    Inst Expt & Clin Vet Med, Natl Sci Ctr, UA-61023 Kharkiv, Ukraine..
    Hernandez, Jorge
    Kalmar Cty Hosp, Dept Clin Microbiol, SE-39185 Kalmar, Sweden..
    Aguirre, Filip
    Kalmar Cty Hosp, Dept Clin Microbiol, SE-39185 Kalmar, Sweden..
    Tok, Atalay
    Uppsala Univ, Dept Med Sci, Zoonosis Sci Ctr, SE-75185 Uppsala, Sweden..
    Soderman, Jan
    Linköping Univ, Dept Clin & Expt Med, Lab Med, Linköping, Sweden..
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ramey, Andrew M.
    US Geol Survey, Alaska Sci Ctr, 4210 Univ Dr, Anchorage, AK 99508 USA..
    Bonnedahl, Jonas
    Linköping Univ, Dept Biomed & Clin Sci, S-58183 Linköping, Sweden.;Region Kalmar Cty, Dept Infect Dis, S-39185 Kalmar, Sweden..
    Genomically diverse carbapenem resistant Enterobacteriaceae fromwild birds provide insight into global patterns of spatiotemporal dissemination2022In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 824, article id 153632Article in journal (Refereed)
    Abstract [en]

    Carbapenem resistant Enterobacteriaceae (CRE) are a threat to public health globally, yet the role of the environment in the epidemiology of CRE remains elusive. Given that wild birds can acquire CRE, likely from foraging in anthropogenically impacted areas, and may aid in the maintenance and dissemination of CRE in the environment, a spatiotemporal comparison of isolates from different regions and timepoints may be useful for elucidating epidemiological information. Thus, we characterized the genomic diversity of CRE from fecal samples opportunistically collected from gulls (Larus spp.) inhabiting Alaska (USA), Chile, Spain, Turkey, and Ukraine and from black kites (Milvus migrans) sampled in Pakistan and assessed evidence for spatiotemporal patterns of dissemination. Within and among sampling locations, a high diversity of carbapenemases was found, including Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-beta-lactamase (NDM), oxacillinase (OXA), and Verona integron Metallo beta-lactamase (VIM). Although the majority of genomic comparisons among samples did not provide evidence for spatial dissemination, we did find strong evidence for dissemination among Alaska, Spain, and Turkey. We also found strong evidence for temporal dissemination among samples collected in Alaska and Pakistan, though the majority of CRE clones were transitory and were not repeatedly detected among locations where samples were collected longitudinally. Carbapenemase-producing hypervirulent K. pneumoniae was isolated from gulls in Spain and Ukraine and some isolates harbored antimicrobial resistance genes conferring resistance to up to 10 different antibiotic classes, including colistin. Our results are consistent with local acquisition of CRE by wild birds with spatial dissemination influenced by intermediary transmission routes, likely involving humans. Furthermore, our results support the premise that anthropogenicallyassociated wild birds may be good sentinels for understanding the burden of clinically-relevant antimicrobial resistance in the local human population.

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  • 10.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr, Uppsala, Sweden..
    Bahlstrom, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Chinthakindi, Praveen K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Nyman, Tomas
    Karolinska Inst, Dept Med Biochem & Biophys, Prot Sci Facil, Stockholm, Sweden..
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala Univ, Zoonosis Sci Ctr, Uppsala, Sweden..
    Palanisamy, Navaneethan
    Univ Freiburg, Inst Biol 2, Freiburg, Germany..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr, Uppsala, Sweden..
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors2021In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 190, article id 105074Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. The NS2B-NS3 protease is essential for flaviviral life cycle and has been studied as a target for the design of inhibitors against several well-known flaviviruses, but not TBEV. In the present study, Compound 86, a known tripeptidic inhibitor of dengue (DENV), West Nile (WNV) and Zika (ZIKV) proteases, was predicted to be active against TBEV protease using a combination of in silico techniques. Further, Compound 86 was found to inhibit recombinant TBEV protease with an IC50 = 0.92 mu M in the in vitro enzymatic assay. Additionally, two more peptidic analogues were synthetized and they displayed inhibitory activities against both TBEV and ZIKV proteases. In particular, Compound 104 inhibited ZIKV protease with an IC50 = 0.25 mu M. These compounds represent the first reported inhibitors of TBEV protease to date and provides valuable information for the further development of TBEV as well as pan-flavivirus protease inhibitors.

  • 11.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Krambrich, Janina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ling, Jiaxin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Chen, Luni
    Department of Microbiology and Tumour and Cell Biology (MTC), Karolinska Institute, Solna, Sweden.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mitigation of the replication of SARS-CoV-2 by nitric oxide in vitro2020In: Redox Biology, E-ISSN 2213-2317, Vol. 37, article id 101734Article in journal (Refereed)
    Abstract [en]

    The ongoing SARS-CoV-2 pandemic is a global public health emergency posing a high burden on nations' health care systems and economies. Despite the great effort put in the development of vaccines and specific treatments, no prophylaxis or effective therapeutics are currently available. Nitric oxide (NO) is a broad-spectrum antimicrobial and a potent vasodilator that has proved to be effective in reducing SARS-CoV replication and hypoxia in patients with severe acute respiratory syndrome. Given the potential of NO as treatment for SARS-CoV-2 infection, we have evaluated the in vitro antiviral effect of NO on SARS-CoV-2 replication. The NO-donor S-nitroso-N-acetylpenicillamine (SNAP) had a dose dependent inhibitory effect on SARS-CoV-2 replication, while the non S-nitrosated NAP was not active, as expected. Although the viral replication was not completely abolished (at 200 μM and 400 μM), SNAP delayed or completely prevented the development of viral cytopathic effect in treated cells, and the observed protective effect correlated with the level of inhibition of the viral replication. The capacity of the NO released from SNAP to covalently bind and inhibit SARS-CoV-2 3CL recombinant protease in vitro was also tested. The observed reduction in SARS-CoV-2 protease activity was consistent with S-nitrosation of the enzyme active site cysteine.

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  • 12.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pourghasemi Lati, Monireh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Krambrich, Janina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berger, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Turunen, Pauliina
    Science for Life Laboratory, Human Antibody Therapeutics, Drug Discovery and Development Platform, Solna, Sweden.
    Gullberg, Hjalmar
    Science for Life Laboratory, Biochemical and Cellular Assay Facility, Drug Discovery and Development Platform, Department of Biochemistry and Biophysics, Stockholm University, Solna, Stockholm, Sweden.
    Moche, Martin
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden.
    Chinthakindi, Praveen Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Nyman, Tomas
    Department of Medical Biochemistry and Biophysics, Protein Science Facility, Karolinska Institutet, Stockholm, Sweden..
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Verho, Oscar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery.
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Identification of unique and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical librariesManuscript (preprint) (Other academic)
  • 13.
    Akerlund, Anna
    et al.
    Div Clin Microbiol, Lab Med, Jönköping, Region Jonkopin, Sweden.;Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.;Linköping Univ Hosp, Dept Clin & Expt Med, Div Clin Microbiol, Linköping, Sweden..
    Petropoulos, Alexandros
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Malmros, Karin
    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, Infection medicine.
    Giske, Christian G.
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Clin Microbiol, Stockholm, Sweden..
    Blood culture diagnostics: a Nordic multicentre survey comparison of practices in clinical microbiology laboratories2022In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 28, no 5Article in journal (Refereed)
    Abstract [en]

    Objectives: Accurate and rapid microbiological diagnostics are crucial to tailor treatment and improve outcomes in patients with severe infections. This study aimed to assess blood culture diagnostics in the Nordic countries and to compare them with those of a previous survey conducted in Sweden in 2013. Methods: An online questionnaire was designed and distributed to the Nordic clinical microbiology laboratories (CMLs) (n = 76) in January 2018. Results: The response rate was 64% (49/76). Around-the-clock incubation of blood cultures (BCs) was supported in 82% of the CMLs (40/49), although in six of these access to the incubators around the clock was not given to all of the cabinets in the catchment area, and 41% of the sites (20/49) did not assist with satellite incubators. Almost half (49%, 24/49) of the CMLs offered opening hours for >= 10 h during weekdays, more commonly in CMLs with an annual output >= 30 000 BCs. Still, positive BCs were left unprocessed for 60-70% of the day due to restrictive opening hours. Treatment advice was given by 23% of CMLs (11/48) in >= 75% of the phone contacts. Rapid analyses (species identification and susceptibility testing with short incubation), performed on aliquots from positive cultures, were implemented in 18% of CMLs (9/49). Compared to 2013, species identification from subcultured colonies (<6 h) had become more common. Conclusions: CMLs have taken action to improve aspects of BC diagnostics, implementing satellite incubators, rapid species identification and susceptibility testing. However, the limited opening hours and availability of clinical microbiologists are confining the advantages of these changes. (C) 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

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  • 14.
    Albinsson, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Lab Clin Microbiol, Uppsala, Sweden..
    Jääskeläine, Anu E.
    Univ Helsinki, Dept Virol, Helsinki, Finland.;Helsinki Univ Hosp Lab Serv HUSLAB, Dept Virol & Immunol, Helsinki, Finland..
    Värv, Kairi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Inst Hlth Dev, Dept Virol & Immunol, Tallinn, Estonia..
    Jelovse, Mateja
    Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia..
    GeurtsvanKessel, Corine
    Erasmus MC, WHO Collaborating Ctr Arbovirus & Viral Haemorrha, Dept Virol, Rotterdam, Netherlands..
    Ven, Sirkka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Reuske, Chantal
    Erasmus MC, WHO Collaborating Ctr Arbovirus & Viral Haemorrha, Dept Virol, Rotterdam, Netherlands.;Natl Inst Publ Hlth & Environm, Ctr Infect Dis Control, Bilthoven, Netherlands..
    Golovljova, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Inst Hlth Dev, Dept Virol & Immunol, Tallinn, Estonia..
    Avsic-Zupan, Tatjana
    Univ Ljubljana, Fac Med, Inst Microbiol & Immunol, Ljubljana, Slovenia..
    Vapalaht, Olli
    Univ Helsinki, Dept Virol, Helsinki, Finland.;Helsinki Univ Hosp Lab Serv HUSLAB, Dept Virol & Immunol, Helsinki, Finland.;Univ Helsinki, Dept Vet Biosci, Helsinki, Finland..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Multi laboratory evaluation of ReaScan TBE IgM rapid test, 2016 to 20172020In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 25, no 12, p. 27-36, article id 1900427Article in journal (Refereed)
    Abstract [en]

    Tick-borne encephalitis (TBE) is a potentially severe neurological disease caused by TBE virus (TBEV). In Europe and Asia, TBEV infection has become a growing public health concern and requires fast and specific detection. Aim: In this observational study, we evaluated a rapid TBE IgM test, ReaScan TBE, for usage in a clinical laboratory setting. Methods: Patient sera found negative or positive for TBEV by serological and/or molecular methods in diagnostic laboratories of five European countries endemic for TBEV (Estonia, Finland, Slovenia, the Netherlands and Sweden) were used to assess the sensitivity and specificity of the test. The patients' diagnoses were based on other commercial or quality assured in-house assays, i.e. each laboratory's conventional routine methods. For specificity analysis, serum samples from patients with infections known to cause problems in serology were employed. These samples tested positive for e.g. Epstein-Barr virus, cytomegalovirus and Anaplasma phagocytophilum, or for flaviviruses other than TBEV, i.e. dengue, Japanese encephalitis, West Nile and Zika viruses. Samples from individuals vaccinated against flaviviruses other than TBEV were also included. Altogether, 172 serum samples from patients with acute TBE and 306 TBE IgM negative samples were analysed. Results: Compared with each laboratory's conventional methods, the tested assay had similar sensitivity and specificity (99.4% and 97.7%, respectively). Samples containing potentially interfering antibodies did not cause specificity problems. Conclusion: Regarding diagnosis of acute TBEV infections, ReaScan TBE offers rapid and convenient complementary IgM detection. If used as a stand-alone, it can provide preliminary results in a laboratory or point of care setting.

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  • 15.
    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.

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  • 16.
    Alexander, Lind
    et al.
    Lund Univ CRC, Dept Clin Sci Malmo, Jan Waldenstromsgata 35, SE-21428 Malmo, Sweden..
    Yang, Cao
    Orebro Univ, Fac Med & Hlth, Sch Med Sci, Clin Epidemiol & Biostat, Orebro, Sweden.;Karolinska Inst, Unit Integrat Epidemiol, Inst Environm Med, Stockholm, Sweden..
    Hugo, Hesser
    Orebro Univ, Ctr Hlth & Med Psychol, Sch Behav Social & Legal Sci, Orebro, Sweden.;Linkoping Univ, Dept Behav Sci & Learning, Linkoping, Sweden..
    Hårdstedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden.;Vansbro Primary Hlth Care Ctr, Vansbro, Sweden..
    Jansson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine. Orebro Univ, Univ Hlth Care Res Ctr, Sch Med Sci, Orebro, Sweden..
    Åke, Lernmark
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Martin, Sundqvist
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden..
    Staffan, Tevell
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden.;Karlstad Hosp, Dept Infect Dis, Karlstad, Sweden.;Reg Varmland, Ctr Clin Res & Educ, Karlstad, Sweden..
    Cheng-ting, Tsai
    Enable Biosci Inc, South San Francisco, CA USA..
    Jeanette, Wahlberg
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden..
    Johan, Jendle
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden..
    Anxiety, depression and quality of life in relation to SARS-CoV-2 antibodies in individuals living with diabetes during the second wave of COVID-192024In: Diabetes Epidemiology and Management, E-ISSN 2666-9706, Vol. 13, article id 100194Article in journal (Refereed)
    Abstract [en]

    Aims: The objective was to compare anxiety, depression, and quality of life (QoL) in individuals living with type 1 (T1D) and type 2 (T2D) diabetes with matched controls during the second wave of the COVID-19 pandemic. Methods: Via randomization, individuals living with diabetes T1D (n = 203) and T2D (n = 413), were identified during February-July 2021 through health-care registers. Population controls (n = 282) were matched for age, gender, and residential area. Questionnaires included self-assessment of anxiety, depression, QoL, and demographics in relation to SARS-CoV-2 exposure. Blood was collected through home-capillary sampling, and SARS-CoV-2 Nucleocapsid (NCP) and Spike antibodies (SC2_S1) were determined by multiplex Antibody Detection by Agglutination-PCR (ADAP) assays. Results: Younger age and health issues were related to anxiety, depression, and QoL, with no differences between the study groups. Female gender was associated with anxiety, while obesity was associated with lower QoL. The SARS-CoV-2 NCP seroprevalence was higher in T1D (8.9 %) compared to T2D (3.9 %) and controls (4.0 %), while the SARS-CoV-2 SC2_S1 seroprevalence was higher for controls (25.5 %) compared to T1D (16.8 %) and T2D (14.0 %). Conclusions: A higher SARS-CoV-2 infection rate in T1D may be explained by younger age and higher employment rate, and the associated increased risk for viral exposure.

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  • 17.
    Alfsnes, Kristian
    et al.
    Norwegian Inst Publ Hlth, Infect Dis Control & Environm Hlth, Oslo, Norway..
    Lagerqvist, Nina
    Publ Hlth Agcy Sweden, Nobels Vag 18, SE-17182 Solna, Sweden..
    Vene, Sirkka
    Publ Hlth Agcy Sweden, Nobels Vag 18, SE-17182 Solna, Sweden..
    Bohlin, Jon
    Norwegian Inst Publ Hlth, Infect Dis Control & Environm Hlth, Oslo, Norway..
    Verner-Carlsson, Jenny
    Publ Hlth Agcy Sweden, Nobels Vag 18, SE-17182 Solna, Sweden..
    Ekqvist, David
    Univ Hosp Linköping, Dept Infect Dis, Linköping, Sweden..
    Bråve, Andreas
    Publ Hlth Agcy Sweden, Nobels Vag 18, SE-17182 Solna, Sweden..
    Holmes, Edward C.
    Univ Sydney, Sch Life & Environm Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia.;Univ Sydney, Sch Med Sci, Sydney, NSW 2006, Australia..
    Shi, Weifeng
    Shandong First Med Univ & Shandong Acad Med Sci, Sch Publ Hlth, Tai An 271016, Shandong, Peoples R China..
    Pettersson, John H.-O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Publ Hlth Agcy Sweden, Nobels Vag 18, SE-17182 Solna, Sweden; Univ Sydney, Sch Life & Environm Sci, Marie Bashir Inst Infect Dis & Biosecur, Sydney, NSW 2006, Australia; Univ Sydney, Sch Med Sci, Sydney, NSW 2006, Australia.
    Retrospective meta-transcriptomic identification of severe dengue in a traveller returning from Africa to Sweden, 19902021In: One Health, ISSN 2352-7714, Vol. 12, article id 100217Article in journal (Refereed)
    Abstract [en]

    Pathogens associated with haemorrhagic fever commonly have zoonotic origins. The first documented imported case of likely viral severe haemorrhagic fever in Sweden occurred in 1990. Despite extensive study, no aetiological agent was identified. Following retrospective investigation with total RNA-sequencing of samples collected between 7 and 36 days from onset of symptoms we identified dengue virus 3 (DENV-3) and a human pegivirus (HPgV). We conclude that the patient likely suffered from haemorrhagic symptoms due to an atypical severe and undiagnosed dengue infection.

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  • 18.
    Allander, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    β-lactam combinations against multidrug-resistant Enterobacterales: Exploring combination effects and resistance development2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The β-lactam antibiotics are a cornerstone in treating bacterial infections, but the increasing prevalence of antibiotic resistance worldwide threatens their effectiveness. The main driver of β-lactam resistance is the production of β-lactamases, which are bacterial enzymes that inactivate the antibiotic. Moreover, resistance to multiple antibiotic classes is common in β-lactamase producing bacteria, further limiting treatment options. At the same time, few novel antibacterial agents are reaching the market. To address this challenge, antibiotic combination therapy is employed to enhance the effects of existing drugs against multidrug-resistant bacteria. Yet, there is a lack of knowledge regarding which antibiotics to combine to achieve the best effect. The investigations in this thesis evaluate the potential and limitations of combinations involving β-lactams, β-lactamase inhibitors and colistin against multidrug-resistant Enterobacterales in vitro

    In the first paper, we investigated resistance mechanisms to three commonly used β-lactam/β-lactamase inhibitor combinations (BLBLIs) in an Escherichia coli strain encoding multiple β-lactamases. We found that β-lactamase gene amplifications were a key driver of resistance, with variations in the amplification pattern depending on the BLBLI combination. Clinical resistance could be reached by gene amplifications for ampicillin-sulbactam and piperacillin-tazobactam, whereas ceftazidime-avibactam resistance required multiple genetic changes. 

    In the second paper, we evaluated the efficacy of double-carbapenem combinations against E. coli and Klebsiella pneumoniae producing carbapenemases (KPC-2, OXA-48, NDM-1, and NDM-5). Synergistic effects were most commonly observed against OXA-48-producing strains, whereas the efficacy was low against KPC-2 and negligible against NDM producers. 

    In the third and fourth papers, we evaluated the antibacterial activity of colistin in combination with BLBLIs. Considering that reduced membrane permeability is associated with decreased susceptibility towards BLBLIs, adding colistin may be beneficial since its membrane-disrupting effect may increase the entry of other drugs. In paper three, we showed synergistic effects with colistin and ceftazidime-avibactam against a KPC-2-producing K. pneumoniae strain with porin deficiencies. However, when systematically assessing the impact of porin loss on the synergistic potential of colistin in combination with BLBLIs in paper four, we did not find any clear association between porin loss and synergy. 

    These studies provide insight into the therapeutic potential and limitations of combinations, including β-lactam antibiotics against strains with different setups of resistance genes. More research is required to understand how to best use the newly introduced BLBLI combinations to preserve their activity and enhance the value of the available antibiotics for future generations.

    List of papers
    1. Evolutionary Trajectories toward High-Level β-Lactam/β-Lactamase Inhibitor Resistance in the Presence of Multiple β-Lactamases
    Open this publication in new window or tab >>Evolutionary Trajectories toward High-Level β-Lactam/β-Lactamase Inhibitor Resistance in the Presence of Multiple β-Lactamases
    2022 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 66, no 6, article id e00290-22Article in journal (Refereed) Published
    Abstract [en]

    β-Lactam antibiotics are the first choice for the treatment of most bacterial infections. However, the increased prevalence of β-lactamases, in particular extended-spectrum β-lactamases, in pathogenic bacteria has severely limited the possibility of using β-lactam treatments. Combining β-lactam antibiotics with β-lactamase inhibitors can restore treatment efficacy by negating the effect of the β-lactamase and has become increasingly important against infections caused by β-lactamase-producing strains. Not surprisingly, bacteria with resistance to even these combinations have been found in patients. Studies on the development of bacterial resistance to β-lactam/β-lactamase inhibitor combinations have focused mainly on the effects of single, chromosomal or plasmid-borne, β-lactamases. However, clinical isolates often carry more than one β-lactamase in addition to multiple other resistance genes. Here, we investigate how the evolutionary trajectories of the development of resistance to three commonly used β-lactam/β-lactamase inhibitor combinations, ampicillin-sulbactam, piperacillin-tazobactam, and ceftazidime-avibactam, were affected by the presence of three common β-lactamases, TEM-1, CTX-M-15, and OXA-1. First-step resistance was due mainly to extensive gene amplifications of one or several of the β-lactamase genes where the amplification pattern directly depended on the respective drug combination. Amplifications also served as a stepping-stone for high-level resistance in combination with additional mutations that reduced drug influx or mutations in the β-lactamase gene blaCTX-M-15. This illustrates that the evolutionary trajectories of resistance to β-lactam/β-lactamase inhibitor combinations are strongly influenced by the frequent and transient nature of gene amplifications and how the presence of multiple β-lactamases shapes the evolution to higher-level resistance.

    Place, publisher, year, edition, pages
    American Society for Microbiology, 2022
    Keywords
    antibiotic resistance, evolution, gene amplification, β-lactam/β-lactamase inhibitor
    National Category
    Microbiology in the medical area Infectious Medicine Evolutionary Biology Genetics
    Research subject
    Microbiology; Biology with specialization in Evolutionary Genetics
    Identifiers
    urn:nbn:se:uu:diva-475663 (URN)10.1128/aac.00290-22 (DOI)000808103400003 ()35652643 (PubMedID)
    Funder
    Swedish Research Council, 2012-1511Carl Tryggers foundation , CTS16:395Åke Wiberg Foundation
    Available from: 2022-06-03 Created: 2022-06-03 Last updated: 2023-10-13Bibliographically approved
    2. Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48-and NDM-Producing Escherichia coli and Klebsiella pneumoniae
    Open this publication in new window or tab >>Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48-and NDM-Producing Escherichia coli and Klebsiella pneumoniae
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    2022 (English)In: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 11, no 11, article id 1646Article in journal (Refereed) Published
    Abstract [en]

    Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing Enterobacterales, but data remain inconclusive. This study evaluated the activity of double-carbapenem combinations against 51 clinical KPC-2-, OXA-48-, NDM-1, and NDM-5-producing Escherichia coli and Klebsiella pneumoniae and against constructed E. coli strains harboring genes encoding KPC-2, OXA-48, or NDM-1 in an otherwise isogenic background. Two-drug combinations of ertapenem, meropenem, and doripenem were evaluated in 24 h time-lapse microscopy experiments with a subsequent spot assay and in static time-kill experiments. An enhanced effect in time-lapse microscopy experiments at 24 h and synergy in the spot assay was detected with one or more combinations against 4/14 KPC-2-, 17/17 OXA-48-, 2/17 NDM-, and 1/3 NDM-1+OXA-48-producing clinical isolates. Synergy rates were higher against meropenem- and doripenem-susceptible isolates and against OXA-48 producers. NDM production was associated with significantly lower synergy rates in E. coli. In time-kill experiments with constructed KPC-2-, OXA-48- and NDM-1-producing E. coli, 24 h synergy was not observed; however, synergy at earlier time points was found against the KPC-2- and OXA-48-producing constructs. Our findings indicate that the benefit of double-carbapenem combinations against carbapenemase-producing E. coli and K. pneumoniae is limited, especially against isolates that are resistant to the constituent antibiotics and produce NDM.

    Place, publisher, year, edition, pages
    MDPI, 2022
    Keywords
    carbapenem resistance, Gram-negative bacteria, combination therapy, synergy
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:uu:diva-492674 (URN)10.3390/antibiotics11111646 (DOI)000894343200001 ()36421290 (PubMedID)
    Funder
    Swedish Research Council, 2019-05911Vinnova, 2021-02699Swedish Research Council, 2020-02320AFA Insurance, 180124
    Available from: 2023-01-10 Created: 2023-01-10 Last updated: 2023-10-13Bibliographically approved
    3. Evaluation of ceftazidime-avibactam in combination with colistin against KPC-2-producing Klebsiella pneumoniae with porin deficiency in static and dynamic time-kill experiments
    Open this publication in new window or tab >>Evaluation of ceftazidime-avibactam in combination with colistin against KPC-2-producing Klebsiella pneumoniae with porin deficiency in static and dynamic time-kill experiments
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:uu:diva-513940 (URN)
    Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2023-10-13
    4. Impact of porin deficiency on the synergistic potential of colistin in combination with β-lactam/β-lactamase inhibitors against Klebsiella pneumoniae 
    Open this publication in new window or tab >>Impact of porin deficiency on the synergistic potential of colistin in combination with β-lactam/β-lactamase inhibitors against Klebsiella pneumoniae 
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:uu:diva-513943 (URN)
    Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2023-10-13
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  • 19.
    Allander, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vickberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fermér, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Söderhäll, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lagerbäck, Pernilla
    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.
    Impact of porin deficiency on the synergistic potential of colistin in combination with β-lactam/β-lactamase inhibitors against Klebsiella pneumoniae Manuscript (preprint) (Other academic)
  • 20.
    Allander, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Vickberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lagerbäck, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Evaluation of In Vitro Activity of Double-Carbapenem Combinations against KPC-2-, OXA-48-and NDM-Producing Escherichia coli and Klebsiella pneumoniae2022In: Antibiotics, ISSN 0066-4774, E-ISSN 2079-6382, Vol. 11, no 11, article id 1646Article in journal (Refereed)
    Abstract [en]

    Double-carbapenem combinations have shown synergistic potential against carbapenemase-producing Enterobacterales, but data remain inconclusive. This study evaluated the activity of double-carbapenem combinations against 51 clinical KPC-2-, OXA-48-, NDM-1, and NDM-5-producing Escherichia coli and Klebsiella pneumoniae and against constructed E. coli strains harboring genes encoding KPC-2, OXA-48, or NDM-1 in an otherwise isogenic background. Two-drug combinations of ertapenem, meropenem, and doripenem were evaluated in 24 h time-lapse microscopy experiments with a subsequent spot assay and in static time-kill experiments. An enhanced effect in time-lapse microscopy experiments at 24 h and synergy in the spot assay was detected with one or more combinations against 4/14 KPC-2-, 17/17 OXA-48-, 2/17 NDM-, and 1/3 NDM-1+OXA-48-producing clinical isolates. Synergy rates were higher against meropenem- and doripenem-susceptible isolates and against OXA-48 producers. NDM production was associated with significantly lower synergy rates in E. coli. In time-kill experiments with constructed KPC-2-, OXA-48- and NDM-1-producing E. coli, 24 h synergy was not observed; however, synergy at earlier time points was found against the KPC-2- and OXA-48-producing constructs. Our findings indicate that the benefit of double-carbapenem combinations against carbapenemase-producing E. coli and K. pneumoniae is limited, especially against isolates that are resistant to the constituent antibiotics and produce NDM.

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  • 21.
    Allander, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vikdahl, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chatzopoulou, Margarita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    O'Jeanson, Amaury
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lagerbäck, Pernilla
    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.
    Evaluation of ceftazidime-avibactam in combination with colistin against KPC-2-producing Klebsiella pneumoniae with porin deficiency in static and dynamic time-kill experimentsManuscript (preprint) (Other academic)
  • 22.
    Allwell-Brown, Gbemisola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Hussain-Alkhateeb, Laith
    Univ Gothenburg, Sch Publ Hlth & Community Med, Sahlgrenska Acad, Inst Med,Global Hlth, SE-40530 Gothenburg, Sweden..
    Sewe, Maquins Odhiambo
    Umeå Univ, Dept Publ Hlth & Clin Med, Sustainable Hlth Sect, SE-90187 Umeå, Sweden..
    Kitutu, Freddy Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Makerere Univ, Sch Hlth Sci, Dept Pharm, Sustainable Pharmaceut Syst SPS Unit, Box 7072, Kampala, Uganda. Uppsala Univ, Dept Med Sci, Infect Dis Sect, SE-75185 Uppsala, Sweden..
    Strömdahl, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    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).
    White Johansson, Emily
    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).
    Determinants of trends in reported antibiotic use among sick children under five years of age across low-income and middle-income countries in 2005-17: A systematic analysis of user characteristics based on 132 national surveys from 73 countries2021In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 108, p. 473-482Article in journal (Refereed)
    Abstract [en]

    Objectives: This study aimed to analyze any reported antibiotic use for children aged <5 years with fever, diarrhea or cough with fast or difficult breathing (outcome) from low-income and middle-income countries (LMICs) during 2005-2017 by user characteristics: rural/urban residence, maternal education, household wealth, and healthcare source visited. Methods: Based on 132 demographic and health surveys and multiple indicator cluster surveys from 73 LMICs, the outcome by user characteristics for all country-years was estimated using a hierarchical Bayesian linear regression model. Results: Across LMICs during 2005-2017, the greatest relative increases in the outcome occurred in rural areas, poorest quintiles and least educated populations, particularly in low-income countries and South-East Asia. In low-income countries, rural areas had a 72% relative increase from 17.8% (Uncertainty Interval (UI): 5.2%-44.9%) in 2005 to 30.6% (11.7%-62.1%) in 2017, compared to a 29% relative increase in urban areas from 27.1% (8.7%- 58.2%) in 2005 to 34.9% (13.3%-67.3%) in 2017. Despite these increases, the outcome was consistently highest in urban areas, wealthiest quintiles, and populations with the highest maternal education. Conclusion: These estimates suggest that the increasing reported antibiotic use for sick children aged <5 years in LMICs during 2005-2017 was driven by gains among groups often underserved by formal health services.

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  • 23.
    Almazan, Nerea Martin
    et al.
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Div Pathol, S-14186 Stockholm, Sweden..
    Rahbar, Afsar
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden..
    Carlsson, Marcus
    Lund Univ, Ctr Math Sci, S-22362 Lund, Sweden..
    Hoffman, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Uppsala Univ, Zoonosis Sci Ctr ZSC, Dept Med Biochem & Microbiol IMBIM, S-1477 Uppsala, Sweden..
    Kolstad, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr ZSC, Dept Med Biochem & Microbiol IMBIM, S-1477 Uppsala, Sweden..
    Rönnberg, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala Univ, Zoonosis Sci Ctr ZSC, Dept Med Biochem & Microbiol IMBIM, S-1477 Uppsala, Sweden..
    Pantalone, Mattia Russel
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden..
    Fuchs, Ilona Lewensohn
    Karolinska Inst, Dept Lab Med, Div Clin Microbiol, S-14186 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Microbiol, S-14186 Stockholm, Sweden..
    Naucler, Anna
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden..
    Ohlin, Mats
    Lund Univ, Dept Immunotechnol, S-22362 Lund, Sweden.;Lund Univ, SciLifeLab Human Antibody Therapeut Infrastruct Un, S-22362 Lund, Sweden..
    Sacharczuk, Mariusz
    Med Univ Warsaw, Fac Pharm, Ctr Preclin Res & Technol, Dept Pharmacodynam,Lab Med Div, Banacha 1B, PL-02091 Warsaw, Poland.;Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Magdalenka, Poland..
    Religa, Piotr
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden.;Polish Acad Sci, Inst Genet & Anim Biotechnol, Dept Expt Genom, Postepu 36A, PL-05552 Magdalenka, Poland..
    Amer, Stefan
    Familjelakarna Saltsjdbaden, S-13334 Saltsjdbaden, Sweden..
    Molnar, Christian
    Familjelakarna Saltsjdbaden, S-13334 Saltsjdbaden, Sweden.;Karolinska Inst, Dept Neurobiol Care Sci & Soc, NVS, S-17177 Stockholm, Sweden..
    Lundkvist, Ake
    Susrud, Andres
    Immunor AS, N-0349 Oslo, Norway..
    Sorensen, Birger
    Immunor AS, N-0349 Oslo, Norway..
    Soderberg-Naucler, Cecilia
    Karolinska Inst, Dept Med, Unit Microbial Pathogenesis, S-17164 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neurol, S-17176 Stockholm, Sweden.;Univ Turku, Inst Biomed, Unit Infect & Immunol, MediCity Res Lab, FI-20014 Turku, Finland..
    Influenza-A mediated pre-existing immunity levels to SARS-CoV-2 could predict early COVID-19 outbreak dynamics2023In: iScience, E-ISSN 2589-0042, Vol. 26, no 12, article id 108441Article in journal (Refereed)
    Abstract [en]

    Susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is highly variable and could be mediated by a cross-protective pre-immunity. We identified 14 cross-reactive peptides between SARS-CoV-2 and influenza A H1N1, H3N2, and human herpesvirus (HHV)-6A/B with potential relevance. The H1N1 peptide NGVEGF was identical to a peptide in the most critical receptor binding motif in SARS-CoV-2 spike protein that interacts with the angiotensin converting enzyme 2 receptor. About 62%-73% of COVID-19-negative blood donors in Stockholm had antibodies to this peptide in the early pre-vaccination phase of the pandemic. Seasonal flu vaccination enhanced neutralizing capacity to SARS-CoV-2 and T cell immunity to this peptide. Mathematical modeling taking the estimated pre -immunity levels to flu into account could fully predict pre-Omicron SARS-CoV-2 outbreaks in Stockholm and India. This cross-immunity provides mechanistic explanations to the epidemiological observation that influenza vaccination protected people against early SARS-CoV-2 infections and implies that flu-mediated cross-protective immunity significantly dampened the first SARS-CoV-2 outbreaks.

  • 24.
    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, 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.

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  • 25.
    Al-Sabti, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Refinement of pharmacokinetic model for bedaquiline and its main metabolite M22020Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Background: Tuberculosis is an infectious disease caused by the bacteria Mycobacterium tuberculosis. Tuberculosis is responsible for the death of at least one million people, according to the World Health Organization. The fear is that it will be an even bigger problem in the future due to multi-drug resistant (MDR) tuberculosis. (1) Fortunately, new treatments are emerging, and one promising idea is combination therapy with the drugs bedaquiline and delamanid. (2) However, one side effect of both drugs is QT-prolongation, and the question is if the combination of the drugs will result in a more severe side-effect (2). The aim in this project was to refine an existing PK-model to make it describe our obtained data properly. Method: In this project an existing PK-model was analyzed in order to observe how well the original model fit our data. Refinements were then made to the model in order to obtain a better fit. The model was tested in several executions through the software NOMNEM. The results were analyzed graphically using the software R amongst others. Results and conclusion: From the results obtained in the project a PK-model was successfully refined. The results from this project is an important step in order to study QT-prolongation of the combination of bedaquiline and delamanid in the future.

  • 26.
    Alsheim, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    CD4-PP a novel strategy to treat and prevent urinary tract infections2021Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
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  • 27.
    Amaratunga, Chanaki
    et al.
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Andrianaranjaka, Voahangy Hanitriniaina
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar;Univ Antananarivo, Fac Sci, Antananarivo, Madagascar.
    Ashley, Elizabeth
    MOCRU, Yangon, Myanmar;Univ Oxford, Ctr Trop Med & Global Hlth, Oxford, England.
    Bethell, Delia
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Bjorkman, Anders
    Karolinska Inst, Dept Mol Tumor & Cell Biol, Stockholm, Sweden.
    Bonnington, Craig A.
    Shoklo Malaria Res Unit, Mae Sot, Thailand.
    Cooper, Roland A.
    Dominican Univ Calif, Dept Nat Sci & Math, San Rafael, CA USA.
    Dhorda, Mehul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Dondorp, Arjen
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand.
    Erhart, Annette
    ITM Antwerp, Dept Publ Hlth, Antwerp, Belgium;Inst Trop Med, MRC Unit Gambia, Fajara, Gambia;Inst Trop Med, MRC Unit Gambia, Fajara, Gambia.
    Fairhurst, Rick M.
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Faiz, Abul
    Dev Care Fdn, Dhaka, Bangladesh.
    Fanello, Caterina
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Oxford Res Unit, Bangkok, Thailand.
    Fukuda, Mark M.
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Guerin, Philippe
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    van Huijsduijnen, Rob Hooft
    Med Malaria Venture, Geneva, Switzerland.
    Hien, Tran Tinh
    Hong, N. V.
    Natl Inst Malariol Parasitol & Entomol, Hanoi, Vietnam.
    Htut, Ye
    Dept Med Res, Yangon, Myanmar.
    Huang, Fang
    Chinese Ctr Dis Control & Prevent, Natl Inst Parasit Dis, Shanghai, Peoples R China.
    Humphreys, Georgina
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Imwong, Mallika
    Mahidol Univ, Fac Trop Med, Dept Mol Trop Med & Genet, Bangkok, Thailand;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Kennon, Kalynn
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England.
    Lim, Pharath
    NIAID, Lab Malaria & Vector Res, Div Intramural Res, NIH, Rockville, MD USA.
    Lin, Khin
    Dept Med Res, Pyin Oo Lwin Branch, Anesakhan, Myanmar.
    Lon, Chanthap
    Armed Forces Res Inst Med Sci, Bangkok, Thailand.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Mayxay, Mayfong
    Lao Oxford Mahosot Hospital, Wellcome Trust Res Unit, LOMWRU, Viangchan, Laos;Univ Hlth Sci, Minist Hlth, Fac Postgrad Studies, Viangchan, Laos;Churchill Hosp, Nuffield Dept Med, Ctr Trop Med & Global Hlth, Oxford, England.
    Mokuolu, Olugbenga
    Univ Ilorin, Coll Hlth Sci, Dept Paediat & Child Hlth, Ilorin, Nigeria;Univ Ilorin, Teaching Hosp, Ctr Malaria & Other Trop Dis Care, Ilorin, Nigeria.
    Morris, Ulrika
    Karolinska Inst, Dept Mol Tumor & Cell Biol, Stockholm, Sweden.
    Ngasala, Billy E.
    Muhimbili Univ Hlth & Allied Sci, Dept Parasitol & Med Entomol, Dar Es Salaam, Tanzania.
    Amambua-Ngwa, Alfred
    Inst Trop Med, MRC Unit Gambia, Fajara, Gambia.
    Noedl, Harald
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria.
    Nosten, Francois
    Shoklo Malaria Res Unit, Mae Sot, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Onyamboko, Marie
    Mahidol Oxford Res Unit, Bangkok, Thailand;Kinshasa Sch Publ Hlth, Kinshasa, DEM REP CONGO.
    Phyo, Aung Pyae
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England;Mahidol Univ, Fac Trop Med, Mahidol Oxford Trop Med Res Unit, Bangkok, Thailand.
    Plowe, Christopher V.
    Duke Univ, Duke Global Hlth Inst, Durham, NC USA.
    Pukrittayakamee, Sasithon
    Mahidol Univ, Dept Clin Trop Med, Bangkok, Thailand;Royal Soc Thailand, Bangkok, Thailand.
    Randrianarivelojosia, Milijaona
    Inst Pasteur Madagascar, Malaria Res Unit, Antananarivo, Madagascar;Univ Toliara, Fac Sci, Toliara, Madagascar.
    Rosenthal, Philip J.
    Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA;Univ Calif San Francisco, Div HIV Infect Dis & Global Med, San Francisco, CA 94143 USA.
    Saunders, David L.
    Armed Forces Res Inst Regenerat Med, Bangkok, Thailand;US Army Med Mat Dev Act, Ft Detrick, MD USA.
    Sibley, Carol Hopkins
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.
    Smithuis, Frank
    Myanmar Oxford Clin Res Unit, Yangon, Myanmar.
    Spring, Michele D.
    Armed Forces Res Inst Med Sci, Dept Immunol & Med, Bangkok, Thailand.
    Sondo, Paul
    Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, WWARN, Oxford, England;CRUN, Ouaga, Burkina Faso.
    Sreng, Sokunthea
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia.
    Starzengruber, Peter
    Med Univ Vienna, Inst Specif Prophylaxis & Trop Med, Vienna, Austria;Med Univ Vienna, Dept Lab Med, Div Clin Microbiol, Vienna, Austria.
    Stepniewska, Kasia
    Univ Oxford, Ctr Trop Med & Global Hlth, WWARN, Oxford, England.
    Suon, Seila
    Natl Ctr Parasitol Entomol & Malaria Control, Phnom Penh, Cambodia.
    Takala-Harrison, Shannon
    Univ Maryland, Sch Med, Inst Global Hlth, Div Malaria Res, Baltimore, MD 21201 USA.
    Thriemer, Kamala
    Inst Trop Med, Antwerp, Belgium;Menzies Sch Hlth Res, Darwin, NT, Australia.
    Thuy-Nhien, Nguyen
    Tun, Kyaw Myo
    Myanmar Oxford Clin Res Unit, Yangon, Myanmar;Def Serv Med Acad, Yangon, Myanmar.
    White, Nicholas J.
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Woodrow, Charles
    Mahidol Univ, Fac Trop Med, Mahidol Oxford Res Unit, Bangkok, Thailand;Univ Oxford, Nuffield Dept Clin Med, Ctr Trop Med, Oxford, England.
    Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments: a WWARN individual patient data meta-analysis2019In: BMC Medicine, E-ISSN 1741-7015, Vol. 17, p. 1-20, article id 1Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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  • 28.
    Amer, Fatma
    et al.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Li, Ruiyun
    Univ Oslo, Dept Biosci, Ctr Ecol & Evolutionary Synth CEES, N-0316 Oslo, Norway..
    Rabie, Neveen
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    El-Husseiny, Mohamed H.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Yehia, Nahed
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Hagag, Naglaa M.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Samy, Mohamed
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Selim, Abdullah
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Hassan, Mohamed K.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Hassan, Wafaa M. M.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Arafa, Abdel-Sattar
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Shahein, Momtaz A.
    Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Naguib, Mahmoud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Agr Res Ctr, Anim Hlth Res Inst, Reference Lab Vet Qual Control Poultry Prod, Giza 12618, Egypt..
    Temporal Dynamics of Influenza A(H5N1) Subtype before and after the Emergence of H5N82021In: Viruses, E-ISSN 1999-4915, Vol. 13, no 8, article id 1565Article in journal (Refereed)
    Abstract [en]

    Highly pathogenic avian influenza (HPAI) viruses continue to circulate worldwide, causing numerous outbreaks among bird species and severe public health concerns. H5N1 and H5N8 are the two most fundamental HPAI subtypes detected in birds in the last two decades. The two viruses may compete with each other while sharing the same host population and, thus, suppress the spread of one of the viruses. In this study, we performed a statistical analysis to investigate the temporal correlation of the HPAI H5N1 and HPAI H5N8 subtypes using globally reported data in 2015-2020. This was joined with an in-depth analysis using data generated via our national surveillance program in Egypt. A total of 6412 outbreaks were reported worldwide during this period, with 39% (2529) as H5N1 and 61% (3883) as H5N8. In Egypt, 65% of positive cases were found in backyards, while only 12% were found in farms and 23% in live bird markets. Overall, our findings depict a trade-off between the number of positive H5N1 and H5N8 samples around early 2017, which is suggestive of the potential replacement between the two subtypes. Further research is still required to elucidate the underpinning mechanisms of this competitive dynamic. This, in turn, will implicate the design of effective strategies for disease control.

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  • 29.
    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)
  • 30.
    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.

  • 31.
    Ancillotti, Mirko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Nilsson, Elin
    Nordvall, Anna-Carin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Oljans, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, SWEDESD - Sustainability Learning and Research Centre.
    The Status Quo Problem and the Role of Consumers Against Antimicrobial Resistance2022In: Frontiers in Sustainable Food Systems, E-ISSN 2571-581X, Vol. 6, article id 834022Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance occurs when microorganisms survive exposure and proliferate in the presence of therapeutic levels of antimicrobial drugs. Because antimicrobial resistance is increasing, it is vital to encourage consumers to change and adopt smarter antibiotic behaviour. Despite World Health Organization's efforts to combat antibiotic resistance and their emphasis on the importance of public involvement, the role of consumers has been overlooked. The manifold responsibility for antibiotic resistance extends across different actors, including food retailers and consumers. Given this shared responsibility, a blame game arises and no action occurs. To overcome this status quo situation, we draw attention to the potential role of individual responsibility and social pressure to encourage consumers to adopt smart antibiotic behaviour but also to empower them. Conditions must be put in place to enable consumers' critical evaluation of the health-related and ethical aspects of their food choices. Such behaviour can be facilitated using digital innovations to support informed choices, in store and online.

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  • 32.
    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.)

  • 33. Anderson, Ryan T
    et al.
    Choi, Hannah S J
    Lenz, Oliver
    Peters, Marion G
    Janssen, Harry L A
    Mishra, Poonam
    Donaldson, Eric
    Westman, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Buchholz, Stephanie
    Miller, Veronica
    Hansen, Bettina E
    Association Between Seroclearance of Hepatitis B Surface Antigen and Long-term Clinical Outcomes of Patients With Chronic Hepatitis B Virus Infection: Systematic Review and Meta-analysis.2021In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 19, no 3, p. 463-472, article id S1542-3565(20)30748-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Seroclearance of hepatitis B surface antigen (HBsAg) is the desired end point of treatment for chronic hepatitis B virus (HBV) infection, according to guidelines. We performed a systematic review and meta-analysis to evaluate the strength of the association between HBsAg seroclearance and long-term clinical outcomes.

    METHODS: We performed a systematic review of the PubMed, EMBASE, and Cochrane Library databases for articles that assessed HBsAg status and reported the incidence of hepatocellular carcinoma (HCC), liver decompensation, liver transplantation, and/or all-cause mortality during follow-up evaluation. We performed a meta-analysis of rate ratios (RR) using a random-effects model independently for each end point and for a composite end point.

    RESULTS: We analyzed data from 28 studies, comprising a total of 188,316 patients with chronic HBV infection (treated and untreated), and 1,486,081 person-years (PY) of follow-up evaluation; 26 reported data on HCC, 7 on liver decompensation, and 13 on liver transplantation and/or death. The composite event rates were 0.19/1000 PY for the HBsAg seroclearance group and 2.45/1000 PY for the HBsAg-persistent group. Pooled RRs for the HBsAg seroclearance group were 0.28 for liver decompensation (95% CI, 0.13-0.59; P = .001), 0.30 for HCC (95% CI, 0.20-0.44; P < .001), 0.22 for liver transplantation and/or death (95% CI, 0.13-0.39; P < .001), and 0.31 for the composite end point (95% CI, 0.23-0.43; P < .001). No differences in RR estimates were observed among subgroups of different study or patient characteristics.

    CONCLUSIONS: In a systematic review and meta-analysis, we found seroclearance of HBsAg to be associated significantly with improved patient outcomes. The results are consistent among different types of studies, in all patient subpopulations examined, and support the use of HBsAg seroclearance as a primary end point of trials of patients with chronic HBV infection.

  • 34.
    Andersson, Dan I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Balaban, Nathalie Q.
    Hebrew Univ Jerusalem, Racah Inst Phys, Edmond J Safra Campus, IL-9190401 Jerusalem, Israel.
    Baquero, Fernando
    Ramon Y Cajal Hlth Res Inst, Dept Microbiol, Ctra Colmenar Viejo Km 9, Madrid 28034, Spain.
    Courvalin, Patrice
    Inst Pasteur, French Natl Reference Ctr Antibiot, 25-28 Rue Dr Roux, F-75015 Paris, France.
    Glaser, Philippe
    Inst Pasteur, Ecol & Evolut Antibiot Resistance, 25-28 Rue Dr Roux, F-75015 Paris, France.
    Gophna, Uri
    Tel Aviv Univ, Sch Mol Cell Biol & Biotechnol, 121 Jack Green Bldg, IL-6997801 Tel Aviv, Israel.
    Kishony, Roy
    Technion, Fac Biol, IL-3200003 Haifa, Israel.
    Molin, Søren
    Tech Univ Denmark, Novo Nordisk Fdn Ctr Biosustainabil, Kemitorvet Bldg 220, DK-2800 Lyngby, Denmark.
    Tønjum, Tone
    Univ Oslo, Dept Microbiol, OUS HF Rikshosp, Postboks 4950, N-0424 Oslo, Norway; Oslo Univ Hosp, POB 4950, N-0424 Oslo, Norway.
    Antibiotic resistance: turning evolutionary principles into clinical reality2020In: FEMS Microbiology Reviews, ISSN 0168-6445, E-ISSN 1574-6976, Vol. 44, no 2, p. 171-188Article, review/survey (Refereed)
    Abstract [en]

    Antibiotic resistance is one of the major challenges facing modern medicine worldwide. The past few decades have witnessed rapid progress in our understanding of the multiple factors that affect the emergence and spread of antibiotic resistance at the population level and the level of the individual patient. However, the process of translating this progress into health policy and clinical practice has been slow. Here, we attempt to consolidate current knowledge about the evolution and ecology of antibiotic resistance into a roadmap for future research as well as clinical and environmental control of antibiotic resistance. At the population level, we examine emergence, transmission and dissemination of antibiotic resistance, and at the patient level, we examine adaptation involving bacterial physiology and host resilience. Finally, we describe new approaches and technologies for improving diagnosis and treatment and minimizing the spread of resistance.

  • 35.
    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, 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.

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  • 36.
    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), International Child Health and Nutrition.
    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.

  • 37.
    Andersson, Maria
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Wu, Jinghua
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Wullimann, David
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Gao, Yu
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Muschiol, Sandra
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Healy, Katie
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden..
    Naud, Sabrina
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden..
    Bogdanovic, Gordana
    Karolinska Univ Hosp, Dept Clin Microbiol, Stockholm, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden..
    Palma, Marzia
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Mellstedt, Hakan
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Chen, Puran
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Ljunggren, Hans-Gustaf
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Hansson, Lotta
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Sallberg Chen, Margaret
    Karolinska Inst, Dept Dent Med, Huddinge, Sweden..
    Buggert, Marcus
    Karolinska Inst, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden..
    Ingelman-Sundberg, Hanna M.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Oncol, Stockholm, Sweden.;Karolinska Univ, Hosp Solna, Dept Oncol, SE-17176 Stockholm, Sweden..
    Osterborg, Anders
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Dept Hematol, Stockholm, Sweden..
    Local and Systemic Immunity During Five Vaccinations Against SARS-CoV-2 in Zanubrutinib-Treated Patients With Chronic Lymphocytic Leukemia2023In: Journal of Hematology, ISSN 1927-1212, Vol. 12, no 4, p. 170-175Article in journal (Refereed)
    Abstract [en]

    Background: Patients with chronic lymphocytic leukemia (CLL) are vulnerable to coronavirus disease 2019 (COVID-19) and are at risk of inferior response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, especially if treated with the first-generation Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib. We aimed to evaluate the impact of the third-generation BTKi, zanubrutinib, on systemic and mucosal response to SARS-CoV-2 vaccination.

    Methods: Nine patients with CLL with ongoing zanubrutinib therapy were included and donated blood and saliva during SARS-CoV-2 vaccination, before vaccine doses 3 and 5 and 2 - 3 weeks after doses 3, 4, and 5. Ibrutinib-treated control patients (n = 7) and healthy aged-matched controls (n = 7) gave blood 2 - 3 weeks after vaccine dose 5. We quantified reactivity and neutralization capacity of SARS-CoV-2-specific IgG and IgA antibodies (Abs) in both serum and saliva, and reactivity of T cells activated with viral peptides.

    Results: Both zanubrutinib- and ibrutinib-treated patients had significantly, up to 1,000-fold, lower total spike-specific Ab levels after dose 5 compared to healthy controls (P < 0.01). Spike-IgG levels in serum from zanubrutinib-treated patients correlated well to neutralization capacity (r = 0.68; P < 0.0001) and were thus functional. Mucosal immunity (specific IgA in serum and saliva) was practically absent in zanubrutinib-treated patients even after five vaccine doses, whereas healthy controls had significantly higher levels (tested in serum after vaccine dose 5) (P < 0.05). In contrast, T-cell reactivity against SARS-CoV-2 peptides was equally high in zanubrutinib- and ibrutinib-treated patients as in healthy control donors.

    Conclusions: In our small cohort of zanubrutinib-treated CLL patients, we conclude that up to five doses of SARS-CoV-2 vaccination induced no detectable IgA mucosal immunity, which likely will impair the primary barrier defence against the infection. Systemic IgG responses were also impaired, whereas T-cell responses were normal. Further and larger studies are needed to evaluate the impact of these findings on disease protection.

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  • 38.
    Angelin, Martin
    et al.
    Umeå Univ, Dept Clin Microbiol, Infect Dis, Umeå, Sweden..
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Kahn, Fredrik
    Lund Univ, Dept Clin Sci, Div Infect Med, Lund, Sweden..
    Ljunghill Hedberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Rosdahl, Anja
    Örebro Univ, Sch Med Sci, Örebro, Sweden.;Örebro Univ Hosp, Dept Infect Dis, Örebro, Sweden..
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Werner, Simon
    Reg Skane, Skane Univ Hosp, Dept Infect Dis, Malmö, Sweden..
    Woxenius, Susanne
    Sahlgrens Univ Hosp, Dept Infect Dis, Gothenburg, Sweden..
    Askling, Helena H.
    Karolinska Inst, Dept Med, Div Infect Dis, Solna, Sweden.;Reg Stockholm, Stockholm Cty Hlth Care Serv, Acad Specialist Ctr, Stockholm, Sweden..
    Qdenga®- A promising dengue fever vaccine; can it be recommended to non-immune travelers?2023In: Travel Medicine and Infectious Disease, ISSN 1477-8939, E-ISSN 1873-0442, Vol. 54, article id 102598Article in journal (Refereed)
    Abstract [en]

    Qdenga®; has been approved by the European Medicines Agency (EMA) for individuals > 4 years of age and for use according to national recommendations. The vaccine shows high efficacy against virologically confirmed dengue and severe dengue in clinical studies on 4-16-year old's living in endemic areas. For individuals 16-60 years old only serological data exists and there is no data for individuals > 60 years. Its use as a travel vaccine is still unclear. We present the studies behind the approval and the recommendations for travelers as issued by the Swedish Society for Infectious Diseases Physicians.

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  • 39.
    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.

  • 40.
    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.

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  • 41.
    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.

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  • 42.
    Appelgren, Daniel
    et al.
    Linkoping Univ, Div Drug Res, Dept Med & Hlth Sci, SE-58185 Linkoping, Sweden.
    Enocsson, Helena
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, SE-58185 Linkoping, Sweden.
    Skogman, Barbro H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. Orebro Univ, Fac Med & Hlth Sci, SE-70281 Orebro, Sweden.
    Nordberg, Marika
    Aland Cent Hosp, Dept Infect Dis, AX-22100 Mariehamn, Aland, Finland.
    Perander, Linda
    Aland Cent Hosp, Dept Infect Dis, AX-22100 Mariehamn, Aland, Finland.
    Nyman, Dag
    Bimelix AB, AX-22100 Mariehamn, Aland, Finland.
    Nyberg, Clara
    Aland Cent Hosp, Dept Infect Dis, AX-22100 Mariehamn, Aland, Finland.
    Knopf, Jasmin
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Internal Med Rheumatol & Immunol 3, Univ Klinikum Erlangen, DE-91054 Erlangen, Germany.
    Munoz, Luis E.
    Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Internal Med Rheumatol & Immunol 3, Univ Klinikum Erlangen, DE-91054 Erlangen, Germany.
    Sjöwall, Christopher
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, SE-58185 Linkoping, Sweden.
    Sjöwall, Johanna
    Linkoping Univ Hosp, Clin Infect Dis, SE-58185 Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, SE-58185 Linkoping, Sweden.
    Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 1, article id 43Article in journal (Refereed)
    Abstract [en]

    Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (r(s) = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.

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  • 43.
    Aranzana-Climent, Vincent
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cao, Sha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Tomczak, Magdalena
    Natl Med Inst, Dept Epidemiol & Clin Microbiol, Warsaw, Poland..
    Urbas, Malgorzata
    Natl Med Inst, Dept Epidemiol & Clin Microbiol, Warsaw, Poland..
    Zabicka, Dorota
    Natl Med Inst, Dept Epidemiol & Clin Microbiol, Warsaw, Poland..
    Lundberg, Carina Vingsbo
    Statens Serum Inst, Bacteria Parasites & Fungi, Copenhagen, Denmark..
    Hansen, Jon
    Statens Serum Inst, Bacteria Parasites & Fungi, Copenhagen, Denmark..
    Lindberg, Johan
    RISE Res Inst Sweden, Södertälje, Sweden..
    Hobbie, Sven N.
    Univ Zurich, Inst Med Microbiol, Zurich, Switzerland..
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia2022In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 28, no 10, p. 1367-1374Article in journal (Refereed)
    Abstract [en]

    Objectives: New drugs and methods to efficiently fight carbapenem-resistant gram-negative pathogens are sorely needed. In this study, we characterized the preclinical pharmacokinetics (PK) and pharmacodynamics of the clinical stage drug candidate apramycin in time kill and mouse lung infection models. Based on in vitro and in vivo data, we developed a mathematical model to predict human efficacy.

    Methods: Three pneumonia-inducing gram-negative species Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied. Bactericidal kinetics were evaluated with time-kill curves; in vivo PK were studied in healthy and infected mice, with sampling in plasma and epithelial lining fluid after subcutaneous administration; in vivo efficacy was measured in a neutropenic mouse pneumonia model. A pharmacokinetic-pharmacodynamic model, integrating all the data, was developed and simulations were performed.

    Results: Good lung penetration of apramycin in epithelial lining fluid (ELF) was shown (area under the curve (AUC)(ELF)/ALI(Cplasma) = 88%). Plasma clearance was 48% lower in lung infected mice compared to healthy mice. For two out of five strains studied, a delay in growth (similar to 5 h) was observed in vivo but not in vitro. The mathematical model enabled integration of lung PK to drive mouse PK and pharmacodynamics. Simulations predicted that 30 mg/kg of apramycin once daily would result in bacteriostasis in patients.

    Discussion: Apramycin is a candidate for treatment of carbapenem-resistant gram-negative pneumonia as demonstrated in an integrated modeling framework for three bacterial species. We show that mathematical modelling is a useful tool for simultaneous inclusion of multiple data sources, notably plasma and lung in vivo PK and simulation of expected scenarios in a clinical setting, notably lung infections.

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  • 44.
    Arnason, Sigurdur
    et al.
    Dept Clin Sci Intervent & Technol CLINTEC, Alfred Nobels 8, S-14152 Huddinge, Sweden.;Astrid Lindgrens Childrens Hosp, Dept Pediat Infect Dis, Karolinska Vagen 22, S-17164 Stockholm, Sweden..
    Hedin Skogman, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Alfred Nobels Alle 8, S-14152 Huddinge, Sweden.;Örebro Univ, Dept Med Sci, Sodra Grev Rosengatan 42 B, S-70362 Örebro, Sweden..
    Effectiveness of antibiotic treatment in children with Lyme neuroborreliosis-a retrospective study2022In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 22, article id 332Article in journal (Refereed)
    Abstract [en]

    Background: Lyme neuroborreliosis (LNB) is a tick-borne infection caused by the spirochete Borrelia burgdorferi sensu lato complex with various neurological manifestations. The recommended treatment for LNB in Swedish children has been intravenous ceftriaxone 50-100 mg/kg x 1 (< 8 years of age) or oral doxycycline 4 mg/kg x 1 (>= 8 years of age) for 10-14 days. Studies on adult LNB patients have shown equal efficacy for ceftriaxone and doxycycline, but no such studies have been conducted on pediatric LNB patients. The aim of this study is to retrospectively evaluate clinical outcome in children with LNB who have received intravenous ceftriaxone or oral doxycycline.

    Results: Clinical and laboratory data from three previously conducted prospective studies on children with LNB (1998-2014) were retrospectively analyzed. A total of 321 children (1-19 years of age), who received antibiotic treatment for definite LNB or possible LNB, were included. Clinical outcome at the 2-month follow-up (recovery/non-recovery) was evaluated using Chi(2) test and logistic multivariate regression analysis. Out of 321 LNB patients, 194 children (60%) had received ceftriaxone and 127 children (40%) had received doxycycline. When comparing clinical outcome between treatment groups, no difference was found (p = 0,217). Results did not change when incorporating relevant clinical and laboratory data into the logistic multivariate regression analysis.

    Conclusion: In this large retrospective study, no difference in clinical outcome was found, independent of age, when comparing children who received ceftriaxone with those who received doxycycline, supporting an equal effectiveness for treatment of LNB pediatric patients. However, future randomized comparative treatment studies are warranted for evaluation of efficacy of antibiotic treatment in pediatric LNB patients.

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  • 45.
    Arnason, Sigurdur
    et al.
    Dept Clin Sci Intervent & Technol CLINTEC, Alfred Nobels Alle 8, S-14152 Stockholm, Sweden.;Astrid Lindgrens Childrens Hosp, Dept Pediat Infect Dis, Eugeniavagen 23, S-17164 Stockholm, Sweden.
    Molewijk, Kesia
    Örebro Univ, Fac Hlth & Med Sci, Sodra Grev Rosengatan 42 B, S-70362 Örebro, Sweden.
    Henningsson, Anna J.
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden.;Linköping Univ, Div Clin Microbiol, Natl Reference Lab Borrelia & Other Tick Borne Ba, Lab Med,Reg Jönköping Cty, Linköping, Sweden.;Linköping Univ, Dept Clin Microbiol Linköping, Linköping, Sweden.
    Tjernberg, Ivar
    Linköping Univ, Dept Biomed & Clin Sci, Div Inflammat & Infect, Linköping, Sweden.;Reg Kalmar Cty, Dept Clin Chem & Transfus Med, Kalmar, Sweden.
    Hedin Skogman, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Örebro Univ, Fac Hlth & Med Sci, Sodra Grev Rosengatan 42 B, S-70362 Örebro, Sweden.;Karolinska Inst, Intervent & Technol CLINTEC, Dept Clin Sci, Alfred Nobels Alle 8, S-14152 Stockholm, Sweden.
    Brain damage markers neuron-specific enolase (NSE) and S100B in serum in children with Lyme neuroborreliosis-detection and evaluation as prognostic biomarkers for clinical outcome2022In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 41, no 7, p. 1051-1057Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis (LB) is the most common tick-borne infection in Europe, with Lyme neuroborreliosis (LNB) its second most frequent clinical manifestation. Prognostic factors for clinical outcomes in LNB have not been identified. Elevated serum levels of the brain damage markers neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) have been associated with poor clinical outcomes in other disorders of the central nervous system. The aim of this study is to assess NSE and S100B in serum as prognostic biomarkers for clinical outcomes in paediatric LNB patients. Children evaluated for LNB (n= 121) in Sweden were prospectively included during 2010-2014, serum samples were collected on admission, and all children underwent a 2-month follow-up. Patients with pleocytosis and anti-Borrelia antibodies in cerebrospinal fluid (CSF) were classified as having LNB (n= 61). Controls were age- and gender-matched non-LNB patients (n= 60). NSE was elevated in 38/61 (62%) LNB patients and in 31/60 (52%) controls. S100B was elevated in 3/60 (5%) LNB patients and 0/59 (0%) controls. NSE and S100B concentrations did not differ significantly when comparing LNB patients with controls. No differences were found in the concentrations when comparing the clinical recovery of LNB patients at the 2-month follow-up. NSE was detectable in the majority of LNB patients and controls, whereas S100B was detectable in only a few LNB patients and no controls. NSE and S100B in serum cannot be recommended as prognostic biomarkers for clinical outcomes in children with LNB.

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  • 46.
    Arrazuria, Rakel
    et al.
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany..
    Kerscher, Bernhard
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany..
    Huber, Karen E.
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany..
    Hoover, Jennifer L.
    Infect Dis Res Unit, GlaxoSmithKline Pharmaceut, Collegeville, PA, United States..
    Lundberg, Carina Vingsbo
    Statens Serum Inst, Dept Bacteria, Parasites Fungi, Copenhagen, Denmark..
    Hansen, Jon Ulf
    Statens Serum Inst, Dept Bacteria, Parasites Fungi, Copenhagen, Denmark..
    Sordello, Sylvie
    Infect Dis, Evotec, Toulouse, France..
    Renard, Stephane
    Infect Dis, Evotec, Toulouse, France..
    Aranzana-Climent, Vincent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gribbon, Philip
    Fraunhofer Inst Translat Med & Pharmacol ITMP, Discovery Res ScreeningPort, Hamburg, Germany..
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bekeredjian-Ding, Isabelle
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany.;Univ Hosp Bonn, Inst Med Microbiol, Immunol & Parasitol, Bonn, Germany..
    Expert workshop summary: Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections2022In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 13, article id 988725Article in journal (Refereed)
    Abstract [en]

    The rise in antimicrobial resistance (AMR), and increase in treatment-refractory AMR infections, generates an urgent need to accelerate the discovery and development of novel anti-infectives. Preclinical animal models play a crucial role in assessing the efficacy of novel drugs, informing human dosing regimens and progressing drug candidates into the clinic. The Innovative Medicines Initiative-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium is establishing a validated and globally harmonized preclinical model to increase reproducibility and more reliably translate results from animals to humans. Toward this goal, in April 2021, COMBINE organized the expert workshop "Advancing toward a standardized murine model to evaluate treatments for AMR lung infections". This workshop explored the conduct and interpretation of mouse infection models, with presentations on PK/PD and efficacy studies of small molecule antibiotics, combination treatments (beta -lactam/beta -lactamase inhibitor), bacteriophage therapy, monoclonal antibodies and iron sequestering molecules, with a focus on the major Gram-negative AMR respiratory pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Here we summarize the factors of variability that we identified in murine lung infection models used for antimicrobial efficacy testing, as well as the workshop presentations, panel discussions and the survey results for the harmonization of key experimental parameters. The resulting recommendations for standard design parameters are presented in this document and will provide the basis for the development of a harmonized and bench-marked efficacy studies in preclinical murine pneumonia model.

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  • 47.
    Arrazuria, Rakel
    et al.
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany..
    Kerscher, Bernhard
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany..
    Huber, Karen E.
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany..
    Hoover, Jennifer L.
    Infect Dis Res Unit, GlaxoSmithKline Pharmaceut, Collegeville, PA, United States..
    Lundberg, Carina Vingsbo
    Statens Serum Inst, Dept Bacteria, Parasites Fungi, Copenhagen, Denmark..
    Hansen, Jon Ulf
    Statens Serum Inst, Dept Bacteria, Parasites Fungi, Copenhagen, Denmark..
    Sordello, Sylvie
    Infect Dis, Evotec, Toulouse, France..
    Renard, Stephane
    Infect Dis, Evotec, Toulouse, France..
    Aranzana-Climent, Vincent
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gribbon, Philip
    Fraunhofer Inst Translat Med & Pharmacol ITMP, Discovery Res ScreeningPort, Hamburg, Germany..
    Friberg, Lena E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bekeredjian-Ding, Isabelle
    Div Microbiol, Paul Ehrlich Inst, Langen, Germany.;Univ Hosp Bonn, Inst Med Microbiol, Immunol & Parasitol, Bonn, Germany..
    Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents2022In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 13, article id 988728Article, review/survey (Refereed)
    Abstract [en]

    Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.

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  • 48. 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)
  • 49.
    Asif, Sana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Kristensen, Bjarne
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation, Metabolism and Child Health Research.
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Weak anti-SARS-CoV-2 antibody response is associated with mortality in a Swedish cohort of COVID-19 patients in critical care2020In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 24, no 1, article id 639Article in journal (Refereed)
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  • 50.
    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.

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