Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Planned maintenance
A system upgrade is planned for 10/12-2024, at 12:00-13:00. During this time DiVA will be unavailable.
Change search
Refine search result
123456 1 - 50 of 294
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Agnarson, Abela Mpobela
    et al.
    Strömdahl, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Levira, Francis
    Masanja, Honorati
    Thorson, Anna Ekéus
    Female-Driven Multiple Concurrent Sexual Partnership Systems in a Rural Part of a Southern Tanzanian Province.2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 12, p. e0145297-, article id e0145297Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Multiple concurrent sexual relationships are one of the major challenges to HIV prevention in Tanzania. This study aims to explore sexual behaviour patterns including the practice of multiple concurrent sexual partnerships in a rural Tanzanian setting.

    METHODS: This qualitative study used focus group discussions and in-depth interviews with men and women from the community as well as ethnographic participant observations. The data was collected during 16 months of fieldwork in 2007, 2008, and 2009. The focus group discussions and in-depth interviews were transcribed verbatim and translated into English. The data was analysed through the process of latent content analysis. An open coding coding process was applied to create categories and assign themes.

    FINDINGS: Mafiga matatu was an expression used in this society to describe women's multiple concurrent sexual partners, usually three partners, which was described as a way to ensure social and financial security for their families as well as to achieve sexual pleasure. Adolescent initiation ceremonies initiated and conducted by grand mothers taught young women why and how to engage successfully in multiple concurrent sexual relationships. Some men expressed support for their female partners to behave according to mafiga matatu, while other men were hesitant around this behaviour. Our findings indicate that having multiple concurrent sexual partners is common and a normative behaviour in this setting. Economical factors and sexual pleasure were identified as drivers and viewed as legitimate reason for women to have multiple concurrent sexual partnerships.

    CONCLUSIONS: Structural changes improving women's financial opportunities and increasing gender equality will be important to enable women to not depend on multiple concurrent sexual partnerships for financial security. Future research should explore how normative sexual behaviour changes as these structural changes take place.

  • 2.
    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.

  • 3.
    Akaberi, Dario
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology, Infection and Immunity.
    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, Infection and Immunity.
    Berger, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Neilsen, Grace
    Strandback, Emilia
    Turunen, S. Pauliina
    Science for Life Laboratory, Human Antibody Therapeutics, Drug Discovery and Development Platform, Solna, Sweden.
    Wannberg, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    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..
    Sarafianos, Stefan G.
    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, Infection and Immunity.
    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 novel and potent inhibitors of SARS-CoV-2 main protease from DNA-encoded chemical libraries2024In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 68, no 10, p. 1-18Article in journal (Refereed)
    Abstract [en]

    In vitro screening of large compound libraries with automated high-throughput screening is expensive and time-consuming and requires dedicated infrastructures. Conversely, the selection of DNA-encoded chemical libraries (DECLs) can be rapidly performed with routine equipment available in most laboratories. In this study, we identified novel inhibitors of SARS-CoV-2 main protease (Mpro) through the affinity-based selection of the DELopen library (open access for academics), containing 4.2 billion compounds. The identified inhibitors were peptide-like compounds containing an N-terminal electrophilic group able to form a covalent bond with the nucleophilic Cys145 of Mpro, as confirmed by x-ray crystallography. This DECL selection campaign enabled the discovery of the unoptimized compound SLL11 (IC50 = 30 nM), proving that the rapid exploration of large chemical spaces enabled by DECL technology allows for the direct identification of potent inhibitors avoiding several rounds of iterative medicinal chemistry. As demonstrated further by x-ray crystallography, SLL11 was found to adopt a highly unique U-shaped binding conformation, which allows the N-terminal electrophilic group to loop back to the S1′ subsite while the C-terminal amino acid sits in the S1 subsite. MP1, a close analog of SLL11, showed antiviral activity against SARS-CoV-2 in the low micromolar range when tested in Caco-2 and Calu-3 (EC50 = 2.3 µM) cell lines. As peptide-like compounds can suffer from low cell permeability and metabolic stability, the cyclization of the compounds will be explored in the future to improve their antiviral activity.

    Download full text (pdf)
    fulltext
  • 4.
    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.

    Download full text (pdf)
    FULLTEXT01
  • 5.
    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
    Show others...
    2022 (English)In: Antibiotics, 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: 2024-07-04Bibliographically 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
    Show others...
    (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
    Download full text (pdf)
    UUThesis_L-Allander-2023
    Download (jpg)
    preview image
  • 6.
    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, 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.

    Download full text (pdf)
    FULLTEXT01
  • 7.
    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.

    Download full text (pdf)
    FULLTEXT01
  • 8.
    Allwell-Brown, Gbemisola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Namugambe, Juliet
    Ssanyu, Jacquellyn
    White Johansson, Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Child Health and Nutrition.
    Hussain-Alkhateeb, Laith
    Strömdahl, Susanne
    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 Sciences, Infectious Diseases.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research Sörmland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Child Health and Nutrition.
    Kitutu, Freddy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Child Health and Nutrition.
    Patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients at primary and secondary healthcare facilities in Bugisu, Eastern Uganda2022In: JAC-Antimicrobial Resistance, Vol. 4, no 5Article in journal (Refereed)
    Abstract [en]

    Objectives: To describe patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients at primary and secondary healthcare facilities across Bugisu, Eastern Uganda.

    Methods: We surveyed 37 public and private-not-for-profit healthcare facilities and conducted a retrospective review of antimicrobial prescribing patterns among febrile under-five outpatients (with a focus on antibiotics) in 2019–20, based on outpatient registers. Multilevel logistic regression analysis was used to identify determinants of antibiotic prescribing at patient- and healthcare facility-levels.

    Results: Antibiotics were prescribed for 62.2% of 3471 febrile under-five outpatients. There were a total of 2478 antibiotic prescriptions of 22 antibiotic types: amoxicillin (52.2%), co-trimoxazole (14.7%), metronidazole (6.9%), gentamicin (5.7%), ceftriaxone (5.3%), ampicillin/cloxacillin (3.6%), penicillin (3.1%), and others (8.6%). Acute upper respiratory tract infection (AURTI) was the commonest single indication for antibiotic prescribing, with 76.3% of children having AURTI as their only documented diagnosis receiving antibiotic prescriptions. Only 9.2% of children aged 2–59 months with non-severe pneumonia received antibiotic prescriptions in line with national guidelines. Higher health centre levels, and private-not-for-profit ownership (adjusted OR, 4.30; 95% CI, 1.91–9.72) were significant contextual determinants of antibiotic prescribing.

    Conclusions: We demonstrated a high antibiotic prescribing prevalence among febrile under-five outpatients in Bugisu, Eastern Uganda, including prescriptions for co-trimoxazole and ampicillin/cloxacillin (which are not indicated in the management of the common causes of under-five febrile illness in Uganda). Study findings may be linked to limited diagnostic capacity and inadequate antibiotic availability, which require prioritization in interventions aimed at improving rational antibiotic prescribing among febrile under-five outpatients.

    Download full text (pdf)
    fulltext
  • 9.
    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.

  • 10.
    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.

    Download full text (pdf)
    FULLTEXT01
  • 11.
    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.

    Download full text (pdf)
    fulltext
  • 12.
    Antoni, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lindström, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Elgland, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Hultström, Michael
    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.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sigfridsson, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lipcsey, Miklos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    In Vivo Visualization and Quantification of Neutrophil Elastase in Lungs of COVID-19 Patients: A First-in-Humans PET Study with 11C-NES2023In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 64, no 1, p. 145-148Article in journal (Refereed)
    Abstract [en]

    COVID-19 can cause life-threatening lung-inflammation that is suggested to be mediated by neutrophils, whose effector mechanisms in COVID-19 is inexplicit. The aim of the present work is to evaluate a novel PET tracer for neutrophil elastase in COVID-19 patients and healthy controls.

    METHODS: In this open-label, First-In-Man study, four patients with hypoxia due to COVID-19 and two healthy controls were investigated with positron emission tomography (PET) using the new selective and specific neutrophil elastase PET-tracer [11C]GW457427 and [15O]water for the visualization and quantification of NE and perfusion in the lungs, respectively.

    RESULTS: [11C]GW457427 accumulated selectively in lung areas with ground-glass opacities on computed tomography characteristic of COVID-19 suggesting high levels on NE in these areas. In the same areas perfusion was severely reduced in comparison to healthy lung tissue as measured with [15O]water.

    CONCLUSION: The data suggests that NE may be responsible for the severe lung inflammation in COVID-19 patients and that inhibition of NE could potentially reduce the acute inflammatory process and improve the condition.

    Download full text (pdf)
    fulltext
  • 13.
    Assadian, Farzaneh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandström, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Bondeson, Kåre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lidian, Adnan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Distribution and Molecular Characterization of Human Adenovirus and Epstein-Barr Virus Infections in Tonsillar Lymphocytes Isolated from Patients Diagnosed with Tonsillar Diseases2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 5, article id e0154814Article in journal (Refereed)
    Abstract [en]

    Surgically removed palatine tonsils provide a conveniently accessible source of T and B lymphocytes to study the interplay between foreign pathogens and the host immune system. In this study we have characterised the distribution of human adenovirus (HAdV), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) in purified tonsillar T and B cell-enriched fractions isolated from three patient age groups diagnosed with tonsillar hypertrophy and chronic/recurrent tonsillitis. HAdV DNA was detected in 93 out of 111 patients (84%), while EBV DNA was detected in 58 patients (52%). The most abundant adenovirus type was HAdV-5 (68%). None of the patients were positive for HCMV. Furthermore, 43 patients (39%) showed a co-infection of HAdV and EBV. The majority of young patients diagnosed with tonsillar hypertrophy were positive for HAdV, whereas all adult patients diagnosed with chronic/recurrent tonsillitis were positive for either HAdV or EBV. Most of the tonsils from patients diagnosed with either tonsillar hypertrophy or chronic/recurrent tonsillitis showed a higher HAdV DNA copy number in T compared to B cell-enriched fraction. Interestingly, in the majority of the tonsils from patients with chronic/recurrent tonsillitis HAdV DNA was detected in T cells only, whereas hypertrophic tonsils demonstrated HAdV DNA in both T and B cell-enriched fractions. In contrast, the majority of EBV positive tonsils revealed a preference for EBV DNA accumulation in the B cell-enriched fraction compared to T cell fraction irrespective of the patients' age.

    Download full text (pdf)
    fulltext
  • 14.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Mourkas, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England.
    Meric, Guillaume
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England.
    Pascoe, Ben
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England;MRC CLIMB Consortium, Bath, Avon, England.
    Wang, Helen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.
    Sheppard, Samuel K.
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England;MRC CLIMB Consortium, Bath, Avon, England.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    The Potential of Isolation Source to Predict Colonization in Avian Hosts: A Case Study in Campylobacter jejuni Strains From Three Bird Species2018In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 9, article id 591Article in journal (Refereed)
    Abstract [en]

    Campylobacter jejuni is the primary cause of bacterial gastroenteritis worldwide, infecting humans mostly through consumption of contaminated poultry. C. jejuni is common in the gut of wild birds, and shows distinct strain-specific association to particular bird species. This contrasts with farm animals, in which several genotypes co-exist. It is unclear if the barriers restricting transmission between host species of such specialist strains are related to environmental factors such as contact between host species, bacterial survival in the environment, etc., or rather to strain specific adaptation to the intestinal environment of specific hosts. We compared colonization dynamics in vivo between two host-specific C. jejuni from a song thrush (ST-1304 complex) and a mallard (ST-995), and a generalist strain from chicken (ST-21 complex) in a wild host, the mallard (Anas platyrhynchos). In 18-days infection experiments, the song thrush strain showed only weak colonization and was cleared from all birds after 10 days, whereas both mallard and chicken strains remained stable. When the chicken strain was given 4 days prior to co-infection of the same birds with a mallard strain, it was rapidly outcompeted by the latter. In contrast, when the mallard strain was given 4 days prior to co-infection with the chicken strain, the mallard strain remained and expansion of the chicken strain was delayed. Our results suggest strain-specific differences in the ability of C. jejuni to colonize mallards, likely associated with host origin. This difference might explain observed host association patterns in C. jejuni from wild birds.

  • 15.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Nykvist, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Natl Vet Inst, Uppsala, Sweden..
    Lustig, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I.
    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, Infection medicine.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Selection of Resistant Bacteria in Mallards Exposed to Subinhibitory Concentrations of Ciprofloxacin in Their Water Environment2021In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 65, no 3, article id e01858-20Article in journal (Refereed)
    Abstract [en]

    Emergence and selection of antibiotic resistance following exposure to high antibiotic concentrations have been repeatedly shown in clinical and agricultural settings, whereas the role of the weak selective pressures exerted by antibiotic levels below the MIC (sub-MIC) in aquatic environments due to anthropogenic contamination remains unclear. Here, we studied how exposure to sub-MIC levels of ciprofloxacin enriches for Escherichia coli with reduced susceptibility to ciprofloxacin using a mallard colonization model. Mallards were inoculated with two isogenic extended-spectrum-beta-lactamase (ESBL)-encoding E. coli strains, differing only by a gyrA mutation that results in increased MICs of ciprofloxacin, and exposed to different levels of ciprofloxacin in their swimming water. Changes in the ratios of mutant to parental strains excreted in feces over time and ESBL plasmid spread within the gut microbiota from individual birds were investigated. Results show that in vivo selection of gyrA mutants occurred in mallards during exposure to ciprofloxacin at concentrations previously found in aquatic environments. During colonization, resistance plasmids were readily transferred between strains in the intestines of the mallards, but conjugation frequencies were not affected by ciprofloxacin exposure. Our results highlight the potential for enrichment of resistant bacteria in wildlife and underline the importance of reducing antibiotic pollution in the environment.

  • 16.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Osbjer, Kristina
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Div Reprod, Uppsala, Sweden; Food & Agr Org United Nations, Phnom Penh, Cambodia.
    Tepper, Viktoria
    Swiss Fed Inst Technol, Inst Environm Engn, Zurich, Switzerland.
    Rajala, Elisabeth
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Div Reprod, Uppsala, Sweden.
    Hernandez, Jorge
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden; Linköping Univ, Kalmar Cty Council, Dept Infect Dis, Dept Clin & Expt Med, Linköping, Sweden; Kalmar Cty Hosp, Diagnost Ctr, Clin Microbiol Lab, Kalmar, Sweden.
    Seng, Sokerya
    Food & Agr Org United Nations, Phnom Penh, Cambodia.
    Holl, Davun
    Minist Agr Forestry & Fisheries, Gen Directorate Anim Hlth & Prod, Phnom Penh, Cambodia.
    Bonnedahl, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden; Linköping Univ, Kalmar Cty Council, Dept Infect Dis, Dept Clin & Expt Med, Linköping, Sweden.
    Börjesson, Stefan
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden; Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.
    Magnusson, Ulf
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Div Reprod, Uppsala, Sweden.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Carriage of carbapenemase- and extended-spectrum cephalosporinase-producing Escherichia coli and Klebsiella pneumoniae in humans and livestock in rural Cambodia: gender and age differences and detection of blaOXA-48 in humans2019In: Zoonoses and Public Health, ISSN 1863-1959, E-ISSN 1863-2378, Vol. 66, no 6, p. 603-617Article in journal (Refereed)
    Abstract [en]

    Objectives: This study investigates the frequency and characteristics of carbapenemase‐producing Escherichia coli/Klebsiella pneumoniae (CPE/K) and extended‐spectrum cephalosporinase‐producing E. coli/K. pneumoniae (ESCE/K) in healthy humans and livestock in rural Cambodia. Additionally, household practices as risk factors for faecal carriage of ESCE/K are identified.

    Methods: Faecal samples were obtained from 307 humans and 285 livestock including large ruminants, pigs and poultry living in 100 households in rural Cambodia in 2011. Each household was interviewed, and multilevel logistic model determined associations between household practices/meat consumption and faecal carriage of ESCE/K. CPE and ESCE/K were detected and further screened for colistin resistance genes.

    Results: CPE/K isolates harbouring blaOXA‐48 were identified in two humans. The community carriage of ESCE/K was 20% in humans and 23% in livestock. The same ESBL genes: blaCTX‐M‐15, blaCTX‐M‐14, blaCTX‐M‐27, blaCTX‐M‐55, blaSHV‐2, blaSHV‐12, blaSHV‐28; AmpC genes: blaCMY‐2, blaCMY‐42, blaDHA‐1; and colistin resistance genes: mcr‐1‐like and mcr‐3‐like were detected in humans and livestock. ESCE/K was frequently detected in women, young children, pigs and poultry, which are groups in close contact. The practice of burning or burying meat waste and not collecting animal manure indoors and outdoors daily were identified as risk factors for faecal carriage of ESCE/K.

    Conclusions: Faecal carriage of E. coli and K. pneumoniae harbouring extended‐spectrum cephalosporinase genes are common in the Cambodian community, especially in women and young children. Exposure to animal manure and slaughter products are risk factors for intestinal colonization of ESCE/K in humans.

     

    Download full text (pdf)
    fulltext
  • 17.
    Bacchus, Philip
    et al.
    Swedish Armed Forces Natl CBRN Def Ctr, Swedish Navy, Umeå, Sweden..
    Nissen, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Berg, Johanna
    Swedish Armed Forces Natl CBRN Def Ctr, Infect Dis, Umeå, Sweden..
    Bråve, Andreas
    Publ Hlth Agcy Sweden, Solna, Sweden..
    Gyll, Jenny
    Swedish Armed Forces Natl CBRN Def Ctr, Umeå, Sweden..
    Larsson, Christer
    Swedish Armed Forces Natl CBRN Def Ctr, Umeå, Sweden..
    Muradrasoli, Shaman
    Publ Hlth Agcy Sweden, Solna, Sweden..
    Tellström, Andreas
    Swedish Armed Forces Natl CBRN Def Ctr, Umeå, Sweden..
    Salaneck, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Swedish Armed Forces Ctr Def Med, Gothenburg, Sweden..
    Civil-military collaboration to facilitate rapid deployment of a mobile laboratory in early response to covid-19: A high-readiness exercise2021In: HEALTH SECURITY, ISSN 2326-5094, Vol. 19, no 5, p. 488-497Article in journal (Refereed)
    Abstract [en]

    Rapid and adaptable diagnostic capabilities are of great importance in the face of emerging infectious diseases. In an outbreak, timely establishment of diagnostic routines is crucial to identifying cases and preventing the spread of the disease, especially when faced with high-consequence pathogens. In this article, we describe a multiagency exercise including the rapid deployment and diagnostic adaptation of the Swedish Armed Forces mobile laboratory (biological field analysis laboratory) in the context of COVID-19. This deployment was initiated as a high-readiness exercise at the end of January 2020, when the global development of the outbreak was still uncertain. Through collaboration with the Public Health Agency of Sweden and a civilian hospital, a real-time reverse transcriptase polymerase chain reaction method specific to SARS-CoV-2 was made available and adapted to the mobile laboratory, and the team established and evaluated a functional and efficient diagnostic asset along with a logistical support chain. We also organized and evaluated mobile testing teams, and the method was later used in large-scale, national, cross-sectional COVID-19 surveys in several regions of Sweden. In this article, we focus on the challenges of overbridging the civil-military interface in this context and identifying lessons learned and added values to the response during the early pandemic. We propose that the experiences from this exercise and governmental agency collaboration are valuable in preparation for future outbreaks.

  • 18.
    Bahnasawy, Salma M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Hanslin, Katja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Hedenstierna laboratory.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Predicting cytokine kinetics during sepsis; a modelling framework from a porcine sepsis model with live Escherichia coli2023In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 169, article id 156296Article in journal (Refereed)
    Abstract [en]

    Background: Describing the kinetics of cytokines involved as biomarkers of sepsis progression could help to optimise interventions in septic patients. This work aimed to quantitively characterise the cytokine kinetics upon exposure to live E. coli by developing an in silico model, and to explore predicted cytokine kinetics at different bacterial exposure scenarios.

    Methods: Data from published in vivo studies using a porcine sepsis model were analysed. A model describing the time courses of bacterial dynamics, endotoxin (ETX) release, and the kinetics of TNF and IL-6 was developed. The model structure was extended from a published model that quantifies the ETX-cytokines relationship. An external model evaluation was conducted by applying the model to literature data. Model simulations were performed to explore the sensitivity of the host response towards differences in the input rate of bacteria, while keeping the total bacterial burden constant.

    Results: The analysis included 645 observations from 30 animals. The blood bacterial count was well described by a one-compartment model with linear elimination. A scaling factor was estimated to quantify the ETX release by bacteria. The model successfully described the profiles of TNF, and IL-6 without a need to modify the ETXcytokines model structure. The kinetics of TNF, and IL-6 in the external datasets were well predicted. According to the simulations, the ETX tolerance development results in that low initial input rates of bacteria trigger the lowest cytokine release.

    Conclusion: The model quantitively described and predicted the cytokine kinetics triggered by E. coli exposure. The host response was found to be sensitive to the bacterial exposure rate given the same total bacterial burden.

    Download full text (pdf)
    fulltext
  • 19.
    Baltekin, Özden
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Boucharin, Alexis
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Elf, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Antibiotic susceptibility testing in less than 30 min using direct single-cell imaging2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 34, p. 9170-9175Article in journal (Refereed)
    Abstract [en]

    The emergence and spread of antibiotic-resistant bacteria are aggravated by incorrect prescription and use of antibiotics. A core problem is that there is no sufficiently fast diagnostic test to guide correct antibiotic prescription at the point of care. Here, we investigate if it is possible to develop a point-of-care susceptibility test for urinary tract infection, a disease that 100 million women suffer from annually and that exhibits widespread antibiotic resistance. We capture bacterial cells directly from samples with low bacterial counts (10(4) cfu/mL) using a custom-designed microfluidic chip and monitor their individual growth rates using microscopy. By averaging the growth rate response to an antibiotic over many individual cells, we can push the detection time to the biological response time of the bacteria. We find that it is possible to detect changes in growth rate in response to each of nine antibiotics that are used to treat urinary tract infections in minutes. In a test of 49 clinical uropathogenic Escherichia coli (UPEC) isolates, all were correctly classified as susceptible or resistant to ciprofloxacin in less than 10 min. The total time for antibiotic susceptibility testing, from loading of sample to diagnostic readout, is less than 30 min, which allows the development of a point-of-care test that can guide correct treatment of urinary tract infection.

  • 20. Baral, Stefan D
    et al.
    Poteat, Tonia
    Strömdahl, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Wirtz, Andrea L
    Guadamuz, Thomas E
    Beyrer, Chris
    Worldwide burden of HIV in transgender women: a systematic review and meta-analysis.2013In: The Lancet - Infectious diseases, ISSN 1473-3099, E-ISSN 1474-4457, Vol. 13, no 3, p. 214-22, article id S1473-3099(12)70315-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous systematic reviews have identified a high prevalence of HIV infection in transgender women in the USA and in those who sell sex (compared with both female and male sex workers). However, little is known about the burden of HIV infection in transgender women worldwide. We aimed to better assess the relative HIV burden in all transgender women worldwide.

    METHODS: We did a systematic review and meta-analysis of studies that assessed HIV infection burdens in transgender women that were published between Jan 1, 2000, and Nov 30, 2011. Meta-analysis was completed with the Mantel-Haenszel method, and random-effects modelling was used to compare HIV burdens in transgender women with that in adults in the countries for which data were available.

    FINDINGS: Data were only available for countries with male-predominant HIV epidemics, which included the USA, six Asia-Pacific countries, five in Latin America, and three in Europe. The pooled HIV prevalence was 19·1% (95% CI 17·4-20·7) in 11 066 transgender women worldwide. In 7197 transgender women sampled in ten low-income and middle-income countries, HIV prevalence was 17·7% (95% CI 15·6-19·8). In 3869 transgender women sampled in five high-income countries, HIV prevalence was 21·6% (95% CI 18·8-24·3). The odds ratio for being infected with HIV in transgender women compared with all adults of reproductive age across the 15 countries was 48·8 (95% CI 21·2-76·3) and did not differ for those in low-income and middle-income countries compared with those in high-income countries.

    INTERPRETATION: Our findings suggest that transgender women are a very high burden population for HIV and are in urgent need of prevention, treatment, and care services. The meta-analysis showed remarkable consistency and severity of the HIV disease burden among transgender women.

    FUNDING: Center for AIDS Research at Johns Hopkins and the Center for Public Health and Human Rights at the JHU Bloomberg School of Public Health.

  • 21. Baral, Stefan D
    et al.
    Strömdahl, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Beyrer, Chris
    The potential uses of preexposure prophylaxis for HIV prevention among people who inject drugs.2012In: Current opinion in HIV and AIDS, ISSN 1746-6318, Vol. 7, no 6, p. 563-8Article in journal (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW: Oral preexposure prophylaxis (PrEP) has shown HIV preventive efficacy for several key populations at risk for HIV infection including MSM and heterosexual men and women in HIV serodiscordant relationships. An efficacy trial of daily oral tenofovir among people who inject drugs (IDU) is underway in Thailand.

    RECENT FINDINGS: Although efficacy data is pending, there is emerging biological and public health plausibility data suggesting the utility of PrEP as an effective component of combination HIV prevention for IDU. Drawing from studies characterizing adherence to antiretroviral therapy for IDU, there are a range of scientific and operational considerations for the potential use of PrEP for IDU. We review here the available literature on the potential use of PrEP for IDU, barriers to uptake and adherence, and potential implementation science questions, which could address, and potently increase, the effectiveness of this intervention.

    SUMMARY: IDU remain the most underserved population in the HIV response worldwide, and have a marked gap in prevention services, making PrEP a potentially promising addition to the prevention toolkit for people who use drugs and, for those already living with HIV infection, for their spouses and other sexual partners.

  • 22.
    Barrueta Tenhunen, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    van der Heijden, Jaap
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Dogné, Sophie
    Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sci-ences (NARILIS), University of Namur (Unamur), Belgium.
    Flamion, Bruno
    Molecular Physiology Research Unit (URPhyM), Namur Research Institute for Life Sci-ences (NARILIS), University of Namur (Unamur), Belgium.
    Weigl, Wojciech
    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.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Tenhunen, Jyrki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    High molecular weight hyaluronan: a potential adjuvant to fluid resuscitation in abdominal sepsis?2023In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 59, no 5, p. 763-770Article in journal (Refereed)
    Abstract [en]

    While fluid resuscitation is fundamental in the treatment of sepsis-induced tissue hypo-perfusion, a sustained positive fluid balance is associated with excess mortality. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water, has not been tested previously as adjuvant to fluid resuscitation in sepsis.

    In a prospective, parallel-grouped, blinded model of porcine peritonitis-sepsis, we randomized animals to intervention with adjuvant hyaluronan (add-on to standard therapy) (n=8) or 0.9% saline (n=8). After the onset of hemodynamic instability the animals received an initial bolus of 0.1 % hyaluronan 1 mg/kg/10 min or placebo (0.9% saline) followed by a continuous infusion of 0.1% hyaluronan (1 mg/kg/h) or saline during the experiment. We hypothesized that the administration of hyaluronan would reduce the volume of fluid administered (aiming at stroke volume variation <13%) and/or attenuate the inflammatory reaction.

    Total volumes of intravenous fluids infused were 17.5 ± 11 ml/kg/h vs. 19.0 ± 7 ml/kg/h in intervention and control groups, respectively (p = 0.442). Plasma IL-6 increased to 2450 (1420 – 6890) pg/ml and 3690 (1410 – 11960) pg/ml (18 hours of resuscitation) in the intervention and control groups (NS). The intervention counteracted the increase in proportion of fragmented hyaluronan associated with peritonitis-sepsis alone (mean peak elution fraction (18 hours of resuscitation) control group: 17.9 ± 0.6 vs. intervention group: 16.8 ± 0.9 (p = 0.031).

    In conclusion, hyaluronan did not reduce the volume needed for fluid resuscitation or decrease the inflammatory reaction, even though it counterbalanced the peritonitis induced shift towards increased proportion of fragmented hyaluronan.

    Download full text (pdf)
    fulltext
  • 23.
    Barrueta Tenhunen, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    van der Heijden, Jaap
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Maccarana, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Hedenstierna laboratory.
    Perchiazzi, Gaetano
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care, Hedenstierna laboratory.
    Tenhunen, Jyrki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Fluid restrictive resuscitation with high molecular weight hyaluronan infusion in early peritonitis sepsis2023In: Intensive Care Medicine Experimental, E-ISSN 2197-425X, Vol. 11, no 1, article id 63Article in journal (Refereed)
    Abstract [en]

    Sepsis is a condition with high morbidity and mortality. Prompt recognition and initiation of treatment is essential. Despite forming an integral part of sepsis management, fluid resuscitation may also lead to volume overload, which in turn is associated with increased mortality. The optimal fluid strategy in sepsis resuscitation is yet to be defined. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water is an important constituent of the endothelial glycocalyx. We hypothesized that exogenously administered hyaluronan would counteract intravascular volume depletion and contribute to endothelial glycocalyx integrity in a fluid restrictive model of peritonitis. In a prospective, blinded model of porcine peritonitis sepsis, we randomized animals to intervention with hyaluronan (n = 8) or 0.9% saline (n = 8). The animals received an infusion of 0.1% hyaluronan 6 ml/kg/h, or the same volume of saline, during the first 2 h of peritonitis. Stroke volume variation and hemoconcentration were comparable in the two groups throughout the experiment. Cardiac output was higher in the intervention group during the infusion of hyaluronan (3.2 ± 0.5 l/min in intervention group vs 2.7 ± 0.2 l/min in the control group) (p = 0.039). The increase in lactate was more pronounced in the intervention group (3.2 ± 1.0 mmol/l in the intervention group and 1.7 ± 0.7 mmol/l in the control group) at the end of the experiment (p < 0.001). Concentrations of surrogate markers of glycocalyx damage; syndecan 1 (0.6 ± 0.2 ng/ml vs 0.5 ± 0.2 ng/ml, p = 0.292), heparan sulphate (1.23 ± 0.2 vs 1.4 ± 0.3 ng/ml, p = 0.211) and vascular adhesion protein 1 (7.0 ± 4.1 vs 8.2 ± 2.3 ng/ml, p = 0.492) were comparable in the two groups at the end of the experiment. In conclusion, hyaluronan did not counteract intravascular volume depletion in early peritonitis sepsis. However, this finding is hampered by the short observation period and a beneficial effect of HMW-HA in peritonitis sepsis cannot be discarded based on the results of the present study.

    Download full text (pdf)
    fulltext
  • 24.
    Behnke, Michael
    et al.
    Charite Univ Med Berlin, Natl Reference Ctr Surveillance Nosocomial Infect, Hindenburgdamm 27, D-12203 Berlin, Germany.;Free Univ Berlin, Hindenburgdamm 27, D-12203 Berlin, Germany.;Humboldt Univ, Inst Hyg & Environm Med, Hindenburgdamm 27, D-12203 Berlin, Germany..
    Valik, John Karlsson
    Karolinska Univ Hosp, Karolinska Inst, Div Infect Dis, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden..
    Gubbels, Sophie
    Statens Serum Inst, Data Integrat & Anal Secretariat, Copenhagen, Denmark..
    Teixeira, Daniel
    Geneva Univ Hosp, Infect Control Programme, Geneva, Switzerland..
    Kristensen, Brian
    Statens Serum Inst, Dept Infect Dis Epidemiol & Prevent, Copenhagen, Denmark..
    Abbas, Mohamed
    Geneva Univ Hosp, Infect Control Programme, Geneva, Switzerland..
    van Rooden, Stephanie M.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.;Natl Inst Publ Hlth & Environm RIVM, Ctr Infect Dis Epidemiol & Surveillance, Bilthoven, Netherlands..
    Gastmeier, Petra
    Charite Univ Med Berlin, Natl Reference Ctr Surveillance Nosocomial Infect, Hindenburgdamm 27, D-12203 Berlin, Germany.;Free Univ Berlin, Hindenburgdamm 27, D-12203 Berlin, Germany.;Humboldt Univ, Inst Hyg & Environm Med, Hindenburgdamm 27, D-12203 Berlin, Germany..
    van Mourik, Maaike S. M.
    Univ Med Ctr Utrecht, Dept Med Microbiol & Infect Control, Utrecht, Netherlands..
    Information technology aspects of large-scale implementation of automated surveillance of healthcare-associated infections2021In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 27, no Suppl 1, p. S29-S39Article in journal (Refereed)
    Abstract [en]

    Introduction: Healthcare-associated infections (HAI) are a major public health concern. Monitoring of HAI rates, with feedback, is a core component of infection prevention and control programmes. Digitalization of healthcare data has created novel opportunities for automating the HAI surveillance process to varying degrees. However, methods are not standardized and vary widely between different healthcare facilities. Most current automated surveillance (AS) systems have been confined to local settings, and practical guidance on how to implement large-scale AS is needed. Methods: This document was written by a task force formed in March 2019 within the PRAISE network (Providing a Roadmap for Automated Infection Surveillance in Europe), gathering experts in HAI surveillance from ten European countries. Results: The document provides an overview of the key e-health aspects of implementing an AS system of HAI in a clinical environment to support both the infection prevention and control team and information technology (IT) departments. The focus is on understanding the basic principles of storage and structure of healthcare data, as well as the general organization of IT infrastructure in surveillance networks and participating healthcare facilities. The fundamentals of data standardization, interoperability and algorithms in relation to HAI surveillance are covered. Finally, technical aspects and practical examples of accessing, storing and sharing healthcare data within a HAI surveillance network, as well as maintenance and quality control of such a system, are discussed. Conclusions: With the guidance given in this document, along with the PRAISE roadmap and governance documents, readers will find comprehensive support to implement large-scale AS in a surveillance network.

    Download full text (pdf)
    fulltext
  • 25. Bergman, Erik
    et al.
    Pasmooij, Anna Maria Gerdina
    Mol, Peter G. M.
    Westman, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Swedish Medical Products Agency, Uppsala, Sweden.
    A full-document analysis of the semantic relation between European Public Assessment Reports and EMA guidelines using a BERT language model2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 12, article id e0294560Article in journal (Refereed)
    Abstract [en]

    In the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance.

    Download full text (pdf)
    fulltext
  • 26.
    Bergman, Erik
    et al.
    Läkemedelsverket.
    Sherwood, Kim
    Läkemedelsverket.
    Forslund, Markus
    Läkemedelsverket.
    Arlett, Peter
    European Medicines Agency, Amsterdam, Netherlands.
    Westman, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine. Läkemedelsverket.
    A natural language processing approach towards harmonisation of European medicinal product information2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 10, article id e0275386Article in journal (Refereed)
    Abstract [en]

    Product information (PI) is a vital part of any medicinal product approved for use within the European Union and consists of a summary of products characteristics (SmPC) for healthcare professionals and package leaflet (PL) for patients, together with the product packaging. In this study, based on the English corpus of the EMA product information documents for all centrally approved medicinal products within the EU, a BERT sentence embedding model was used together with clustering and dimensional reduction techniques to identify sentence similarity clusters that could be candidates for standardization. A total of 1258 medicinal products were included in the study. From these, a total of 783 K sentences were extracted from SmPC and PL documents which were aggregated into a total of 284 and 129 semantic similarity clusters, respectively. The spread distribution among clusters shows separation into different cluster types. Examples of clusters with low spread include those with identical word embeddings due to current standardization, such as section headings and standard phrases. Others show minor linguistic variations, while the group with the largest variability contains variable wording but with significant semantic overlap. The sentence clusters identified could serve as candidates for further standardization of the PI. Moving from free text human wording to auto-generated text elements based on multiple-choice input for appropriate parts of the package leaflet and summary of product characteristics, could reduce both time and complexity for applicants as well as regulators, and ultimately provide patients and prescribers with documents that are easier to understand and better adapted for search availabilities.

    Download full text (pdf)
    fulltext
  • 27.
    Bergqvist, Anders
    et al.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Bondeson, Kåre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Loss of DNA-binding and new transcriptional trans-activation function in polyomavirus large T-antigen with mutation of zinc finger motif.1990In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962Article in journal (Refereed)
  • 28.
    Borgmästars, Emmy
    et al.
    Natl Food Agcy, Div Sci, Dept Biol, Hamnesplanaden 5, S-75319 Uppsala, Sweden..
    Jazi, Mehrdad Mousavi
    Natl Food Agcy, Div Sci, Dept Biol, Hamnesplanaden 5, S-75319 Uppsala, Sweden..
    Persson, Sofia
    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. Natl Food Agcy, Div Sci, Dept Biol, Hamnesplanaden 5, S-75319 Uppsala, Sweden.
    Jansson, Linda
    Lund Univ, Appl Microbiol, Naturvetarvagen 14, S-22362 Lund, Sweden..
    Radstrom, Peter
    Lund Univ, Appl Microbiol, Naturvetarvagen 14, S-22362 Lund, Sweden..
    Simonsson, Magnus
    Natl Food Agcy, Div Sci, Dept Biol, Hamnesplanaden 5, S-75319 Uppsala, Sweden..
    Hedman, Johannes
    Lund Univ, Appl Microbiol, Naturvetarvagen 14, S-22362 Lund, Sweden.;Swedish Natl Forens Ctr, Brigadgatan 13, S-58194 Linkoping, Sweden..
    Eriksson, Ronnie
    Natl Food Agcy, Div Sci, Dept Biol, Hamnesplanaden 5, S-75319 Uppsala, Sweden..
    Improved Detection of Norovirus and Hepatitis A Virus in Surface Water by Applying Pre-PCR Processing2017In: Food and Environmnetal Virology, ISSN 1867-0334, E-ISSN 1867-0342, Vol. 9, no 4, p. 395-405Article in journal (Refereed)
    Abstract [en]

    Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) detection of waterborne RNA viruses generally requires concentration of large water volumes due to low virus levels. A common approach is to use dead-end ultrafiltration followed by precipitation with polyethylene glycol. However, this procedure often leads to the co-concentration of PCR inhibitors that impairs the limit of detection and causes false-negative results. Here, we applied the concept of pre-PCR processing to optimize RT-qPCR detection of norovirus genogroup I (GI), genogroup II (GII), and hepatitis A virus (HAV) in challenging water matrices. The RT-qPCR assay was improved by screening for an inhibitor-tolerant master mix and modifying the primers with twisted intercalating nucleic acid molecules. Additionally, a modified protocol based on chaotropic lysis buffer and magnetic silica bead nucleic acid extraction was developed for complex water matrices. A validation of the modified extraction protocol on surface and drinking waters was performed. At least a 26-fold improvement was seen in the most complex surface water studied. The modified protocol resulted in average recoveries of 33, 13, 8, and 4% for mengovirus, norovirus GI, GII, and HAV, respectively. The modified protocol also improved the limit of detection for norovirus GI and HAV. RT-qPCR inhibition with C (q) shifts of 1.6, 2.8, and 3.5 for norovirus GI, GII, and HAV, respectively, obtained for the standard nucleic acid extraction were completely eliminated by the modified protocol. The standard nucleic acid extraction method worked well on drinking water with no RT-qPCR inhibition observed and average recoveries of 80, 124, 89, and 32% for mengovirus, norovirus GI, GII, and HAV, respectively.

  • 29.
    Borgström, Emilie W.
    et al.
    Dept Lab Med, Clin Microbiol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden..
    Edvinsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Perez, Lucia P.
    Karolinska Inst, Dept Lab Med, Biomol & Cellular Med, Stockholm, Sweden..
    Norlin, Anna C.
    Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Enoksson, Sara L.
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Hansen, Susanne
    Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden..
    Fasth, Anders
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden..
    Friman, Vanda
    Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Infect Dis, Gothenburg, Sweden..
    Kämpe, Olle
    Karolinska Inst, Dept Med, Expt Endocrinol, Stockholm, Sweden..
    Månsson, Robert
    Karolinska Inst, Dept Lab Med, Biomol & Cellular Med, Stockholm, Sweden..
    Estupinan, Hernando Y.
    Karolinska Inst, Dept Lab Med, Biomol & Cellular Med, Stockholm, Sweden.;Univ Ind Santander, Dept Ciencias Basicas, Bucaramanga 680002, Colombia..
    Wang, Qing
    Ziyang, Tan
    Lakshmikanth, Tadepally
    Karolinska Inst, Sci Life Lab, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Smith, Carl Inge E.
    Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden.;Translat Res Ctr Karolinska TRACK, Dept Lab Med, Stockholm, Sweden..
    Brodin, Petter
    Karolinska Inst, Sci Life Lab, Dept Womens & Childrens Hlth, Stockholm, Sweden.;Imperial Coll London, Dept Immunol & Inflammat, London, England..
    Bergman, Peter
    Dept Lab Med, Clin Microbiol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden..
    Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors2023In: Journal of Clinical Immunology, ISSN 0271-9142, E-ISSN 1573-2592, Vol. 43, p. 136-150Article in journal (Refereed)
    Abstract [en]

    Purpose; The aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors.

    Methods: Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans.

    Results: Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-gamma and CXCL10 were downregulated.

    Conclusions: The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.

    Download full text (pdf)
    FULLTEXT01
  • 30.
    Bulman, Zackery P.
    et al.
    Univ Illinois, Dept Pharm Practice, Chicago, IL 60612 USA..
    Wicha, Sebastian G.
    Univ Hamburg, Inst Pharm, Dept Clin Pharm, Hamburg, Germany..
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lenhard, Justin R.
    Calif Northstate Univ, Dept Clin & Adm Sci, Coll Pharm, Elk Grove, CA USA..
    Nation, Roger L.
    Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Melbourne, Vic, Australia..
    Theuretzbacher, Ursula
    Ctr Antiinfect Agents, Vienna, Austria..
    Derendorf, Hartmut
    Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA..
    Tängdén, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Zeitlinger, Markus
    Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria..
    Landersdorfer, Cornelia B.
    Monash Univ, Ctr Med Use & Safety, Monash Inst Pharmaceut Sci, Melbourne, Vic, Australia..
    Bulitta, Jürgen B.
    Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, Orlando, FL USA..
    Friberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Li, Jian
    Monash Univ, Monash Biomed Discovery Inst, Infect & Immun Program, Melbourne, Vic, Australia.;Monash Univ, Dept Microbiol, Melbourne, Vic, Australia..
    Tsuji, Brian T.
    Univ Buffalo, Dept Pharm Practice, Buffalo, NY USA..
    Research priorities towards precision antibiotic therapy to improve patient care2022In: LANCET MICROBE, ISSN 2666-5247, Vol. 3, no 10, p. e795-e802Article in journal (Refereed)
    Abstract [en]

    Antibiotic resistance presents an incessant threat to our drug armamentarium that necessitates novel approaches to therapy. Over the past several decades, investigation of pharmacokinetic and pharmacodynamic (PKPD) principles has substantially improved our understanding of the relationships between the antibiotic, pathogen, and infected patient. However, crucial gaps in our understanding of the pharmacology of antibacterials and their optimal use in the care of patients continue to exist; simply attaining antibiotic exposures that are considered adequate based on traditional targets can still result in treatment being unsuccessful and resistance proliferation for some infections. It is this salient paradox that points to key future directions for research in antibiotic therapeutics. This Personal View discusses six priority areas for antibiotic pharmacology research: (1) antibiotic-pathogen interactions, (2) antibiotic targets for combination therapy, (3) mechanistic models that describe the time-course of treatment response, (4) understanding and modelling of host response to infection, (5) personalised medicine through therapeutic drug management, and (6) application of these principles to support development of novel therapies. Innovative approaches that enhance our understanding of antibiotic pharmacology and facilitate more accurate predictions of treatment success, coupled with traditional pharmacology research, can be applied at the population level and to individual patients to improve outcomes.

    Download full text (pdf)
    FULLTEXT01
  • 31.
    Bösl, Korbinian
    et al.
    Norwegian Univ Sci & Technol, Ctr Mol Inflammat Res, Trondheim, Norway;Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
    Ianevski, Aleksandr
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
    Than, Thoa T.
    Inst Pasteur Korea, Seongnam, South Korea.
    Andersen, Petter I.
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
    Kuivanen, Suvi
    Univ Helsinki, Dept Virol, Helsinki, Finland.
    Teppor, Mona
    Univ Tartu, Inst Technol, Tartu, Estonia.
    Zusinaite, Eva
    Univ Tartu, Inst Technol, Tartu, Estonia.
    Dumpis, Uga
    Pauls Stradins Clin Univ Hosp, Riga, Latvia.
    Vitkauskiene, Astra
    Lithuanian Univ Hlth Sci, Dept Lab Med, Kaunas, Lithuania.
    Cox, Rebecca J.
    Univ Bergen, Dept Clin Sci, Influenza Ctr, Bergen, Norway.
    Kallio-Kokko, Hannimari
    Univ Helsinki, Dept Virol & Immunol, Helsinki Univ Hosp, Helsinki, Finland.
    Bergqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Tenson, Tanel
    Univ Tartu, Inst Technol, Tartu, Estonia.
    Merits, Andres
    Univ Tartu, Inst Technol, Tartu, Estonia.
    Oksenych, Valentyn
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
    Björås, Magnar
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
    Anthonsen, Marit W.
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway.
    Shum, David
    Inst Pasteur Korea, Seongnam, South Korea.
    Kaarbö, Mari
    Oslo Univ Hosp, Dept Microbiol, Oslo, Norway.
    Vapalahti, Olli
    Univ Helsinki, Dept Vet Biosci, Helsinki, Finland.
    Windisch, Marc P.
    Inst Pasteur Korea, Seongnam, South Korea.
    Superti-Furga, Giulio
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria;Med Univ Vienna, Ctr Physiol & Pharmacol, Vienna, Austria.
    Snijder, Berend
    Swiss Fed Inst Technol, Inst Mol Syst Biol, Dept Biol, Zurich, Switzerland.
    Kainov, Denis
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway;Swiss Fed Inst Technol, Inst Mol Syst Biol, Dept Biol, Zurich, Switzerland.
    Kandasamy, Richard K.
    Norwegian Univ Sci & Technol, Ctr Mol Inflammat Res, Trondheim, Norway;Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway;Univ Oslo, Nord EMBL Partnership, Ctr Mol Med Norway NCMM, Oslo, Norway;Univ Massachusetts, Sch Med, Dept Med, Program Innate Immun,Div Infect Dis & Immunol, Worcester, MA 01655 USA.
    Common Nodes of Virus-Host Interaction Revealed Through an Integrated Network Analysis2019In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 2186Article in journal (Refereed)
    Abstract [en]

    Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape.

    Download full text (pdf)
    FULLTEXT01
  • 32.
    Bülow Anderberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Thoraxanestesin, Uppsala Akademiska Sjukhus.
    Luther, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Stephanie, Franzén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Department of Medicine, Division Nephrology, Cardio-Renal Physiology and Medicine, University of Alabama at Birmingham.
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Forkman, Johannes
    Department of Crop Production Ecology, Swedish University of Agricultural Sciences.
    Hultenby, Kjell
    Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wernerson, Annika
    Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden.
    Frithiof, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hydrocortisone improves renal oxygen utilization and ameliorates renal dysfunction in ovine gram-negative sepsisManuscript (preprint) (Other academic)
  • 33.