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  • 1.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Bonnedahl, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Council, Sweden.
    Woksepp, Hanna
    Kalmar Cty Hosp, Sweden.
    Hernandez, Jorge
    Kalmar Cty Hosp, Sweden.
    Reed, John A.
    US Geol Survey, AK 99508 USA.
    Tibbitts, Lee
    US Geol Survey, AK 99508 USA.
    Olsen, Bjoern
    Uppsala Univ, Sweden.
    Douglas, David C.
    US Geol Survey, AK USA.
    Ramey, Andrew M.
    US Geol Survey, 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 (amp;lt;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.

  • 2.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Woksepp, Hanna
    Kalmar Council, Sweden.
    Bonnedahl, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Council, Sweden.
    Early emergence of mcr-1-positive Enterobacteriaceae in gulls from Spain and Portugal2019In: Environmental Microbiology Reports, ISSN 1758-2229, E-ISSN 1758-2229Article in journal (Refereed)
    Abstract [en]

    We tested extended-spectrum beta-lactamase producing bacteria from wild gulls (Larus spp.) sampled in 2009 for the presence of mcr-1. We report the detection of mcr-1 and describe genome characteristics of four Escherichia coli and one Klebsiella pneumoniae isolate from Spain and Portugal that also exhibited colistin resistance. Results represent the earliest evidence for colistin-resistant bacteria in European wildlife.

  • 3.
    Ahlstrom, Christina A.
    et al.
    US Geol Survey, AK 99508 USA.
    Ramey, Andrew M.
    US Geol Survey, AK 99508 USA.
    Woksepp, Hanna
    Dept Dev and Publ and Hlth, Sweden.
    Bonnedahl, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Dept Infect Dis, Sweden.
    Repeated Detection of Carbapenemase-Producing Escherichia coil in Gulls Inhabiting Alaska2019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 8, article id e00758-19Article in journal (Refereed)
    Abstract [en]

    Here, we report the first detection of carbapenemase-producing Escherichia coli in Alaska and in wildlife in the United States. Wild bird (gull) feces sampled at three locations in Southcentral Alaska yielded isolates that harbored plasmidencoded bla(kpc-2), or chromosomally encoded bla(OXA-48) and genes associated with antimicrobial resistance to up to eight antibiotic classes.

  • 4.
    Andersson, Maria
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Östholm Balkhed, Åse
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Holmbom, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Berg, Sören
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Delay of appropriate antibiotic treatment is associated with high mortality in patients with community-onset sepsis in a Swedish setting2019In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 38, no 7, p. 1223-1234Article in journal (Refereed)
    Abstract [en]

    Early appropriate antimicrobial therapy is crucial in patients with sepsis and septic shock. Studies often focus on time to first dose of appropriate antibiotics, but subsequent dosing is equally important. Our aim was to investigate the impact of fulfillment of early treatment, with focus on appropriate administration of first and second doses of antibiotics, on 28-day mortality in patients with community-onset severe sepsis and septic shock. A retrospective study on adult patients admitted to the emergency department with community-onset sepsis and septic shock was conducted 2012-2013. The criterion early appropriate antibiotic treatment was defined as administration of the first dose of adequate antibiotics within 1h, and the second dose given with less than 25% delay after the recommended dose interval. A high-risk patient was defined as a septic patient with either shock within 24h after arrival or red triage level on admittance according to the Medical Emergency Triage and Treatment System Adult. Primary endpoint was 28-day mortality. Of 90 patients, less than one in four (20/87) received early appropriate antibiotic treatment, and only one in three (15/44) of the high-risk patients. The univariate analysis showed a more than threefold higher mortality among high-risk patients not receiving early appropriate antibiotic treatment. Multivariable analysis identified early non-appropriate antibiotic treatment as an independent predictor of mortality with an odds ratio for mortality of 10.4. Despite that the importance of early antibiotic treatment has been established for decades, adherence to this principle was very poor.

  • 5.
    Atterby, Clara
    et al.
    Uppsala Univ, Sweden.
    Osbjer, Kristina
    Swedish Univ Agr Sci SLU, Sweden; Food and Agr Org United Nations, Cambodia.
    Tepper, Viktoria
    Swiss Fed Inst Technol, Switzerland.
    Rajala, Elisabeth
    Swedish Univ Agr Sci SLU, Sweden.
    Hernandez, Jorge
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Council, Dept Infect Dis, Sweden; Linnaeus Univ, Sweden; Kalmar Cty Hosp, Sweden.
    Seng, Sokerya
    Food and Agr Org United Nations, Cambodia.
    Holl, Davun
    Minist Agr Forestry and Fisheries, Cambodia.
    Bonnedahl, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Linnaeus Univ, Sweden.
    Börjesson, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Natl Vet Inst SVA, Sweden.
    Magnusson, Ulf
    Swedish Univ Agr Sci SLU, Sweden.
    Jarhult, Josef D.
    Uppsala Univ, Sweden.
    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 bla(OXA-48 )in humans2019In: Zoonoses and Public Health, ISSN 1863-1959, E-ISSN 1863-2378Article 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 bla(OXA-48 )were identified in two humans. The community carriage of ESCE/K was 20% in humans and 23% in livestock. The same ESBL genes: bla(CTX-M-15), bla(CTX-M-14), bla(CTX-M-27), bla(CTX-M-55), bla(SHV-2), bla(SHV-12), bla(SHV-28); AmpC genes: bla(CMY-2), bla(CMY-42,) bla(DHA-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.

  • 6.
    Bivik Stadler, Caroline
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Arefin, Md Badrul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia.
    PIP degron-stabilized Dacapo/p21(Cip)(1) and mutations in ago act in an anti- versus pro-proliferative manner, yet both trigger an increase in Cyclin E levels2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 13, article id UNSP dev175927Article in journal (Refereed)
    Abstract [en]

    During cell cycle progression, the activity of the CycE-Cdk2 complex gates S-phase entry. CycE-Cdk2 is inhibited by CDK inhibitors (CKIs) of the Cip/Kip family, which include the human p21(Cip)(1) and Drosophila Dacapo (Dap) proteins. Both the CycE and Cip/Kip family proteins are under elaborate control via protein degradation, mediated by the Cullin-RING ligase (CRL) family of ubiquitin ligase complexes. The CRL complex SCFFoxw7/Ago targets phosphorylated CycE, whereas p21(Cip)(1) and Dap are targeted by the CRLCdf2 complex, binding to the PIP degron. The role of CRL-mediated degradation of CycE and Cip/Kip proteins during CNS development is not well understood. Here, we analyse the role of ago (Fbxw7)-mediated CycE degradation, and of Dap and p21(Cip)(1) degradation during Drosophila CNS development. We find that ago mutants display over-proliferation, accompanied by elevated CycE expression levels. By contrast, expression of PIP degron mutant Dap and p21(Cip)(1) transgenes inhibit proliferation. However, surprisingly, this is also accompanied by elevated CycE levels. Hence, ago mutation and PIP degron Cip/Kip transgenic expression trigger opposite effects on proliferation, but similar effects on CycE levels.

  • 7.
    Das, Jyotirmoy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Mika
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naive subjects2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 6, p. 589-601Article in journal (Refereed)
    Abstract [en]

    The protection against tuberculosis induced by the Bacille Calmette Guerin (BCG) vaccine is unpredictable. In our previous study, altered DNA methylation pattern in peripheral blood mononuclear cells (PBMCs) in response to BCG was observed in a subgroup of individuals, whose macrophages killed mycobacteria effectively (responders). These macrophages also showed production of Interleukin-1 beta (IL-1 beta) in response to mycobacterial stimuli before vaccination. Here, we hypothesized that the propensity to respond to the BCG vaccine is reflected in the DNA methylome. We mapped the differentially methylated genes (DMGs) in PBMCs isolated from responders/non-responders at the time point before vaccination aiming to identify possible predictors of BCG responsiveness. We identified 43 DMGs and subsequent bioinformatic analyses showed that these were enriched for actin-modulating pathways, predicting differences in phagocytosis. This could be validated by experiments showing that phagocytosis of mycobacteria, which is an event preceding mycobacteria-induced IL-1 beta production, was strongly correlated with the DMG pattern.

  • 8.
    Dellgren, Linus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases. inkoping, Sweden.
    Claesson, Carina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Högdahl, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Forsberg, Jon
    Not Found:Linkoping Univ, Dept Clin and Expt Med, Linkoping, Sweden; Linkoping Univ, Dept Urol, Linkoping, Sweden.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Hällgren, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Phenotypic screening for quinolone resistance in Escherichia coli2019In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 38, no 9, p. 1765-1771Article in journal (Refereed)
    Abstract [en]

    Recent studies show that rectal colonization with low-level ciprofloxacin-resistant Escherichia coli (ciprofloxacin minimal inhibitory concentration (MIC) above the epidemiological cutoff point, but below the clinical breakpoint for resistance), i.e., in the range amp;gt; 0.06-0.5 mg/L is an independent risk factor for febrile urinary tract infection after transrectal ultrasound-guided biopsy (TRUS-B) of the prostate, adding to the other risk posed by established ciprofloxacin resistance in E. coli (MIC amp;gt; 0.5 mg/L) as currently defined. We aimed to identify the quinolone that by disk diffusion best discriminates phenotypic wild-type isolates (ciprofloxacin MIC amp;lt;= 0.06 mg/L) of E. coli from isolates with acquired resistance, and to determine the resistance genotype of each isolate. The susceptibility of 108 E. coli isolates was evaluated by ciprofloxacin, levofloxacin, moxifloxacin, nalidixic acid, and pefloxacin disk diffusion and correlated to ciprofloxacin MIC (broth microdilution) using EUCAST methodology. Genotypic resistance was identified by PCR and DNA sequencing. The specificity was 100% for all quinolone disks. Sensitivity varied substantially, as follows: ciprofloxacin 59%, levofloxacin 46%, moxifloxacin 59%, nalidixic acid 97%, and pefloxacin 97%. We suggest that in situations where low-level quinolone resistance might be of importance, such as when screening for quinolone resistance in fecal samples pre-TRUS-B, a pefloxacin (S amp;gt;= 24 mm) or nalidixic acid (S amp;gt;= 19 mm) disk, or a combination of the two, should be used. In a setting where plasmid-mediated resistance is prevalent, pefloxacin might perform better than nalidixic acid.

  • 9.
    Elkington, Paul
    et al.
    Univ Southampton, England.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Kapoor, Nidhi
    Florida Hosp Adventist Hlth Syst, FL USA.
    Mahon, Robert
    NIAID, MD 20892 USA.
    Pienaar, Elsje
    Purdue Univ, IN 47907 USA.
    Huh, Dongeun
    Univ Penn, PA 19104 USA.
    Kaushal, Deepak
    Texas Biomed Res Inst, TX USA.
    Schlesinger, Larry S.
    Texas Biomed Res Inst, TX USA.
    In Vitro Granuloma Models of Tuberculosis: Potential and Challenges2019In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 219, no 12, p. 1858-1866Article, review/survey (Refereed)
    Abstract [en]

    Despite intensive research efforts, several fundamental disease processes for tuberculosis (TB) remain poorly understood. A central enigma is that host immunity is necessary to control disease yet promotes transmission by causing lung immunopathology. Our inability to distinguish these processes makes it challenging to design rational novel interventions. Elucidating basic immune mechanisms likely requires both in vivo and in vitro analyses, since Mycobacterium tuberculosis is a highly specialized human pathogen. The classic immune response is the TB granuloma organized in three dimensions within extracellular matrix. Several groups are developing cell culture granuloma models. In January 2018, NIAID convened a workshop, entitled "3-D Human in vitro TB Granuloma Model" to advance the field. Here, we summarize the arguments for developing advanced TB cell culture models and critically review those currently available. We discuss how integrating complementary approaches, specifically organoids and mathematical modeling, can maximize progress, and conclude by discussing future challenges and opportunities.

  • 10.
    Frölund, Maria
    et al.
    Research Unit for Reproductive Microbiology, Statens Serum Institut, Copenhagen S, Denmark.
    Falk, Lars
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Dermatology and Venerology.
    Ahrens, Peter
    Research Unit for Reproductive Microbiology, Statens Serum Institut, Copenhagen S, Denmark.
    Jensen, Jorgen Skov
    Research Unit for Reproductive Microbiology, Statens Serum Institut, Copenhagen S, Denmark.
    Detection of ureaplasmas and bacterial vaginosis associated bacteria and their association with non-gonococcal urethritis in men2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Article in journal (Refereed)
    Abstract [en]

    No aetiology is found in up to 40% of men with symptomatic urethritis. Male partners of women with bacterial vaginosis (BV) may be at higher risk of non-gonococcal urethritis (NGU). The aim of this study was to examine the role of BV associated bacteria in first-void urine (FVU) in 97 asymptomatic men without urethritis (controls) and 44 men (cases) with NGU including 20 men with idiopathic urethritis (IU) attending a Swedish STD-clinic between January and October 2010. BV-associated bacteria and ureaplasmas were detected by quantitative PCR assays. All BV associated bacteria, except Megasphaera-like type 1, were strongly positively correlated with Uurealyticum p<0.005 and even stronger with the combined Uurealyticum and Uparvum load (p<0.0005) suggesting that ureaplasma induced elevated pH may stimulate the growth of BV associated bacteria. No statistically significant differences were found between IU cases and controls in the prevalence or load of BV associated bacteria or ureaplasmas. In multiple logistic regression, Megasphaera-like type 1 was associated with IU (p = 0.03), but most positive FVU samples contained very few bacteria and the finding may not be clinically relevant.

  • 11.
    Ji, Xiang
    et al.
    Shandong Univ, Peoples R China.
    Zheng, Beiwen
    Zhejiang Univ, Peoples R China.
    Berglund, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Zhejiang Univ, Peoples R China.
    Zou, Huiyun
    Shandong Univ, Peoples R China.
    Sun, Qiang
    Shandong Univ, Peoples R China.
    Chi, Xiaohui
    Shandong Univ, Peoples R China.
    Ottoson, Jakob
    Natl Food Agcy, Sweden.
    Li, Xuewen
    Shandong Univ, Peoples R China.
    Lundborg, Cecilia Stalsby
    Karolinska Inst, Sweden.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Dissemination of extended-spectrum beta-lactamase-producing Escherichia coli carrying mcr-1 among multiple environmental sources in rural China and associated risk to human health2019In: Environmental Pollution, ISSN 0269-7491, E-ISSN 1873-6424, Vol. 251, p. 619-627Article in journal (Refereed)
    Abstract [en]

    Antibiotic resistance among gram-negative bacteria is increasingly becoming a problem of global concern. Particularly problematic is the emergence of resistance to last-resort antibiotics such as carbapenems and colistin. The increasing number of reports on the plasmid-mediated colistin resistance gene mcr-1 in isolates worldwide is raising concerns for the future usefulness of this class of antibiotics. Dissemination of mcr-1 is believed to have originated mainly from animal breeding, however, the role of the environment as a transmission source is not yet fully understood. In the current study, 89 extended spectrum beta-lactamase-producing Escherichia coli isolated from 231 samples from different environmental sources in 12 villages in a rural area of Shandong, China, were screened for mcr-1.17 (19.1%) mcr-1-positive isolates were found from different environmental sources, aggregated in 6 villages. Plasmids of three different Inc-groups carrying mcr-1 were confirmed, indicating that the widespread geographical distribution of mcr-1 in the local area is due to a number of different plasmids. Additionally, almost a third (29.4%) of the isolates carried virulence factors associated to intestinal pathogenic E. coli. These results illustrate the high complexity of the transmission patterns of mcr-1 among different environmental matrices on a local scale and the potential for the environment to facilitate dissemination and emergence of antibiotic-resistant and virulent strains of bacteria. (C) 2019 Elsevier Ltd. All rights reserved.

  • 12.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Who controls the Wnt?2019In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 108Article in journal (Other academic)
    Abstract [en]

    n/a

  • 13.
    Lange, C.
    et al.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany; Karolinska Inst, Sweden.
    Aarnoutse, R. E.
    Radboud Univ Nijmegen, Netherlands.
    Alffenaar, J. W. C.
    Univ Groningen, Netherlands.
    Bothamley, G.
    Homerton Univ Hosp, England; QMUL, England; London Sch Hyg and Trop Med, England.
    Brinkmann, F.
    Ruhr Univ Bochum, Germany.
    Costa, J.
    Ctr Hosp Leiria, Portugal; Ctr Innovat Technol and Hlth Care, Portugal.
    Chesov, D.
    Nicoale Testemitanu State Univ Med and Pharm, Moldova; Res Ctr Borstel, Germany.
    van Crevel, R.
    Radboud Univ Nijmegen, Netherlands; Univ Oxford, England.
    Dedicoat, M.
    Univ Hosp Birmingham, England.
    Dominguez, J.
    Univ Autonoma Barcelona, Spain.
    Duarte, R.
    Portuguese Natl TB Program, Portugal; Ctr Hosp Vila Nova de Gaia, Portugal; Univ Porto, Portugal; Univ Porto, Portugal.
    Grobbel, H. P.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany.
    Guenther, G.
    Res Ctr Borstel, Germany; Univ Namibia, Namibia.
    Guglielmetti, L.
    Hop Univ Pitie Salpetriere Charles Foix, France; Univ Pierre and Marie Curie 06, France.
    Heyckendorf, J.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany.
    Kay, A. W.
    Texas Childrens Hosp, TX 77030 USA; Baylor Coll Med, TX 77030 USA; Baylor Coll Med Childrens Fdn, Swaziland.
    Kirakosyan, O.
    MSF France OCP, Armenia.
    Kirk, O.
    Univ Copenhagen, Denmark; Univ Southern Denmark, Denmark.
    Koczulla, R. A.
    Philipps Univ Marburg, Germany; German Ctr Lung Res DZL, Germany.
    Kudriashov, G. G.
    St Petersburg State Res Inst Phthisiopulmonol, Russia.
    Kuksa, L.
    Riga East Univ Hosp, Latvia; Riga Stradins Univ, Latvia.
    van Leth, F.
    Univ Amsterdam, Netherlands.
    Magis-Escurra, C.
    Radboud Univ Nijmegen, Netherlands.
    Mandalakas, A. M.
    Texas Childrens Hosp, TX 77030 USA; Baylor Coll Med, TX 77030 USA.
    Molina-Moya, B.
    Univ Autonoma Barcelona, Spain.
    Peloquin, C. A.
    Univ Florida, FL USA.
    Reimann, M.
    Res Ctr Borstel, Germany; Univ Lubeck, Germany; German Ctr Infect Res DZIF, Germany.
    Rumetshofer, R.
    Otto Wagner Hosp Vienna, Austria.
    Schaaf, H. S.
    Stellenbosch Univ, South Africa.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Tiberi, S.
    Barts Hlth NHS Trust, England; Queen Mary Univ, England.
    Valda, J.
    Otto Wagner Hosp Vienna, Austria.
    Yablonskii, P. K.
    St Petersburg State Res Inst Phthisiopulmonol, Russia; St Petersburg State Univ, Russia.
    Dheda, K.
    Univ Cape Town, South Africa.
    Management of patients with multidrug-resistant tuberculosis2019In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 23, no 6, p. 645-662Article in journal (Refereed)
    Abstract [en]

    The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

  • 14.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Bengtsson, Torbjorn
    Orebro Univ, Sweden.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Starkhammar Johansson, Carin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Public Dental Health Care.
    Palm, Eleonor
    Orebro Univ, Sweden.
    Nayeri, Fariba
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Davies, Julia
    Malmo Univ, Sweden.
    Svensater, Gunnel
    Malmo Univ, Sweden.
    Lönn, Johanna
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Orebro Univ, Sweden; Malmo Univ, Sweden.
    Modified lipoproteins in periodontitis: a link to cardiovascular disease?2019In: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 39, no 3, article id BSR20181665Article in journal (Refereed)
    Abstract [en]

    There is a strong association between periodontal disease and atherosclerotic cardiovascular disorders. A key event in the development of atherosclerosis is accumulation of modified lipoproteins within the arterial wall. We hypothesise that patients with periodontitis have an altered lipoprotein profile towards an atherogenic form. Therefore, the present study aims at identifying modifications of plasma lipoproteins in periodontitis. Lipoproteins from ten female patients with periodontitis and gender- and age-matched healthy controls were isolated by density-gradient ultracentrifugation. Proteins were separated by 2D gel-electrophoresis and identified by map-matching or by nano-LC followed by MS. Apolipoprotein (Apo) A-I (ApoA-I) methionine oxidation, Oxyblot, total antioxidant capacity and a multiplex of 71 inflammation-related plasma proteins were assessed. Reduced levels of apoJ, phospholipid transfer protein, apoF, complement C3, paraoxonase 3 and increased levels of alpha-1-antichymotrypsin, apoA-II, apoC-III were found in high-density lipoprotein (HDL) from the patients. In low-density lipoprotein (LDL)/very LDL (VLDL), the levels of apoL-1 and platelet-activating factor acetylhydrolase (PAF-AH) as well as apo-B fragments were increased. Methionine oxidation of apoA-I was increased in HDL and showed a relationship with periodontal parameters. alpha-1 antitrypsin and alpha-2-HS glycoprotein were oxidised in LDL/VLDL and antioxidant capacity was increased in the patient group. A total of 17 inflammation-related proteins were important for group separation with the highest discriminating proteins identified as IL-21, Fractalkine, IL-17F, IL-7, IL-1RA and IL-2. Patients with periodontitis have an altered plasma lipoprotein profile, defined by altered protein levels as well as post-translational and other structural modifications towards an atherogenic form, which supports a role of modified plasma lipoproteins as central in the link between periodontal and cardiovascular disease (CVD).

  • 15.
    Moparthi, Lavanya
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Koch, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Wnt signaling in intestinal inflammation2019In: Differentiation, ISSN 0301-4681, E-ISSN 1432-0436, Vol. 108, p. 24-32Article, review/survey (Refereed)
    Abstract [en]

    Chronic inflammatory bowel diseases, including Crohns disease and ulcerative colitis, are a major health burden worldwide. Numerous conserved signaling pathways control tissue injury and repair during colitis, but owing to the complexity of the inflammatory process, their individual contribution remains poorly understood. A key regulatory pathway in the intestinal mucosa is Wnt/beta-catenin signaling, which acts as the central organizer of epithelial stem cell identity and maintenance. Apart from this core function, there is mounting evidence that the Wnt pathway is highly interconnected with numerous other signaling cascades, and that combinatorial signaling events shape epithelial homeostasis and tissue regeneration. Here we provide an updated view of how Wnt signaling intersects with major inflammatory pathways, with a particular focus on intestinal inflammation. Elucidating the reciprocal actions of Wnt ligands and cytokines has the potential to reveal new treatment options for chronic colitis and other inflammatory disorders.

  • 16.
    Niward, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Towards individualised treatment of tuberculosis2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Each year, around 10 million of individuals develop active tuberculosis (TB). Worldwide, TB is the leading cause of death from an infectious agent surpassing both malaria and HIV. Current treatment regimens are long and therefore encompass a risk of nonadherence and development of acquired drug-resistance, reflected in the increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Indeed, this calls for prudent use of existing TB drugs and improvement of TB treatment strategies. The aim of this thesis was to investigate the current drug susceptibility testing (DST) breakpoints for Mycobacterium tuberculosis (M. tuberculosis), the pharmacokinetics and pharmacodynamics (PK/PD) of TB treatment and to explore the role of therapeutic drug monitoring (TDM) for optimising TB treatment.

    Drug resistance in M. tuberculosis is expressed over a continuous scale and for some drugs it may be identified as low- and high-level resistance. This has been poorly reflected in currently used binary susceptibility breakpoints for TB drugs. Results from genome sequencing and phenotypic DST of ofloxacin and levofloxacin were compared in study I and current breakpoints were found to misclassify up to 25% of M. tuberculosis isolates with resistance mutations in gyrA as susceptible to fluoroquinolones. This finding may have implications for the classification of XDR-TB, treatment of MDR-TB and the evaluation of fluoroquinolones in clinical studies.

    Study II was a prospective cohort study of susceptible TB in Sweden, where drug concentrations of first-line TB drugs were measured along with the susceptibility level of the bacteria defined by the minimum inhibitory concentration (MIC) of M. tuberculosis. First-line drug concentrations below the reference range (16-42%) were common and most pronounced for rifampicin (13/31, 42%). An exploratory investigation of PK/PD parameters displayed a wide distribution of ratios between drug exposures and MICs. Rifampicin exhibited higher level of individual fluctuations over time during TB treatment compared with isoniazid. In study III the plasma drug concentrations of rifampicin were compared to the tuberculosis drug activity assay (TDA) and results showed that rifampicin drug levels, but not drug levels of the other first-line drugs, correlated with TDA. Patients with rifampicin drug levels below 8 mg/L had significantly lower median TDA. This finding supports the use of TDA as a potential indicator for low rifampicin exposure in resource-constrained settings without access to drug concentration analysis. The study design in study II has been further developed in study IV, which is a prospective cohort study of MDR-TB in China, where drug exposure will be explored in relation to individual bacterial MIC and measurements of treatment outcome.

    In summary, the work in this thesis emphasises the importance of reliable DST of M. tuberculosis and the need to re-evaluate the currently used breakpoints. Therapeutic drug monitoring (TDM) based on drug concentrations and MICs is a useful tool to avoid suboptimal drug exposure and to individualise TB treatments. Such strategies may improve treatment regimens and avoid further development of resistance.

    List of papers
    1. Susceptibility testing breakpoints for Mycobacterium tuberculosis categorize isolates with resistance mutations in gyrA as susceptible to fluoroquinolones: implications for MDR-TB treatment and the definition of XDR-TB.
    Open this publication in new window or tab >>Susceptibility testing breakpoints for Mycobacterium tuberculosis categorize isolates with resistance mutations in gyrA as susceptible to fluoroquinolones: implications for MDR-TB treatment and the definition of XDR-TB.
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    2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 2, p. 333-338Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: Fluoroquinolones (FQs) are important in the treatment of MDR-TB and in the definition of XDR-TB. Our objective was to investigate how discrepancies in the phenotypic and genotypic methods for antimicrobial susceptibility testing could affect the interpretation of antimicrobial susceptibility test results.

    METHODS: We analysed MICs of ofloxacin and levofloxacin in Middlebrook 7H10 broth (7H10) as well as sequencing of the quinolone resistance-determining region of the gyrA gene and the MTBDRsl assay in 75 resistant isolates, including MDR and XDR strains of Mycobacterium tuberculosis.

    RESULTS: Among 75 resistant isolates, 27 had mutations associated with FQ resistance. Among isolates with resistance mutations in gyrA, 26% (seven of 27) were susceptible to levofloxacin and ofloxacin by phenotypic testing at 1 mg/L and 2 mg/L. The most common mutation was in codon 94 and these isolates had significantly increased MICs of levofloxacin (2-8 mg/L) compared with isolates with mutations in codon 90 (0.25-2 mg/L, P < 0.05). The sensitivity and specificity for the MTBDRsl assay compared with gyrA sequencing were 96% and 98%, respectively.

    CONCLUSION: Current critical concentrations may classify up to 26% of isolates with gyrA mutations as susceptible to FQs due to a close relationship between susceptible and resistant populations. These results should be considered while improving clinical breakpoints for M. tuberculosis and may have an impact on the definition of XDR-TB.

    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:liu:diva-124557 (URN)10.1093/jac/dkv353 (DOI)000372427600008 ()26538509 (PubMedID)
    Note

    Funding agencies: Heart and Lung Foundation; Swedish Society of Antimicrobial Chemotherapy (SSAC); Swedish Medical Association; Marianne and Marcus Wallenberg Foundation

    Available from: 2016-02-03 Created: 2016-02-03 Last updated: 2019-04-24
    2. Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
    Open this publication in new window or tab >>Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
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    2018 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 10, p. 2838-2845Article in journal (Refereed) Published
    Abstract [en]

    Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (amp;lt;8 mg/L), 19% for isoniazid (amp;lt;3 mg/L), 27% for pyrazinamide (amp;lt;35 mg/L) and 16% for ethambutol (amp;lt;2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

    Place, publisher, year, edition, pages
    OXFORD UNIV PRESS, 2018
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:liu:diva-153707 (URN)10.1093/jac/dky268 (DOI)000452914200032 ()30124844 (PubMedID)
    Note

    Funding Agencies|Research Council of Southeast Sweden; Region of Ostergotland; Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Swedish Research Council; Stockholm County Council [ALF20160331]

    Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-05-02
    3. Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
    Open this publication in new window or tab >>Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
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    2018 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 5, article id e00218-18Article in journal (Refereed) Published
    Abstract [en]

    The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h post-dose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.

    Place, publisher, year, edition, pages
    AMER SOC MICROBIOLOGY, 2018
    Keywords
    pharmacokinetics; Mycobacterium tuberculosis; rifampin; isoniazid
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:liu:diva-147915 (URN)10.1128/AAC.00218-18 (DOI)000431341200022 ()29483112 (PubMedID)
    Note

    Funding Agencies|Research Council of Southeast Sweden (FORSS); Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Region of Ostergotland, Sweden; Swedish Research Council

    Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2019-05-01
    4. Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study
    Open this publication in new window or tab >>Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study
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    2018 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, no 9, article id e023899Article in journal (Refereed) Published
    Abstract [en]

    Introduction Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB. Methods and analysis Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960. Ethics and dissemination This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal. Trial registration number NCT02816931; Pre-results.

    Place, publisher, year, edition, pages
    BMJ Publishing Group Ltd, 2018
    Keywords
    tuberculosis; clinical pharmacology; public health; microbiology
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:liu:diva-153393 (URN)10.1136/bmjopen-2018-023899 (DOI)000450417800153 ()30287613 (PubMedID)2-s2.0-85054436449 (Scopus ID)
    Note

    Funding Agencies|Swedish Heart Lung Foundation [20150508]; Swedish National Research Council [540-2013-8797]; National Research Foundation of China [81361138019]

    Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-05-01Bibliographically approved
  • 17.
    Peters, Lynn
    et al.
    Karolinska Inst, Sweden.
    Olson, Linus
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Khu, Dung T. K.
    Karolinska Inst, Sweden; Vietnam Natl Childrens Hosp, Vietnam.
    Linnros, Sofia
    Karolinska Inst, Sweden.
    Le, Ngai K.
    Karolinska Inst, Sweden; Vietnam Natl Childrens Hosp, Vietnam.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Hoang, Ngoc T. B.
    Vietnam Natl Childrens Hosp, Vietnam.
    Tran, Dien M.
    Res Inst Child Hlth, Vietnam; Vietnam Natl Childrens Hosp, Vietnam.
    Larsson, Mattias
    Karolinska Inst, Sweden; Karolinska Inst, Sweden.
    Multiple antibiotic resistance as a risk factor for mortality and prolonged hospital stay: A cohort study among neonatal intensive care patients with hospital-acquired infections caused by gram-negative bacteria in Vietnam2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0215666Article in journal (Refereed)
    Abstract [en]

    Background Antibiotic resistance (ABR) is an increasing burden for global health. The prevalence of ABR in Southeast Asia is among the highest worldwide, especially in relation to hospital acquired infections (HAI) in intensive care units (ICU). However, little is known about morbidity and mortality attributable to ABR in neonates. Aim This study aimed to assess mortality and the length of hospitalization attributable to ABR in gram-negative bacteria (GNB) causing HAI in a Vietnamese neonatal ICU (NICU). Methods We conducted a prospective cohort study (n = 296) in a NICU in Hanoi, Vietnam, from March 2016 to October 2017. Patients isolated with HAI caused by GNB were included. The exposure was resistance to multiple antibiotic classes, the two outcomes were mortality and length of hospital stay (LOS). Data were analysed using two regression models, controlling for confounders and effect modifiers such as co-morbidities, time at risk, severity of illness, sex, age, and birthweight. Results The overall case fatality rate was 44.3% and the 30 days mortality rate after infection was 31.8%. For every additional resistance to an antibiotic class, the odds of a fatal outcome increased by 27% and LOS increased by 2.1 days. These results were statistically significant (p amp;lt; 0.05). Conclusion ABR was identified as a significant risk factor for adverse outcomes in neonates with HAI. These findings are generally in line with previous research in children and adults. However, heterogeneous study designs, the neglect of important confounders and varying definitions of ABR impair the validity, reliability, and comparability of results.

  • 18.
    Protudjer, Jennifer L. P.
    et al.
    Karolinska Inst, Sweden; Karolinska Inst, Sweden; Univ Manitoba, Canada; George and Fay Yee Ctr Healthcare Innovat, Canada; Childrens Hosp Res Inst Manitoba, Canada.
    Middelveld, Roelinde
    Karolinska Inst, Sweden.
    Ballardini, Natalia
    Karolinska Inst, Sweden; Soder Sjukhuset, Sweden; Kings Coll London, England.
    Wai, Hay Mar
    Karolinska Inst, Sweden.
    Ahlstedt, Staffan
    Karolinska Inst, Sweden.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Kivisto, Juho E.
    Tampere Univ Hosp, Finland; Univ Tampere, Finland.
    Epinephrine dispensings, allergy hospitalizations and the elimination of co-payments in Sweden2019In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 6, p. 1197-1200Article in journal (Other academic)
    Abstract [en]

    n/a

  • 19.
    Raffetseder, Johanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Iakobachvili, Nino
    Division of Nanoscopy, The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Peters, Peter J.
    Division of Nanoscopy, The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Retention of EsxA in the Capsule-Like Layer of Mycobacterium tuberculosis Is Associated with Cytotoxicity and Is Counteracted by Lung Surfactant2019In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 87, no 3, article id e00803-18Article in journal (Refereed)
    Abstract [en]

    Mycobacterium tuberculosis, the pathogen that causes tuberculosis, primarily infects macrophages but withstands the host cells bactericidal effects. EsxA, also called virulence factor 6-kDa early secretory antigenic target (ESAT-6), is involved in phagosomal rupture and cell death. We provide confocal and electron microscopy data showing that M. tuberculosis bacteria grown without detergent retain EsxA on their surface. Lung surfactant has detergent-like properties and effectively strips off this surface-associated EsxA, which advocates a novel mechanism of lung surfactant-mediated defense against pathogens. Upon challenge of human macrophages with these M. tuberculosis bacilli, the amount of surface-associated EsxA rapidly declines in a phagocytosis-independent manner. Furthermore, M. tuberculosis bacteria cultivated under exclusion of detergent exert potent cytotoxic activity associated with bacterial growth. Together, this study suggests that the surface retention of EsxA contributes to the cytotoxicity of M. tuberculosis and highlights how cultivation conditions affect the experimental outcome.

  • 20.
    Schaufler, Katharina
    et al.
    Ernst Moritz Arndt Univ Greifswald, Germany; Free Univ Berlin, Germany.
    Semmler, Torsten
    Robert Koch Inst, Germany.
    Wieler, Lothar H.
    Robert Koch Inst, Germany.
    Trott, Darren J.
    Univ Adelaide, Australia.
    Pitout, Johann
    Calgary Lab Serv, Canada; Univ Calgary, Canada.
    Peirano, Gisele
    Calgary Lab Serv, Canada; Univ Calgary, Canada.
    Bonnedahl, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Council, Sweden.
    Dolejska, Monika
    Univ Vet and Pharmaceut Sci Brno, Czech Republic; Univ Vet and Pharmaceut Sci Brno, Czech Republic.
    Literak, Ivan
    Univ Vet and Pharmaceut Sci Brno, Czech Republic; Univ Vet and Pharmaceut Sci Brno, Czech Republic.
    Fuchs, Stephan
    Robert Koch Inst, Germany.
    Ahmed, Niyaz
    Int Ctr Diarrheal Dis Res Bangladesh, Bangladesh.
    Grobbel, Mirjam
    German Fed Inst Risk Assessment, Germany.
    Torres, Carmen
    Univ La Rioja, Spain.
    McNally, Alan
    Univ Birmingham, England.
    Pickard, Derek
    Wellcome Trust Sanger Inst, England.
    Ewers, Christa
    Justus Liebig Univ Giessen, Germany.
    Croucher, Nicholas J.
    Imperial Coll, England.
    Corander, Jukka
    Wellcome Trust Sanger Inst, England; Univ Helsinki, Finland; Univ Oslo, Norway.
    Guenther, Sebastian
    Free Univ Berlin, Germany; Ernst Moritz Arndt Univ Greifswald, Germany.
    Genomic and Functional Analysis of Emerging Virulent and Multidrug-Resistant Escherichia coli Lineage Sequence Type 6482019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 6, article id e00243-19Article in journal (Refereed)
    Abstract [en]

    The pathogenic extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli lineage ST648 is increasingly reported from multiple origins. Our study of a large and global ST648 collection from various hosts (87 whole-genome sequences) combining core and accessory genomics with functional analyses and in vivo experiments suggests that ST648 is a nascent and generalist lineage, lacking clear phylogeographic and host association signals. By including large numbers of ST131 (n = 107) and ST10 (n = 96) strains for comparative genomics and phenotypic analysis, we demonstrate that the combination of multidrug resistance and high-level virulence are the hallmarks of ST648, similar to international high-risk clonal lineage ST131. Specifically, our in silico, in vitro, and in vivo results demonstrate that ST648 is well equipped with biofilm-associated features, while ST131 shows sophisticated signatures indicative of adaption to urinary tract infection, potentially conveying individual ecological niche adaptation. In addition, we used a recently developed NFDS (negative frequency-dependent selection) population model suggesting that ST648 will increase significantly in frequency as a cause of bacteremia within the next few years. Also, ESBL plasmids impacting biofilm formation aided in shaping and maintaining ST648 strains to successfully emerge worldwide across different ecologies. Our study contributes to understanding what factors drive the evolution and spread of emerging international high-risk clonal lineages.

  • 21.
    Sun, Chengtao
    et al.
    China Agr Univ, Peoples R China.
    Chen, Baoli
    Shandong Ctr Dis Control and Prevent, Peoples R China.
    Hulth, Anette
    Publ Hlth Agcy Sweden, Sweden; Karolinska Inst, Sweden.
    Schwarz, Stefan
    China Agr Univ, Peoples R China; Free Univ Berlin, Germany.
    Ji, Xing
    China Agr Univ, Peoples R China.
    Nilsson, Lennart E
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Ma, Shizhen
    China Agr Univ, Peoples R China.
    Sun, Qiang
    Shandong Univ, Peoples R China.
    Bi, Zhenwang
    Shandong Ctr Dis Control and Prevent, Peoples R China.
    Wang, Yang
    China Agr Univ, Peoples R China.
    Bi, Zhenqiang
    Shandong Ctr Dis Control and Prevent, Peoples R China.
    Wu, Congming
    China Agr Univ, Peoples R China.
    Börjesson, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Natl Vet Inst SVA, Sweden.
    Genomic analysis of Staphylococcus aureus along a pork production chain and in the community, Shandong Province, China2019In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 54, no 1Article in journal (Refereed)
    Abstract [en]

    Livestock-associated meticillin-resistant Staphylococcus aureus (LA-MRSA) is an increasingly important public health concern worldwide; however, data on LA-MRSA from Asian countries is scarce. As such, a comprehensive molecular epidemiological survey of S. aureus along a pork production chain and in the community was undertaken in Shandong Province, China. spa typing and whole-genome sequencing were used to survey the occurrence and potential transmission of S. aureus in various sectors, including 899 porcine samples (snout or skin swabs, carcass swabs and pork portions), 845 human nasal samples and 239 environmental samples from commercial farms, a slaughterhouse, a pork wholesale market and the surrounding community. MRSA was detected in higher frequencies in samples from two commercial pig farms (pigs, 49%; farm workers, 64%; environmental samples, 16%) than in samples from the slaughterhouse (fatteners, 8.2%; carcasses, 1.1%; operation workers, 0%; environmental samples, 3.8%), the pork wholesale market (pork, 14%; sellers, 0%) and individuals in the community (6.8%). There were significant differences in population structures, antimicrobial susceptibility profiles, and the presence of resistance and virulence genes between human- and pig-associated isolates. The phylogenetic analysis confirmed the dissemination of LA-MRSA between various segments along the pork production chain. However, MRSA of the same sequence type was not found to be disseminated between the commercial farms and the surrounding communities. Furthermore, one MRSA ST398 was observed, and a novel CC9 variant ST3597 was detected within the chain. The high MRSA carriage rates and the emergence of a new MRSA CC9 variant identified in this study highlight the need for MRSA surveillance. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  • 22.
    Svensson, Robin J.
    et al.
    Uppsala Univ, Sweden.
    Niward, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Forsman, Lina Davies
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Paues, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Eliasson, Erik
    Karolinska Univ Hosp Huddinge, Sweden.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Simonsson, Uirika S. H.
    Uppsala Univ, Sweden.
    Individualised dosing algorithm and personalised treatment of high-dose rifampicin for tuberculosis2019In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125Article in journal (Refereed)
    Abstract [en]

    Aims To propose new exposure targets for Bayesian dose optimisation suited for high-dose rifampicin and to apply them using measured plasma concentrations coupled with a Bayesian forecasting algorithm allowing predictions of future doses, considering rifampicins auto-induction, saturable pharmacokinetics and high interoccasion variability. Methods Rifampicin exposure targets for Bayesian dose optimisation were defined based on literature data on safety and anti-mycobacterial activity in relation to rifampicins pharmacokinetics i.e. highest plasma concentration up to 24 hours and area under the plasma concentration-time curve up to 24 hours (AUC(0-24h)). Targets were suggested with and without considering minimum inhibitory concentration (MIC) information. Individual optimal doses were predicted for patients treated with rifampicin (10 mg/kg) using the targets with Bayesian forecasting together with sparse measurements of rifampicin plasma concentrations and baseline rifampicin MIC. Results The suggested exposure target for Bayesian dose optimisation was a steady state AUC(0-24h) of 181-214 h x mg/L. The observed MICs ranged from 0.016-0.125 mg/L (mode: 0.064 mg/L). The predicted optimal dose in patients using the suggested target ranged from 1200-3000 mg (20-50 mg/kg) with a mode of 1800 mg (30 mg/kg, n = 24). The predicted optimal doses when taking MIC into account were highly dependent on the known technical variability of measured individual MIC and the dose was substantially lower compared to when using the AUC(0-24h)-only target. Conclusions A new up-to-date exposure target for Bayesian dose optimisation suited for high-dose rifampicin was derived. Using measured plasma concentrations coupled with Bayesian forecasting allowed prediction of the future dose whilst accounting for the auto-induction, saturable pharmacokinetics and high between-occasion variability of rifampicin.

  • 23.
    Taxbro, Knut
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Hammarskjöld, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Cty Hosp, Sweden.
    Thelin, Bo
    Ryhov Cty Hosp, Sweden.
    Lewin, Freddi
    Ryhov Cty Hosp, Sweden.
    Hagman, Helga
    Skane Univ Hosp, Sweden.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Berg, Sören
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Clinical impact of peripherally inserted central catheters vs implanted port catheters in patients with cancer: an open-label, randomised, two-centre trial2019In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 122, no 6, p. 734-741Article in journal (Refereed)
    Abstract [en]

    Background

    Centrally inserted totally implanted vascular access ports (PORTs) and peripherally inserted central catheters (PICCs) are widely used for the administration of chemotherapy. Our aim was to study the incidence of catheter-related deep venous thrombosis in patients with cancer receiving chemotherapy through either a PICC or a PORT.

    Methods

    Adults with non-haematological cancer (mainly breast and colorectal) from two Swedish oncology centres were included and followed for up to 1 yr. Patients were randomly assigned to receive a single-lumen PICC or PORT. The primary end point was the occurrence of a clinically significant catheter-related deep venous thrombosis, and the secondary end point was a composite of adverse events related to the catheter: insertion complication, thrombosis, occlusion, infection, and mechanical problems.

    Results

    The trial recruited 399 participants (PICC, n=201; PORT, n=198) between March 2013 and February 2017. The PICCs were associated with 16 (8%) deep venous thromboses compared with two (1%) in the PORT group (HR=10.2; 95% confidence interval, 2.3–44.6; P=0.002). The overall incidence of composite adverse events was higher for patients with a PICC compared with those with a PORT (HR=2.7; 95% confidence interval, 1.6–4.6; P<0.001).

    Conclusions

    PICCs are associated with higher risk for catheter-related deep venous thrombosis and other adverse events when compared with PORTs. This increased risk should be considered when choosing a vascular access device for chemotherapy, especially in patients with solid malignancy.

    The full text will be freely available from 2020-04-17 09:18
  • 24.
    Tran, Dien M.
    et al.
    Vietnam National Children’s Hospital, Hanoi, Vietnam,.
    Larsson, Mattias
    Training and Research Academic Collaboration Sweden-Vietnam / Department of Public Health Sciences, Karolinska Institutet, Sweden.
    Olson, Linus
    Training and Research Academic Collaboration Sweden-Vietnam / Department of Public Health Sciences, Karolinska Institutet, Sweden.
    Hoang, Ngoc T.B.
    Vietnam National Children’s Hospital, Hanoi, Vietnam.
    Le, Ngai K.
    Vietnam National Children’s Hospital, Hanoi, Vietnam / Training and Research Academic Collaboration Sweden-Vietnam.
    Khu, Dung T.K.
    Vietnam National Children’s Hospital, Hanoi, Vietnam / Training and Research Academic Collaboration Sweden-Vietnam.
    Nguyen, Hung D.
    St Paul Hospital, Hanoi, Vietnam.
    Vu, Tam V.
    Uong Bi Hospital, Quang Ninh, Vietnam.
    Trinh, Tinh H.
    Binh Dinh General Hospital, Vietnam.
    Le, Thinh Q.
    Children’s Hospital 1, Ho Chi Minh City (HCMC), Vietnam.
    Phan, Phuong T.T.
    Phu San Hanoi, Vietnam.
    Nguyen, Binh G.
    Bach Mai Hospital, Hanoi, Vietnam.
    Pham, Nhung H.
    Bach Mai Hospital, Hanoi, Vietnam.
    Mai, Bang H.
    108 Military Central Hospital, Hanoi, Vietnam.
    Nguyen, Tuan V.
    108 Military Central Hospital, Hanoi, Vietnam.
    Nguyen, Phuong T.K.
    108 Military Central Hospital, Hanoi, Vietnam.
    Le, Nhan D.
    Da Nang General Hospital, Vietnam.
    Huynh, Tuan M.
    University Medical Clinic, HCMC, Vietnam.
    Thu, Le T.H.
    Cho Ray Hospital, HCMC, Vietnam.
    Thanh, Tran Chi
    Training and Research Academic Collaboration Sweden-Vietnam.
    Berglund, Björn
    Vietnam National Children’s Hospital, Hanoi, Vietnam / St Paul Hospital, Hanoi, Vietnam.
    Nilsson, Lennart E.
    Vietnam National Children’s Hospital, Hanoi, Vietnam / St Paul Hospital, Hanoi, Vietnam.
    Bornefall, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Song, Le H.
    108 Military Central Hospital, Hanoi, Vietnam.
    Hanberger, Håkan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases. Training and Research Academic Collaboration Sweden-Vietnam.
    High prevalence of colonisation with carbapenem-resistant Enterobacteriaceae among patients admitted to Vietnamese hospitals: Risk factors and burden of disease2019In: Journal of Infection, ISSN 0163-4453, E-ISSN 1532-2742, Vol. 79, no 2, p. 115-122Article in journal (Refereed)
    Abstract [en]

    Background

    Carbapenem-resistant Enterobacteriaceae (CRE) is an increasing problem worldwide, but particularly problematic in low- and middle-income countries (LMIC) due to limitations of resources for surveillance of CRE and infection prevention and control (IPC).

    Methods

    A point prevalence survey (PPS) with screening for colonisation with CRE was conducted on 2233 patients admitted to neonatal, paediatric and adult care at 12 Vietnamese hospitals located in northern, central and southern Vietnam during 2017 and 2018. CRE colonisation was determined by culturing of faecal specimens on selective agar for CRE. Risk factors for CRE colonisation were evaluated. A CRE admission and discharge screening sub-study was conducted among one of the most vulnerable patient groups; infants treated at an 80-bed Neonatal ICU from March throughout June 2017 to assess CRE acquisition, hospital-acquired infection (HAI) and treatment outcome.

    Results

    A total of 1165 (52%) patients were colonised with CRE, most commonly Klebsiella pneumoniae (n=805), Escherichia coli (n=682) and Enterobacter spp. (n=61). Duration of hospital stay, HAI and treatment with a carbapenem were independent risk factors for CRE colonisation. The PPS showed that the prevalence of CRE colonisation increased on average 4.2 % per day and mean CRE colonisation rates increased from 13% on the day of admission to 89% at day 15 of hospital stay. At the NICU CRE colonisation increased from 32% at admission to 87% at discharge, mortality was significantly associated (OR 5•5, P < 0•01) with CRE colonisation and HAI on admission.

    Conclusion

    These data indicate that there is an epidemic spread of CRE in Vietnamese hospitals with rapid transmission to hospitalised patients.

  • 25.
    Zou, Huiyun
    et al.
    Shandong Univ, Peoples R China.
    Zheng, Beiwen
    Zhejiang Univ, Peoples R China.
    Sun, Mingli
    Ctr Dis Prevent and Control, Peoples R China.
    Ottoson, Jakob
    Natl Food Agcy, Sweden.
    Li, Yubo
    Ctr Dis Prevent and Control, Peoples R China.
    Berglund, Björn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Zhejiang Univ, Peoples R China.
    Chi, Xiaohui
    Shandong Univ, Peoples R China.
    Ji, Xiang
    Shandong Univ, Peoples R China.
    Li, Xuewen
    Shandong Univ, Peoples R China.
    Lundborg, Cecilia Stalsby
    Karolinska Inst, Sweden.
    Nilsson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Evaluating Dissemination Mechanisms of Antibiotic-Resistant Bacteria in Rural Environments in China by Using CTX-M-Producing Escherichia coli as an Indicator2019In: Microbial Drug Resistance, ISSN 1076-6294, E-ISSN 1931-8448Article in journal (Refereed)
    Abstract [en]

    It is becoming increasingly recognized that the environment plays an important role both in the emergence and in dissemination of antibiotic-resistant bacteria (ARB), Mechanisms and factors facilitating this development are, however, not yet well understood. The high detection rate of CTX-M genes in environmental sources provides an opportunity to explore this issue. In this study, 88 CTX-M-producing Escherichia coli were isolated from 30 pig feces samples from 30 pig farms and 201 environmental samples. CTX-M-producing E. coli was detected with the following frequencies in the different types of samples: pig feces, 73%; river water, 64%; river sediment, 52%; wastewater, 31%; drinking water, 23%; outlet sediment, 21%; soil, 17%; and vegetables, 4.4%. Dissemination of CTX-M-producing E. coli to different environmental matrices was evaluated by analyzing the genetic relatedness of isolates from different environmental sources, and putative transmission routes through bird feces, pig feces, drinking water, river sediment, river water, and wastewater were hypothesized. Dissemination through these routes is likely facilitated by anthropogenic activities and environmental factors. Wild birds as potential vectors for dissemination of CTX-M-producing E. coli have the capacity to spread ARB across long distances. Regional dissemination between different environmental matrices of CTX-M-producing E. coli increases the exposure risk of humans and animals in the area.

    The full text will be freely available from 2020-05-22 08:00
  • 26.
    Zurkirchen, Luis
    et al.
    Univ Zurich, Switzerland.
    Varum, Sandra
    Univ Zurich, Switzerland.
    Giger, Sonja
    Univ Zurich, Switzerland.
    Klug, Annika
    Univ Zurich, Switzerland.
    Hausel, Jessica
    Univ Zurich, Switzerland.
    Bossart, Raphael
    Univ Zurich, Switzerland.
    Zemke, Martina
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Atak, Zeynep Kalender
    Katholieke Univ Leuven, Belgium.
    Zamboni, Nicola
    Swiss Fed Inst Technol, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Sommer, Lukas
    Univ Zurich, Switzerland.
    Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner2019In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 2192Article in journal (Refereed)
    Abstract [en]

    The transcription factor Yin Yang 1 (YY1) plays an important role in human disease. It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. Here, we show that Yy1 controls murine cerebral cortex development in a stage-dependent manner. By regulating a wide range of metabolic pathways and protein translation, Yy1 maintains proliferation and survival of neural progenitor cells (NPCs) at early stages of brain development. Despite its constitutive expression, however, the dependence on Yy1 declines over the course of corticogenesis. This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Thus, our study unravels a novel role for Yy1 as a stage-dependent regulator of brain development and shows that biosynthetic demands of NPCs dynamically change throughout development.

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