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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.
    Berglund, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Bich Hoang, Ngoc Thi
    Vietnam Natl Childrens Hosp, Vietnam.
    Tärnberg, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Kien Le, Ngai
    Vietnam Natl Childrens Hosp, Vietnam.
    Nilsson, Maud
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Khanh Khu, Dung Thi
    Vietnam Natl Childrens Hosp, Vietnam; TRAC Sweden Vietnam, Vietnam.
    Svartstrom, Olov
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology.
    Welander, Jenny
    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.
    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.
    Olson, Linus
    TRAC Sweden Vietnam, Vietnam; Karolinska Inst, Sweden.
    Minh Dien, Tran
    Vietnam Natl Childrens Hosp, Vietnam.
    Thanh Le, Hai
    Vietnam Natl Childrens Hosp, Vietnam; TRAC Sweden Vietnam, Vietnam.
    Larsson, Mattias
    TRAC Sweden Vietnam, Vietnam; Karolinska Inst, 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. TRAC Sweden Vietnam, Vietnam.
    Molecular and phenotypic characterization of clinical isolates belonging to a KPC-2-producing strain of ST15 Klebsiella pneumoniae from a Vietnamese pediatric hospital2019In: Antimicrobial Resistance and Infection Control, ISSN 2047-2994, E-ISSN 2047-2994, Vol. 8, no 1, article id 156Article in journal (Refereed)
    Abstract [en]

    Background Carbapenem-resistant Klebsiella pneumoniae are becoming increasingly common in hospital settings worldwide and are a source of increased morbidity, mortality and health care costs. The global epidemiology of carbapenem-resistant K. pneumoniae is characterized by different strains distributed geographically, with the strain ST258 being predominant in Europe and USA, and ST11 being most common in East Asia. ST15 is a less frequently occurring strain but has nevertheless been reported worldwide as a source of hospital outbreaks of carbapenem-resistant K. pneumoniae. Methods In this study, whole-genome sequencing and antimicrobial susceptibility testing was used to characterize 57 clinical isolates of carbapenem-resistant K. pneumoniae belonging to a strain of ST15, which were collected at a Vietnamese pediatric hospital from February throughout September 2015. Results Aside from the carbapenem resistance gene bla(KPC-2), which was carried by all isolates, prevalence of resistance genes to other antibiotics including aminoglycosides, macrolides, quinolones, fosfomycin and trimethoprim, was also high. All isolates were multidrug-resistant. Susceptibility was highest to ceftazidime/avibactam (96%), gentamicin (91%) and tigecycline (82%). Notably, the colistin resistance rate was very high (42%). Single-nucleotide polymorphism analysis indicated that most isolates belonged to a single clone. Conclusions The diverse variety of antibiotic resistance genes and the high antibiotic resistance rates to last-resort antibiotics such as carbapenems and colistin, is indicative of a highly adaptable strain. This emphasizes the importance of implementation of infection controls measures, continued monitoring of antibiotic resistance and prudent use of antibiotics to prevent further selection of resistant strains and the emergence of pan-resistant clones.

  • 7.
    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.

  • 8.
    Cohen, Adam
    et al.
    St Olavs Hosp, Norway.
    Mathiasen, Victor Dahl
    Statens Serum Inst, Denmark; Aarhus Univ Hosp, Denmark.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Wejse, Christian
    INDEPTH Network, Guinea Bissau; Aarhus Univ GloHAU, Denmark.
    The global prevalence of latent tuberculosis: a systematic review and meta-analysis2019In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54, no 3, article id 1900655Article, review/survey (Refereed)
    Abstract [en]

    In 1999, the World Health Organization (WHO) estimated that one-third of the worlds population had latent tuberculosis infection (LTBI), which was recently updated to one-fourth. However, this is still based on controversial assumptions in combination with tuberculin skin test (TST) surveys. Interferon-gamma release assays (IGRAs) with a higher specificity than TST have since been widely implemented, but never used to estimate the global LTBI prevalence. We conducted a systematic review and meta-analysis of LTBI estimates based on both IGRA and TST results published between 2005 and 2018. Regional and global estimates of LTBI prevalence were calculated. Stratification was performed for low, intermediate and high TB incidence countries and a pooled estimate for each area was calculated using a random effects model. Among 3280 studies screened, we included 88 studies from 36 countries with 41 IGRA (n=67 167) and 67 TST estimates (n=284 644). The global prevalence of LTBI was 24.8% (95% CI 19.7-30.0%) and 21.2% (95% CI 17.9-24.4%), based on IGRA and a 10-mm TST cut-off, respectively. The prevalence estimates correlated well to WHO incidence rates (Rs=0.70, pamp;lt;0.001). In the first study of the global prevalence of LTBI derived from both IGRA and TST surveys, we found that one-fourth of the worlds population is infected. This is of relevance, as both tests, although imperfect, are used to identify individuals eligible for preventive therapy. Enhanced efforts are needed targeting the large pool of latently infected individuals, as this constitutes an enormous source of potential active tuberculosis.

  • 9.
    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.

  • 10.
    Davies Forsman, Lina
    et al.
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Jonsson, Jerker
    Karolinska Inst, Sweden; Publ Hlth Agcy Sweden, Sweden.
    Wagrell, Charlotta
    Karolinska Inst, Sweden.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Sweden.
    Mansjo, Mikael
    Publ Hlth Agcy Sweden, Sweden.
    Wijkander, Maria
    Publ Hlth Agcy Sweden, Sweden.
    Groenheit, Ramona
    Publ Hlth Agcy Sweden, Sweden.
    Hammar, Ulf
    Karolinska Inst, Sweden.
    Giske, Christian G.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, 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.
    Bruchfeld, Judith
    Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
    Minimum Inhibitory Concentrations of Fluoroquinolones and Pyrazinamide Susceptibility Correlate to Clinical Improvement in Multidrug-resistant Tuberculosis Patients: A Nationwide Swedish Cohort Study Over 2 Decades2019In: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 69, no 8, p. 1394-1402Article in journal (Refereed)
    Abstract [en]

    Background. Minimum inhibitory concentration (MIC) testing, unlike routine drug susceptibility testing (DST) at a single critical concentration, quantifies drug resistance. The association of MICs and treatment outcome in multidrug-resistant (MDR)-tuberculosis patients is unclear. Therefore, we correlated MICs of first- and second-line tuberculosis drugs with time to sputum culture conversion (tSCC) and treatment outcome in MDR-tuberculosis patients. Methods. Clinical and demographic data of MDR-tuberculosis patients in Sweden, including DST results, were retrieved from medical records from 1992 to 2014. MIC determinations were performed retrospectively for the stored individual Mycobacterium tuberculosis (Mtb) isolates using broth microdilution in Middlebrook 7H9. We fitted Cox proportional hazard models correlating MICs, DST results, and clinical variables to tSCC and treatment outcome. Results. Successful treatment outcome was observed in 83.5% (132/158) of MDR-tuberculosis patients. Increasing MICs of fluoroquinolones, diabetes, and age amp;gt;40 years were significantly associated with unsuccessful treatment outcome. Patients treated with pyrazinamide (PZA) had a significantly shorter tSCC compared to patients who were not (median difference, 27 days). Conclusions. Increasing MICs of fluoroquinolones were correlated with unsuccessful treatment outcome in MDR-tuberculosis patients. Further studies, including MIC testing and clinical outcome data to define clinical Mtb breakpoints, are warranted. PZA treatment was associated with shorter tSCC, highlighting the importance of PZA DST.

  • 11.
    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.

  • 12.
    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.

  • 13.
    Eskeland, Sveinung
    et al.
    Norwegian Univ Life Sci, Norway.
    Stuen, Snorre
    Norwegian Univ Life Sci, Norway.
    Crosby, Francy L.
    Univ Florida, FL 32608 USA.
    Lybeck, Kari
    Norwegian Vet Inst, Norway.
    Barbet, Anthony F.
    Univ Florida, FL 32608 USA.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Tollefsen, Stig
    Norwegian Vet Inst, Norway.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Tollersrud, Tore S.
    Norwegian Meat and Poultry Res Ctr, Norway.
    Makvandi-Nejad, Shokouh
    Norwegian Vet Inst, Norway.
    Granquist, Erik G.
    Norwegian Univ Life Sci, Norway.
    Assessing the clinical and bacteriological outcomes of vaccination with recombinant Asp14 and OmpA against A. phagocytophilum in sheep2019In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 218, article id UNSP 109936Article in journal (Refereed)
    Abstract [en]

    Anaplasma phagocytophilum is a tick borne bacterium, causing disease in sheep and other mammals, including humans. The bacterium has great economic and animal welfare implications for sheep husbandry in Northern Europe. With the prospect of a warmer and more humid climate, the vector availability will likely increase, resulting in a higher prevalence of A. phagocytophilum. The current preventive measures, as pyrethroids acting on ticks or long acting antibiotics controlling bacterial infection, are suboptimal for prevention of the disease in sheep. Recently, the increased awareness on antibiotic- and pyrethorid resistance, is driving the search for a new prophylactic approach in sheep against A. phagocytophilum. Previous studies have used an attenuated vaccine, which gave insufficient protection from challenge with live bacteria. Other studies have focused on bacterial membrane surface proteins like Asp14 and OmpA. An animal study using homologous proteins to Asp14 and OmpA of A. marginate, showed no protective effect in heifers. In the current study, recombinant proteins of Asp14 (rAsp14) and OmpA (rOmpA) of A. phagocytophilum were produced and prepared as a vaccine for sheep. Ten lambs were vaccinated twice with an adjuvant emulsified with rAsp14 or rOmpA, three weeks apart and challenged with a live strain of A. phagocytophilum (GenBank acc.nr M73220) on day 42. The control group consisted of five lambs injected twice with PBS and adjuvant. Hematology, real time qPCR, immunodiagnostics and flow cytometric analyses of peripheral blood mononuclear cells were performed. Vaccinated lambs responded with clinical signs of A.phagocytophilum infection after challenge and bacterial load in the vaccinated group was not reduced compared to the control group. rAsp14 vaccinated lambs generated an antibody response against the vaccine, but a clear specificity for rAsp14 could not be established. rOmpA-vaccinated lambs developed a strong specific antibody response on days 28 after vaccination and 14 days post-challenge. Immunofluorescent staining and flow cytometric analysis of peripheral blood mononuclear monocytes revealed no difference between the three groups, but the percentage of CD4, CD8(+), gamma delta TcR+, lambda-Light chain(+), CD11b(+), CD14(+) and MHC II+ cells, within the groups changed during the study, most likely due to the adjuvant or challenge with the bacterium. Although an antigen specific antibody response could be detected against rOmpA and possibly rAsp14, the vaccines seemed to be ineffective in reducing clinical signs and bacterial load caused by A. phagocytophilum. This is the first animal study with recombinant Asp14 and OmpA aimed at obtaining clinical protection against A. phagocytophilum in sheep.

  • 14.
    Jaenson, Thomas G. T.
    et al.
    Uppsala Univ, Sweden.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Reg Jonkoping Cty, Sweden.
    First records of tick-borne pathogens in populations of the taiga tick Ixodes persulcatus in Sweden2019In: Parasites & Vectors, ISSN 1756-3305, E-ISSN 1756-3305, Vol. 12, no 1, article id 559Article in journal (Refereed)
    Abstract [en]

    Background: The common tick Ixodes ricinus and the taiga tick I. persulcatus are the main tick vectors of Borrelia spirochaetes, TBE virus (TBEV) and of several other zoonotic pathogens in the western and eastern areas, respectively of the Palaearctic region. Recently, populations of the taiga tick were, for the first time, detected in northern Sweden. This prompted us to investigate if they harbour human pathogens. Methods: A total of 276 I. persulcatus ticks (136 males, 126 females and 14 nymphs) and one I. ricinus nymph was collected by the cloth-dragging method in northern Sweden in July-August 2015 and May-July 2016. In addition, 8 males and 10 females of I. persulcatus were collected from two dogs (16 and 2 ticks, respectively) in two of the localities. All ticks were microscopically and molecularly identified to developmental stage and species and screened for B. burgdorferi (sensu lato), B. miyamotoi, Anaplasma phagocytophilum, Rickettsia spp., Neoehrlichia mikurensis, Babesia spp. and TBEV using real-time PCR followed by species identification by sequencing the PCR-products of conventional PCR assays. Results: Of the ticks collected by the cloth-dragging method, 55% (152/277) were positive for Borrelia. There was no significant difference between the proportions of Borrelia-infected nymphs (33%, 5/15) and Borrelia-infected adult ticks (56%, 147/262), and no significant difference between the proportions of Borrelia-infected males (54%, 74/136) and Borrelia-infected females (58%, 73/126). Three different Borrelia species were identified. Borrelia afzelii was the predominant species and detected in 46% of all Borrelia-infected ticks followed by B. garinii, 35%, B. valaisiana, 1%, and mixed infections of different Borrelia species, 1%; 17% of all Borrelia-infections were untypeable. One I. persulcatus female contained Rickettsia helvetica, and one nymph contained Rickettsia sp. Of the 277 ticks analysed, all were negative for A. phagocytophilum, Babesia spp., Borrelia miyamotoi, N. mikurensis and TBEV. The ticks collected from the two dogs were negative for all pathogens examined except for Borrelia spp., that was detected in 5 out of 16 ticks removed from one of the dogs. Conclusions: To our knowledge, this is the first time that I. persulcatus from Sweden has been analysed for the presence of tick-borne pathogens. The examined tick populations had a low diversity of tick-borne pathogens but a high prevalence of B. burgdorferi (s.l.).

  • 15.
    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.

  • 16.
    Jonsson Henningsson, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Asgeirsson, Hilmir
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Hammas, Berit
    Karolinska Univ Hosp, Sweden.
    Karlsson, Elias
    Danderyd Hosp, Sweden.
    Parke, Asa
    Karolinska Univ Hosp, Sweden.
    Hoornstra, Dieuwertje
    Acad Med Ctr, Netherlands.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Hovius, Joppe W.
    Acad Med Ctr, Netherlands.
    Two Cases of Borrelia miyamotoi Meningitis, Sweden, 20182019In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 25, no 10, p. 1965-1968Article in journal (Refereed)
    Abstract [en]

    We report 2 human cases of Borrelia miyamotoi disease diagnosed in Sweden, including 1 case of meningitis in an apparently immunocompetent patient. The diagnoses were confirmed by 3 different independent PCR assays and DNA sequencing from cerebrospinal fluid, supplemented by serologic analyses.

  • 17.
    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

  • 18.
    Lager, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Dessau, Ram B.
    Department of Clinical Microbiology, Slagelse Hospital, Slagelse, Denmark.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Nyman, D.
    The Åland Group for Borrelia Research, Åland, Mariehamn, Finland.
    Jensen, G.F.
    Department of Medical Microbiology, Sørlandet Hospital, Kristiansand, Norway.
    Matussek, A.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Division of Clinical Microbiology, Laboratory Medicine, Jönköping Region Jönköping County, Sweden, Ryhov County Hospital, Jönköping, Sweden; Karolinska University Laboratory, Stockholm, Sweden; Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Jonsson Henningsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Division of Clinical Microbiology, Laboratory Medicine, Jönköping Region Jönköping County, Sweden.
    Serrander, Lena (Contributor)
    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.
    Serological diagnostics of Lyme borreliosis: comparison of assays in twelve clinical laboratories in Northern Europe2019In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 38, no 10, p. 1933-1945Article in journal (Refereed)
    Abstract [en]

    Lyme borreliosis (LB), caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex, is the most common tick-borne infection in Europe. Laboratory diagnosis of LB is mainly based on the patients’ medical history, clinical signs and symptoms in combination with detection of Borrelia-specific antibodies where indirect enzyme-linked-immunosorbent assay (ELISA) is the most widely used technique. The objective of the study was to evaluate and compare the diagnostic accuracy (sensitivities and specificities) of serological tests that are currently in use for diagnosis of LB in clinical laboratories in Northern Europe, by use of a large serum panel. The panel consisted of 195 serum samples from well-characterized and classified patients under investigation for clinically suspected LB (n = 59) including patients with Lyme neuroborreliosis, Lyme arthritis, acrodermatitis chronica atrophicans, erythema migrans or other diseases (n = 112). A total of 201 serum samples from healthy blood donors were also included. The panel (396 serum samples altogether) was sent to 12 clinical laboratories (using five different ELISA methods) as blinded for group affiliation and the laboratories were asked to perform serological analysis according to their routine procedure. The results from the study demonstrated high diagnostic concordance between the laboratories using the same diagnostic assay and lower diagnostic concordance between laboratories using different diagnostic assays. For IgG, the results were in general rather homogenous and showed an average sensitivity of 88% (range 85–91%) compared to IgM which showed lower average sensitivity of 59% (range 50–67%) and more heterogeneous results between assays and laboratories. © 2019, The Author(s).

  • 19.
    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.

  • 20.
    Li, Jiyun
    et al.
    China Agr Univ, Peoples R China; Hunan Agr Univ, Peoples R China.
    Bi, Zhenwang
    Shandong Acad Clin Med, Peoples R China.
    Ma, Shizhen
    China Agr Univ, Peoples R China.
    Chen, Baoli
    Shandong Ctr Dis Control and Prevent, Peoples R China.
    Cai, Chang
    Zhejiang Agr and Forestry Univ, Peoples R China; Murdoch Univ, Australia.
    He, Junjia
    China Agr Univ, Peoples R China.
    Schwarz, Stefan
    China Agr Univ, Peoples R China; Free Univ Berlin, Germany.
    Sun, Chengtao
    China Agr Univ, Peoples R China.
    Zhou, Yuqing
    China Agr Univ, Peoples R China.
    Yin, Jia
    Shandong Univ, Peoples R China; Shandong Univ, Peoples R China.
    Hulth, Anette
    Karolinska Inst, Sweden; Publ Hlth Agcy Sweden, Sweden.
    Wang, Yongqiang
    China Agr Univ, Peoples R China.
    Shen, Zhangqi
    China Agr Univ, Peoples R China.
    Wang, Shaolin
    China Agr Univ, Peoples R China.
    Wu, Congming
    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.
    Walsh, Timothy R.
    China Agr Univ, Peoples R China; Cardiff Univ, Wales.
    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.
    Shen, Jianzhong
    China Agr Univ, Peoples R China.
    Sun, Qiang
    Shandong Univ, Peoples R China.
    Wang, Yang
    China Agr Univ, Peoples R China.
    Inter-host Transmission of Carbapenemase-Producing Escherichia coli among Humans and Backyard Animals2019In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 127, no 10, article id 107009Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The rapidly increasing dissemination of carbapenem-resistant Enterobacteriaceae (CRE) in both humans and animals poses a global threat to public health. However, the transmission of CRE between humans and animals has not yet been well studied. OBJECTIVES: We investigated the prevalence, risk factors, and drivers of CRE transmission between humans and their backyard animals in rural China. METHODS: We conducted a comprehensive sampling strategy in 12 villages in Shandong, China. Using the household [residents and their backyard animals (farm and companion animals)] as a single surveillance unit, we assessed the prevalence of CRE at the household level and examined the factors associated with CRE carriage through a detailed questionnaire. Genetic relationships among human- and animal-derived CRE were assessed using whole-genome sequencing-based molecular methods. RESULTS: A total of 88 New Delhi metallo-beta-lactamases-type carbapenem-resistant Escherichia coli (NDM-EC), including 17 from humans, 44 from pigs, 12 from chickens, 1 from cattle, and 2 from dogs, were isolated from 65 of the 746 households examined. The remaining 12 NDM-EC were from flies in the immediate backyard environment. The NDM-EC colonization in households was significantly associated with a) the number of species of backyard animals raised/kept in the same household, and b) the use of human and/or animal feces as fertilizer. Discriminant analysis of principal components (DAPC) revealed that a large proportion of the core genomes of the NDM-EC belonged to strains from hosts other than their own, and several human isolates shared closely related core single-nucleotide polymorphisms and bla(NDM)( )genetic contexts with isolates from backyard animals. CONCLUSIONS: To our knowledge, we are the first to report evidence of direct transmission of NDM-EC between humans and animals. Given the rise of NDM-EC in community and hospital infections, combating NDM-EC transmission in backyard farm systems is needed.

  • 21.
    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).

  • 22.
    Marti, M.
    et al.
    Linköping University, Department of Thematic Studies, Tema Environmental Change. Linköping University, Faculty of Arts and Sciences.
    Nilsson, M. B.
    Swedish Univ Agr Sci, Sweden.
    Danielsson, Åsa
    Linköping University, Department of Thematic Studies, Tema Environmental Change. Linköping University, Faculty of Arts and Sciences.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Svensson, Bo
    Linköping University, Department of Thematic Studies, Tema Environmental Change. Linköping University, Faculty of Arts and Sciences.
    Strong long-term interactive effects of warming and enhanced nitrogen and sulphur deposition on the abundance of active methanogens in a boreal oligotrophic mire2019In: Mires and Peat, ISSN 1819-754X, E-ISSN 1819-754X, Vol. 24, p. 1-14, article id 29Article in journal (Refereed)
    Abstract [en]

    Peatlands play a key role in the carbon cycle by being a considerable source of atmospheric methane. Thus, an understanding of the microbial production of methane is important in relation to environmental changes of peatlands. We applied real-time PCR on the mcrA gene and transcript to investigate the peat methanogen community response to the combined effect of 18 years of simulated warming and deposition of nitrogen (N) and sulphur (S) at a boreal oligotrophic mire in Sweden. The long-term effects of the experimental treatments on the methanogens was highly dependent on interactions between the treatment factors Enhanced N deposition amplified the effect of warming, resulting in a further increase of the abundance of active methanogens. The effect of the perturbations was modulated by the depth horizon, with the strongest effect at the water level, where the interaction between enhanced N and S deposition, and warming, resulted in an increase of active methanogens. These results indicate that increasing average temperatures and simultaneously higher N deposition rates will substantially increase the methanogenic activity in northern ombrotrophic peatlands. These findings strongly highlight the importance of accounting for any possible interactive perturbation effects when investigating the response of peat methanogens to environmental change.

  • 23.
    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.

  • 24.
    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.
    Pizzolato, Giulia
    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 activator FOXB2 drives the neuroendocrine differentiation of prostate cancer2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 44, p. 22189-22195Article in journal (Refereed)
    Abstract [en]

    The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces multiple Wnt ligands, including WNT7B, which increases TCF/LEF-dependent transcription without activating Wnt coreceptor LRP6 or beta-catenin. Proximity ligation and functional complementation assays identified several transcription regulators, including YY1, JUN, and DDX5, as cofactors required for FOXB2-dependent pathway activation. Although FOXB2 expression is limited in adults, it is induced in select cancers, particularly advanced prostate cancer. RNA-seq data analysis suggests that FOXB2/WNT7B expression in prostate cancer is associated with a transcriptional program that favors neuronal differentiation and decreases recurrence-free survival. Consistently, FOXB2 controls Wnt signaling and neuroendocrine differentiation of prostate cancer cell lines. Our results suggest that FOXB2 is a tissue-specific Wnt activator that promotes the malignant transformation of prostate cancer.

  • 25.
    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.

  • 26.
    Ocias, Lukas Frans
    et al.
    Statens Serum Inst, Denmark; Rigshosp, Denmark.
    Wilhelmsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Sjöwall, Johanna
    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.
    Jonsson Henningsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Nordberg, Marika
    Aland Cent Hosp, Finland.
    Jorgensen, Charlotte Svaerke
    Statens Serum Inst, Denmark.
    Krogfelt, Karen Angeliki
    Statens Serum Inst, Denmark; Roskilde Univ, Denmark.
    Forsberg, Pia
    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.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Ryhov, Sweden.
    Emerging tick-borne pathogens in the Nordic countries: A clinical and laboratory follow-up study of high-risk tick-bitten individuals2020In: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 11, no 1, article id UNSP 101303Article in journal (Refereed)
    Abstract [en]

    Despite the presence of several microorganisms, other than Borrelia burgdorferi sensu lato (Bbsl) and TBE virus, in Ixodes ricinus ticks from the Nordic countries, data is lacking on their pathogenic potential in humans. In this study, we wanted to investigate the aetiology and clinical manifestations of tick-transmitted infections in individuals seeking medical care following a tick-bite. The sampling frame was participants of a large-scale, prospective, multi-centre, follow-up study of tick-bitten volunteers recruited in Sweden, Finland and Norway in the years 2007-2015. Participants who sought medical care during the three-month follow-up period and from whom blood samples were collected during this healthcare visit (n=92) were tested, using PCR, for exposure to spotted fever group (SFG) Rickettsia spp., Anaplasma phagocytophilum and Babesia spp. Moreover, 86 of these individuals had two serum samples, collected three months apart, tested serologically for six tick-borne microorganisms. The selected organisms-Bbsl, SFG rickettsiae, Anaplasma phagocytophilum, TBE virus, Babesia microti and Bartonella henselae-have all been detected in field-collected ticks from the Nordic countries. Medical records were reviewed and questionnaires were completed to determine clinical manifestations. We found Lyme borreliosis to be the most common tick-transmitted infection as seen in 46 (54%) of the 86 participants with available medical records. Among the 86 participants with paired sera, serological or molecular evidence of recent exposure to other microorganisms than Bbsl could be demonstrated in eight (9%). Five participants (6%) exhibited serological evidence of recent concomitant exposure to more than one tick-borne microorganism. Clinical presentations were mild with one exception (TBE). In conclusion, our data suggest a low risk of infection with tick-borne microorganisms, other than Bbsl, in immunocompetent tick-bitten persons from the examined regions, a low occurrence of co-infection and mostly mild or no overt clinical signs of infection in immunocompetent persons exposed to the studied agents.

  • 27.
    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.

  • 28.
    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

  • 29.
    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.

  • 30.
    Sandholm, Kerstin
    et al.
    Linnaeus University, Kalmar, Sweden.
    Carlsson, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Department of Clinical Chemistry and Transfusion Medicine, Kalmar, Region Kalmar County.
    Persson, Barbro
    Uppsala University, Uppsala, Sweden.
    Skattum, Lillemor
    Lund University, Lund, Sweden; Clinical Immunology and Transfusion Medicine, Lund, Sweden..
    Tjernberg, Ivar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Nilsson, Bo
    Uppsala University, Uppsala, Sweden.
    Ekdahl, Kristina N
    Linnaeus University, Kalmar, Sweden; Uppsala University, Uppsala, Sweden.
    Discrepancies in plasma levels of complement components measured by a newly introduced commercially available magnetic bead technique compared to presently available clinical reference intervals2019In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, article id e12831Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Complement system aberrations are implicated in numerous pathological conditions. Techniques used in complement diagnostic include monitoring of individual proteins, activation products or function using different types of immunoassays. Most recent techniques include multiplex assays which enable simultaneous detection of multiple complement components or activation products in the same sample thereby saving both sample volume and time.

    MATERIALS AND METHODS: We have tested the performance of the commercially available Human Complement Magnetic Bead multiplex assay MILLIPLEX MAP H (EMD Millipore Corporation, Billerica, MA, USA) for simultaneous determination of C1q, C4, C3, factor B, properdin and factor H as well as MBL, C2, factor D, factor I, C5 and C9 using plasma from 68 healthy blood donors.

    RESULTS: The main observation was very low levels of C3 determined by the MILLIPLEX assay: median value 16.4 mg/L (range 7.7-57.4) compared to the present reference value of 670-1290 mg/L used in the clinic (i.e., 60-fold lower). Discrepancies (although not as pronounced as for C3) were also found for C1q, factor B, factor H, C2 and C9.

    CONCLUSION: The MILLIPEX assay is highly inaccurate regarding C3 and less reliable for several other analytes, and implies that the company should reconstruct their assay for C3 since the results are not on par with the standard of other techniques used today.

  • 31.
    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.

  • 32.
    Schulman, H.
    et al.
    Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    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.
    Abate, E.
    Univ Gondar, Ethiopia; Ethiopian Publ Hlth Inst, Ethiopia.
    Idh, Jonna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Axenram, P.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bornefall, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Forsgren, S.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jakobsson, J.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ohrling, C.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kron, M.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Diro, E.
    Univ Gondar, Ethiopia.
    Kebede, A. Getachew
    Addis Ababa Univ, Ethiopia.
    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.
    Bruchfeld, J.
    Karolinska Inst, Sweden.
    Wejse, C.
    Indepth Network, Guinea Bissau; Aarhus Univ Hosp, Denmark; Aarhus Univ, Denmark.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Sedimentation rate and suPAR in relation to disease activity and mortality in patients with tuberculosis2019In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 23, no 11, p. 1155-1161Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE : To investigate how levels of the soluble urokinase plasminogen activator receptor (suPAR) and erythrocyte sedimentation rate (ESR) correlate with disease activity and prognosis in pulmonary tuberculosis (PTB). DESIGN: This was a retrospective analysis of patients with active PTB (n = 500) in Gondar, Ethiopia, for whom the suPAR (n = 301) and ESR (n = 330) were analysed at the start of treatment. Both biomarkers were available for 176 patients. Human immunodeficiency virus (HIV) status, chest X-ray (CXR) findings, classification according to the clinical TBscore and treatment outcome were all recorded. RESULTS : In a multivariable logistic regression analysis adjusted for age, sex and HIV status, surrogate markers of disease activity such as advanced CXR patterns correlated with increased levels of suPAR (adjusted OR [aOR] 8.24, Pamp;lt; 0.001) and of ESR (aOR 1.63, P = 0.030), whereas ESR only correlated significantly with a TBscore amp;gt;6 points. Increased levels of both suPAR and ESR were associated with unsuccessful treatment outcomes (aOR 2.93, P = 0.013; aOR 2.52, P = 0.025). The highest quartile of suPAR (aOR 13.3, P = 0.029) but not ESR levels correlated independently with increased mortality. CONCLUSION: SuPAR and ESR levels correlate with disease activity in PTB; however, the clinical role of these potentially prognostic biomarkers needs to be verified in prospective studies.

  • 33.
    Schön, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    The evaluation of routine immunological tests to estimate the risk of progression into active tuberculosis2019In: The International Journal of Tuberculosis and Lung Disease, ISSN 1027-3719, E-ISSN 1815-7920, Vol. 23, no 11, p. 1127-1128Article in journal (Other academic)
    Abstract [en]

    n/a

  • 34.
    Seitanidou, Maria S
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Blomgran, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Pushpamithran, Giggil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
    Berggren, Magnus
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Simon, Daniel
    Linköping University, Department of Science and Technology, Laboratory of Organic Electronics. Linköping University, Faculty of Science & Engineering.
    Modulating Inflammation in Monocytes Using Capillary Fiber Organic Electronic Ion Pumps2019In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 8, no 19, article id 1900813Article in journal (Refereed)
    Abstract [en]

    An organic electronic ion pump (OEIP) delivers ions and drugs from a source, through a charge selective membrane, to a target upon an electric bias. Miniaturization of this technology is crucial and will provide several advantages, ranging from better spatiotemporal control of delivery to reduced invasiveness for implanted OEIPs. To miniaturize OEIPs, new configurations have been developed based on glass capillary fibers filled with an anion exchange membrane (AEM). Fiber capillary OEIPs can be easily implanted in proximity to targeted cells and tissues. Herein, the efficacy of such a fiber capillary OEIP for modulation of inflammation in human monocytes is demonstrated. The devices are located on inflammatory monocytes and local delivery of salicylic acid (SA) is initiated. Highly localized SA delivery results in a significant decrease in cytokine (tumor necrosis factor alpha and interleukin 6) levels after lipopolysaccharide stimulation. The findings-the first use of such capillary OEIPs in mammalian cells or systems-demonstrate the utility of the technology for optimizing transport and delivery of different therapeutic substances at low concentrations, with the benefit of local and controlled administration that limits the adverse effect of oral/systemic drug delivery.

    The full text will be freely available from 2020-09-10 13:45
  • 35.
    Simonsson, Per
    et al.
    Siemens healthineers, Solna, Sweden.
    Tjernberg, Ivar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Landstinget i Kalmar län, Kalmar, Sweden.
    Egenordinerad provtagning kan ge laboratoriemedicinen ny roll [Patient-initiated diagnostics - a challenge for laboratory medicine]2019In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, article id FIFWArticle in journal (Other academic)
    Abstract [sv]

    Citizens can now order their own laboratory investigations. Self-testing is in line with increasing patient empowerment and in conflict with existing routines in medicine where all tests are ordered by the physician. Several challenges have to be faced by laboratory medicine to secure the quality and increase the medical benefits of patient-initiated diagnostics.

  • 36.
    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.

  • 37.
    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.

  • 38.
    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
  • 39.
    Tien Viet Dung, Vu
    et al.
    Univ Oxford, Vietnam.
    Thi Thuy Nga, Do
    Univ Oxford, Vietnam.
    Rydell, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Olson, Linus
    Karolinska Inst, Sweden; Training and Res Acad Collaborat Sweden Viet Nam, Vietnam.
    Larsson, Mattias
    Univ Oxford, Vietnam; Karolinska Inst, Sweden; Training and Res Acad Collaborat Sweden Viet Nam, 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 Res Acad Collaborat Sweden Viet Nam, Vietnam.
    Choisy, Marc
    Univ Oxford, Vietnam; French Natl Res Inst Sustainable Dev, France; French Natl Ctr Sci Res, France; Univ Montpellier, France.
    Tuyet Trinh, Dao
    Natl Hosp Trop Dis, Vietnam.
    van Doorn, H. Rogier
    Univ Oxford, Vietnam.
    Van Kinh, Nguyen
    Natl Hosp Trop Dis, Vietnam.
    Vu Trung, Nguyen
    Natl Hosp Trop Dis, Vietnam.
    Wertheim, Heiman F. L.
    Univ Oxford, Vietnam; Radboudumc, Netherlands; Radboudumc, Netherlands.
    Antimicrobial susceptibility testing and antibiotic consumption results from 16 hospitals in Viet Nam: The VINARES project 2012-20132019In: Journal of Global Antimicrobial Resistance, ISSN 2213-7165, E-ISSN 2213-7173, Vol. 18, p. 269-278Article in journal (Refereed)
    Abstract [en]

    Objective: To establish a hospital-based surveillance network with national coverage for antimicrobial resistance (AMR) and antibiotic consumption in Viet Nam. Methods: A 16-hospital network (Viet Nam Resistance: VINARES) was established and consisted of national and provincial-level hospitals across the country. Antimicrobial susceptibility testing results from routine clinical diagnostic specimens and antibiotic consumption data in Defined Daily Dose per 1000 bed days (DDD/1000 patient-days) were prospectively collected and analysed between October 2012 and September 2013. Results: Data from a total of 24 732 de-duplicated clinical isolates were reported. The most common bacteria were: Escherichia coli (4437 isolates, 18%), Klebsiella spp. (3290 isolates, 13%) and Acinetobacter spp. (2895 isolates, 12%). The hospital average antibiotic consumption was 918 DDD/1000 patient-days. Third-generation cephalosporins were the most frequently used antibiotic class (223 DDD/1000 patient-days, 24%), followed by fluoroquinolones (151 DDD/1000 patient-days, 16%) and second-generation cephalosporins (112 DDD/1000 patient-days, 12%). Proportions of antibiotic resistance were high: 1098/1580 (69%) Staphylococcus aureus isolates were methicillin-resistant (MRSA); 115/344 isolates (33%) and 90/358 (25%) Streptococcus pneumoniae had reduced susceptibility to penicillin and ceftriaxone, respectively. A total of 180/2977 (6%) E. coli and 242/1526 (16%) Klebsiella pneumoniae were resistant to imipenem, respectively; 602/1826 (33%) Pseudomonas aeruginosa were resistant to ceftazidime and 578/1765 (33%) to imipenem. Of Acinetobacter spp. 1495/2138 (70%) were resistant to carbapenems and 2/333 (1%) to colistin. Conclusions: These data are valuable in providing a baseline for AMR among common bacterial pathogens in Vietnamese hospitals and to assess the impact of interventions. (C) 2019 The Authors. Published by Elsevier Ltd on behalf of International Society for Antimicrobial Chemotherapy.

  • 40.
    Tjernberg, Anna Rockert
    et al.
    Kalmar Cty Hosp, Sweden; Orebro Univ, Sweden.
    Woksepp, Hanna
    Kalmar Cty Hosp, Sweden.
    Sandholm, Kerstin
    Linnaeus Univ, Sweden.
    Johansson, Marcus
    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.
    Dahle, Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ludvigsson, Jonas F.
    Karolinska Inst, Sweden; Orebro Univ Hosp, 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.
    Nilsson, Per
    Linnaeus Univ, Sweden; Univ Oslo, Norway.
    Ekdahl, Kristina Nilsson
    Linnaeus Univ, Sweden; Uppsala Univ, Sweden.
    Celiac disease and complement activation in response to Streptococcus pneumoniae2019In: European Journal of Pediatrics, ISSN 0340-6199, E-ISSN 1432-1076Article in journal (Refereed)
    Abstract [en]

    Individuals with celiac disease (CD) are at increased risk of invasive pneumococcal disease (IPD). The aim of this study was to explore whether the complement response to Streptococcus pneumoniae differed according to CD status, and could serve as an explanation for the excess risk of IPD in CD. Twenty-two children with CD and 18 controls, born 1999-2008, were included at Kalmar County Hospital, Sweden. The degree of complement activation was evaluated by comparing levels of activation products C3a and sC5b-9 in plasma incubated for 30 min with Streptococcus pneumoniae and in non-incubated plasma. Complement analyses were performed with enzyme-linked immunosorbent assay (ELISA). Pneumococcal stimulation caused a statistically significant increase in C3a as well as sC5b-9 in both children with CD and controls but there was no difference in response between the groups. After incubation, C3a increased on average 4.6 times and sC5b-9 22 times in both the CD and the control group (p = 0.497 and p = 0.724 respectively). Conclusion: Complement response to Streptococcus pneumoniae seems to be similar in children with and without CD and is thus unlikely to contribute to the increased susceptibility to invasive pneumococcal disease in CD.

  • 41.
    Tjernberg, Ivar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Landstinget i Kalmar län, Kalmar, Sweden.
    Dags för laboratoriesvar 2.0 [Time for laboratory results 2.0]2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, article id EFDTArticle in journal (Other academic)
    Abstract [sv]

    Det är dags att öka nyttan av laborerandet. Bättre informationssystem och förbättrade beslutsstöd i patientjournalsystemen för laboratorieresultat efterlyses.

  • 42.
    Tjernberg, Ivar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Kalmar County, Kalmar, Sweden.
    Johansson, Marcus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Kalmar County, Kalmar, Sweden.
    Henningsson, Anna J.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Microbiology. Region Jönköping County, Jönköping, Sweden.
    Diagnostic performance of cerebrospinal fluid free light chains in Lyme neuroborreliosis: a pilot study2019In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 57, no 12, p. 2008-2018Article in journal (Refereed)
    Abstract [en]

    Background

    The aim of this study was to evaluate the diagnostic performance of cerebrospinal fluid (CSF) free light chains (FLCs) in the diagnosis of Lyme neuroborreliosis (LNB).

    Methods

    Serum and CSF levels of κ- and λ-FLC, albumin and total concentration of immunoglobulin M (IgM) were determined together with CSF chemokine CXCL13 in 23 patients with definite LNB, 35 inflammatory neurological disease control (INDC) and 18 non-inflammatory control (NIC) patients. Indices and intrathecal fractions (IFs) of FLC and IgM were calculated.

    Results

    Significant differences in FLC indices and IFs were found between the LNB group and both control groups, p ≤ 0.007. Sensitivity of intrathecal κ- and λ-FLC synthesis reached 78%–87% in LNB patients with a specificity of 94%–100% in NIC patients, whereas specificity in INDC patients was 69%. The corresponding frequencies of positive results for IF and index of IgM and CSF CXCL13 in these three diagnostic groups were 74%–96% in LNB patients, 0% in NIC patients and 3%–6% in INDC patients at the chosen cut-off levels.

    Conclusions

    The findings of this study show a moderate to high sensitivity of CSF κ- and λ-FLC in LNB patients with a high specificity in NIC patients. However, overlap in CSF κ- and λ-FLC levels between LNB and INDC patients calls for caution in the interpretation and limits the diagnostic usefulness in the LNB diagnosis. CSF CXCL13 appears to be the most valuable additional biomarker of LNB aside from routine parameters such as CSF pleocytosis and anti-Borrelia antibody index.

  • 43.
    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.

  • 44.
    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
  • 45.
    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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