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  • 1.
    Ahmad, Irma
    et al.
    Department of Radiation Oncology, Stanford University, Stanford, CA, United States.
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Granvik, Christoffer
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kumm Persson, Lowa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Tevell, Staffan
    Department of Infectious Diseases, Karlstad Hospital, Karlstad, Sweden; Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden; School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Månsson, Emeli
    Centre for Clinical Research, Region Västmanland—Uppsala University, Västmanland Hospital Västerås, Västerås, Sweden.
    Magnuson, Anders
    Center for Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Marklund, Ingela
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Persson, Ida-Lisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Kauppi, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sundh, Josefin
    Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lange, Anna
    Department of Radiation Oncology, Stanford University, Stanford, CA, United States.
    Cajander, Sara
    Department of Radiation Oncology, Stanford University, Stanford, CA, United States.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-192023In: Frontiers In Public Health, ISSN 2296-2565, Vol. 11, article id 1104267Article in journal (Refereed)
    Abstract [en]

    Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae. Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression. Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+. Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.

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  • 2. Albrecht, Letusa
    et al.
    Moll, Kirsten
    Blomqvist, Karin
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Chen, Qijun
    Wahlgren, Mats
    var gene transcription and PfEMP1 expression in the rosetting and cytoadhesive Plasmodium falciparum clone FCR3S1.22011In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 10, article id 17Article in journal (Refereed)
    Abstract [en]

    Background: The pathogenicity of Plasmodium falciparum is in part due to the ability of the parasitized red blood cell (pRBC) to adhere to intra- vascular host cell receptors and serum-proteins. Binding of the pRBC is mediated by Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a large multi-variant molecule encoded by a family of approximate to 60 var genes. Methods: The study of var gene transcription in the parasite clone FCR3S1.2 was performed by semi-quantitative PCR and quantitative PCR (qPCR). The expression of the major PfEMP1 in FCR3S1.2 pRBC was analysed with polyclonal sera in rosette disruption assays and immunofluorecence. Results: Transcripts from var1 (FCR3S1.2(var1); IT4var21) and other var genes were detected by semi-quantitative PCR but results from qPCR showed that one var gene transcript dominated over the others (FCR3S1.2var2; IT4var60). Antibodies raised in rats to the recombinant NTS-DBL1a of var2 produced in E. coli completely and dosedependently disrupted rosettes (approximate to 95% at a dilution of 1/5). The sera reacted with the Maurer's clefts in trophozoite stages (IFA) and to the infected erythrocyte surface (FACS) indicating that FCR3S1.2var2 encodes the dominant PfEMP1 expressed in this parasite. Conclusion: The major transcript in the rosetting model parasite FCR3S1.2 is FCR3S1.2var2 (IT4var60). The results suggest that this gene encodes the PfEMP1-species responsible for the rosetting phenotype of this parasite. The activity of previously raised antibodies to the NTS-DBL1a of FCR3S1.2var1 is likely due to cross-reactivity with NTS-DBL1 alpha of the var2 encoded PfEMP1.

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  • 3.
    Bergström, Sven
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Microbiological features distinguishing Lyme disease and relapsing fever spirochetes2018In: Wiener Klinische Wochenschrift, ISSN 0043-5325, E-ISSN 1613-7671, Vol. 130, no 15-16, p. 484-490Article in journal (Refereed)
    Abstract [en]

    The recent proposal of splitting the genus Borrelia into two genera in the newly formed family of Borreliaceae, i.aEuro<overline>e. Borrelia and Borreliella has motivated us to reflect upon how these organisms has been characterized and differentiated. This article therefore aims to take a closer look on the biology and virulence attributes of the two suggested genera, i.aEuro<overline>e. those causing Lyme borreliosis and relapsing fever borreliosis. Both genera have much in common with similar infection biological features. They are both characterized as bacterial zoonoses, transmitted by hematophagous arthropods with almost identical microbiological appearance. Nevertheless, a closer look at the genotypic and phenotypic characteristics clearly reveals several differences that might motivate the suggested split. On the other hand, a change of this well-established classification within the genus Borrelia might impose an economical burden as well as a great confusion in society, including medical and scientific societies as well as the general population.

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  • 4.
    Björsell, Tove
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Infectious Diseases, Karlstad Hospital, Karlstad, Sweden; Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Sundh, Josefin
    Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lange, Anna
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Tevell, Staffan
    Department of Infectious Diseases, Karlstad Hospital, Karlstad, Sweden; Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden; Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Cajander, Sara
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Risk factors for impaired respiratory function post COVID-19: a prospective cohort study of nonhospitalized and hospitalized patients2023In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 293, no 5, p. 600-614Article in journal (Refereed)
    Abstract [en]

    Background: Severe COVID-19 increases the risk for long-term respiratory impairment, but data after mild COVID-19 are scarce. Our aims were to determine risk factors for reduced respiratory function 3–6 months after COVID-19 infection and to investigate if reduced respiratory function would relate to impairment of exercise performance and breathlessness. Methods: Patients with COVID-19 were enrolled at the University Hospitals of Umeå and Örebro, and Karlstad Central Hospital, Sweden. Disease severity was defined as mild (nonhospitalized), moderate (hospitalized with or without oxygen treatment), and severe (intensive care). Spirometry, including diffusion capacity (DLCO), was performed 3–6 months after hospital discharge or study enrollment (for nonhospitalized patients). Breathlessness (defined as ≥1 according to the modified Medical Research Council scale) and functional exercise capacity (1-min sit-to-stand test; 1-MSTST) were assessed. Results: Between April 2020 and May 2021, 337 patients were enrolled in the study. Forced vital capacity and DLCO were significantly lower in patients with severe COVID-19. Among hospitalized patients, 20% had reduced DLCO, versus 4% in nonhospitalized. Breathlessness was found in 40.6% of the participants and was associated with impaired DLCO. A pathological desaturation or heart rate response was observed in 17% of participants during the 1-MSTST. However, this response was not associated with reduced DLCO. Conclusion: Reduced DLCO was the major respiratory impairment 3–6 months following COVID-19, with hospitalization as the most important risk factor. The lack of association between impaired DLCO and pathological physiological responses to exertion suggests that these physiological responses are not primarily related to decreased lung function.

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  • 5.
    Cagigi, Alberto
    et al.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Yu, Meng
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Österberg, Björn
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Svensson, Julia
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Falck-Jones, Sara
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Vangeti, Sindhu
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Åhlberg, Eric
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Azizmohammadi, Lida
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Warnqvist, Anna
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Falck-Jones, Ryan
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
    Gubisch, Pia C.
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Ödemis, Mert
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Ghafoor, Farangies
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Eisele, Mona
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Lenart, Klara
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Bell, Max
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; Department of Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm, Sweden.
    Johansson, Niclas
    Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden.
    Albert, Jan
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Division of Clinical Microbiology, Karolinska University Laboratory, Karolinska University Hospital Solna, Stockholm, Sweden.
    Sälde, Jörgen
    Närakut SLSO, Karolinska University Hospital Solna, Stockholm, Sweden.
    Pettie, Deleah D.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Murphy, Michael P.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Carter, Lauren
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    King, Neil P.
    Department of Biochemistry, University of Washington, WA, Seattle, United States; Institute for Protein Design, University of Washington, WA, Seattle, United States.
    Ols, Sebastian
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Forsell, Mattias N.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Färnert, Anna
    Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital Solna, Stockholm, Sweden.
    Loré, Karin
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Smed-Sörensen, Anna
    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination2021In: JCI Insight, ISSN 2379-3708, Vol. 6, no 22, article id e151463Article in journal (Refereed)
    Abstract [en]

    Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.

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  • 6.
    Elbir, Haitham
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Larsson, Pär
    Division of CBRN Security and Defence, FOI Swedish Defence Research Agency, Umeå, Sweden.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Upreti, Mukunda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Korenberg, Edward
    Gamaleya Research Institute for Epidemiology and Microbiology, Russian Academy of Medical Sciences, Moscow, Russian Federation.
    Larsson, Christer
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Genome Sequence of the Asiatic Species Borrelia persica2014In: Genome Announcements, E-ISSN 2169-8287, Vol. 2, no 1, article id e01127-13Article in journal (Refereed)
    Abstract [en]

    We report the complete genome sequence of Borrelia persica, the causative agent of tick-borne relapsing fever borreliosis on the Asian continent. Its genome of 1,784,979 bp contains 1,850 open reading frames, three ribosomal RNAs, and 32 tRNAs. One clustered regularly interspaced short palindromic repeat (CRISPR) was detected.

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  • 7.
    Elbir, Haitham
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Larsson, Pär
    Division of CBRN Security and Defence, FOI Swedish Defence Research Agency, Umeå, Sweden.
    Upreti, Mukunda
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Normark, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Genome sequence of the relapsing fever borreliosis species Borrelia hispanica2014In: Genome Announcements, E-ISSN 2169-8287, Vol. 2, no 1, article id e01171-13Article in journal (Refereed)
    Abstract [en]

    Borrelia hispanica is the etiological pathogen of tick-borne relapsing fever, transmitted to humans by infected Ornithodoros erraticus ticks. Here we present the 1,783,846-bp draft genome sequence, with an average G+C content of 28%. It has 2,140 open reading frames, 3 ribosomal RNAs, and 32 transfer RNAs.

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  • 8.
    Engström, Patrik
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Krishnan, K. Syam
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ngyuen, Bidong D.
    Chorell, Erik
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Silver, Jim
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bastidas, Robert J.
    Welch, Matthew D.
    Hultgren, Scott J.
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Valdivia, Raphael H.
    Almqvist, Fredrik
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of Chlamydia trachomatis2015In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 6, no 1, article id e02304-14Article in journal (Refereed)
    Abstract [en]

    In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.

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  • 9.
    Engström, Patrik
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nguyen, Bidong D.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Ingela
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Bastidas, Robert J.
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Elofsson, Mikael
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fields, Kenneth A.
    Valdivia, Raphael H.
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity2013In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 195, no 18, p. 4221-4230Article in journal (Refereed)
    Abstract [en]

    Salicylidene acylhydrazides (SAHs) inhibit the type III secretion system (T3S) of Yersinia and other Gram-negative bacteria. In addition, SAHs restrict the growth and development of Chlamydia species. However, since the inhibition of Chlamydia growth by SAH is suppressed by the addition of excess iron and since SAHs have an iron-chelating capacity, their role as specific T3S inhibitors is unclear. We investigated here whether SAHs exhibit a function on C. trachomatis that goes beyond iron chelation. We found that the iron-saturated SAH INP0341 (IS-INP0341) specifically affects C. trachomatis infectivity with reduced generation of infectious elementary body (EB) progeny. Selection and isolation of spontaneous SAH-resistant mutant strains revealed that mutations in hemG suppressed the reduced infectivity caused by IS-INP0341 treatment. Structural modeling of C. trachomatis HemG predicts that the acquired mutations are located in the active site of the enzyme, suggesting that IS-INP0341 inhibits this domain of HemG and that protoporphyrinogen oxidase (HemG) and heme metabolism are important for C. trachomatis infectivity.

  • 10.
    Fernández, Leyden
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Physics. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Rosvall, Martin
    Umeå University, Faculty of Science and Technology, Department of Physics. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fällman, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Physics. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Avican, Kemal
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Science and Technology, Department of Physics. Integrated Science Lab (Icelab), Umeå University, Umeå, Sweden.
    Co-PATHOgenex web application for assessing complex stress responses in pathogenic bacteria2024In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 12, no 1, article id e02781-23Article in journal (Refereed)
    Abstract [en]

    Pathogenic bacteria encounter various stressors while residing in the host. They respond through intricate mechanisms of gene expression regulation, ensuring their survival and adaptation. Understanding how bacteria adapt to different stress conditions through regulatory processes of specific genes requires exploring complex transcriptional responses using gene co-expression networks. We employed a large transcriptome data set comprising 32 diverse human bacterial pathogens exposed to the same 11 host-mimicking stress conditions. Using the weighted gene co-expression network analysis algorithm, we generated bacterial gene co-expression networks. By associating modular eigengene expression with specific stress conditions, we identified gene co-expression modules and stress-specific stimulons, including genes with unique expression patterns under specific stress conditions. Suggesting a new potential role of the frm operon in responding to bile stress in enteropathogenic bacteria demonstrates the effectiveness of our approach. We also revealed the regulation of streptolysin S genes, involved in the production, processing, and export of streptolysin S, a toxin responsible for the beta-hemolytic phenotype of group A Streptococcus. In a comparative analysis of stress responses in three Escherichia coli strains from the core transcriptome, we revealed shared and unique expression patterns across the strains, offering insights into convergent and divergent stress responses. To help researchers perform similar analyses, we created the user-friendly web application Co-PATHOgenex. This tool aids in deepening our understanding of bacterial adaptation to stress conditions and in deciphering complex transcriptional responses of bacterial pathogens.IMPORTANCEUnveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition. Unveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition.

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  • 11.
    Gröning, Remigius
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Dernstedt, Andy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption2023In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1219560Article in journal (Refereed)
    Abstract [en]

    Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

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  • 12.
    Gröning, Remigius
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Dernstedt, Andy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Gardfjäll, Jenny
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Variable immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis after rituximab treatment interruptionManuscript (preprint) (Other academic)
  • 13.
    Kaku, Chengzi I.
    et al.
    United States.
    Bergeron, Alan J.
    Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, United States; Department of Microbiology and Immunology, Dartmouth College, Hanover, United States.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sakharkar, Mrunal
    United States.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Walker, Laura M.
    Waltham, United States.
    Recall of preexisting cross-reactive B cell memory after Omicron BA.1 breakthrough infection2022In: Science immunology, E-ISSN 2470-9468, Vol. 7, no 73, article id eabq3511Article in journal (Refereed)
    Abstract [en]

    Understanding immune responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses after Omicron/BA.1 infection in messenger RNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells. BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit, which is highly conserved across SARS-CoV-2 variants of concern (VOCs), and toward the antigenically variable receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 VOCs. Together, these findings provide insights into the role of preexisting immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.

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  • 14.
    Kaku, Chengzi I.
    et al.
    Adimab, NH, Lebanon, United States; Thayer School of Engineering, Dartmouth College, NH, Hanover, United States.
    Champney, Elizabeth R.
    Adimab, NH, Lebanon, United States.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Garcia, Marina
    Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Johnson, Carl E.
    Adimab, NH, Lebanon, United States.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Christ, Wanda
    Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Sakharkar, Mrunal
    Adimab, NH, Lebanon, United States.
    Ackerman, Margaret E.
    Thayer School of Engineering, Dartmouth College, NH, Hanover, United States; Geisel School of Medicine, Dartmouth College, NH, Hanover, United States.
    Klingström, Jonas
    Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Walker, Laura M.
    Adimab, NH, Lebanon, United States; Adagio Therapeutics, MA, Waltham, United States.
    Broad anti–SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 vaccination2022In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 375, no 6584, p. 1041-1047Article in journal (Refereed)
    Abstract [en]

    Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy We longitudinally profiled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific serological and memory B cell (MBC) responses in individuals who received either homologous (ChAdOx1: ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous messenger RNA (mRNA) booster immunization induced higher serum neutralizing antibody and MBC responses against SARS-CoV-2 variants of concern (VOCs) compared with that of homologous ChAdOx1 boosting. Specificity mapping of circulating B cells revealed that mRNA-1273 boost immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273–booste participants displayed overall higher binding affinities and increased breadth of reactivity against VOCs relativ to those isolated from ChAdOx1-boosted individuals. Overall, the results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination.

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  • 15.
    Möller, Marika
    et al.
    Department of Clinical Sciences, Division of Rehabilitation Medicine, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.
    Borg, Kristian
    Department of Clinical Sciences, Division of Rehabilitation Medicine, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.
    Janson, Christer
    Department of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    Lerm, Maria
    Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Niward, Katarina
    Department of Infectious Diseases, and Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection, Linköping University, Linköping, Sweden.
    Cognitive dysfunction in post-COVID-19 condition: mechanisms, management, and rehabilitation2023In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Journal of Internal Medicine, ISSN 0954-6820, Vol. 294, no 5, p. 563-581Article, review/survey (Refereed)
    Abstract [en]

    The long-term effects of COVID-19 on cognitive function have become an area of increasing concern. This paper provides an overview of characteristics, risk factors, possible mechanisms, and management strategies for cognitive dysfunction in post-COVID-19 condition (PCC). Prolonged cognitive dysfunction is one of the most common impairments in PCC, affecting between 17% and 28% of the individuals more than 12 weeks after the infection and persisting in some cases for several years. Cognitive dysfunctions can be manifested as a wide range of symptoms including memory impairment, attention deficit, executive dysfunction, and reduced processing speed. Risk factors for developing PCC, with or without cognitive impairments, include advanced age, preexisting medical conditions, and the severity of acute illness. The underlying mechanisms remain unclear, but proposed contributors include neuroinflammation, hypoxia, vascular damage, and latent virus reactivation not excluding the possibility of direct viral invasion of the central nervous system, illustrating complex viral pathology. As the individual variation of the cognitive impairments is large, a neuropsychological examination and a person-centered multidimensional approach are required. According to the World Health Organization, limited evidence on COVID-19-related cognitive impairments necessitates implementing rehabilitation interventions from established practices of similar conditions. Psychoeducation and compensatory skills training are recommended. Assistive products and environmental modifications adapted to individual needs might be helpful. In specific attention- and working memory dysfunctions, cognitive training—carefully monitored for intensity—might be effective for people who do not suffer from post-exertional malaise. Further research is crucial for evidence-based interventions specific to COVID-19-related cognitive impairments.

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  • 16.
    Nelson, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Niemic, Maria Joanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nahrevanian, Shahab
    Urban, Constantin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Malaria-enhanced Neutrophil Dependent Clearance of S. pneumoniae in an in vivo Co-infection ModelManuscript (preprint) (Other (popular science, discussion, etc.))
  • 17.
    Normark, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nelson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Engström, Patrik
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.
    Andersson, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Björk, Rafael
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Moritz, Thomas
    Umeå Plant Science Centre (UPSC), Swedish University of Agricultural Sciences (SLU), Umeå, Sweden.
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7, article id e103295Article in journal (Refereed)
    Abstract [en]

    In the Plasmodium infected host, a balance between pro- and anti-inflammatory responses is required to clear the parasites without inducing major host pathology. Clinical reports suggest that bacterial infection in conjunction with malaria aggravates disease and raises both mortality and morbidity in these patients. In this study, we investigated the immune responses in BALB/c mice, co-infected with Plasmodium berghei NK65 parasites and the relapsing fever bacterium Borrelia duttonii. In contrast to single infections, we identified in the co-infected mice a reduction of L-Arginine levels in the serum. It indicated diminished bioavailability of NO, which argued for a dysfunctional endothelium. Consistent with this, we observed increased sequestration of CD8+ cells in the brain as well over expression of ICAM-1 and VCAM by brain endothelial cells. Co-infected mice further showed an increased inflammatory response through IL-1 beta and TNF-alpha, as well as inability to down regulate the same through IL-10. In addition we found loss of synchronicity of pro- and anti-inflammatory signals seen in dendritic cells and macrophages, as well as increased numbers of regulatory T-cells. Our study shows that a situation mimicking experimental cerebral malaria (ECM) is induced in co-infected mice due to loss of timing and control over regulatory mechanisms in antigen presenting cells.

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  • 18.
    Normark, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Vikström, Linnea
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Yong-Dae, Gwon
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Persson, Ida-Lisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Björsell, Tove
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Dernstedt, Andy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Christ, Wanda
    Tevell, Staffan
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Klingström, Jonas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination2021In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 385, no 11, p. 1049-1051Article in journal (Refereed)
  • 19. Orikiiriza, Judy
    et al.
    Nakawesi, Jane
    Kikaire, Ben
    Turitwenka, Dorothy
    Schlech, Walter
    Kambugu, Andrew
    Lamorde, Mohammed
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hennessy, Martina
    Musiime, Victor
    Rujumba, Joseph
    Ndeezi, Grace
    Tumwesigye, Nazarius M
    Doherty, Derek G
    Achan, Jane
    Unmet needs persist in pediatric HIV programs: lessons from selected case studies in Uganda2017In: AIDS, ISSN 0269-9370, E-ISSN 1473-5571, Vol. 31, no 8, p. 1196-1199Article in journal (Refereed)
  • 20. Orikiiriza, Judy
    et al.
    Surowiec, Izabella
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindquist, Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Bonde, Mari
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lipid response patterns in acute phase paediatric Plasmodium falciparum malaria2017In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 13, no 4, article id 41Article in journal (Refereed)
    Abstract [en]

    Introduction: Several studies have observed serum lipid changes during malaria infection in humans. All of them were focused at analysis of lipoproteins, not specific lipid molecules. The aim of our study was to identify novel patterns of lipid species in malaria infected patients using lipidomics profiling, to enhance diagnosis of malaria and to evaluate biochemical pathways activated during parasite infection.

    Methods: Using a multivariate characterization approach, 60 samples were representatively selected, 20 from each category (mild, severe and controls) of the 690 study participants between age of 0.5–6 years. Lipids from patient’s plasma were extracted with chloroform/methanol mixture and subjected to lipid profiling with application of the LCMS-QTOF method.

    Results: We observed a structured plasma lipid response among the malaria-infected patients as compared to healthy controls, demonstrated by higher levels of a majority of plasma lipids with the exception of even-chain length lysophosphatidylcholines and triglycerides with lower mass and higher saturation of the fatty acid chains. An inverse lipid profile relationship was observed when plasma lipids were correlated to parasitaemia.

    Conclusions: This study demonstrates how mapping the full physiological lipid response in plasma from malaria-infected individuals can be used to understand biochemical processes during infection. It also gives insights to how the levels of these molecules relate to acute immune responses.

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  • 21. Reuterswärd, Philippa
    et al.
    Bergström, Sofia
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Svahn, Helene Andersson
    Ayoglu, Burcu
    Uhlén, Mathias
    Wahlgren, Mats
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ribacke, Ulf
    Nilsson, Peter
    Levels of human proteins in plasma associated with acute paediatric malaria2018In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 17, article id 426Article in journal (Refereed)
    Abstract [en]

    Background: The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts.

    Results: An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values < 0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values < 10−14) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values < 0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria.

    Conclusion: In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis.

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  • 22.
    Ribacke, Ulf
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, United States.
    Moll, Kirsten
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Albrecht, Letusa
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; de Genética, Evolução e Bioagentes, UNICAMP, Instituto de Biologia Cidade, Universitaria Zeferino Vaz, Campinas, São Paulo, Brazil.
    Ahmed Ismail, Hodan
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Normark, Johan
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Flaberg, Emilie
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Szekely, Laszlo
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Hultenby, Kjell
    Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Persson, Kristina E. M.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Egwang, Thomas G.
    Med Biotech Laboratories, Kampala, Uganda.
    Wahlgren, Mats
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Improved in vitro culture of plasmodium falciparum permits establishment of clinical isolates with preserved multiplication, invasion and rosetting phenotypes2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 7, article id e69781Article in journal (Refereed)
    Abstract [en]

    To be able to robustly propagate P. falciparum at optimal conditions in vitro is of fundamental importance for genotypic and phenotypic studies of both established and fresh clinical isolates. Cryo-preserved P. falciparum isolates from Ugandan children with severe or uncomplicated malaria were investigated for parasite phenotypes under different in vitro growth conditions or studied directly from the peripheral blood. The parasite cultures showed a minimal loss of parasite-mass and preserved percentage of multiple infected pRBCs to that in peripheral blood, maintained adhesive phenotypes and good outgrowth and multiplication rates when grown in suspension and supplemented with gas. In contrast, abnormal and greatly fluctuating levels of multiple infections were observed during static growth conditions and outgrowth and multiplication rates were inferior. Serum, as compared to Albumax, was found necessary for optimal presentation of PfEMP1 at the pRBC surface and/or for binding of serum proteins (immunoglobulins). Optimal in vitro growth conditions of P. falciparum therefore include orbital shaking (50 rev/min), human serum (10%) and a fixed gas composition (5% O2, 5% CO2, 90% N2). We subsequently established 100% of 76 frozen patient isolates and found rosetting with schizont pRBCs in every isolate (>26% schizont rosetting rate). Rosetting during schizogony was often followed by invasion of the bound RBC as seen by regular and time-lapse microscopy as well as transmission electron microscopy. The peripheral parasitemia, the level of rosetting and the rate of multiplication correlated positively to one another for individual isolates. Rosetting was also more frequent with trophozoite and schizont pRBCs of children with severe versus uncomplicated malaria (p<0.002; p<0.004). The associations suggest that rosetting enhances the ability of the parasite to multiply within the human host. 

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  • 23.
    Schagatay, Felix
    et al.
    Department of Infectious Diseases, CKF Region Västmanland, Västerås Hospital, Västerås, Sweden.
    Diamant, Klara
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Lidén, Mats
    Department of Radiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Athlin, Simon
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Hultgren, Olof
    Department of Laboratory medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Savilampi, Johanna
    Department of Anaesthesiology and Intensive Care, Örebro University, Örebro, Sweden.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lange, Anna
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Cajander, Sara
    Department of Infectious Diseases, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-192022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 945603Article in journal (Refereed)
    Abstract [en]

    Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored.

    Aim: To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19.

    Methods: Herein we report a prospective observational study of patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in Örebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Umeå (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO <50% FiO2), and severe hypoxemia (HFNO ≥50% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI.

    Results: Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (Örebro; p=0.01, Umeå; p<0.01). The degree of pulmonary involvement measured by CT correlated with eCIRP, rs=0.30, p<0.01 (n=97).

    Conclusion: High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.

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  • 24.
    Staessen, Jan A.
    et al.
    Non-Profit Research Institute Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium; Biomedical Sciences Group, Faculty of Medicine, University of Leuven, Leuven, Belgium.
    Wendt, Ralph
    Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany.
    Yu, Yu-Ling
    Research Unit Environment and Health, Department of Public Health and Primary Care, University of Leuven, Leuven, Belgium.
    Kalbitz, Sven
    Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany.
    Thijs, Lutgarde
    Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
    Siwy, Justyna
    Mosaiques-Diagnostics, Hannover, Germany.
    Raad, Julia
    Mosaiques-Diagnostics, Hannover, Germany.
    Metzger, Jochen
    Mosaiques-Diagnostics, Hannover, Germany.
    Neuhaus, Barbara
    Centre for Clinical Trials, Medizinische Hochschule, Hannover, Germany.
    Papkalla, Armin
    Centre for Clinical Trials, Medizinische Hochschule, Hannover, Germany.
    von der Leyen, Heiko
    Centre for Clinical Trials, Medizinische Hochschule, Hannover, Germany.
    Mebazaa, Alexandre
    Department of Anaesthesiology and Intensive Care, Hospital Saint Louis-Lariboisière, Paris, France.
    Dudoignon, Emmanuel
    Department of Anaesthesiology and Intensive Care, Hospital Saint Louis-Lariboisière, Paris, France.
    Spasovski, Goce
    Cyril and Methodius University, Skopje, North Macedonia.
    Milenkova, Mimoza
    Cyril and Methodius University, Skopje, North Macedonia.
    Canevska-Taneska, Aleksandra
    Cyril and Methodius University, Skopje, North Macedonia.
    Salgueira Lazo, Mercedes
    Hospital Virgen Macarena, Sevilla, Spain.
    Psichogiou, Mina
    First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
    Rajzer, Marek W.
    First Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jagiellonian University Medical College, Kraków, Poland.
    Fuławka, Łukasz
    Molecular Pathology Centre Cellgen, Wrocław, Poland.
    Dzitkowska-Zabielska, Magdalena
    Faculty of Physical Education, Gdańsk University of Physical Education and Sport and Centre of Translational Medicine, Medical University of Gdańsk, Gdańsk, Poland.
    Weiss, Guenter
    Department of Internal Medicine II, Medical University Innsbruck, Innsbruck, Austria.
    Feldt, Torsten
    Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty of Heinrich Heine University, Düsseldorf, Germany.
    Stegemann, Miriam
    Department of Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Zoufaly, Alexander
    Department of Medicine IV, Clinic Favoriten and Faculty of Medicine, Sigmund Freud University, Vienna, Austria.
    Schmiedel, Stefan
    Medical Department I and Bernhard-Nocht-Clinic for Tropical Medicine, University Medical Centre Hamburg Eppendorf, Hamburg, Germany.
    Seilmaier, Michael
    Department of Haematology, Oncology, Immunology, Palliative Care, Infectious Disease and Tropical Medicine, München Klinik Schwabing, München, Germany.
    Rumpf, Benedikt
    Nephrology and Dialysis, Internal Medicine III, Medical University of Vienna, Vienna, Austria.
    Banasik, Mirosław
    Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland.
    Krajewska, Magdalena
    Department of Nephrology and Transplantation Medicine, Wrocław Medical University, Wrocław, Poland.
    Catanese, Lorenzo
    Department of Nephrology, Angiology and Rheumatology, Hospital Bayreuth, Bayreuth, Germany.
    Rupprecht, Harald D.
    Department of Nephrology, Angiology and Rheumatology, Hospital Bayreuth, Bayreuth, Germany.
    Czerwieńska, Beata
    University of Silesia, Katowice, Poland.
    Peters, Björn
    Department of Nephrology, Skaraborg Hospital, Skövde and Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden; Research and Development Centre, Skaraborg Hospital, Skövde, Sweden.
    Nilsson, Åsa
    Research and Development Centre, Skaraborg Hospital, Skövde, Sweden.
    Rothfuss, Katja
    Department of Gastroenterology, Hepatology and Endocrinology, Robert Bosch Hospital, Stuttgart, Germany.
    Lübbert, Christoph
    Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany; Division of Infectious Diseases and Tropical Medicine, Leipzig University Medical Centre, Leipzig, Germany.
    Mischak, Harald
    Mosaiques-Diagnostics, Hannover, Germany; Institute of Cardiovascular and Medical Sciences, Glasgow, United Kingdom.
    Beige, Joachim
    Department of Infectious Diseases and Tropical Medicine, Nephrology and Kuratorium für Dialyse und Nierentransplantation Renal Unit and Rheumatology, St Georg Hospital, Leipzig, Germany; Martin-Luther-University Halle-Wittenberg, Halle an der Saale, Halle, Germany.
    Predictive performance and clinical application of COV50, a urinary proteomic biomarker in early COVID-19 infection: a prospective multicentre cohort study2022In: The Lancet Digital Health, E-ISSN 2589-7500, Vol. 4, no 10, p. e727-e737Article in journal (Refereed)
    Abstract [en]

    Background: The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker.

    Methods: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country.

    Findings: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1–3 in 445 (44%) participants, 4–5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05–2·92) unadjusted and 1·67 (1·34–2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60–2·01) when unadjusted and 1·63 (1·41–1·91) when adjusted (p<0·0001 for all). The predictive accuracy of the optimised COV50 thresholds was 74·4% (71·6–77·1%) for mortality (threshold 0·47) and 67·4% (64·4–70·3%) for disease progression (threshold 0·04). When adjusted for covariables and the baseline WHO score, these thresholds improved AUCs from 0·835 to 0·853 (p=0·033) for death and from 0·697 to 0·730 (p=0·0008) for progression. Of 196 participants who received ambulatory care, 194 (99%) did not reach the 0·04 threshold. The cost reductions associated with 1 day less hospitalisation per 1000 participants were million Euro (M€) 0·887 (5–95% percentile interval 0·730–1·039) in participants at a low risk (COV50 <0·04) and M€2·098 (1·839-2·365) in participants at a high risk (COV50 ≥0·04).

    Interpretation: The urinary proteomic COV50 marker might be predictive of adverse COVID-19 outcomes. Even in people with mild-to-moderate PCR-confirmed infections (WHO scores 1–4), the 0·04 COV50 threshold justifies earlier drug treatment, thereby potentially reducing the number of days in hospital and associated costs. Funding: German Federal Ministry of Health.

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  • 25.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Magambo, Jimmy
    Muhinda, Charles
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children2017In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 358Article in journal (Refereed)
    Abstract [en]

    Background: Oxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism.

    Methods: Detection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA (R)) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis).

    Results: Forty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls.

    Conclusions: It was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed.

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  • 26.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Erik
    Stenlund, Hans
    Swedish Metabolomics Centre, Umeå, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Umeå, Sweden.
    Quantification of run order effect on chromatography: mass spectrometry profiling data2018In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1568, p. 229-234Article in journal (Refereed)
    Abstract [en]

    Chromatographic systems coupled with mass spectrometry detection are widely used in biological studies investigating how levels of biomolecules respond to different internal and external stimuli. Such changes are normally expected to be of low magnitude and therefore all experimental factors that can influence the analysis need to be understood and minimized. Run order effect is commonly observed and constitutes a major challenge in chromatography-mass spectrometry based profiling studies that needs to be addressed before the biological evaluation of measured data is made. So far there is no established consensus, metric or method that quickly estimates the size of this effect. In this paper we demonstrate how orthogonal projections to latent structures (OPLS®) can be used for objective quantification of the run order effect in profiling studies. The quantification metric is expressed as the amount of variation in the experimental data that is correlated to the run order. One of the primary advantages with this approach is that it provides a fast way of quantifying run-order effect for all detected features, not only internal standards. Results obtained from quantification of run order effect as provided by the OPLS can be used in the evaluation of data normalization, support the optimization of analytical protocols and identification of compounds highly influenced by instrumental drift. The application of OPLS for quantification of run order is demonstrated on experimental data from plasma profiling performed on three analytical platforms: GCMS metabolomics, LCMS metabolomics and LCMS lipidomics.

  • 27.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy
    Karlsson, Elisabeth
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nelson, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kyamanwa, Patrick
    Karenzi, Ben
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Normark, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. nfectious Diseases Institute, School of Medicine and Health Sciences, Makerere University, Uganda.
    Metabolic signature profiling as a diagnostic and prognostic tool in paediatric Plasmodium falciparum malaria2015In: Open Forum Infectious Diseases, ISSN 2328-8957, Vol. 2, no 2Article in journal (Refereed)
    Abstract [en]

    Background: Accuracy in malaria diagnosis and staging is vital in order to reduce mortality and post infectious sequelae. Herein we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods: A group of 421 patients between six months and six years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192 and 122 individuals respectively. A multivariate design was used as basis for representative selection of twenty patients in each category. Patient plasma was subjected to Gas Chromatography-Mass Spectrometry analysis and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in-vivo model where metabolic profiles were discernible over time of infection. Results: A two-component principal component analysis (PCA) revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, two sub-groups could be identified in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusion: Metabolite signature profiling could be used both for decision support in disease staging and prognostication.

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  • 28.
    Surowiec, Izabella
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Tvistevägen 48, 907 36 Umeå, Sweden.
    Skotare, Tomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjögren, Rickard
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Tvistevägen 48, 907 36 Umeå, Sweden.
    Gouveia-Figueira, Sandra C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orikiiriza, Judy Tatwan
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Stedim Data Analytics, Tvistevägen 48, 907 36 Umeå, Sweden.
    Joint and unique multiblock analysis of biological data: multiomics malaria study2019In: Faraday discussions, ISSN 1359-6640, E-ISSN 1364-5498, Vol. 218, p. 268-283Article in journal (Refereed)
    Abstract [en]

    Modern profiling technologies enable obtaining large amounts of data which can be later used for comprehensive understanding of the studied system. Proper evaluation of such data is challenging, and cannot be faced by bare analysis of separate datasets. Integrated approaches are necessary, because only data integration allows finding correlation trends common for all studied data sets and revealing hidden structures not known a priori. This improves understanding and interpretation of the complex systems. Joint and Unique MultiBlock Analysis (JUMBA) is an analysis method based on the OnPLS-algorithm that decomposes a set of matrices into joint parts containing variation shared with other connected matrices and variation that is unique for each single matrix. Mapping unique variation is important from a data integration perspective, since it certainly cannot be expected that all variation co-varies. In this work we used JUMBA for integrated analysis of lipidomic, metabolomic and oxylipin datasets obtained from profiling of plasma samples from children infected with P. falciparum malaria. P. falciparum is one of the primary contributors to childhood mortality and obstetric complications in the developing world, what makes development of the new diagnostic and prognostic tools, as well as better understanding of the disease, of utmost importance. In presented work JUMBA made it possible to detect already known trends related to disease progression, but also to discover new structures in the data connected to food intake and personal differences in metabolism. By separating the variation in each data set into joint and unique, JUMBA reduced complexity of the analysis, facilitated detection of samples and variables corresponding to specific structures across multiple datasets and by doing this enabled fast interpretation of the studied system. All this makes JUMBA a perfect choice for multiblock analysis of systems biology data.

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  • 29. Vasiliu, Anca
    et al.
    Köhler, Niklas
    Altpeter, Ekkehardt
    Ægisdóttir, Tinna Rán
    Amerali, Marina
    de Oñate, Wouter Arrazola
    Bakos, Ágnes
    D'Amato, Stefania
    Cirillo, Daniela Maria
    van Crevel, Reinout
    Davidaviciene, Edita
    Demuth, Irène
    Domínguez, Jose
    Duarte, Raquel
    Günther, Gunar
    Guthmann, Jean-Paul
    Hatzianastasiou, Sophia
    Holm, Louise Hedevang
    Herrador, Zaida
    Hribar, Urška
    Huberty, Conny
    Ibraim, Elmira
    Jackson, Sarah
    Jensenius, Mogens
    Josefsdottir, Kamilla Sigridur
    Koch, Anders
    Korzeniewska-Kosela, Maria
    Kuksa, Liga
    Kunst, Heinke
    Lienhardt, Christian
    Mahler, Beatrice
    Makek, Mateja Janković
    Muylle, Inge
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Pace-Asciak, Analita
    Petrović, Goranka
    Pieridou, Despo
    Russo, Giulia
    Rzhepishevska, Olena
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Salzer, Helmut J. F.
    Marques, Marta Sá
    Schmid, Daniela
    Solovic, Ivan
    Sukholytka, Mariya
    Svetina, Petra
    Tyufekchieva, Mariya
    Vasankari, Tuula
    Viiklepp, Piret
    Villand, Kersti
    Wallenfels, Jiri
    Wesolowski, Stefan
    Mandalakas, Anna-Maria
    Martinez, Leonardo
    Zenner, Dominik
    Lange, Christoph
    Tuberculosis incidence in foreign-born people residing in European countries in 20202023In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 28, no 42, article id 2300051Article in journal (Refereed)
    Abstract [en]

    Background: European-specific policies for tuberculosis (TB) elimination require identification of key populations that benefit from TB screening.

    Aim: We aimed to identify groups of foreign-born individuals residing in European countries that benefit most from targeted TB prevention screening.

    Methods: The Tuberculosis Network European Trials group collected, by cross-sectional survey, numbers of foreign-born TB patients residing in European Union (EU) countries, Iceland, Norway, Switzerland and the United Kingdom (UK) in 2020 from the 10 highest ranked countries of origin in terms of TB cases in each country of residence. Tuberculosis incidence rates (IRs) in countries of residence were compared with countries of origin.

    Results: Data on 9,116 foreign-born TB patients in 30 countries of residence were collected. Main countries of origin were Eritrea, India, Pakistan, Morocco, Romania and Somalia. Tuberculosis IRs were highest in patients of Eritrean and Somali origin in Greece and Malta (both > 1,000/100,000) and lowest among Ukrainian patients in Poland (3.6/100,000). They were mainly lower in countries of residence than countries of origin. However, IRs among Eritreans and Somalis in Greece and Malta were five times higher than in Eritrea and Somalia. Similarly, IRs among Eritreans in Germany, the Netherlands and the UK were four times higher than in Eritrea.

    Conclusions: Country of origin TB IR is an insufficient indicator when targeting foreign-born populations for active case finding or TB prevention policies in the countries covered here. Elimination strategies should be informed by regularly collected country-specific data to address rapidly changing epidemiology and associated risks.

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  • 30.
    Vikström, Linnea
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fjällström, Peter
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Gwon, Yong-Dae
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sheward, Daniel J.
    The Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
    Wigren-Byström, Julia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bladh, Oscar
    The Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Widerström, Micael
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Molnar, Christian
    Familjeläkarna, Stockholm, Sweden.
    Rasmussen, Gunlög
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Bennet, Louise
    Department of Clinical Sciences, Clinical Studies Sweden, Forum South, Skåne University Hospital, Lund University, Lund, Sweden.
    Åberg, Mikael
    The Department of Medical Sciences, Clinical Chemistry and SciLifeLab, Uppsala University, Uppsala, Sweden.
    Björk, Jonas
    The Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
    Tevell, Staffan
    Faculty of Medicine and Health, The Department of Infectious Diseases, Karlstad Hospital and Centre for Clinical Research and Education, Region Värmland, Örebro University, Örebro, Sweden.
    Thålin, Charlotte
    The Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital, Stockholm, Sweden.
    Blom, Kim
    The Swedish Public Health Agency, Stockholm, Sweden.
    Klingström, Jonas
    The Department of Biomedical Clinical Sciences, Linköpings University, Linköping, Sweden.
    Murrell, Ben
    The Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Johansson, Anders F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Vaccine-induced correlate of protection against fatal COVID-19 in older and frail adults during waves of neutralization-resistant variants of concern: an observational study2023In: The Lancet Regional Health: Europe, E-ISSN 2666-7762, Vol. 30, article id 100646Article in journal (Refereed)
    Abstract [en]

    Background: To inform future preventive measures including repeated vaccinations, we have searched for a clinically useful immune correlate of protection against fatal COVID-19 among nursing homes residents.

    Methods: We performed repeated capillary blood sampling with analysis of S-binding IgG in an open cohort of nursing home residents in Sweden. We analyzed immunological and registry data from 16 September 2021 to 31 August 2022 with follow-up of deaths to 30 September 2022. The study period included implementation of the 3rd and 4th mRNA monovalent vaccine doses and Omicron virus waves.

    Findings: A total of 3012 nursing home residents with median age 86 were enrolled. The 3rd mRNA dose elicited a 99-fold relative increase of S-binding IgG in blood and corresponding increase of neutralizing antibodies. The 4th mRNA vaccine dose boosted levels 3.8-fold. Half-life of S-binding IgG was 72 days. A total 528 residents acquired their first SARS-CoV-2 infection after the 3rd or the 4th vaccine dose and the associated 30-day mortality was 9.1%. We found no indication that levels of vaccine-induced antibodies protected against infection with Omicron VOCs. In contrast, the risk of death was inversely correlated to levels of S-directed IgG below the 20th percentile. The death risk plateaued at population average above the lower 35th percentile of S-binding IgG.

    Interpretation: In the absence of neutralizing antibodies that protect from infection, quantification of S-binding IgG post vaccination may be useful to identify the most vulnerable for fatal COVID-19 among the oldest and frailest. This information is of importance for future strategies to protect vulnerable populations against neutralization resistant variants of concern.

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  • 31.
    Wigren, Julia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Xerum AB, Umeå, Sweden.
    Vikström, Linnea
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gröning, Remigius
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Gwon, Yong-Dae
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sharma, Atin
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Espaillat, Akbar
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hanke, Leo
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    McInerney, Gerald
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Puhar, Andrea
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Karlsson Hedestam, Gunilla B.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Thunberg, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Monsen, Tor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Johansson, Anders F.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Normark, Johan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    At-home sampling to meet geographical challenges for serological assessment of SARS-CoV-2 exposure in a rural region of northern Sweden, March to May 2021: a retrospective cohort study2023In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 28, no 13, article id 2200432Article in journal (Refereed)
    Abstract [en]

    Background: The current SARS-CoV-2 pandemic has highlighted a need for easy and safe blood sampling in combination with accurate serological methodology. Venipuncture for testing is usually performed by trained staff at healthcare centres. Long travel distances to healthcare centres in rural regions may introduce a bias of testing towards relatively large communities with closer access. Rural regions are therefore often not represented in population-based data.

    Aim: The aim of this retrospective cohort study was to develop and implement a strategy for at-home testing in a rural region of Sweden during spring 2021, and to evaluate its role to provide equal health care for its inhabitants.

    Methods: We developed a sensitive method to measure antibodies to the S-protein of SARS-CoV-2 and optimised this assay for clinical use together with a strategy of at-home capillary blood sampling.

    Results: We demonstrated that our ELISA gave comparable results after analysis of capillary blood or serum from SARS-CoV-2-experienced individuals. We demonstrated stability of the assay under conditions that reflected temperature and humidity during winter or summer. By assessment of capillary blood samples from 4,122 individuals, we could show both feasibility of the strategy and that implementation shifted the geographical spread of testing in favour of rural areas.

    Conclusion: Implementation of at-home sampling enabled citizens living in remote rural areas access to centralised and sensitive laboratory antibody tests. The strategy for testing used here could therefore enable disease control authorities to get rapid access to information concerning immunity to infectious diseases, even across vast geographical distance.

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  • 32.
    Zhou, Sirui
    et al.
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, QC, Montréal, Canada.
    Butler-Laporte, Guillaume
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, QC, Montréal, Canada.
    Nakanishi, Tomoko
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Human Genetics, McGill University, QC, Montréal, Canada; Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan.
    Morrison, David R.
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Afilalo, Jonathan
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, QC, Montréal, Canada; Department of Medicine, Division of Cardiology, McGill University, QC, Montréal, Canada.
    Afilalo, Marc
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Emergency Medicine, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Laurent, Laetitia
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Pietzner, Maik
    MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
    Kerrison, Nicola
    MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
    Zhao, Kaiqiong
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, QC, Montréal, Canada.
    Brunet-Ratnasingham, Elsa
    Research Centre of the Centre Hospitalier de l’Université de Montréal, QC, Montréal, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, QC, Montréal, Canada.
    Henry, Danielle
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Kimchi, Nofar
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Afrasiabi, Zaman
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Rezk, Nardin
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Bouab, Meriem
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Petitjean, Louis
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Guzman, Charlotte
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Xue, Xiaoqing
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Tselios, Chris
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Vulesevic, Branka
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Adeleye, Olumide
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Abdullah, Tala
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Almamlouk, Noor
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Chen, Yiheng
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Human Genetics, McGill University, QC, Montréal, Canada.
    Chassé, Michaël
    Research Centre of the Centre Hospitalier de l’Université de Montréal, QC, Montréal, Canada.
    Durand, Madeleine
    Research Centre of the Centre Hospitalier de l’Université de Montréal, QC, Montréal, Canada.
    Paterson, Clare
    SomaLogic, Inc., CO, Boulder, United States.
    Normark, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Wallenberg Center for Molecular Medicine, Umeå Universitet, Sverige.
    Frithiof, Robert
    Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Lipcsey, Miklós
    Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Hedenstierna Laboratory, CIRRUS, Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Hultström, Michael
    Anaesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden; Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
    Greenwood, Celia M. T.
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, QC, Montréal, Canada; Gerald Bronfman Department of Oncology, McGill University, QC, Montréal, Canada.
    Zeberg, Hugo
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Langenberg, Claudia
    MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; Computational Medicine, Berlin Institute of Health, Charité University Medicine Berlin, Berlin, Germany.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pollak, Michael
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Departments of Medicine and Oncology, McGill University, QC, Montréal, Canada.
    Mooser, Vincent
    Department of Human Genetics, McGill University, QC, Montréal, Canada.
    Forgetta, Vincenzo
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada.
    Kaufmann, Daniel E.
    Research Centre of the Centre Hospitalier de l’Université de Montréal, QC, Montréal, Canada; Department of Medicine, Université de Montréal, QC, Montréal, Canada.
    Richards, J. Brent
    Lady Davis Institute, Jewish General Hospital, McGill University, QC, Montréal, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, QC, Montréal, Canada; Department of Human Genetics, McGill University, QC, Montréal, Canada; Department of Twin Research, King’s College London, London, United Kingdom.
    A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity2021In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 27, p. 659-667Article in journal (Refereed)
    Abstract [en]

    To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.

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