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Holm, A., Schindele, A., Allard, A., Eriksson, I., Sandström, K., Laurell, G., . . . Olofsson, K. (2019). Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease. Laryngoscope Investigative Otolaryngology, 4(3), 285-291
Open this publication in new window or tab >>Mapping of Human Papilloma Virus, p16, and Epstein-Barr Virusin Non-Malignant Tonsillar Disease
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2019 (English)In: Laryngoscope Investigative Otolaryngology, E-ISSN 2378-8038, Vol. 4, no 3, p. 285-291Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objectives: Due to their location in the entrance of the aero‐digestive tract, tonsils are steadily exposed to viruses. Human papilloma virus (HPV) and Epstein‐Barr virus (EBV) are two potentially oncogenic viruses that tonsils encounter. The incidence of HPV positive tonsillar cancer is on the rise and it is unknown when infection with HPV occurs.

Aim: To investigate if tonsils are infected with HPV and EBV, to study the co‐expression of HPV and its surrogate marker p16, and to evaluate the number of EBV positive cells in benign tonsillar disease.

Materials and Methods: Tonsils from 40 patients in a university hospital were removed due to hypertrophy, chronic or recurrent infection. These were analyzed for presence of HPV, its surrogate marker p16, and EBV. HPV was studied using PapilloCheck (a PCR method), while p16 was identified in epithelial and lymphoid tissue with immunohistochemistry and EBV using EBER‐ISH (Epstein‐Barr encoding region–in situ hybridization).

Results: HPV was not detected, and p16 was present at low numbers in all epithelial samples as well as in 92.5% of the lymphoid tonsillar samples. At least one EBER‐positive cell was seen in 65% of cases. Larger numbers of EBER‐expressing cells were only seen in two cases.

Conclusion: These findings demonstrate that EBV and HPV infect tonsils independently, but further studies are warranted to confirm their infectious relationship.

Level of Evidence: Cross‐sectional study

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
Keywords
Human papillomavirus, Epstein-Barr virus, non-malignant tonsillar disease, EBER-ISH, PapilloCheck, immunohistochemistry
National Category
Otorhinolaryngology
Research subject
Oto-Rhino-Laryngology
Identifiers
urn:nbn:se:umu:diva-158485 (URN)10.1002/lio2.260 (DOI)000471907200002 ()
Funder
Västerbotten County Council
Available from: 2019-04-29 Created: 2019-04-29 Last updated: 2019-07-11Bibliographically approved
Kaján, G. L., Lipiec, A., Bartha, D., Allard, A. & Arnberg, N. (2018). A multigene typing system for human adenoviruses reveals a new genotype in a collection of Swedish clinical isolates. PLoS ONE, 13(12), Article ID e0209038.
Open this publication in new window or tab >>A multigene typing system for human adenoviruses reveals a new genotype in a collection of Swedish clinical isolates
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209038Article in journal (Refereed) Published
Abstract [en]

Human adenoviruses (HAdVs) are common pathogens that can cause respiratory, gastrointestinal, urogenital, and ocular infections. They are divided into seven species containing 85 genotypes. Straightforward typing systems might help epidemiological investigations. As homologous recombination frequently shapes the evolution of HAdVs, information on a single gene is seldom sufficient to allow accurate and precise typing, and complete genome-based methods are recommended. Even so, complete genome analyses are not always easy to perform for practical reasons, and in such cases a multigene system can provide considerably more information about the strain under investigation than single-gene-based methods. Here we present a rapid, generic, multigene typing system for HAdVs based on three main deterministic regions of these viruses. Three PCR systems were used to amplify the genes encoding the DNA polymerase, the penton base hypervariable Arg-Gly-Asp-containing loop, and the hexon loop 1 (hypervariable region 1–6). Using this system, we typed 281 clinical isolates, detected members of six out of seven HAdV species (Human mastadenovirus AF), and could also detect not only divergent strains of established types but also a new recombinant strain with a previously unpublished combination of adenovirus genomes. This strain was accepted by the Human Adenovirus Working Group as a novel genotype: HAdV-86. Seven strains that could not be typed with sufficient accuracy were also investigated using a PCR based on part of the fiber gene. By analysis of corresponding sequences of the 86 known HAdV genotypes, we determined that the proposed typing system should be able to distinguish all non-recombinant types, and with additional fiber information, all known HAdV genotypes.

Place, publisher, year, edition, pages
Public Library Science, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-155105 (URN)10.1371/journal.pone.0209038 (DOI)000453248000040 ()30550551 (PubMedID)
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Westerberg, S., Hagbom, M., Rajan, A., Loitto, V., Persson, D., Allard, A., . . . Svensson, L. (2018). Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells. Journal of Virology, 92(7), Article ID e00026-18.
Open this publication in new window or tab >>Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells
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2018 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 92, no 7, article id e00026-18Article in journal (Refereed) Published
Abstract [en]

Human adenovirus 41 (HAdV-41) causes acute gastroenteritis in young children. The main characteristics of HAdV-41 infection are diarrhea and vomiting. Nevertheless, the precise mechanism of HAdV-41-induced diarrhea is unknown, as a suitable small-animal model has not been described. In this study, we used the human midgut carcinoid cell line GOT1 to investigate the effect of HAdV-41 infection and the individual HAdV-41 capsid proteins on serotonin release by enterochromaffin cells and on enteric glia cell (EGC) activation. We first determined that HAdV-41 could infect the enterochromaffin cells. Immunofluorescence staining revealed that the cells expressed HAdV-41-specific coxsackievirus and adenovirus receptor (CAR); flow cytometry analysis supported these findings. HAdV-41 infection of the enterochromaffin cells induced serotonin secretion dose dependently. In contrast, control infection with HAdV-5 did not induce serotonin secretion in the cells. Confocal microscopy studies of enterochromaffin cells infected with HAdV-41 revealed decreased serotonin immunofluorescence compared to that in uninfected cells. Incubation of the enterochromaffin cells with purified HAdV-41 short fiber knob and hexon proteins increased the serotonin levels in the harvested cell supernatant significantly. HAdV-41 infection could also activate EGCs, as shown in the significantly altered expression of glia fibrillary acidic protein (GFAP) in EGCs incubated with HAdV-41. The EGCs were also activated by serotonin alone, as shown in the significantly increased GFAP staining intensity. Likewise, EGCs were activated by the cell supernatant of HAdV-41-infected enterochromaffin cells.

Keywords
gastroenteritis, enteric adenovirus, EC cells, serotonin, enteric glia cells
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-146907 (URN)10.1128/JVI.00026-18 (DOI)000428409800002 ()29367250 (PubMedID)
Funder
Swedish Research Council, 320301
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-06-27Bibliographically approved
Edin, A., Granholm, S., Koskiniemi, S., Allard, A., Sjöstedt, A. & Johansson, A. (2015). Development and Laboratory Evaluation of a Real-Time PCR Assay for Detecting Viruses and Bacteria of Relevance for Community-Acquired Pneumonia. Journal of Molecular Diagnostics, 17(3), 315-324
Open this publication in new window or tab >>Development and Laboratory Evaluation of a Real-Time PCR Assay for Detecting Viruses and Bacteria of Relevance for Community-Acquired Pneumonia
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2015 (English)In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 3, p. 315-324Article in journal (Refereed) Published
Abstract [en]

Community-acquired pneumonia may present with similar clinical symptoms, regardless of viral or bacterial cause. Diagnostic assays are needed to rapidly discriminate between causes, because this will guide decisions on appropriate treatment. Therefore, a quantitative real-time PCR (qPCR) assay with duplex reactions targeting eight bacteria and six viruses was developed. Technical performance was examined with linear plasmids. Upper and Lower respiratory tract specimens were used to compare the qPCR assay with standard microbiological methods. The limit of detection was 5 to 20 DNA template copies with approximately 1000-fold differences in concentrations of the two competing templates. SDs for positive controls were <5%. The use of the qPCR assay resulted in 113 positive identifications in 94 respiratory specimens compared with 38 by using standard diagnostics. Diagnostic accuracy of the qPCR assay varied between 60% positive agreement with standard tests for Streptococcus pneumoniae and 100% for Mycoplasma pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus. Negative percentage of agreement was >95% for M. pneumoniae, Streptococcus pyogenes, respiratory syncytial virus, and influenza A virus; whereas it was only 56% for Haemophilus influenzae. Multiple microbial agents were identified in 19 of 44 sputum and 19 of 50 nasopharynx specimens. We conclude that in parallel qPCR detection of the targeted respiratory bacteria and viruses is feasible. The results indicate good technical performance of the assay in clinical specimens.

National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:umu:diva-103727 (URN)10.1016/j.jmoldx.2015.01.005 (DOI)000353843900011 ()25772704 (PubMedID)
Available from: 2015-06-09 Created: 2015-05-28 Last updated: 2018-06-07Bibliographically approved
Swartling, L. P., Allard, A., Torlen, J., Ljungman, P., Mattsson, J. & Sparrelid, E. (2015). Prolonged Outbreak of Adenovirus A31 Among Allogeneic Stem Cell Transplant Recipients. Paper presented at 41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation. Bone Marrow Transplantation, 50 1, S77-S77
Open this publication in new window or tab >>Prolonged Outbreak of Adenovirus A31 Among Allogeneic Stem Cell Transplant Recipients
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2015 (English)In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 50 1, p. S77-S77Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:umu:diva-102372 (URN)000351632900133 ()
Conference
41st Annual Meeting of the European-Society-for-Blood-and-Marrow-Transplantation
Note

Supplement: 1 Meeting Abstract: O132

Available from: 2015-05-28 Created: 2015-04-23 Last updated: 2018-06-07Bibliographically approved
Swartling, L., Allard, A., Torlen, J., Ljungman, P., Mattsson, J. & Sparrelid, E. (2015). Prolonged outbreak of adenovirus A31 in allogeneic stem cell transplant recipients. Transplant Infectious Disease, 17(6), 785-794
Open this publication in new window or tab >>Prolonged outbreak of adenovirus A31 in allogeneic stem cell transplant recipients
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2015 (English)In: Transplant Infectious Disease, ISSN 1398-2273, E-ISSN 1399-3062, Vol. 17, no 6, p. 785-794Article in journal (Refereed) Published
Abstract [en]

Background: An outbreak of human adenovirus (HAdV) A31 occurred from December 2011 to March 2012 at the Center for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital in Sweden. We analyzed the outbreak, the routes of transmission, and report the medical consequences.

Methods: The medical records of all patients admitted to CAST during the outbreak period were studied. Phylogenetic analysis of the patient HAdV strains was performed by sequencing the hexon gene and the more variable E3 gene.

Results: We identified 9 cases of HAdV A31. Hygiene measures were implemented, but transmission continued for 2 months. All 9 patients had been admitted to the ward, but 2 had no connection in time to other known HAdV A31 cases. DNA sequencing of the patient strains strongly suggested nosocomial transmission. Transplantation was postponed and then cancelled in 1 patient, and 5 patients were treated with cidofovir because of high levels of viremia. In 7 patients, concomitant graft-versus-host disease (GVHD) grade II–V complicated the clinical picture, as it was difficult to distinguish symptoms of GVHD from those of HAdV infection.

Conclusion: An outbreak of HAdV in HSCT recipients can be difficult to control. Although none of the patients had severe disease, the medical consequences were significant. It is possible that unidentified cases with mild symptoms may have caused continuous transmission at the unit. Regular testing of all patients several weeks beyond the last case identified may be an important measure to control transmission.

Keywords
adenovirus A31, stem cell transplantation, outbreak, phylogenetic analysis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-116761 (URN)10.1111/tid.12443 (DOI)000368526900002 ()
Available from: 2016-02-19 Created: 2016-02-11 Last updated: 2018-06-07Bibliographically approved
Rusiol, M., Fernandez-Cassi, X., Hundesa, A., Vieira, C., Kern, A., Eriksson, I., . . . Girones, R. (2014). Application of human and animal viral microbial source tracking tools in fresh and marine waters from five different geographical areas. Water Research, 59, 119-129
Open this publication in new window or tab >>Application of human and animal viral microbial source tracking tools in fresh and marine waters from five different geographical areas
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2014 (English)In: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 59, p. 119-129Article in journal (Refereed) Published
Abstract [en]

Integrated river basin management planning to mitigate the impacts of economic, demographic and climate change is an important issue for the future protection of water resources. Identifying sources of microbial contamination via the emerging science of Microbial Source Tracking (MST) plays a key role in risk assessment and the design of remediation strategies. Following an 18-month surveillance program within the EU-FP7-funded VIROCLIME project, specific MST tools were used to assess human markers such as adenoviruses (HAdV) and JC polyomaviruses (JCPyV) and porcine and bovine markers such as porcine adenoviruses (PAdV) and bovine polyomaviruses (BPyV) via quantification with real-time PCR to analyze surface water collected from five sites within different climatic zones: the Negro River (Brazil), Glafkos River (Greece), Tisza River (Hungary), Llobregat River (Spain) and Umealven River (Sweden). The utility of the viral MST tools and the prevalence and abundance of specific human and animal viruses in the five river catchments and adjacent seawater, which is impacted by riverine contributions from the upstream catchments, were examined. In areas where no sanitation systems have been implemented, sewage can directly enter surface waters, and river water exhibited high viral loads; HAdV and JCPyV could be detected at mean concentrations of 10(5) and 10(4) Genome Copies/Liter (GC/L), respectively. In general, river water samples upstream of urban discharges presented lower human viral loads than downstream sampling sites, and those differences appeared to increase with urban populations but decrease in response to high river flow, as the elevated river water volume dilutes microbial loads. During dry seasons, river water flow decreases dramatically, and secondary effluents can represent the bulk of the riverine discharge. We also observed that ice cover that formed over the river during the winter in the studied areas in North Europe could preserve viral stability due to the low temperatures and/or the lack of solar inactivation. Porcine and bovine markers were detected where intensive livestock and agricultural activities were present; mean concentration values of 10(3) GC/L indicated that farms were sometimes unexpected and important sources of fecal contamination in water. During spring and summer, when livestock is outdoors and river flows are low, animal pollution increases due to diffuse contamination and direct voiding of feces onto the catchment surface. The field studies described here demonstrate the dynamics of fecal contamination in all catchments studied, and the data obtained is currently being used to develop dissemination models of fecal contamination in water with respect to future climate change scenarios. The results concerning human and animal targets presented in this study demonstrate the specificity and applicability Of the viral quantitative parameters developed to widely divergent geographical areas and their high interest as new indicators of human and animal fecal contamination in water and as MST tools.

Keywords
Microbial Source Tracking (MST), Adenovirus, Polyomavirus, River water, Seawater
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-91252 (URN)10.1016/j.watres.2014.04.013 (DOI)000337861400012 ()
Available from: 2014-07-31 Created: 2014-07-28 Last updated: 2018-06-07Bibliographically approved
Strand, M., Islam, K., Edlund, K., Öberg, C. T., Allard, A., Bergström, T., . . . Wadell, G. (2012). 2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 2. Antimicrobial Agents and Chemotherapy, 56(11), 5735-5743
Open this publication in new window or tab >>2-[4,5-Difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, an antiviral compound with activity against acyclovir-resistant isolates of herpes simplex virus type 1 and 2
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2012 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 11, p. 5735-5743Article in journal (Refereed) Published
Abstract [en]

Herpes simplex viruses (HSV-1 and HSV-2) are responsible for life-long latent infections in humans, with periods of viral reactivation associated with recurring ulcerations in the orofacial and genital tract. In immunosuppressed patients and neonates, HSV infections are associated with severe morbidity, and in some cases even mortality. Today, acyclovir is the standard therapy for management of HSV infections. However, the need for novel antiviral agents is apparent since HSV isolates resistant to acyclovir therapy are frequently isolated in immunosuppressed patients. In this study, we assessed the anti-HSV activity of the anti-adenoviral compounds 2-[2-(2-benzoylamino)-benzoylamino]benzoic acid, (Benzavir-1) and 2-[4,5-difluoro-2-(2-fluorobenzoylamino)-benzoylamino]benzoic acid, (Benzavir-2) on HSV-1 and HSV-2. Both compounds were active against both viruses. Importantly, Benzavir-2 had similar potency to acyclovir against both HSV types and it was active against clinical acyclovir-resistant HSV isolates.

Place, publisher, year, edition, pages
American Society Microbiology, 2012
Keywords
Herpes simplex virus, HSV, inhibitor, 2-[2-(benzoylamino)benzoylamino]benzoic acid, antiviral, Benzavir
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-60354 (URN)10.1128/AAC.01072-12 (DOI)000310055800039 ()22908173 (PubMedID)
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2018-06-08Bibliographically approved
Andersson, E. K., Strand, M., Edlund, K., Lindman, K., Enquist, P.-A., Spjut, S., . . . Wadell, G. (2010). Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound. Antimicrobial Agents and Chemotherapy, 54(9), 3871-3877
Open this publication in new window or tab >>Small molecule screening using a whole cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel anti-adenoviral compound
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2010 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, no 9, p. 3871-3877Article in journal (Refereed) Published
Abstract [en]

Adenovirus infections are widespread in society and are occasionally associated with severe, but rarely with life-threatening, disease in otherwise healthy individuals. In contrast, adenovirus infections present a real threat to immunocompromised individuals and can result in disseminated and fatal disease. The number of patients undergoing immunosuppressive therapy for solid organ or hematopoietic stem cell transplantation is steadily increasing, as is the number of AIDS patients, and this makes the problem of adenovirus infections even more urgent to solve. There is no formally approved treatment of adenovirus infections today, and existing antiviral agents evaluated for their anti-adenoviral effect give inconsistent results. We have developed a whole cell-based assay for high-throughput screening of potential anti-adenoviral compounds. The assay is unique in that it is based on a replication competent adenovirus type 11p GFP-expressing vector (RCAd11pGFP). This allows measurement of fluorescence changes as a direct result of RCAd11pGFP genome expression. Using this assay, we have screened 9,800 commercially available small organic compounds. Initially, we observed approximately 400 compounds that inhibited adenovirus expression in vitro by >/= 80% but only 24 were later confirmed as dose-dependent inhibitors of adenovirus. One compound in particular, 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid, turned out to be a potent inhibitor of adenovirus replication.

Place, publisher, year, edition, pages
American society for microbiology, 2010
Keywords
rapid colorimetric assay; adenovirus infection; transplant recipients; in-vitro; immunocompromised host; formazan assay; renal-failure; cidofovir; growth; proliferation
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-35281 (URN)10.1128/AAC.00203-10 (DOI)000281005900048 ()20585112 (PubMedID)
Available from: 2010-08-11 Created: 2010-08-11 Last updated: 2018-06-08Bibliographically approved
Johansen, K., Mannerqvist, K., Allard, A., Andersson, Y., Burman, L. G., Dillner, L., . . . Widell, A. (2008). Norovirus strains belonging to the GII.4 genotype dominate as a cause of nosocomial outbreaks of viral gastroenteritis in Sweden 1997--2005: Arrival of new variants is associated with large nation-wide epidemics. Journal of Clinical Virology, 42(2), 129-134
Open this publication in new window or tab >>Norovirus strains belonging to the GII.4 genotype dominate as a cause of nosocomial outbreaks of viral gastroenteritis in Sweden 1997--2005: Arrival of new variants is associated with large nation-wide epidemics
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2008 (English)In: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 42, no 2, p. 129-134Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In recent years an increase of the incidence of nosocomial outbreaks caused by noroviruses has been observed throughout Sweden, with high peaks noted in the winter seasons 2002/2003 and 2004/2005, respectively. OBJECTIVES: To phylogenetically characterize norovirus strains causing nosocomial outbreaks from 1997 to 2005 and estimate the impact of norovirus-like disease on the Swedish health care system during the peak season 2002/2003 when a new variant of norovirus occurred. STUDY DESIGN: Stool samples from 115 randomly selected nosocomial outbreaks occurring during 1997--2005 throughout Sweden were studied by RT-PCR and sequencing. In addition, to investigate the impact on the health-care system, a questionnaire was distributed to infection control units (n=90) serving all Swedish hospitals, nursing homes and other health-care institutions during the largest epidemic of nosocomial outbreaks. RESULTS: Sequencing of 279 nucleotides of the norovirus RNA polymerase gene in stools containing norovirus RNA showed that strains belonging to the GII.4 genotype dominated. Each of the two large epidemics was due to a new variant within this cluster. The questionnaire revealed that 30,000-35,000 episodes of nosocomial norovirus-like infections occurred in 80 of 82 major Swedish hospitals affected in 2002/2003. CONCLUSION: New norovirus variants within the cluster GGII.4 may have a major impact on the health-care system.

Place, publisher, year, edition, pages
Elsevier, 2008
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-21119 (URN)10.1016/j.jcv.2007.12.012 (DOI)18304864 (PubMedID)
Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2018-06-09Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-6949-1213

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