Lars Peter Nielsen

University of Copenhagen Herlev Hospital, Herlev, Capital Region, Denmark

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Publications (72)238.16 Total impact

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    ABSTRACT: One of the leading causes of severe childhood gastroenteritis are group A rotaviruses, and they have been found to be associated with ∼40% of the annual gastroenteritis-associated hospitalizations in young children < 5 years of age (Fischer et al., 2011). In this study the diversity of rotavirus strains circulating among young children < 5 years of age, presenting with gastroenteritis disease either at the general practitioner or in the hospital, during the period 2009-2013 is investigated. A total of 831 rotavirus positive stool samples were genotyped in the study period, and the majority of samples (74%) were from hospitalized children. G and P genotypes were successfully determined for 826 of samples, with G1P[8] being the most commonly detected genotype. Detection of G1showed a decreasing trend over time, and an inverse trend was seen for the emerging G9P. The common human genotypes (G1/G3/G4/G9P[8] and G2P[4]) were detected in the majority of samples (n=733, 88.2%). Rare genotype combinations such as G6P[14] were detected in <1% of samples. Rare genotype strains and strains which failed to amplify in genotyping RT-PCR were subjected to genetic characterization by sequencing one or all of the following genes; VP7, VP4, VP6 and NSP4. Sequences of sufficient length and quality were available for all 4 genes for 28 strains. Phylogenetic analysis revealed that reassortant G9P[4] strains circulated with 3 different genotype combinations. As rotavirus vaccines are not widely used in Denmark or its neighbouring countries, the diversity of rotavirus strains identified in this study most likely reflects naturally occurring selection pressures and viral evolution.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 07/2014; · 3.22 Impact Factor
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    ABSTRACT: Multiple viruses have been detected in cardiac tissue, but their role in causing myocarditis remains controversial. Viral diagnostics are increasingly used in forensic medicine, but the interpretation of the results can sometimes be challenging. In this study, we examined the prevalence of adenovirus, enterovirus, and parvovirus B19 (PVB) in myocardial autopsy samples from myocarditis related deaths and in non-inflamed control hearts in an effort to clarify their significance as the causes of myocarditis in a forensic material. We collected all autopsy cases diagnosed with myocarditis from 1992 to 2010. Eighty-four suicidal deaths with morphologically normal hearts served as controls. Polymerase chain reaction was used for the detection of the viral genomes (adenovirus, enterovirus, and PVB) in myocardial tissue specimens. The distinction between acute and persistent PVB infection was made by the serological determination of PVB-specific immunoglobulins M and G. PVB was detected in 33 of 112 (29 %) myocarditis cases and 37 of 84 (44 %) control cases. All of the samples were negative for the presence of adenovirus and enterovirus. Serological evidence of an acute PVB infection, determined by the presence of immunoglobulin M, was only present in one case. In the remaining cases, PVB was considered to be a bystander with no or limited association to myocardial inflammation. In this study, adenovirus, enterovirus, and PVB were found to be rare causes of myocarditis. The detection of PVB in myocardial autopsy samples most likely represents a persistent infection with no or limited association with myocardial inflammation. The forensic investigation of myocardial inflammation demands a thorough examination, including special attention to non-viral causes and requires a multidisciplinary approach.
    Forensic Science Medicine and Pathology 04/2014; · 2.44 Impact Factor
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    ABSTRACT: A medication error (ME) is an error that causes damage or poses a threat of harm to a patient. Several studies have shown that only a minority of MEs actually causes harm, and this might explain why medication reviews at hospital admission reduce the number of MEs without showing an effect on length of hospital stay, readmissions, or death. The purpose of this study was to define drugs that actually cause serious MEs. We conducted a literature search of medication reviews and other preventive efforts. A systematic search in PubMed, Embase, Cochrane Reviews, Psycinfo, and SweMed+ was performed. Danish databases containing published patient complaints, patient compensation, and reported medication errors were also searched. Articles and case reports were included if they contained information of an ME causing a serious adverse reaction (AR) in a patient. Information concerning AR seriousness, causality, and preventability was required for inclusion. This systematic literature review revealed that 47 % of all serious MEs were caused by seven drugs or drug classes: methotrexate, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDS), digoxin, opioids, acetylic salicylic acid, and beta-blockers; 30 drugs or drug classes caused 82 % of all serious MEs. The top ten drugs involved in fatal events accounted for 73 % of all drugs identified. Increasing focus on seven drugs/drug classes can potentially reduce hospitalizations, extended hospitalizations, disability, life-threatening conditions, and death by almost 50 %.
    European Journal of Clinical Pharmacology 03/2014; · 2.74 Impact Factor
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    ABSTRACT: The aim of this study was to establish quantitative diagnostic criteria for lymphocytic myocarditis on autopsy samples by using a stereological cell profile counting method. We quantified and compared the presence of lymphocytes and macrophages in myocardial autopsy specimens from 112 deceased individuals who had been diagnosed with myocarditis according to the Dallas criteria and 86 control subjects with morphologically normal hearts. We found the mean number to be 52.7lymphocyte profiles/mm(2) (range 3.7-946; standard deviation 131) in the myocarditis group and 9.7 (range 2.1-25.9; standard deviation 4.6) in the control group. The cut-off value for the diagnosis of myocarditis was determined by calculating sensitivity plus specificity, which reached the highest combination at 13lymphocyte profiles/mm(2) (sensitivity 68%; specificity 83%). A considerable proportion of subjects in both the myocarditis and control groups had lymphocyte profile counts below 30/mm(2), representing a diagnostic challenge due to the increased risk of creating false negative or false positive results. We found it practically impossible to obtain a reliable macrophage count. The present data add new important information on lymphocyte counts in inflamed and non-inflamed myocardium. We suggest a cut-off value in the range of 11-16lymphocyte profiles/mm(2) for a reliable diagnosis of lymphocytic myocarditis from autopsy samples. To evaluate small inflammatory changes at low lymphocyte counts, a multidisciplinary approach should be implemented, in which diagnostic tools are used ancillary to histological examination. We advise against semi-quantification of macrophages based on cell profile counting.
    Forensic science international 02/2014; 238C:9-15. · 2.10 Impact Factor
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    ABSTRACT: Transposable elements (TEs) are ubiquitous in eukaryotic genomes. Barbara McClintock's famous notion of TEs acting as controlling elements modifying the genetic response of an organism upon exposure to stressful environments has since been solidly supported in a series of model organisms. This requires the TE activity response to possess an element of specificity and be targeted toward certain parts of the genome. We propose that a similar TE response is present in human cells, and that this stress response may drive the onset of human cancers. As such, TE-driven cancers may be viewed as an evolutionary by-product of organisms' abilities to genetically adapt to environmental stress.
    Frontiers in Genetics 01/2014; 5:156.
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    ABSTRACT: Molecular detection of viruses has been aided by high-throughput sequencing, permitting the genomic characterization of emerging strains. In this study, we comprehensively screened 500 respiratory secretions from children with upper and/or lower respiratory tract infections for viral pathogens. The viruses detected are described, including a divergent human parainfluenza virus type 4 from GS FLX pyrosequencing of 92 specimens. Complete full-genome characterization of the virus followed, using Single Molecule, Real-Time (SMRT) sequencing. Subsequent "primer walking" combined with Sanger sequencing validated the RS platform's utility in viral sequencing from complex clinical samples. Comparative genomics reveals the divergent strain clusters with the only completely sequenced HPIV4a subtype. However, it also exhibits various structural features present in one of the HPIV4b reference strains, opening questions regarding their lifecycle and evolutionary relationships among these viruses. Clinical data from patients infected with the strain, as well as viral prevalence estimates using real-time PCR, is also described.
    Scientific Reports 09/2013; 3:2468. · 5.08 Impact Factor
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    ABSTRACT: Medication reviews have the potential to lower the incidence of prescribing errors. To benefit from a medication review, the prescriber must adhere to medication counselling. Adherence rates vary from 39-100%. The aim of this study was to examine counselling-naive hospital physicians' perspectives and demands to medication counselling as well as study factors that might increase adherence to the counselling. This article is protected by copyright. All rights reserved.
    Basic & Clinical Pharmacology & Toxicology 07/2013; · 2.18 Impact Factor
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    ABSTRACT: As the number of new enteroviruses and human parechoviruses seems ever growing, the necessity for updated diagnosis using an enterovirus assay and combined it with a published assay for human parechovirus resulting in a multiplex one-step RT-PCR assay. The multiplex assay was validated by analysing the sensitivity and specificity of the assay compared to the respective monoplex assays, and a good concordance was found. Furthermore, the enterovirus assay was able to detect 42 reference strains from all 4 species, and an additional 9 genotypes during panel testing and routine usage. During 15 months of routine use, from October 2008 to December 2009, we received and analysed 2187 samples, stool samples, cerebrospinal fluids, blood samples, respiratory samples and autopsy samples were tested, from 1546 patients and detected enteroviruses and parechoviruses in 171 (8%) and 66 (3%) of the samples, respectively. 180 of the positive samples could be genotyped by PCR and sequencing and the most common genotypes found were human parechovirus type 3, echovirus 9, enterovirus 71, Coxsackievirus A16, and echovirus 25. During 2009 in Denmark, both enterovirus and human parechovirus type 3 had a similar seasonal pattern with a peak during the summer and autumn. Human parechovirus type 3 was almost invariably found in children less than 4 months of age. In conclusion, a multiplex assay was developed allowing simultaneous detection of 2 viruses, which can cause similar clinical symptoms.
    Journal of virological methods 07/2013; · 2.13 Impact Factor
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    ABSTRACT: Our aim was to determine the frequency of 12 common respiratory viruses in patients admitted to intensive care units with respiratory symptoms, evaluate the clinical characteristics and to compare the results to routine microbiological diagnostics. Throat swabs from 122 intensive care-patients >18 years with acute respiratory symptoms were collected upon admission and analysed with multiplex real-time polymerase chain reaction, for 12 community respiratory viruses. Blood and respiratory tract specimens were analysed for bacteria and fungi upon clinicians' request. Clinical and paraclinical data were collected. Viruses were detected in 19 (16%) of the 122 study patients. Five virus-positive patients (26%) had possible clinically relevant bacteria or fungi co-detected. Patients with exacerbation in COPD were associated with a viral infection (p = 0.02). Other comorbidities, clinical and paraclinical parameters, and death were independent of a viral infection or co-detection of bacteria/fungi. In conclusion, respiratory viruses were frequently detected in the patients. The investigated clinical and paraclinical parameters were not different in viral infections compared to other agents, thus respiratory viruses likely have similar impact on the clinical course as other agents. In 25% of the virus-positive patients, polymicrobial aetiology was identified. Comprehensive and sensitive diagnostic methods should be emphasized to enhance respiratory diagnostics.
    Apmis 05/2013; · 2.07 Impact Factor
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    ABSTRACT: BACKGROUND: During the last few years many new human picornaviruses have been discovered due to advances in metagenomics and other molecular biological approaches. The clinical significance and the occurrence are only sparsely described. OBJECTIVES: To determine the epidemiology and clinical significance of infections with the novel human picornaviruses, aichi virus, cosavirus, salivirus, and saffold virus in infants in Denmark. STUDY DESIGN: We tested 1393 stool samples from a birth cohort of 454 children for these viruses. Samples were collected at ages 6, 10 and 15 months, and at episodes of gastroenteritis. Samples were tested by real-time reverse-transcriptase polymerase chain reaction assays. Each study participant had a diary, where the parents reported episodes of disease, including gastroenteritis. RESULTS: Aichi virus, salivirus and saffold virus were detected in 6, 9 and 38 of the children, respectively, but cosavirus was not detected in any of the children. There was a clear seasonal variation with most infections occurring in autumn and winter. A statistically significant association between the findings of salivirus and gastrointestinal disease was demonstrated. There was no association between gastrointestinal disease and the presence of aichi virus or saffold virus. CONCLUSIONS: The newly discovered human picornaviruses aichi virus, saffold virus, and salivirus are circulating in Danish children, with the most common being saffold virus. Saffold virus was seen almost exclusively in the autumn and winter period. Salivirus was the only virus, which was significantly associated with gastroenteritis, although the number of positive samples was rather low.
    Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 04/2013; · 3.12 Impact Factor
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    ABSTRACT: BACKGROUND: Influenza viruses such as swine-origin influenza A(H1N1) virus (A(H1N1)pdm09) generate genetic diversity due to the high error rate of their RNA polymerase, often resulting in mixed genotype populations (intra-host variants) within a single infection. This variation helps influenza to rapidly respond to selection pressures, such as those imposed by the immunological host response and antiviral therapy. We have applied deep sequencing to characterize influenza intra-host variation in a transmission chain consisting of three cases due to oseltamivir-sensitive viruses, and one derived oseltamivir-resistant case. METHODS: Following detection of the A(H1N1)pdm09 infections, we deep-sequenced the complete NA gene from two of the oseltamivir-sensitive virus-infected cases, and all eight gene segments of the viruses causing the remaining two cases. RESULTS: No evidence for the resistance-causing mutation (resulting in NA H275Y substitution) was observed in the oseltamivir-sensitive cases. Furthermore, deep sequencing revealed a subpopulation of oseltamivir-sensitive viruses in the case carrying resistant viruses. We detected higher levels of intra-host variation in the case carrying oseltamivir-resistant viruses than in those infected with oseltamivir-sensitive viruses. CONCLUSIONS: Oseltamivir-resistance was only detected after prophylaxis with oseltamivir, suggesting that the mutation was selected for as a result of antiviral intervention. The persisting oseltamivir-sensitive virus population in the case carrying resistant viruses suggests either that a small proportion survive the treatment, or that the oseltamivir-sensitive virus rapidly re-establishes itself in the virus population after the bottleneck. Moreover, the increased intra-host variation in the oseltamivir-resistant case is consistent with the hypothesis that the population diversity of a RNA virus can increase rapidly following a population bottleneck.
    Virology Journal 04/2013; 10(1):116. · 2.09 Impact Factor
  • Maja Hellfritzsch, Pernille Lassen, Lars Peter Nielsen
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    ABSTRACT: We describe the case of a woman, aged 41 years, who received a combination chemotherapy including vincristine, doxorubicine, ifosfamide and etoposide due to Ewings sarcoma. She was treated prophylactic with fluconazole to prevent oral candidosis. Unexpectedly, she developed severe neurotoxic side effects. Treatment with multiple substrates of cytochrome P450 3A4 combined with inhibition of the enzyme by fluconazole impairs metabolism and thereby increase plasma concentrations of vincristine, which is considered to be the main reason for the neurotoxic side effects.
    Ugeskrift for laeger 04/2013; 175(15):1042-1043.
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    ABSTRACT: To investigate the frequency, type, and potential severity of errors in several stages of the medication process in an inpatient psychiatric setting. A cross-sectional study using three methods for detecting errors: (1) direct observation; (2) unannounced control visits in the wards collecting dispensed drugs; and (3) chart reviews. All errors, except errors in discharge summaries, were assessed for potential consequences by two clinical pharmacologists. Three psychiatric wards with adult patients at Aalborg University Hospital, Denmark, from January 2010-April 2010. The individual handling of medication (prescribing, dispensing, and administering). In total, 189 errors were detected in 1,082 opportunities for error (17%) of which 84/998 (8%) were assessed as potentially harmful. The frequency of errors was: prescribing, 10/189 (5%); dispensing, 18/189 (10%); administration, 142/189 (75%); and discharge summaries, 19/189 (10%). The most common errors were omission of pro re nata dosing regime in computerized physician order entry, omission of dose, lack of identity control, and omission of drug. Errors throughout the medication process are common in psychiatric wards to an extent which resembles error rates in somatic care. Despite a substantial proportion of errors with potential to harm patients, very few errors were considered potentially fatal. Medical staff needs greater awareness of medication safety and guidelines related to the medication process. Many errors in this study might potentially be prevented by nursing staff when handling medication and observing patients for effect and side effects of medication. The nurses' role in psychiatric medication safety should be further explored as nurses appear to be in the unique position to intercept errors before they reach the patient.
    Risk Management and Healthcare Policy 01/2013; 6:23-31.
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    ABSTRACT: Varicella zoster virus (VZV) is known to cause VZV vasculopathy, which may be associated with stroke. A recent study found an increased risk of stroke within one year of herpes zoster. We aimed to investigate the short and long-term effects of herpes zoster on the risk of stroke. Using Danish national registers, we constructed a cohort consisting of all Danish adults ≥18 years old between 1995 and 2008 (n = 4.6 million; person-years of follow-up = 52.9 million). Individual-level information on prescriptions for herpes zoster antiviral treatment and diagnoses of stroke was obtained from national registers. We compared the risk of stroke in persons who had received the specific dosage of acyclovir for herpes zoster with persons who had never received antiviral treatment by Poisson regression. During follow-up, 2.5% received treatment for herpes zoster and 5.0% were diagnosed with stroke. Individuals who had received medication had a 127% (95% CI 83-182%) increased risk the first two weeks, 17% (CI 9-24%) between two weeks and one year, and 5% (2-9%) after the first year. The increased risk was greatest in the youngest age group (<40). To control for healthcare-seeking behaviour, we conducted parallel analyses investigating the risk of selected fractures after herpes zoster and found no similar increased risks. This large nationwide cohort study found an increased risk of stroke after treatment for herpes zoster. Although the short-term risk was particularly high, we cannot rule out the possibility of a small but important long-term risk.
    PLoS ONE 01/2013; 8(7):e69156. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: We hypothesized that rates and reasons for treatment modifications have changed since the implementation of combination antiretroviral therapy (cART) due to improvements in therapy. METHODS: From a nationwide population-based cohort study we identified all HIV-1 infected adults who initiated cART in Denmark 1997-2009 and were followed (3)1 year. Incidence rate ratios (IRR) and reasons for treatment modifications were estimated and compared between patients, who initiated treatment in 1997-1999, 2000-2004 and 2005-2009. Rates of discontinuation of individual antiretroviral drugs (ARVs) were evaluated. RESULTS: 3,107 patients were followed median 7.3 years (IQR 3.8-10.8). Rates of first treatment modification ≤1 year after cART initiation did not change (IRR 0.88 (95% CI 0.78-1.01) and 1.03 (95% CI 0.90-1.18) in 2000-2004 and 2005-2009 compared to 1997-1999). Rates of multiple modifications decreased markedly (2000-2004: IRR 0.60 (95% CI 0.53-0.67) and 2005-2009 0.38 (95% CI 0.32-0.46)). Rates of treatment modifications due to virological failure, toxicity and other/unknown reasons decreased (IRR 0.25 (95% CI 0.14-0.45), 0.69 (95% CI 0.56-0.83) and 0.45 (95% CI 0.36-0.57) in 2005-2009 compared to 1997-1999), while the rate of modifications with the aim of simplification increased (IRR 1.85 (95% CI 1.52-2.25)). CONCLUSIONS: Rates of first treatment modification ≤1 year after cART initiation have not changed since the early cART era, while the risk of multiple modifications has decreased markedly. Modifications due to virological failure and toxicity have decreased substantially, while rates of switch to simpler and less toxic regimens have increased.
    Antiviral therapy 10/2012; · 3.07 Impact Factor
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    ABSTRACT: INTRODUCTION: Continued research is needed to evaluate and improve the immunogenicity of influenza vaccines in HIV infected patients. We aimed to determine the antibody responses after one or two doses of the AS03-adjuvanted pandemic influenza A (H1N1) vaccine in HIV infected patients. METHOD: Following the influenza season 2009/2010, 219 HIV infected patients were included and divided into three groups depending on whether they received none (n=60), one (n=31) or two (n=128) doses of pandemic influenza A (H1N1) vaccine. At inclusion, antibody titers for all patients were analyzed and compared to pre-pandemic antibody titers analyzed from serum samples in a local storage facility. RESULTS: 4-9 months after a single immunization, we found a seroprotection rate of 77.4% and seroconversion rate of 67.7%. After two immunizations the rates increased significantly to seroprotection rate of 97.7% and seroconversion rate of 86.7%. CONCLUSION: A single dose of AS03-adjuvanted pandemic influenza A (H1N1) vaccine created an adequate immune response in HIV infected patients lasting as long as 4-9 months. Two doses improved the immunogenicity further.
    Vaccine 10/2012; · 3.77 Impact Factor
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    ABSTRACT: In 2010, a chimpanzee died at Copenhagen Zoo following an outbreak of respiratory disease among chimpanzees in the zoo. Identification of coxsackie B3 virus, a common human pathogen, as the causative agent, and its severe manifestation, raise questions about pathogenicity and transmissibility among humans and other primates.
    Emerging Infectious Diseases 07/2012; 18(7):1163-5. · 6.79 Impact Factor
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    M Lisby, L P Nielsen, B Brock, J Mainz
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    ABSTRACT: Definitions of medication errors vary widely in the literature, and prevalence from 2-75% in part because of this lack of consensus. Thus, clarification of the concept is urgently needed. The objective was to develop a clear-cut definition of medication errors and specify relevant error types in the medication process. Based on existing taxonomy and through a modified Delphi-process consensus of definition and error types were reached among Danish experts appointed by 13 healthcare organisations and the project group. The experts prioritised five definitions of medication errors and score the relevance of 76 error types. Based on explicit criteria, the project group settled non-consensus cases. The panel consisted of 12 physicians, seven pharmacists, and six nurses. Consensus was reached for the definition "An error in the stages of the medication process - ordering, dispensing, administering and monitoring the effect - causing harm or implying a risk of harming the patient". Moreover, consensus for 60 of 76 error types was achieved. Applied to a historic dataset the definition reduced the number of medication errors from 34% to 7%. Experts deemed a definition using harm or risk of harm as cut-off point as the most appropriate in Danish hospital settings. In addition, they agreed on a list of 60 error types covering the medication process. Interestingly, a substantial lower occurrence of medication errors was found when applied to historic data. The definition is in accordance with international taxonomy, thus is assumed to be applicable to modern healthcare settings abroad.
    Scandinavian Journal of Public Health 03/2012; 40(2):203-10. · 1.97 Impact Factor
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    ABSTRACT: The first human virus in the genus Cardiovirus was described in 2007 and named Saffold virus (SAFV). Cardioviruses can cause severe infections of the myocardium and central nervous system in animals, but SAFV has not yet been convincingly associated with disease in humans. To study a possible association between SAFV and infections in the human central nervous system, we designed a real-time PCR for SAFV and tested cerebrospinal fluid (CSF) samples from children <4 years of age. SAFV was detected in 2 children: in the CSF and a fecal sample from 1 child with monosymptomatic ataxia caused by cerebellitis; and in the CSF, blood, and myocardium of another child who died suddenly with no history of illness. Virus from each child was sequenced and shown to be SAFV type 2. These findings demonstrate that SAFV can cause serious invasive infection in children.
    Emerging Infectious Diseases 01/2012; 18(1):7-12. · 6.79 Impact Factor

Publication Stats

816 Citations
238.16 Total Impact Points

Institutions

  • 2014
    • University of Copenhagen Herlev Hospital
      Herlev, Capital Region, Denmark
  • 2008–2014
    • Statens Serum Institut
      • • Department of Epidemiology Research
      • • Department of Infectious Disease Immunology
      København, Capital Region, Denmark
    • Rigshospitalet
      • Department of Infectious Diseases
      Copenhagen, Capital Region, Denmark
  • 1996–2013
    • Aarhus University Hospital
      • • Department of Clinical Epidemiology
      • • Department of Clinical Pharmacology
      Aarhus, Central Jutland, Denmark
  • 2012
    • University of Copenhagen
      København, Capital Region, Denmark
  • 2009–2012
    • University of Southern Denmark
      Odense, South Denmark, Denmark
  • 2001–2008
    • Aarhus University
      • Department of Clinical Pharmacology
      Aarhus, Central Jutland, Denmark
  • 2006
    • Odense University Hospital
      • Department of Clinical Microbiology
      Odense, South Denmark, Denmark
  • 2000
    • Frederiksberg Hospital
      Фредериксберг, Capital Region, Denmark
  • 1994–1996
    • Copenhagen University Hospital
      København, Capital Region, Denmark