[Show abstract][Hide abstract] ABSTRACT: Although nearly one fifth of all human cancers have an infectious aetiology, the causes for the majority of cancers remain unexplained. Despite the enormous data output from high-throughput shotgun sequencing, viral DNA in a clinical sample typically constitutes a proportion of host DNA that is too small to be detected. Sequence variation among virus genomes complicates application of sequence-specific, and highly sensitive, PCR methods. Therefore, we aimed to develop and characterize a method that permits sensitive detection of sequences despite considerable variation. We demonstrate that our low-stringency in-solution hybridization method enables detection of <100 viral copies. Furthermore, distantly related proviral sequences may be enriched by orders of magnitude, enabling discovery of hitherto unknown viral sequences by high-throughput sequencing. The sensitivity was sufficient to detect retroviral sequences in clinical samples. We used this method to conduct an investigation for novel retrovirus in samples from three cancer types. In accordance with recent studies our investigation revealed no retroviral infections in human B-cell lymphoma cells, cutaneous T-cell lymphoma or colorectal cancer biopsies. Nonetheless, our generally applicable method makes sensitive detection possible and permits sequencing of distantly related sequences from complex material.
[Show abstract][Hide abstract] ABSTRACT: A risk stratification approach is needed to identify patients at high risk of medication errors and a resulting high need of medication review. The aim of this study was to perform risk stratification (distinguishing between low-risk, medium-risk and high-risk drugs) for drugs found to cause serious adverse reactions due to medication errors. The study employed a modified Delphi technique.
Drugs from a systematic literature search were included into two rounds of a Delphi process. A panel of experts was asked to evaluate each identified drug's potential for harm and for clinically relevant drug-drug interactions on a scale from 1 (low risk) to 9 (high risk).
A total of 36 experts were appointed to serve on the panel. Consensus was reached for 29/57 (51%) drugs or drug classes that cause harm, and for 32/57 (56%) of the drugs or drug classes that cause interactions. For the remaining drugs, a decision was made based on the median score. Two lists, one stating the drugs' potential for causing harm and the other stating clinically relevant drug-drug interactions, were stratified into low-risk, medium-risk and high-risk drugs.
Based on a modified Delphi technique, we created two lists of drugs stratified into a low-risk, a medium-risk and a high-risk group of clinically relevant interactions or risk of harm to patients. The lists could be incorporated into a risk-scoring tool that stratifies the performance of medication reviews according to patients' risk of experiencing adverse reactions.
Danish Medical Journal 08/2015; 62(8). · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Medication errors (MEs) are preventable and can result in patient harm and increased expenses in the health care system in terms of hospitalization, prolonged hospitalizations and even death. We aimed to develop a screening tool to detect acutely admitted patients at low or high risk of MEs comprised by items found by literature search and use of theoretical weighting. Predictive variables used for the development of the risk score were found by literature search. Three retrospective patient populations and one prospective pilot population were used for modelling. The final risk score was evaluated for precision by use of sensitivity, specificity and area under the ROC (Receiver Operating Characteristic) curves. The variables used in the final risk score were reduced renal function, the total number of drugs and the risk of individual drugs to cause harm and drug-drug interactions. We found a risk score in the prospective population with an area under the ROC curve of 0.76. The final risk score was found to be quite robust as it showed an area under the ROC curve of 0.87 in a recent patient population, 0.74 in a population of internal medicine and 0.66 in an orthopaedic population. We developed a simple and robust score, MERIS, with the ability to detect patients and divide them according to low and high risk of MEs in a general population admitted at acute admissions unit. The accuracy of the risk score was at least as good as other models reported using multiple regression analysis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the serological response in pregnant Danish women immunized during the 2009 pandemic by serologic infection or by vaccination with influenza A (H1N1) Pandemrix(®) and describe levels of passively acquired maternal antibody in their offspring.
Observational cohort study.
Department of Obstetrics, Aarhus University Hospital, Skejby, Denmark, October to December 2009.
Pregnant women and their offspring.
Serological analysis of antibodies to Influenza A (H1N1)pdm09 by hemagglutination inhibition assay in 197 women and their offspring. Blood samples were collected consecutively at delivery from the mother and the umbilical cord. In a subgroup of 124 of the 197 women, an additional blood sample from gestational week 9-12 was available for analysis.
Seroconversion, geometric mean titer, geometric mean-fold rise and protective antibodies.
Thirty-three of the 124 subgroup women (27%) seroconverted during pregnancy. Seventy-nine percent after vaccination, and 17% after serologic infection (p<0.001). The geometric mean titer after delivery in non-vaccinated, non-serologically infected women was 17.1 [95%CI 15.7-18.6]. The geometric mean titer increased significantly after serologic infection with H1N1 (76.5 [95%CI 51.3-113.9], p<0.001) and after vaccination (589.6 [95%CI 339.3-1024.7], p<0.001). The geometric mean-fold rise (mother at delivery/mother early pregnancy) was significantly higher after vaccination (2.23 [1.93-2.54]) than serologic infection (1.73 [1.59-1.87], p=0.013). In newborns of vaccinated mothers 89.5% had protective antibody levels compared to 15.8% in newborns of serologically infected mothers (p<0.001).
Influenza vaccination during pregnancy confers passive immunity to the newborn. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Viral infections cause many different diseases stemming both from well-characterized viral pathogens but also from emerging viruses, and the search for novel viruses continues to be of great importance. High-throughput sequencing is an important technology for this purpose. However, viral nucleic acids often constitute a minute proportion of the total genetic material in a sample from infected tissue. Techniques to enrich viral targets in high-throughput sequencing have been reported, but the sensitivity of such methods is not well established. This study compares different library preparation techniques targeting both DNA and RNA with and without virion enrichment. By optimizing the selection of intact virus particles, both by physical and enzymatic approaches, we assessed the effectiveness of the specific enrichment of viral sequences as compared to non-enriched sample preparations by selectively looking for and counting read sequences obtained from shotgun sequencing. Using shotgun sequencing of total DNA or RNA, viral targets were detected at concentrations corresponding to the predicted level, providing a foundation for estimating the effectiveness of virion enrichment. Virion enrichment typically produced a 1000-fold increase in the proportion of DNA virus sequences. For RNA virions the gain was less pronounced with a maximum 13-fold increase. This enrichment varied between the different sample concentrations, with no clear trend. Despite that less sequencing was required to identify target sequences, it was not evident from our data that a lower detection level was achieved by virion enrichment compared to shotgun sequencing.
PLoS ONE 04/2015; 10(4):e0122636. DOI:10.1371/journal.pone.0122636 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated the health-related effect of systematic medication review performed by a clinical pharmacist and a clinical pharmacologist on nonelective elderly orthopedic patients.
This is a nonblinded randomized controlled study of 108 patients 65 years or older treated with at least 4 drugs. For the intervention, the clinical pharmacist reviewed the participants' medication after completion of the usual medication routine. Information was collected from medical charts, interviews with participants, and database registrations of drug purchase. Results were conferred with the clinical pharmacologist, and recommendations were delivered directly to the ward physicians. The control was usual medication routine, that is, physicians prescribing admitting orders. The primary outcome was time to the first unplanned contact to a physician after discharge (i.e., general practitioner, emergency department visit, or readmission) during 3-month follow-up. Secondary outcomes included other health-related outcomes, for example, length of in-hospital stay, mortality, and quality of life.
Time to the first unplanned contact to a physician was 14.9 days (95% confidence interval, 8.9-21.0) in the intervention group compared with 27.3 days (95% confidence interval, 18.9-35.7) in the controls (P = 0.05). Overall, no statistically significant differences were seen in the secondary outcomes apart from "number of" and "time to first" emergency department visits, which were in favor of the intervention group. A marked hesitation of the ward physicians to comply with recommendations was noted (18%).
The study showed that the patients receiving usual care had a significantly longer time to the first unplanned contact to a physician after discharge; however, the fact that less than 1 of 5 recommendations was adopted by the physicians raises concerns as to whether this finding could be attributable to the intervention.
Journal of Patient Safety 03/2015; Publish Ahead of Print. DOI:10.1097/PTS.0000000000000173 · 1.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In order to reduce the numbers of medication errors (MEs) that cause adverse reactions (ARs) many authors have tried to identify patient-related risk factors; however, the evidence remains controversial. The aim was to systematically review the evidence on the relationship between patient-related risk factors and the risk of serious ARs.
A systematic search in Pubmed, Embase, Cochrane Systematic Reviews, Psychinfo and SweMed+ was performed. Included full text articles were hand searched for further references. Peer reviewed papers including adults from primary and secondary healthcare were included if they clearly defined seriousness of the adverse reactions and described correlations to risk factors by statistical analysis.
A total of 28 studies were identified including 85,212 patients with 3,385 serious ARs, resulting in an overall frequency of serious ARs in 4 % of patients. Age, gender and number of drugs were by far the most frequently investigated risk factors. The total number of drugs was the most consistent correlated risk factor found in both univariate and multivariate analyses.
The number of drugs is the most frequently documented independent patient-related risk factor for serious ARs in both the general adult population as well as in the elderly. The existing evidence is however conflicting due to heterogeneity of populations and study methods. The knowledge of patient-related risk factors for experiencing ARs could be used for electronic risk stratification of patients and thereby allocation of healthcare resources to high risk patients. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
British Journal of Clinical Pharmacology 02/2015; DOI:10.1111/bcp.12600 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Present understanding of increased risk of Epstein-Barr virus (EBV)-related infectious mononucleosis among children of low birth order or small sibships is mainly based on old and indirect evidence. Societal changes and methodological limitations of previous studies call for new data.
We used data from the Danish Civil Registration System and the Danish National Hospital Discharge Register to study incidence rates of inpatient hospitalizations for infectious mononucleosis before the age of 20 years in a cohort of 2,543,225 Danes born between 1971 and 2008, taking individual sibship structure into account.
A total of 12,872 cases of infectious mononucleosis were observed during 35.3 million person-years of follow-up. Statistical modelling showed that increasing sibship size was associated with a reduced risk of infectious mononucleosis and that younger siblings conferred more protection from infectious mononucleosis than older siblings. In addition to this general association with younger and older siblings, children aged less than 4 years transiently increased their siblings’ infectious mononucleosis risk. Our results were confirmed in an independent sample of blood donors followed up retrospectively for self-reported infectious mononucleosis.
Younger siblings, and to a lesser degree older siblings, seem to be important in the transmission of EBV within families. Apparently the dogma of low birth order in a sibship as being at the highest risk of infectious mononucleosis is no longer valid.
International Journal of Epidemiology 10/2014; 43(5):1607-14. DOI:10.1093/ije/dyu118 · 9.18 Impact Factor
[Show abstract][Hide abstract] 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 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 and G2P) were detected in the majority of samples (n=733, 88.2%). Rare genotype combinations such as G6P 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 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; 27. DOI:10.1016/j.meegid.2014.07.008 · 3.02 Impact Factor
[Show abstract][Hide abstract] 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 05/2014; 5:156. DOI:10.3389/fgene.2014.00156
[Show abstract][Hide abstract] 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; 10(3). DOI:10.1007/s12024-014-9570-7 · 1.98 Impact Factor
[Show abstract][Hide abstract] 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; 70(6). DOI:10.1007/s00228-014-1668-z · 2.97 Impact Factor
[Show abstract][Hide abstract] 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. DOI:10.1016/j.forsciint.2014.02.012 · 2.14 Impact Factor