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Rydén, Patrik
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Publications (10 of 52) Show all publications
Thysell, E., Vidman, L., Bovinder Ylitalo, E., Jernberg, E., Crnalic, S., Iglesias-Gato, D., . . . Wikström, P. (2019). Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor. Molecular Oncology, 13(8), 1763-1777
Open this publication in new window or tab >>Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor
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2019 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, no 8, p. 1763-1777Article in journal (Refereed) Published
Abstract [en]

Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
bone metastasis, gene expression, gene set enrichment analysis, morphology, survival, unsupervised cluster analysis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-162668 (URN)10.1002/1878-0261.12526 (DOI)000478600200009 ()31162796 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-05Bibliographically approved
Simonyté Sjödin, K., Hammarström, M.-L., Rydén, P., Sjödin, A., Hernell, O., Engstrand, L. & West, C. E. (2019). Temporal and long-term gut microbiota variation in allergic disease: a prospective study from infancy to school age. Allergy. European Journal of Allergy and Clinical Immunology, 74(1), 176-185
Open this publication in new window or tab >>Temporal and long-term gut microbiota variation in allergic disease: a prospective study from infancy to school age
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2019 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 1, p. 176-185Article in journal (Refereed) Published
Abstract [en]

Background: Compositional changes in the early‐life gut microbiota have been implicated in IgE‐associated allergic diseases, but there is lack of longitudinal studies. We examined gut microbiota development from infancy to school age in relation to onset of IgE‐associated allergic diseases. At 8 years of age, we also examined the relationship between gut microbiota and T‐cell regulation, estimated as responses to polyclonal T‐cell activation.

Methods: Stool samples were collected from 93 children at 4, 6, 13 months, and 8 years of age. The gut microbiota was profiled using 16S rRNA gene sequencing. Peripheral blood was drawn from all children, and mononuclear cells were polyclonally activated. Levels of IL‐10 and FOXP3 mRNA copies were determined using real‐time quantitative reverse transcriptase‐PCR.

Results: At 8 years of age, 21 children were diagnosed with IgE‐associated allergic disease and 90% displayed allergic comorbidity. Seventy‐two children were nonallergic and nonsensitized. Statistical tests with multiple testing corrections demonstrated temporal underrepresentation of Ruminococcus and consistent underrepresentation of Bacteroides, Prevotella, and Coprococcus in allergic compared to nonallergic children from infancy to school age. The gut microbiota of the allergic 8‐year‐olds was enriched in Bifidobacteriumand depleted of Lactobacillus, Enterococcus, and Lachnospira. In allergic 8‐year-olds, Faecalibacterium correlated with IL‐10 mRNA levels (rs = 0.49, Padj = 0.02) with the same trend for FOXP3 (rs = 0.39, Padj = 0.08).

Conclusions: We identified both temporal and long‐term variation in the differential abundance of specific bacterial genera in children developing IgE‐associated allergic disease. Improved dietary interventions aiming at expanding immune‐modulatory taxa could be studied for prevention of allergic disease.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
allergy, diversity, intestinal colonization, microbiome, T-cell response
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-157612 (URN)10.1111/all.13485 (DOI)000459664100017 ()29786876 (PubMedID)
Available from: 2019-03-27 Created: 2019-03-27 Last updated: 2019-03-27Bibliographically approved
Källberg, D., Belyaev, Y. & Rydén, P. (2018). A moment-distance hybrid method for estimating a mixture of two symmetric densities. Modern Stochastics: Theory and Applications, 5(1), 1-36
Open this publication in new window or tab >>A moment-distance hybrid method for estimating a mixture of two symmetric densities
2018 (English)In: Modern Stochastics: Theory and Applications, ISSN 2351-6054, Vol. 5, no 1, p. 1-36Article in journal (Refereed) Published
Abstract [en]

In clustering of high-dimensional data a variable selection is commonly applied to obtain an accurate grouping of the samples. For two-class problems this selection may be carried out by fitting a mixture distribution to each variable. We propose a hybrid method for estimating a parametric mixture of two symmetric densities. The estimator combines the method of moments with the minimum distance approach. An evaluation study including both extensive simulations and gene expression data from acute leukemia patients shows that the hybrid method outperforms a maximum-likelihood estimator in model-based clustering. The hybrid estimator is flexible and performs well also under imprecise model assumptions, suggesting that it is robust and suited for real problems.

Keywords
inference for mixtures, method of moments, minimum distance, model-based clustering
National Category
Probability Theory and Statistics
Research subject
Mathematical Statistics
Identifiers
urn:nbn:se:umu:diva-144644 (URN)10.15559/17-VMSTA93 (DOI)000434875200001 ()
Funder
Swedish Research Council, 340-2013-5185
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-09-19Bibliographically approved
De Pascalis, R., Hahn, A., Brook, H. M., Ryden, P., Donart, N., Mittereder, L., . . . Elkins, K. L. (2018). A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis. PLoS ONE, 13(5), Article ID e0198140.
Open this publication in new window or tab >>A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0198140Article in journal (Refereed) Published
Abstract [en]

There are no defined correlates of protection for any intracellular pathogen, including the bacterium Francisella tularensis, which causes tularemia. Evaluating vaccine efficacy against sporadic diseases like tularemia using field trials is problematic, and therefore alternative strategies to test vaccine candidates like the Francisella Live Vaccine Strain (LVS), such as testing in animals and applying correlate measurements, are needed. Recently, we described a promising correlate strategy that predicted the degree of vaccine-induced protection in mice given parenteral challenges, primarily when using an attenuated Francisella strain. Here, we demonstrate that using peripheral blood lymphocytes (PBLs) in this approach predicts LVS-mediated protection against respiratory challenge of Fischer 344 rats with fully virulent F. tularensis, with exceptional sensitivity and specificity. Rats were vaccinated with a panel of LVS-derived vaccines and subsequently given lethal respiratory challenges with Type A F. tularensis. In parallel, PBLs from vaccinated rats were evaluated for their functional ability to control intramacrophage Francisella growth in in vitro co-culture assays. PBLs recovered from co-cultures were also evaluated for relative gene expression using a large panel of genes identified in murine studies. In vitro control of LVS intramacrophage replication reflected the hierarchy of protection. Further, despite variability between individuals, 22 genes were significantly more up-regulated in PBLs from rats vaccinated with LVS compared to those from rats vaccinated with the variant LVS-R or heat killed LVS, which were poorly protective. These genes included IFN-gamma, IL-21, NOS2, LTA, T-bet, IL-12rβ2, and CCL5. Most importantly, combining quantifications of intramacrophage growth control with 5-7 gene expression levels using multivariate analyses discriminated protected from non-protected individuals with greater than 95% sensitivity and specificity. The results therefore support translation of this approach to non-human primates and people to evaluate new vaccines against Francisella and other intracellular pathogens.

Place, publisher, year, edition, pages
Public Library of Science, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-149021 (URN)10.1371/journal.pone.0198140 (DOI)000433153400040 ()29799870 (PubMedID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Eneslätt, K., Golovliov, I., Rydén, P. & Sjöstedt, A. (2018). Vaccine-mediated mechanisms controlling replication of Francisella tularensis in human peripheral blood mononuclear cells using a co-culture system. Frontiers in Cellular and Infection Microbiology, 8, Article ID 27.
Open this publication in new window or tab >>Vaccine-mediated mechanisms controlling replication of Francisella tularensis in human peripheral blood mononuclear cells using a co-culture system
2018 (English)In: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, article id 27Article in journal (Refereed) Published
Abstract [en]

Cell-mediated immunity (CMI) is normally required for efficient protection against intracellular infections, however, identification of correlates is challenging and they are generally lacking. Francisella tularensis is a highly virulent, facultative intracellular bacterium and CMI is critically required for protection against the pathogen, but how this is effectuated in humans is poorly understood. To understand the protective mechanisms, we established an in vitro co-culture assay to identify how control of infection of F. tularensis is accomplished by human cells and hypothesized that the model will mimic in vivo immune mechanisms. Non-adherent peripheral blood mononuclear cells (PBMCs) were expanded with antigen and added to cultures with adherent PBMC infected with the human vaccine strain, LVS, or the highly virulent SCHU S4 strain. Intracellular numbers of F. tularensis was followed for 72 h and secreted and intracellular cytokines were analyzed. Addition of PBMC expanded from naïve individuals, i.e., those with no record of immunization to F. tularensis, generally resulted in little or no control of intracellular bacterial growth, whereas addition of PBMC from a majority of F. tularensis-immune individuals executed static and sometimes cidal effects on intracellular bacteria. Regardless of infecting strain, statistical differences between the two groups were significant, P < 0.05. Secretion of 11 cytokines was analyzed after 72 h of infection and significant differences with regard to secretion of IFN-γ, TNF, and MIP-1β was observed between immune and naïve individuals for LVS-infected cultures. Also, in LVS-infected cultures, CD4 T cells from vaccinees, but not CD8 T cells, showed significantly higher expression of IFN-γ, MIP-1β, TNF, and CD107a than cells from naïve individuals. The co-culture system appears to identify correlates of immunity that are relevant for the understanding of mechanisms of the protective host immunity to F. tularensis.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
F. tularensis, in vitro model, human immune response, IFN-gamma, TNF, MIP-1 beta, correlates of immunity
National Category
Microbiology in the medical area Immunology
Identifiers
urn:nbn:se:umu:diva-144645 (URN)10.3389/fcimb.2018.00027 (DOI)000424355900001 ()29468144 (PubMedID)
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-08-20Bibliographically approved
Monsen, T. & Ryden, P. (2017). A new concept and a comprehensive evaluation of SYSMEX UF-1000i flow cytometer to identify culture-negative urine specimens in patients with UTI. European Journal of Clinical Microbiology and Infectious Diseases, 36(9), 1691-1703
Open this publication in new window or tab >>A new concept and a comprehensive evaluation of SYSMEX UF-1000i flow cytometer to identify culture-negative urine specimens in patients with UTI
2017 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 36, no 9, p. 1691-1703Article in journal (Refereed) Published
Abstract [en]

Urinary tract infections (UTIs) are among the most common bacterial infections in men and urine culture is gold standard for diagnosis. Considering the high prevalence of culture-negative specimens, any method that identifies such specimens is of interest. The aim was to evaluate a new screening concept for flow cytometry analysis (FCA). The outcomes were evaluated against urine culture, uropathogen species and three conventional screening methods. A prospective, consecutive study examined 1,312 urine specimens, collected during January and February 2012. The specimens were analyzed using the Sysmex UF1000i FCA. Based on the FCA data culture negative specimens were identified in a new model by use of linear discriminant analysis (FCA-LDA). In total 1,312 patients were included. In- and outpatients represented 19.6% and 79.4%, respectively; 68.3% of the specimens originated from women. Of the 610 culture-positive specimens, Escherichia coli represented 64%, enterococci 8% and Klebsiella spp. 7%. Screening with FCA-LDA at 95% sensitivity identified 42% (552/1312) as culture negative specimens when UTI was defined according to European guidelines. The proposed screening method was either superior or similar in comparison to the three conventional screening methods. In conclusion, the proposed/suggested and new FCA-LDA screening method was superior or similar to three conventional screening methods. We recommend the proposed screening method to be used in clinic to exclude culture negative specimens, to reduce workload, costs and the turnaround time. In addition, the FCA data may add information that enhance handling and support diagnosis of patients with suspected UTI pending urine culture.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
UTI, Screening, Urine culture, Flow-cytometry, Sysmex UF-1000i
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-139138 (URN)10.1007/s10096-017-2964-1 (DOI)000407582200022 ()
Note

Errata European Journal of Clinical Microbiology & Infectious Diseases (2017) 36: 1705. https://doi.org/10.1007/s10096-017-3059-8

Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2018-06-09Bibliographically approved
Schelin, L., Tengman, E., Ryden, P. & Häger, C. (2017). A statistically compiled test battery for feasible evaluation of knee function after rupture of the Anterior Cruciate Ligament - derived from long-term follow-up data.. PLoS ONE, 12(5), Article ID e0176247.
Open this publication in new window or tab >>A statistically compiled test battery for feasible evaluation of knee function after rupture of the Anterior Cruciate Ligament - derived from long-term follow-up data.
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176247Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Clinical test batteries for evaluation of knee function after injury to the Anterior Cruciate Ligament (ACL) should be valid and feasible, while reliably capturing the outcome of rehabilitation. There is currently a lack of consensus as to which of the many available assessment tools for knee function that should be included. The present aim was to use a statistical approach to investigate the contribution of frequently used tests to avoid redundancy, and filter them down to a proposed comprehensive and yet feasible test battery for long-term evaluation after ACL injury.

METHODS: In total 48 outcome variables related to knee function, all potentially relevant for a long-term follow-up, were included from a cross-sectional study where 70 ACL-injured (17-28 years post injury) individuals were compared to 33 controls. Cluster analysis and logistic regression were used to group variables and identify an optimal test battery, from which a summarized estimator of knee function representing various functional aspects was derived.

RESULTS: As expected, several variables were strongly correlated, and the variables also fell into logical clusters with higher within-correlation (max ρ = 0.61) than between clusters (max ρ = 0.19). An extracted test battery with just four variables assessing one-leg balance, isokinetic knee extension strength and hop performance (one-leg hop, side hop) were mathematically combined to an estimator of knee function, which acceptably classified ACL-injured individuals and controls. This estimator, derived from objective measures, correlated significantly with self-reported function, e.g. Lysholm score (ρ = 0.66; p<0.001).

CONCLUSIONS: The proposed test battery, based on a solid statistical approach, includes assessments which are all clinically feasible, while also covering complementary aspects of knee function. Similar test batteries could be determined for earlier phases of ACL rehabilitation or to enable longitudinal monitoring. Such developments, established on a well-grounded consensus of measurements, would facilitate comparisons of studies and enable evidence-based rehabilitation.

National Category
Physiotherapy Probability Theory and Statistics
Identifiers
urn:nbn:se:umu:diva-135155 (URN)10.1371/journal.pone.0176247 (DOI)000400645000024 ()28459885 (PubMedID)
Available from: 2017-05-19 Created: 2017-05-19 Last updated: 2018-06-09Bibliographically approved
Desvars-Larrive, A., Liu, X., Hjertqvist, M., Sjöstedt, A., Johansson, A. & Ryden, P. (2017). High-risk regions and outbreak modelling of tularemia in humans. Epidemiology and Infection, 145(3), 482-490
Open this publication in new window or tab >>High-risk regions and outbreak modelling of tularemia in humans
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2017 (English)In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 145, no 3, p. 482-490Article in journal (Refereed) Published
Abstract [en]

Sweden reports large and variable numbers of human tularemia cases, but the high-risk regions are anecdotally defined and factors explaining annual variations are poorly understood. Here, high-risk regions were identified by spatial cluster analysis on disease surveillance data for 1984-2012. Negative binomial regression with five previously validated predictors (including predicted mosquito abundance and predictors based on local weather data) was used to model the annual number of tularemia cases within the high-risk regions. Seven high-risk regions were identified with annual incidences of 3.8-44 cases/100 000 inhabitants, accounting for 56.4% of the tularemia cases but only 9.3% of Sweden's population. For all high-risk regions, most cases occurred between July and September. The regression models explained the annual variation of tularemia cases within most high-risk regions and discriminated between years with and without outbreaks. In conclusion, tularemia in Sweden is concentrated in a few high-risk regions and shows high annual and seasonal variations. We present reproducible methods for identifying tularemia high-risk regions and modelling tularemia cases within these regions. The results may help health authorities to target populations at risk and lay the foundation for developing an early warning system for outbreaks.

Place, publisher, year, edition, pages
CAMBRIDGE UNIV PRESS, 2017
Keywords
Epidemiology, modelling, spatial cluster analysis, tularemia
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-132814 (URN)10.1017/S0950268816002478 (DOI)000393759000010 ()27806741 (PubMedID)
Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2018-06-09Bibliographically approved
Kheir, S. M., Kafi, S. K., Ryden, P., Elbir, H., Soliman, M. A., Ali, S., . . . Abu-Aisha, H. (2017). Results of application of the ISPD guidelines to the management of peritoneal dialysis in a single center in Sudan. Journal of Infection and Public Health, 10(3), 348-352
Open this publication in new window or tab >>Results of application of the ISPD guidelines to the management of peritoneal dialysis in a single center in Sudan
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2017 (English)In: Journal of Infection and Public Health, ISSN 1876-0341, E-ISSN 1876-035X, Vol. 10, no 3, p. 348-352Article in journal (Refereed) Published
Abstract [en]

The culture negative peritonitis in Sudan 2010 was 46% exceeding 20% of the recommended ISPD (International Society for Peritoneal Dialysis) guidelines. This study reports an update after applying the standard ISPD protocol. The routine method was replaced by ISPD protocol. The culture negative rate using the ISPD guidelines dropped from 46% in the year 2010, to 39% in the year 2011, to 5% in the 2012 and to zero percent in the year 2013. Bacterial and fungal species represent (86.76%) and (13.23%) of infection and most isolates showed low resistance rate to antibiotics. Touch contamination added significantly (p = 0.0006) to the risk of contracting Peritonitis. The risk of contracting Peritonitis was 1.53 times higher in the group exposed by touch contamination. None of the other risk factors contributed significantly to Peritonitis. The study highlights the importance of implementing high hygiene practice. (C) 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Limited. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Place, publisher, year, edition, pages
ELSEVIER SCIENCE LONDON, 2017
Keywords
Sudan, Culture negative, Peritonitis, CAPD
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-137005 (URN)10.1016/j.jiph.2016.08.008 (DOI)000402466400015 ()27717678 (PubMedID)
Available from: 2017-06-29 Created: 2017-06-29 Last updated: 2018-06-09Bibliographically approved
Stattin, E.-L., Henning, P., Klar, J., McDermott, E., Stecksen-Blicks, C., Sandström, P.-E., . . . Lerner, U. H. (2017). SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts. Scientific Reports, 7, Article ID 3012.
Open this publication in new window or tab >>SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3012Article in journal (Refereed) Published
Abstract [en]

Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-136033 (URN)10.1038/s41598-017-02533-2 (DOI)000402879800068 ()28592808 (PubMedID)
Available from: 2017-06-13 Created: 2017-06-13 Last updated: 2018-08-31Bibliographically approved
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