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Lind, L., Salihovic, S., Ganna, A., Sundström, J., Broeckling, C. D., Magnusson, P. K., . . . Arnlov, J. (2020). A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke. Journal of Stroke & Cerebrovascular Diseases, 29(2), Article ID 104476.
Open this publication in new window or tab >>A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke
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2020 (English)In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 29, no 2, article id 104476Article in journal (Refereed) Published
Abstract [en]

Background and Purpose:

To search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach.

Methods:

We identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites.

Results:

In TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR.69 per SD change, 95% CI.57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively).

Conclusions:

An inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.

Keywords
Epidemiology, metabolomics, stroke, risk factor
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-402618 (URN)10.1016/j.jstrokecerebrovasdis.2019.104476 (DOI)000505793800001 ()31806450 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-01-17Bibliographically approved
Titova, O. E., Lindberg, E., Tan, X., Elmståhl, S., Lind, L., Schiöth, H. B. & Benedict, C. (2020). Association between sleep duration and executive function differs between diabetic and non-diabetic middle-aged and older adults.. Psychoneuroendocrinology, 111, Article ID 104472.
Open this publication in new window or tab >>Association between sleep duration and executive function differs between diabetic and non-diabetic middle-aged and older adults.
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2020 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 111, article id 104472Article in journal (Refereed) Published
Abstract [en]

Executive function is defined as a set of cognitive skills that are necessary to plan, monitor, and execute a sequence of goal-directed complex actions. Executive function is influenced by a variety of factors, including habitual sleep duration and diabetes. In the present study, we investigated in 18,769 Swedish adults (mean age: 61 y) the association between executive function, diabetes, and self-reported sleep duration. We observed a significant interaction between diabetes and sleep duration for the Trail Making Test (TMT) ratio (P < 0.01). This ratio is a measure of executive function where higher values indicate worse performance. Among diabetic participants (n = 1,523), long (defined as ≥9 h per day) vs. normal sleep duration (defined as 7-8 hours per day) was associated with a higher TMT ratio (P < 0.05). Similar significant results were observed in diabetic individuals without pharmacological treatment for diabetes (n = 1,062). Among non-diabetic participants (n = 17,246), no association between long sleep duration and the TMT ratio was observed (P > 0.05). Instead, short (defined as <7 h per day) vs. normal sleep duration was linked to a higher TMT ratio (P < 0.05). These findings suggest that the association between sleep duration and executive function differs between diabetic and non-diabetic middle-aged and older adults. Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations.

Keywords
Cohort study, Diabetes, Executive function, Sleep duration
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-401482 (URN)10.1016/j.psyneuen.2019.104472 (DOI)000503085600005 ()31610410 (PubMedID)
Funder
Novo Nordisk, NNF190C0056777The Swedish Brain Foundation, F02019-0028Swedish Research Council, 2015-03100Åke Wiberg Foundation, M18-0169Fredrik och Ingrid Thurings Stiftelse, 2018-00365Swedish Society for Medical Research (SSMF), P18-0084
Available from: 2020-01-08 Created: 2020-01-08 Last updated: 2020-01-22Bibliographically approved
Fellström, B., Helmersson-Karlqvist, J., Lind, L., Soveri, I., Wu, P.-H., Thulin, M., . . . Larsson, A. (2020). Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females. Journal of Interferon and Cytokine Research, 40(2), 71-74
Open this publication in new window or tab >>Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females
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2020 (English)In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 40, no 2, p. 71-74Article in journal (Refereed) Published
Abstract [en]

There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1 alpha, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.

Keywords
HDL cholesterol, apolipoprotein A1, cytokines, multiplex assays, urine
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-394993 (URN)10.1089/jir.2019.0074 (DOI)000510520300001 ()31599692 (PubMedID)
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2020-03-20Bibliographically approved
Shah, S., Henry, A., Roselli, C., Lin, H., Sveinbjornsson, G., Fatemifar, G., . . . Ye, B. (2020). Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nature Communications, 11(1), Article ID 163.
Open this publication in new window or tab >>Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
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2020 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 163Article in journal (Refereed) Published
Abstract [en]

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2020
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-407649 (URN)10.1038/s41467-019-13690-5 (DOI)000511898900014 ()31919418 (PubMedID)
Funder
AstraZenecaNovo Nordisk
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30Bibliographically approved
Lind, L., Salihovic, S., Risérus, U., Kullberg, J., Johansson, L., Ahlström, H., . . . Oscarsson, J. (2020). THE PLASMA METABOLOMIC PROFILE IS DIFFERENTLY ASSOCIATED WITH LIVER FAT, VISCERAL ADIPOSE TISSUE AND PANCREATIC FAT: Supplementary Table 1..
Open this publication in new window or tab >>THE PLASMA METABOLOMIC PROFILE IS DIFFERENTLY ASSOCIATED WITH LIVER FAT, VISCERAL ADIPOSE TISSUE AND PANCREATIC FAT: Supplementary Table 1.
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2020 (English)Data set
Keywords
Ectopic fat, MRI, liver fat, pancreatic fat, metabolomics, obesity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-407950 (URN)
Available from: 2020-04-01 Created: 2020-04-01 Last updated: 2020-04-02Bibliographically approved
Lind, L., Gigante, B., Borne, Y., Mälarstig, A., Sundström, J., Ärnlöv, J., . . . Engström, G. (2020). The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb: A meta-analysis and a longitudinal evaluation. Atherosclerosis, 295, 25-30
Open this publication in new window or tab >>The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb: A meta-analysis and a longitudinal evaluation
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2020 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 295, p. 25-30Article in journal (Refereed) Published
Abstract [en]

Background and aims: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.

Methods: In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n > 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.

Results: In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p < 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).

Conclusions: Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.

Place, publisher, year, edition, pages
ELSEVIER IRELAND LTD, 2020
Keywords
Atherosclerosis, Proteomics, Carotid artery, Meta-analysis, Ultrasound
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-407188 (URN)10.1016/j.atherosclerosis.2020.01.011 (DOI)000512990500004 ()31981948 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research CouncilStockholm County Council
Available from: 2020-03-20 Created: 2020-03-20 Last updated: 2020-03-20Bibliographically approved
Wuttke, M., Li, Y., Li, M., Sieber, K. B., Feitosa, M. F., Gorski, M., . . . Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972
Open this publication in new window or tab >>A catalog of genetic loci associated with kidney function from analyses of a million individuals
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-387933 (URN)10.1038/s41588-019-0407-x (DOI)000469996900008 ()31152163 (PubMedID)
Funder
AstraZenecaNovo NordiskNIH (National Institute of Health)
Note

Group Authors: Lifelines COHort Study

Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Lind, L. (2019). A detailed lipoprotein profile in relation to intima-media thickness and echogenicity of three major arteries. Clinical Physiology and Functional Imaging, 39(6), 415-421
Open this publication in new window or tab >>A detailed lipoprotein profile in relation to intima-media thickness and echogenicity of three major arteries
2019 (English)In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 39, no 6, p. 415-421Article in journal (Refereed) Published
Abstract [en]

Objective

To investigate differences in risk‐factor profile, with special emphasis on detailed characterization of the lipoprotein profile, for intima‐media thickness (IMT) and echogenicity of the intima‐media complex (IM‐GSM) in three major arteries: the carotid, femoral and brachial arteries.

Methods

IMT and IM‐GSM were measured by ultrasound in the carotid, femoral and brachial arteries in 778 subjects, all aged 75 years (50% women), in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, in which a detailed lipoprotein profile was also determined by nuclear magnetic resonance spectroscopy.

Results

First, IMT was considerably lower, and IM‐GSM higher, in the brachial artery compared to the other two arteries. Second, IMT and IM‐GSM in the arteries were related to each other. Third, significant different traditional risk‐factor profiles were seen for both IMT and IM‐GSM, with generally weaker relationships for IMT in the femoral and brachial arteries compared with the carotid artery. Fourth, the strength of associations between an atherogenic lipoprotein profile and IMT in the carotid artery was attenuated in the femoral artery and virtually absent in the brachial artery. Fifth, slightly different lipoprotein profiles were seen for IM‐GSM in the three arteries.

Conclusion

Differences between the carotid, femoral and brachial artery IMT and IM‐GSM were seen regarding the traditional risk factors, as well as the lipoprotein profile.

Keywords
brachial, carotid, femoral, lipids, ultrasound
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-397119 (URN)10.1111/cpf.12594 (DOI)000493090000007 ()31529768 (PubMedID)
Available from: 2019-11-15 Created: 2019-11-15 Last updated: 2019-11-15Bibliographically approved
Sjöholm, T., Ekström, S., Strand, R., Ahlström, H., Lind, L., Malmberg, F. & Kullberg, J. (2019). A whole-body FDG PET/MR atlas for multiparametric voxel-based analysis. Scientific Reports, 9, Article ID 6158.
Open this publication in new window or tab >>A whole-body FDG PET/MR atlas for multiparametric voxel-based analysis
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 6158Article in journal (Refereed) Published
Abstract [en]

Quantitative multiparametric imaging is a potential key application for Positron Emission Tomography/Magnetic Resonance (PET/MR) hybrid imaging. To enable objective and automatic voxel-based multiparametric analysis in whole-body applications, the purpose of this study was to develop a multimodality whole-body atlas of functional 18F-fluorodeoxyglucose (FDG) PET and anatomical fat-water MR data of adults. Image registration was used to transform PET/MR images of healthy control subjects into male and female reference spaces, producing a fat-water MR, local tissue volume and FDG PET whole-body normal atlas consisting of 12 male (66.6 +/- 6.3 years) and 15 female (69.5 +/- 3.6 years) subjects. Manual segmentations of tissues and organs in the male and female reference spaces confirmed that the atlas contained adequate physiological and anatomical values. The atlas was applied in two anomaly detection tasks as proof of concept. The first task automatically detected anomalies in two subjects with suspected malignant disease using FDG data. The second task successfully detected abnormal liver fat infiltration in one subject using fat fraction data.

National Category
Medical Image Processing
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-382934 (URN)10.1038/s41598-019-42613-z (DOI)000464652400029 ()30992502 (PubMedID)
Available from: 2019-04-16 Created: 2019-05-07 Last updated: 2020-02-05Bibliographically approved
Hober, A., Edfors, F., Ryaboshapkina, M., Malmqvist, J., Rosengren, L., Percy, A. J., . . . Miliotis, T. (2019). Absolute Quantification of Apolipoproteins Following Treatment with Omega-3 Carboxylic Acids and Fenofibrate Using a High Precision Stable Isotope-labeled Recombinant Protein Fragments Based SRM Assay. Molecular & Cellular Proteomics, 18(12), 2433-2446
Open this publication in new window or tab >>Absolute Quantification of Apolipoproteins Following Treatment with Omega-3 Carboxylic Acids and Fenofibrate Using a High Precision Stable Isotope-labeled Recombinant Protein Fragments Based SRM Assay
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2019 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, no 12, p. 2433-2446Article in journal (Refereed) Published
Abstract [en]

Stable isotope-labeled standard (SIS) peptides are used as internal standards in targeted proteomics to provide robust protein quantification, which is required in clinical settings. However, SIS peptides are typically added post trypsin digestion and, as the digestion efficiency can vary significantly between peptides within a protein, the accuracy and precision of the assay may be compromised. These drawbacks can be remedied by a new class of internal standards introduced by the Human Protein Atlas project, which are based on SIS recombinant protein fragments called SIS PrESTs. SIS PrESTs are added initially to the sample and SIS peptides are released on trypsin digestion. The SIS PrEST technology is promising for absolute quantification of protein biomarkers but has not previously been evaluated in a clinical setting. An automated and scalable solid phase extraction workflow for desalting and enrichment of plasma digests was established enabling simultaneous preparation of up to 96 samples. Robust high-precision quantification of 13 apolipoproteins was achieved using a novel multiplex SIS PrEST-based LC-SRM/MS Tier 2 assay in non-depleted human plasma. The assay exhibited inter-day coefficients of variation between 1.5% and 14.5% (median = 3.5%) and was subsequently used to investigate the effects of omega-3 carboxylic acids (OM3-CA) and fenofibrate on these 13 apolipoproteins in human plasma samples from a randomized placebo-controlled trial, EFFECT I (NCT02354976). No significant changes were observed in the OM3-CA arm, whereas treatment with fenofibrate significantly increased apoAII and reduced apoB, apoCI, apoE and apoCIV levels. The reduction in apoCIV following fenofibrate treatment is a novel finding. The study demonstrates that SIS PrESTs can facilitate the generation of robust multiplexed biomarker Tier 2 assays for absolute quantification of proteins in clinical studies. Applications of LC-SRM in clinical research are still limited. SIS PrEST are a novel class of standards added prior to trypsinization. We have developed a semi-automated sample preparation workflow and a SIS PrEST LC-SRM/MS Tier 2 assay for absolute quantification of 13 apolipoproteins in human plasma and applied it on clinical samples from the EFFECT I study. We demonstrate, for the first time, that SIS PrEST can be applied for exploratory biomarker research in clinical settings and capture drug effects.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2019
Keywords
Clinical trials, assay development, targeted mass spectrometry, selected reaction monitoring, absolute quantification, apolipoproteins, fenofibrate and omega-3 carboxylic acids, NAFLD, SIS PrEST
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-400666 (URN)10.1074/mcp.RA119.001765 (DOI)000501288700007 ()31591263 (PubMedID)
Available from: 2020-01-03 Created: 2020-01-03 Last updated: 2020-01-03Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2335-8542

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