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Wanhainen, A., Mani, K., Kullberg, J., Svensjö, S., Bersztel, A., Karlsson, L., . . . Björck, M. (2020). The effect of ticagrelor on growth of small abdominal aortic aneurysms: a randomized controlled trial. Cardiovascular Research, 116(2), 450-456
Open this publication in new window or tab >>The effect of ticagrelor on growth of small abdominal aortic aneurysms: a randomized controlled trial
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2020 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 116, no 2, p. 450-456Article in journal (Refereed) Published
Abstract [en]

AIM: To evaluate if ticagrelor, an effective platelet inhibitor without known non-responders, could inhibit growth of small AAAs.

METHODS AND RESULTS: In this multi-center randomized controlled trial, double-blinded for ticagrelor and placebo, acetylic salicylic acid naïve patients with AAA and with a maximum aortic diameter 35-49 mm were included. The primary outcome was mean reduction in log-transformed AAA volume growth rate (%) measured with magnetic resonance imaging (MRI) at 12 months compared with baseline. Secondary outcomes include AAA-diameter growth rate and ILT volume enlargement rate. 144 patients from eight Swedish centers were randomized (72 in each group). MRI AAA volume increase was 9.1% for the ticagrelor-group and 7.5% for the placebo-group (p = 0.205) based on intention-to-treat analysis, and 8.5% vs 7.4% in a per-protocol-analysis (p = 0.372). MRI diameter change was 2.5 mm vs 1.8 mm (p = 0.113), US diameter change 2.3 mm vs 2.2 mm (p = 0.778), and ILT volume change 12.9% vs 10.4% (p = 0.590).

CONCLUSION: In this RCT platelet inhibition with ticagrelor did not reduce growth of small AAAs. Whether the ILT has an important pathophysiological role for AAA growth cannot be determined based on this study due to the observed lack of thrombus modulating effect of ticagrelor.

Keywords
Abdominal aortic aneurysm, Growth inhibitor, Intraluminal thrombus, Ticagrelor, Anti-platelet treatment, Randomized controlled trial, Aortic volume, Aortic diameter, bleeding
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-392825 (URN)10.1093/cvr/cvz133 (DOI)000515095600028 ()31135888 (PubMedID)
Funder
AstraZeneca
Available from: 2019-09-10 Created: 2019-09-10 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
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
Pilia, M., Kullberg, J., Ahlström, H., Malmberg, F., Ekström, S. & Strand, R. (2019). Average volume reference space for large scale registration of whole-body magnetic resonance images. PLoS ONE, 14(10), Article ID e0222700.
Open this publication in new window or tab >>Average volume reference space for large scale registration of whole-body magnetic resonance images
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 10, article id e0222700Article in journal (Refereed) Published
National Category
Medical Image Processing
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-397325 (URN)10.1371/journal.pone.0222700 (DOI)
Funder
Swedish Research Council, 2016–01040Swedish Heart Lung Foundation, HLF 20170492
Available from: 2019-10-01 Created: 2019-11-19 Last updated: 2019-11-20Bibliographically approved
Lundström, E., Ljungberg, J., Andersson, J., Manell, H., Strand, R., Forslund, A., . . . Kullberg, J. (2019). Brown adipose tissue estimated with the magnetic resonance imaging fat fraction is associated with glucose metabolism in adolescents. Pediatric Obesity, 14(9), Article ID e12531.
Open this publication in new window or tab >>Brown adipose tissue estimated with the magnetic resonance imaging fat fraction is associated with glucose metabolism in adolescents
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2019 (English)In: Pediatric Obesity, ISSN 2047-6302, E-ISSN 2047-6310, Vol. 14, no 9, article id e12531Article in journal (Refereed) Published
Abstract [en]

Background

Despite therapeutic potential against obesity and diabetes, the associations of brown adipose tissue (BAT) with glucose metabolism in young humans are relatively unexplored.

Objectives

To investigate possible associations between magnetic resonance imaging (MRI) estimates of BAT and glucose metabolism, whilst considering sex, age, and adiposity, in adolescents with normal and overweight/obese phenotypes.

Methods

In 143 subjects (10‐20 years), MRI estimates of BAT were assessed as cervical‐supraclavicular adipose tissue (sBAT) fat fraction (FF) and T*2 from water‐fat MRI. FF and T*2 of neighbouring subcutaneous adipose tissue (SAT) were also assessed. Adiposity was estimated with a standardized body mass index, the waist‐to‐height ratio, and abdominal visceral and subcutaneous adipose tissue volumes. Glucose metabolism was represented by the 2h plasma glucose concentration, the Matsuda index, the homeostatic model assessment of insulin resistance, and the oral disposition index; obtained from oral glucose tolerance tests.

Results

sBAT FF and T*2 correlated positively with adiposity before and after adjustment for sex and age. sBAT FF, but not T*2, correlated with 2h glucose and Matsuda index, also after adjustment for sex, age, and adiposity. The association with 2h glucose persisted after additional adjustment for SAT FF.

Conclusions

The association between sBAT FF and 2h glucose, observed independently of sex, age, adiposity, and SAT FF, indicates a role for BAT in glucose metabolism, which potentially could influence the risk of developing diabetes. The lacking association with sBAT T*2 might be due to FF being a superior biomarker for BAT and/or to methodological limitations in the T*2 quantification.

Keywords
adolescent, brown adipose tissue, glucose metabolism, magnetic resonance imaging
National Category
Pediatrics Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-380052 (URN)10.1111/ijpo.12531 (DOI)000482155600007 ()31290284 (PubMedID)
Funder
Swedish Heart Lung Foundation, 2170492Swedish Research Council, 2016-01040EU, FP7, Seventh Framework Programme, 279153
Available from: 2019-07-09 Created: 2019-03-22 Last updated: 2019-10-23Bibliographically approved
Johansson, H.-E., Edholm, D., Kullberg, J., Rosqvist, F., Rudling, M., Straniero, S., . . . Risérus, U. (2019). Energy restriction in obese women suggest linear reduction of hepatic fat content and time-dependent metabolic improvements. Nutrition & Diabetes, 9(1), Article ID 34.
Open this publication in new window or tab >>Energy restriction in obese women suggest linear reduction of hepatic fat content and time-dependent metabolic improvements
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2019 (English)In: Nutrition & Diabetes, ISSN 2044-4052, E-ISSN 2044-4052, Vol. 9, no 1, article id 34Article in journal (Refereed) Published
Abstract [en]

Energy restriction reduces liver fat, improves hepatic insulin resistance and lipid metabolism. However, temporal data in which these metabolic improvements occur and their interplay is incomplete. By performing repeated MRI scans and blood analysis at day 0, 3, 7, 14 and 28 the temporal changes in liver fat and related metabolic factors were assessed at five times during a low-calorie diet (LCD, 800-1100 kcal/day) in ten obese non-diabetic women (BMI 41.7 ± 2.6 kg/m2) whereof 6 had NAFLD. Mean weight loss was 7.4 ± 1.2 kg (0.7 kg/day) and liver fat decreased by 51 ± 16%, resulting in only three subjects having NAFLD at day 28. Marked alteration of insulin, NEFA, ALT and 3-hydroxybuturate was evident 3 days after commencing LCD, whereas liver fat showed a moderate but a linear reduction across the 28 days. Other circulating-liver fat markers (e.g. triglycerides, adiponectin, stearoyl-CoA desaturase-1 index, fibroblast growth factor 21) demonstrated modest and variable changes. Marked elevations of NEFA, 3-hydroxybuturate and ALT concentrations occurred until day 14, likely reflecting increased tissue lipolysis, fat oxidation and upregulated hepatic fatty acid oxidation. In summary, these results suggest linear reduction in liver fat, time-specific changes in metabolic markers and insulin resistance in response to energy restriction.

National Category
Endocrinology and Diabetes Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-397554 (URN)10.1038/s41387-019-0100-2 (DOI)000497994200004 ()31685793 (PubMedID)
Available from: 2019-11-21 Created: 2019-11-21 Last updated: 2019-12-18Bibliographically approved
Andersson, J., Lundström, E., Engström, M., Lubberink, M., Ahlström, H. & Kullberg, J. (2019). Estimating the cold-induced brown adipose tissue glucose uptake rate measured by 18F-FDG PET using infrared thermography and water-fat separated MRI. Scientific Reports, 9, Article ID 12358.
Open this publication in new window or tab >>Estimating the cold-induced brown adipose tissue glucose uptake rate measured by 18F-FDG PET using infrared thermography and water-fat separated MRI
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 12358Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue (BAT) expends chemical energy to produce heat, which makes it a potential therapeutic target for combating metabolic dysfunction and overweight/obesity by increasing its metabolic activity. The most well-established method for measuring BAT metabolic activity is glucose uptake rate (GUR) measured using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). However, this is expensive and exposes the subjects to potentially harmful radiation. Cheaper and safer methods are warranted for large-scale or longitudinal studies. Potential alternatives include infrared thermography (IRT) and magnetic resonance imaging (MRI). The aim of this study was to evaluate and further develop these techniques. Twelve healthy adult subjects were studied. The BAT GUR was measured using 18F-FDG PET during individualized cooling. The temperatures of the supraclavicular fossae and a control region were measured using IRT during a simple cooling protocol. The fat fraction and effective transverse relaxation rate of BAT were measured using MRI without any cooling intervention. Simple and multiple linear regressions were employed to evaluate how well the MRI and IRT measurements could estimate the GUR. Results showed that both IRT and MRI measurements correlated with the GUR. This suggest that these measurements may be suitable for estimating the cold-induced BAT GUR in future studies.

Keywords
brown adipose tissue, 18F-FDG positron emission tomography, infrared thermography, magnetic resonance imagingm PET/MRI, water–fat signal separation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Research subject
Radiology
Identifiers
urn:nbn:se:uu:diva-390410 (URN)10.1038/s41598-019-48879-7 (DOI)000482564800014 ()31451711 (PubMedID)
Funder
Swedish Research Council, 2016-01040Swedish Heart Lung Foundation, 2170492EXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-10-18Bibliographically approved
Langner, T., Hedström, A., Mörwald, K., Weghuber, D., Forslund, A., Bergsten, P., . . . Kullberg, J. (2019). Fully convolutional networks for automated segmentation of abdominal adipose tissue depots in multicenter water–fat MRI. Magnetic Resonance in Medicine, 81(4), 2736-2745
Open this publication in new window or tab >>Fully convolutional networks for automated segmentation of abdominal adipose tissue depots in multicenter water–fat MRI
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2019 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 81, no 4, p. 2736-2745Article in journal (Refereed) Published
Abstract [en]

Purpose: An approach for the automated segmentation of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in multicenter water–fat MRI scans of the abdomen was investigated, using 2 different neural network architectures.

Methods: The 2 fully convolutional network architectures U‐Net and V‐Net were trained, evaluated, and compared using the water–fat MRI data. Data of the study Tellus with 90 scans from a single center was used for a 10‐fold cross‐validation in which the most successful configuration for both networks was determined. These configurations were then tested on 20 scans of the multicenter study beta‐cell function in JUvenile Diabetes and Obesity (BetaJudo), which involved a different study population and scanning device.

Results: The U‐Net outperformed the used implementation of the V‐Net in both cross‐validation and testing. In cross‐validation, the U‐Net reached average dice scores of 0.988 (VAT) and 0.992 (SAT). The average of the absolute quantification errors amount to 0.67% (VAT) and 0.39% (SAT). On the multicenter test data, the U‐Net performs only slightly worse, with average dice scores of 0.970 (VAT) and 0.987 (SAT) and quantification errors of 2.80% (VAT) and 1.65% (SAT).

Conclusion: The segmentations generated by the U‐Net allow for reliable quantification and could therefore be viable for high‐quality automated measurements of VAT and SAT in large‐scale studies with minimal need for human intervention. The high performance on the multicenter test data furthermore shows the robustness of this approach for data of different patient demographics and imaging centers, as long as a consistent imaging protocol is used.

Keywords
abdominal, adipose tissue, deep learning, fully convolutional networks, segmentation, water-fat MRI
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-364355 (URN)10.1002/mrm.27550 (DOI)000462092100044 ()30311704 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 279153
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2019-04-17Bibliographically approved
Manell, H., Kristinsson, H., Kullberg, J., Ubhayasekera, S. J., Mörwald, K., Staaf, J., . . . Bergsten, P. (2019). Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose tolerance. Pediatric Diabetes, 20(7), 880-891
Open this publication in new window or tab >>Hyperglucagonemia in youth is associated with high plasma free fatty acids, visceral adiposity and impaired glucose tolerance
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2019 (English)In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 20, no 7, p. 880-891Article in journal (Refereed) Published
Abstract [en]

Objective: To delineate mechanisms for fasting hyperglucagonemia in childhood obesity bystudying the associations between fasting plasma glucagon concentrations and plasmalipid parameters and fat compartments.

Methods: Cross-sectional study of children and adolescents with obesity (n=147) and leancontrols (n=43). Differences in free fatty acids (FFA), triglycerides, insulin and fatcompartments (quantified by magnetic resonance imaging) across quartiles of fastingplasma glucagon concentration were analysed. Differences in OGTT glucagonresponse was tested in high vs low FFAs, triglycerides and insulin. Human islets ofLangerhans were cultured at 5.5 mmol/l glucose and in the absence or presence of aFFA mixture with total FFA concentration of 0.5 mmol/l and glucagon secretionquantified.

Results: In children with obesity, the quartile with the highest fasting glucagon had higherinsulin (201±174 vs 83±39 pmol/l, p<0.01), FFAs (383±52 vs 338±109 μmol/l,p=0.02), triglycerides (1.5±0.9 vs 1.0±0.7 mmol/l, p<0.01), visceral adipose tissuevolume (1.9±0.8 vs 1.2±0.3 dm3, p<0.001) and a higher prevalence of impairedglucose tolerance (41% vs 8%, p=0.01) than the lowest quartile. During OGTT,children with obesity and high insulin had a worse suppression of glucagon during thefirst 10 minutes after glucose intake. Glucagon secretion was 2.6-fold higher in isletstreated with FFAs than in those not treated with FFAs.4

Conclusion: Hyperglucagonemia in childhood obesity is associated with hyperinsulinemia, highplasma FFAs, high plasma triglycerides, visceral adiposity and impaired glucosetolerance. The glucagonotropic effect of FFAs on isolated human islets provides apotential mechanism linking high fasting plasma FFAs and glucagon levels.

Keywords
Childhood obesity, glucagon, free fatty acids, insulin, visceral adiposity, impaired glucose tolerance, type 2 diabetes
National Category
Pediatrics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-380313 (URN)10.1111/pedi.12890 (DOI)000476081000001 ()31271247 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 279153EXODIAB - Excellence of Diabetes Research in SwedenErnfors FoundationErik, Karin och Gösta Selanders FoundationSwedish Research Council, 2015-4870Swedish Diabetes Association
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-12-06Bibliographically approved
Kjellberg, E., Roswall, J., Andersson, J., Bergman, S., Karlsson, A.-K., Svensson, P.-A., . . . Dahlgren, J. (2019). Metabolic Risk Factors Associated with Visceral and Subcutaneous Adipose Tissue in a Sex-Specific Manner in Seven-Year-Olds. Obesity, 27(6), 982-988
Open this publication in new window or tab >>Metabolic Risk Factors Associated with Visceral and Subcutaneous Adipose Tissue in a Sex-Specific Manner in Seven-Year-Olds
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2019 (English)In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 27, no 6, p. 982-988Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: This study aimed to investigate how visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volumes were associated with metabolic risk factors in 7-year-old children.

METHODS: A total of 81 children (52% girls) from a Swedish birth cohort were studied. At 6 years of age, anthropometric data, fasting insulin, glucose, cholesterol, and blood pressure were collected on 53 children with normal weight and 28 children with overweight or obesity, and insulin resistance was estimated. At 7 years of age, magnetic resonance imaging quantified VAT and SAT. Sex and regression analyses were conducted.

RESULTS: SAT was more strongly associated with metabolic risk factors than VAT. The associations between VAT and metabolic risk factors were stronger in girls (P < 0.05). When VAT was adjusted for birth weight and maternal BMI and education, it accounted for 51% of insulin variance (β = 11.72; P = 0.001) but only in girls. The key finding of this study was that adjusted SAT accounted for 63% of the fasting insulin variance in girls (β = 2.76; P < 0.001). Waist circumference was the best anthropometric marker for insulin resistance.

CONCLUSIONS: Insulin resistance was associated with abdominal adipose tissue and its associated metabolic risk factors in children as young as 7 years old.

National Category
Endocrinology and Diabetes Nutrition and Dietetics Pediatrics
Identifiers
urn:nbn:se:uu:diva-382942 (URN)10.1002/oby.22453 (DOI)000468798100018 ()31004397 (PubMedID)
Funder
Swedish Research Council, 2016-01040Swedish Research Council, 2013-2003Swedish Nutrition Foundation (SNF)
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2019-05-07 Created: 2019-05-07 Last updated: 2019-06-24Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8205-7569

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