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Shirdel, M., Anderson, F., Myte, R., Axelsson, J., Rutegård, M., Blomqvist, L., . . . Gylling, B. (2020). Body composition measured by computed tomography is associated with colorectal cancer survival, also in early-stage disease. Acta Oncologica
Open this publication in new window or tab >>Body composition measured by computed tomography is associated with colorectal cancer survival, also in early-stage disease
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2020 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226XArticle in journal (Refereed) Epub ahead of print
Abstract [en]

Background: Cachexia and sarcopenia are associated with poor survival after colorectal cancer (CRC) diagnosis. Computed tomography (CT) can be used to measure aspects of cachexia including sarcopenia, myosteatosis and the amount of subcutaneous and visceral adipose tissue. The aim of this study was to relate CT-based body composition variables with survival outcomes in CRC. Material and methods: In this population-based, retrospective cohort study, CT scans of 974 patients with pathological stages I-IV CRCs, collected at or very near diagnosis (years 2000-2016), were used to measure cross-sectional fat and muscle tissue areas. Body composition variables based on these measurements were assessed in relation to tumor stage and site and cancer-specific survival in stages I-III CRC (n = 728) using Cox proportional hazards models and Kaplan-Meier estimators. Results: Sarcopenia was associated with decreased cancer-specific survival, especially in patients with stages I-II tumors. The hazard ratio (HR) for the lowest versus highest tertile of skeletal muscle index (SMI) was 1.67; 95% confidence interval (CI), 1.08-2.58 for all stages, and HR 2.22; 95% CI 1.06-4.68, for stages I-II. Myosteatosis was also associated with decreased cancer-specific survival [(HR 2.03; 95% CI 1.20-3.34 for the lowest versus the highest tertile of skeletal muscle radiodensity (SMR)]. SMI and SMR were lower in patients with right-sided CRC, independent of age and sex. No adipose tissue measurement was significantly associated with cancer-specific survival. Conclusion: In concordance with previous studies, sarcopenia and myosteatosis were associated with decreased cancer-specific survival. The strong association between sarcopenia and poor cancer-specific survival in early-stage disease could have clinical implications for personalizing therapy decisions, including nutritional support.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-169844 (URN)10.1080/0284186X.2020.1744716 (DOI)000523671400001 ()32228271 (PubMedID)
Available from: 2020-05-26 Created: 2020-05-26 Last updated: 2020-05-26
Egorova, O., Myte, R., Schneede, J., Hägglöf, B., Bölte, S., Domellöf, E., . . . Silfverdal, S.-A. (2020). Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers. Molecular Autism, 11, Article ID 7.
Open this publication in new window or tab >>Maternal blood folate status during early pregnancy and occurrence of autism spectrum disorder in offspring: a study of 62 serum biomarkers
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2020 (English)In: Molecular Autism, ISSN 2040-2392, Vol. 11, article id 7Article in journal (Refereed) Published
Abstract [en]

Background: Autism spectrum disorder (ASD) evolves from an interplay between genetic and environmental factors during prenatal development. Since identifying maternal biomarkers associated with ASD risk in offspring during early pregnancy might result in new strategies for intervention, we investigated maternal metabolic biomarkers in relation to occurrence of ASD in offspring using both univariate logistic regression and multivariate network analysis.

Methods: Serum samples from 100 women with an offspring diagnosed with ASD and 100 matched control women with typically developing offspring were collected at week 14 of pregnancy. Concentrations of 62 metabolic biomarkers were determined, including amino acids, vitamins (A, B, D, E, and K), and biomarkers related to folate (vitamin B9) metabolism, lifestyle factors, as well as C-reactive protein (CRP), the kynurenine-tryptophan ratio (KTR), and neopterin as markers of inflammation and immune activation.

Results: We found weak evidence for a positive association between higher maternal serum concentrations of folate and increased occurrence of ASD (OR per 1 SD increase: 1.70, 95% CI 1.22–2.37, FDR adjusted P = 0.07). Multivariate network analysis confirmed expected internal biochemical relations between the biomarkers. Neither inflammation markers nor vitamin D3 levels, all hypothesized to be involved in ASD etiology, displayed associations with ASD occurrence in the offspring.

Conclusions: Our findings suggest that high maternal serum folate status during early pregnancy may be associated with the occurrence of ASD in offspring. No inference about physiological mechanisms behind this observation can be made at the present time because blood folate levels may have complex relations with nutritional intake, the cellular folate status and status of other B-vitamins. Therefore, further investigations, which may clarify the potential role and mechanisms of maternal blood folate status in ASD risk and the interplay with other potential risk factors, in larger materials are warranted.

Place, publisher, year, edition, pages
BioMed Central, 2020
Keywords
Autism, Pregnancy, One-carbon metabolism, Folate, Vitamin B, Vitamin D, Vitamin A, Inflammation
National Category
Psychiatry
Research subject
Psychiatry
Identifiers
urn:nbn:se:umu:diva-167467 (URN)10.1186/s13229-020-0315-z (DOI)000513660200001 ()
Available from: 2020-01-22 Created: 2020-01-22 Last updated: 2020-03-20Bibliographically approved
Myte, R., Sundkvist, A., van Guelpen, B. & Harlid, S. (2019). Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort. Epigenetics, 14(7), 649-659
Open this publication in new window or tab >>Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort
2019 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 7, p. 649-659Article in journal (Refereed) Published
Abstract [en]

DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
DNA methylation, inflammation, biomarkers, C, reactive protein, colorectal cancer, risk factors, epigenetics, proteomics
National Category
Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-160622 (URN)10.1080/15592294.2019.1603962 (DOI)000470485500001 ()31033411 (PubMedID)
Funder
Västerbotten County Council, VLL-547711Västerbotten County Council, VLL-680921Västerbotten County Council
Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved
Huyghe, J. R., Bien, S. A., Harrison, T. A., Kang, H. M., Chen, S., Schmit, S. L., . . . Peters, U. (2019). Discovery of common and rare genetic risk variants for colorectal cancer. Nature Genetics, 51(1), 76-+
Open this publication in new window or tab >>Discovery of common and rare genetic risk variants for colorectal cancer
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 76-+Article in journal (Refereed) Published
Abstract [en]

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155208 (URN)10.1038/s41588-018-0286-6 (DOI)000454108800015 ()30510241 (PubMedID)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Murphy, N., Ward, H. A., Jenab, M., Rothwell, J. A., Boutron-Ruault, M.-C., Carbonnel, F., . . . Gunter, M. J. (2019). Heterogeneity of Colorectal Cancer Risk Factors by Anatomical Subsite in 10 European Countries: A Multinational Cohort Study. Clinical Gastroenterology and Hepatology, 17(7), 1323-1331
Open this publication in new window or tab >>Heterogeneity of Colorectal Cancer Risk Factors by Anatomical Subsite in 10 European Countries: A Multinational Cohort Study
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2019 (English)In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 17, no 7, p. 1323-1331Article in journal (Refereed) Published
Abstract [en]

Background & Aims: Colorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most studies have been of insufficient size to identify heterogeneous associations with precision.

Methods: In the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumorsat different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests.

Results: After a median of 14.9 years of follow-up of 521,330 men and women, 6291 colorectal cancer cases occurred. Physical activity was related inversely to proximal colon and distal colon cancer, but not to rectal cancer (P heterogeneity = .03). Height was associated positively with proximal and distal colon cancer only, but not rectal cancer (P heterogeneity = .0001). For men, but not women, heterogeneous relationships were observed for body mass index (P heterogeneity = .008) and waist circumference (P heterogeneity = .03), with weaker positive associations found for rectal cancer, compared with proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P heterogeneity = .05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors.

Conclusions: The relationships between physical activity, anthropometry, and smoking with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Colorectal Cancer, Risk Factors, Anatomic Subsite, Heterogeneity, Proximal Colon, Distal Colon, Rectum
National Category
Gastroenterology and Hepatology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-159850 (URN)10.1016/j.cgh.2018.07.030 (DOI)000468432400025 ()30056182 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilRegion SkåneVästerbotten County Council
Available from: 2019-06-11 Created: 2019-06-11 Last updated: 2019-06-11Bibliographically approved
Myte, R., Gylling, B., Häggström, J., Häggström, C., Zingmark, C., Löfgren Burström, A., . . . van Guelpen, B. (2019). Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status. International Journal of Cancer, 145(2), 327-337
Open this publication in new window or tab >>Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 2, p. 327-337Article in journal (Refereed) Published
Abstract [en]

Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
BRAF, KRAS, colorectal cancer, metabolic factors, microsatellite instability, risk factors
National Category
Cancer and Oncology Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-158782 (URN)10.1002/ijc.32104 (DOI)30613980 (PubMedID)2-s2.0-85060622510 (Scopus ID)
Note

Originally included in thesis in manuscript form with title [Metabolic factors and colorectal cancer risk by KRAS and BRAF mutation status]

Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-06-11Bibliographically approved
Gylling, B., Myte, R., Ulvik, A., Ueland, P. M., Midttun, Ø., Schneede, J., . . . Palmqvist, R. (2019). One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk. International Journal of Cancer, 144(5), 947-956
Open this publication in new window or tab >>One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 5, p. 68p. 947-956Article in journal (Refereed) Published
Abstract [en]

Background: One-carbon metabolism biomarker are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs.

Objective: We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk.

Design: The relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case-control study of 613 CRC cases and 1211 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5´-phosphate, and riboflavin. Associations with CRC risk were estimated using conditional logistic regression.

Results: The ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. Associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high versus low B-vitamin status).

Conclusions: Ratio-based B-vitamin markers were good predictors of total B-vitamin status, and displayed similar associations with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice to aid interpretation of tHcy results.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. p. 68
Keywords
Biomarkers, colorectal cancer, metabolite ratios, B-vitamins, one-carbon metabolism
National Category
Clinical Laboratory Medicine
Research subject
Cancer Epidemiology
Identifiers
urn:nbn:se:umu:diva-142854 (URN)10.1002/ijc.31606 (DOI)000455041700003 ()29786139 (PubMedID)2-s2.0-85058103565 (Scopus ID)
Funder
Swedish Cancer Society, 12/501Swedish Cancer Society, 14/780
Note

Originally included in thesis in manuscript form

Available from: 2017-12-12 Created: 2017-12-12 Last updated: 2020-05-18Bibliographically approved
Sundkvist, A., Myte, R., Palmqvist, R., Harlid, S. & van Guelpen, B. (2019). Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer [Letter to the editor]. Gut, 68(2), 373-374
Open this publication in new window or tab >>Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer
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2019 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 2, p. 373-374Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
Keywords
cancer, colorectal cancer, epidemiology, gastrointestinal hormones
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-146376 (URN)10.1136/gutjnl-2018-316110 (DOI)000459027800022 ()29491131 (PubMedID)
Available from: 2018-04-06 Created: 2018-04-06 Last updated: 2019-04-16Bibliographically approved
Bodén, S., Myte, R., Wennberg, M., Harlid, S., Johansson, I., Shivappa, N., . . . Nilsson, L. M. (2019). The inflammatory potential of diet in determining cancer risk: a prospective investigation of two dietary pattern scores. PLoS ONE, 14(4), Article ID e0214551.
Open this publication in new window or tab >>The inflammatory potential of diet in determining cancer risk: a prospective investigation of two dietary pattern scores
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0214551Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Inflammation-related mechanisms may contribute to the link between diet and cancer. We sought to investigate the inflammatory impact of diet on cancer risk using the Dietary inflammatory index (DII) and an adapted Mediterranean diet score (MDS).

METHODS: This population-based, prospective cohort study used self-reported dietary data from the Västerbotten Intervention Programme, including 100,881 participants, of whom 35,393 had repeated measures. Associations between dietary patterns and cancer risk were evaluated using Cox proportional hazards regression. We also used restricted cubic splines to test for potential non-linear associations.

RESULTS: A total of 9,250 incident cancer cases were diagnosed during a median follow-up of 15 years. The two dietary patterns were moderately correlated to each other and had similar associations with cancer risk, predominantly lung cancer in men (DII per tertile decrease: Hazard ratio (HR) 0.81 (0.66-0.99), MDS per tertile increase: HR 0.86 (0.72-1.03)), and gastric cancer in men (DII: 0.73 (0.53-0.99), MDS: 0.73 (0.56-0.96)). Associations were, in general, found to be linear. We found no longitudinal association between 10-year change in diet and cancer risk.

CONCLUSION: We confirm small, but consistent and statistically significant associations between a more anti-inflammatory or healthier diet and reduced risk of cancer, including a lower risk of lung and gastric cancer in men. The dietary indexes produced similar associations with respect to the risk of cancer.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-158790 (URN)10.1371/journal.pone.0214551 (DOI)000464349000016 ()30978193 (PubMedID)
Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-05-27Bibliographically approved
Van Hemelrijck, M., Ulmer, H., Nagel, G., Peter, R. S., Fritz, J., Myte, R., . . . Stocks, T. (2018). Longitudinal study of body mass index, dyslipidemia, hyperglycemia, and hypertension in 60,000 men and women in Sweden and Austria. PLoS ONE, 13(6), Article ID e0197830.
Open this publication in new window or tab >>Longitudinal study of body mass index, dyslipidemia, hyperglycemia, and hypertension in 60,000 men and women in Sweden and Austria
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0197830Article in journal (Refereed) Published
Abstract [en]

Background: Obesity is suggested to underlie development of other metabolic aberrations, but longitudinal relationships between metabolic factors at various ages has not been studied in detail. Methods: Data from 27,379 men and 32,275 women with in total 122,940 health examinations in the Västerbotten Intervention Project, Sweden and the Vorarlberg Health Monitoring and Prevention Programme, Austria were used to investigate body mass index (BMI), mid-blood pressure, and fasting levels of glucose, triglycerides, and total cholesterol at baseline in relation to 10-year changes of these factors and weight. We included paired examinations performed 10 +/- 2 years apart and used them for longitudinal analysis with linear regression of changes between the ages 30 and 40, 40 and 50, or 50 and 60 years. Results: Higher levels of BMI were associated with increases in glucose and mid-blood pressure as well as triglycerides levels, and, to a lesser extent, decreases in cholesterol levels. For instance, per 5 kg/m(2) higher BMI at age 40, glucose at age 50 increased by 0.24 mmol/l (95%Cl:0.22-0.26) and mid-blood pressure increased by 1.54 mm Hg (95%Cl: 1.35-1.74). The strongest association observed was between BMI at age 30 and mid-blood pressure, which was 2.12 mm Hg (95% CI: 1.79-2.45) increase over ten years per 5 kg/m(2) higher BMI level. This association was observed at an age when blood pressure levels on average remained stable. Other associations than those with BMI at baseline were much weaker. However, triglyceride levels were associated with future glucose changes among individuals with elevated BMI, particularly in the two older age groups. Conclusion: BMI was most indicative of long-term changes in metabolic factors, and the strongest impact was observed for increases in blood pressure between 30 and 40 years of age. Our study supports that lifestyle interventions preventing metabolic aberrations should focus on avoiding weight increases.

Place, publisher, year, edition, pages
Public Library Science, 2018
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-150785 (URN)10.1371/journal.pone.0197830 (DOI)000435090700031 ()29897925 (PubMedID)
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2974-2003

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