Publications by authors named "Timo A Lakka"

194 Publications

Longitudinal and cross-sectional associations of adherence to 24-hour movement guidelines with cardiometabolic risk.

Scand J Med Sci Sports 2021 Oct 13. Epub 2021 Oct 13.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

This study aimed to examine (1) adherence to 24 h movement guidelines over a 2 years follow-up in children aged 6-8 years and (2) association of this adherence with cardiometabolic risk factors. Physical activity and sleep were assessed by a monitor combining heart rate and accelerometry measurements. Screen time was reported by the parents. Body fat percentage, waist circumference, blood glucose, serum insulin, plasma lipids, and blood pressure were assessed, and a cardiometabolic risk score was calculated using z-scores. Children were classified as meeting the guidelines if they had on average ≥60 min/day of moderate-to-vigorous physical activity during the valid days; ≤120 min/day of screen time; and 9-11 h/day of sleep. In total, 485 children had valid data at baseline or at 2 years follow-up. Analyses were conducted using adjusted logistic and linear regression models. Most children adhered to the 24 h movement guidelines at baseline, but the adherence decreased over the 2 years follow-up. Meeting physical activity guidelines individually, or in combination with screen time and/or sleep, was longitudinally associated with a lower cardiometabolic risk score, insulin and waist circumference, and cross-sectionally additionally with lower diastolic blood pressure and higher high-density lipoprotein cholesterol. However, these associations became statistically non-significant after adjustment for body fat. In conclusion, meeting 24 h movement guidelines at baseline increases the odds of meeting them at 2 years follow-up in school-aged children. Furthermore, meeting 24 h movement guidelines is associated with lower levels of cardiometabolic risk factors, but these associations are partly explained by lower body fat. Thus, promoting movement behaviors, especially physical activity, and healthy weight in early childhood is important in supporting cardiometabolic health in children.
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http://dx.doi.org/10.1111/sms.14081DOI Listing
October 2021

Cost-effectiveness of physical activity intervention in children - results based on the Physical Activity and Nutrition in Children (PANIC) study.

Int J Behav Nutr Phys Act 2021 09 6;18(1):116. Epub 2021 Sep 6.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

Background: We assessed the cost-effectiveness of a 2-year physical activity (PA) intervention combining family-based PA counselling and after-school exercise clubs in primary-school children compared to no intervention from an extended service payer's perspective.

Methods: The participants included 506 children (245 girls, 261 boys) allocated to an intervention group (306 children, 60 %) and a control group (200 children, 40 %). The children and their parents in the intervention group had six PA counselling visits, and the children also had the opportunity to participate in after-school exercise clubs. The control group received verbal and written advice on health-improving PA at baseline. A change in total PA over two years was used as the outcome measure. Intervention costs included those related to the family-based PA counselling, the after-school exercise clubs, and the parents' taking time off to travel to and participate in the counselling. The cost-effectiveness analyses were performed using the intention-to-treat principle. The costs per increased PA hour (incremental cost-effectiveness ratio, ICER) were based on net monetary benefit (NMB) regression adjusted for baseline PA and background variables. The results are presented with NMB and cost-effectiveness acceptability curves.

Results: Over two years, total PA increased on average by 108 h in the intervention group (95 % confidence interval [CI] from 95 to 121, p < 0.001) and decreased by 65.5 h (95 % CI from 81.7 to 48.3, p < 0.001) in the control group, the difference being 173.7 h. the incremental effectiveness was 87 (173/2) hours. For two years, the intervention costs were €619 without parents' time use costs and €860 with these costs. The costs per increased PA hour were €6.21 without and €8.62 with these costs. The willingness to pay required for 95 % probability of cost-effectiveness was €14 and €19 with these costs. The sensitivity analyses revealed that the ICER without assuming this linear change in PA were €3.10 and €4.31.

Conclusions: The PA intervention would be cost-effective compared to no intervention among children if the service payer's willingness-to-pay for a 1-hour increase in PA is €8.62 with parents' time costs.

Trial Registration: ClinicalTrials.gov: NCT01803776. Registered 4 March 2013 - Retrospectively registered, https://clinicaltrials.gov/ct2/results?cond=&term=01803776&cntry=&state=&city=&dist= .
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http://dx.doi.org/10.1186/s12966-021-01181-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419957PMC
September 2021

The Positive Relationship between Moderate-to-Vigorous Physical Activity and Bone Mineral Content Is Not Mediated by Free Leptin Index in Prepubertal Children: The PANIC Study.

Int J Environ Res Public Health 2021 05 18;18(10). Epub 2021 May 18.

Institute of Biomedicine, Kuopio Campus, University of Eastern Finland, FI-70211 Kuopio, Finland.

Purpose: Moderate-to-vigorous physical activity (MVPA) positively influences bone mineral content (BMC) in prepubertal children, but it is unknown whether this relationship is partially mediated by free leptin index. The aim of this study was to examine whether the relationship between MVPA and total body less head (TBLH) BMC is mediated or moderated by free leptin index in prepubertal children.

Methods: We performed a cross-sectional analysis on 401 children (194 girls) from baseline examinations of the Physical Activity and Nutrition in Childhood Study. We applied the four-way decomposition mediation analysis method to assess whether free leptin index, measured from fasted blood samples, mediated the relationship between accelerometer-measured MVPA and TBLH BMC measured by dual-energy X-ray absorptiometry.

Results: MVPA had a positive controlled direct effect on TBLH BMC in girls and boys (β = 0.010 to 0.011, < 0.05). There was no mediation or interaction between MVPA, free leptin index and TBLH BMC in girls or boys (β = -0.000 to 0.001, > 0.05).

Conclusion: Our study indicates that MVPA positively influences TBLH BMC through pathways not related to free leptin index in predominantly normal-weight prepubertal children, likely primarily through mechanical loading. The relationships between MVPA, free leptin index and TBLH BMC may be influenced by other factors such as pubertal status and adiposity, so it is unknown whether these observations extend to overweight and obese children at different stages of puberty.
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http://dx.doi.org/10.3390/ijerph18105365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157575PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.

Mol Psychiatry 2021 Apr 15. Epub 2021 Apr 15.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
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http://dx.doi.org/10.1038/s41380-021-01087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517040PMC
April 2021

Longitudinal associations of physical activity, sedentary time, and cardiorespiratory fitness with arterial health in children - the PANIC study.

J Sports Sci 2021 Sep 8;39(17):1980-1987. Epub 2021 Apr 8.

School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.

We investigated the longitudinal associations of physical activity (PA), sedentary time (ST), and cardiorespiratory fitness (CRF) with arterial health among children. In our primary analyses, we investigated 245 children (girls 51.8%) aged 6-9 years participating in the baseline examinations who had data on arterial health at 2-year follow-up. We also utilized a subsample of 90 children who had a complete arterial health data at baseline and 2-year follow-up. ST (≤1.5 METs), light PA (>1.5-4 METs), moderate PA (>4-7 METs), vigorous PA (>7METs), and moderate-to-vigorous PA (MVPA, >4 METs) were assessed by combined movement and heart rate monitoring and CRF by maximal exercise testing on a cycle ergometer at baseline and 2-year follow-up. Stiffness index (SI) as a measure of arterial stiffness and change in reflection index during exercise test (DRI) as a measure of arterial dilation capacity were assessed by pulse contour analysis. Two-year change in vigorous PA was associated with DRI in boys but not in girls (p=0.021 for interaction). In a subsample analyses, 2-year changes in MPA, VPA, and MVPA were inversely associated with 2-year change in SI. In conclusion, promoting PA at higher intensities may confer larger benefits on arterial health than reducing ST and increasing LPA.
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http://dx.doi.org/10.1080/02640414.2021.1912450DOI Listing
September 2021

Exercise, diet, and cognition in a 4-year randomized controlled trial: Dose-Responses to Exercise Training (DR's EXTRA).

Am J Clin Nutr 2021 06;113(6):1428-1439

Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

Background: Evidence for the effects of exercise and dietary interventions on cognition from long-term randomized controlled trials (RCTs) in large general populations remains insufficient.

Objective: The objective of our study was to investigate the independent and combined effects of resistance and aerobic exercise and dietary interventions on cognition in a population sample of middle-aged and older individuals.

Methods: We conducted a 4-y RCT in 1401 men and women aged 57-78 y at baseline. The participants were randomly assigned to the resistance exercise, aerobic exercise, diet, combined resistance exercise and diet, combined aerobic exercise and diet, or control group. Exercise goals were at least moderate-intensity resistance exercise ≥2 times/wk and at least moderate-intensity aerobic exercise ≥5 times/wk. Dietary goals were ≥400 g/d of vegetables, fruit, and berries; ≥2 servings of fish/wk; ≥14 g fiber/1000 kcal; and ≤10% of energy of daily energy intake from SFAs. The primary outcome was the change in global cognition measured by the total score of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological tests [CERAD total score (CERAD-TS)]. The data were analyzed using the intention-to-treat principle and linear mixed-effects models.

Results: There was a trend toward improved CERAD-TS over 4 y in the combined aerobic exercise and diet group compared with the control group (net increase: 1.4 points; 95% CI: 0.1, 2.7; P = 0.06) adjusted for age, sex, years of education, symptoms of depression, and waist circumference at baseline. No other differences in CERAD-TS changes were found across the 6 study groups. Diet did not potentiate the effect of aerobic or resistance exercise on CERAD-TS.

Conclusions: A combination of at least moderate-intensity aerobic exercise and a healthy diet may improve cognition in older individuals over 4 y, but there was no effect of either of these interventions alone, resistance training alone, or resistance exercise with a healthy diet on cognition.
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http://dx.doi.org/10.1093/ajcn/nqab018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244125PMC
June 2021

Leisure-time cross-country skiing and the risk of venous thromboembolism: A prospective cohort study.

Eur J Prev Cardiol 2020 Mar 3. Epub 2020 Mar 3.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland.

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http://dx.doi.org/10.1177/2047487320908978DOI Listing
March 2020

Associations of physical activity, sedentary time, and diet quality with biomarkers of inflammation in children.

Eur J Sport Sci 2021 Mar 14:1-10. Epub 2021 Mar 14.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

We investigated the associations of physical activity (PA), sedentary time (ST), and diet quality with biomarkers of inflammation in 390 children (192 girls, 198 boys) aged 6-8 years. PA energy expenditure (PAEE), light PA, moderate PA (MPA), vigorous PA (VPA), moderate-to-vigorous PA (MVPA), and ST were assessed by combined movement and heart rate sensor. Finnish Children Healthy Eating Index was calculated using data from 4 d food records. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry. High-sensitivity C-reactive protein (Hs-CRP), leptin, interleukin-6 (IL-6), adiponectin, tumour necrosis factor-α, and glycoprotein acetyls were measured from fasting blood samples. PAEE, MPA, VPA, and MVPA were inversely associated with hs-CRP (β=-191 to -139, 95% CI=-0.294 to -0.024), leptin (β=-0.409 to -0.301, 95% CI=-0.499 to -0.107), IL-6 (β=-0.136 to -0.104, 95% CI=-0.240 to -0.001) and PAEE, MPA, and MVPA were inversely associated with glycoprotein acetyls (β=-0.117 to -0.103, 95% CI=-0.213 to -0.001). ST was directly associated with hs-CRP (β=0.170, 95% CI=0.070-0.269), leptin (β=0.355, 95% CI=0.265-0.445), and IL-6 (β=0.105, 95% CI=0.005-0.205). VPA was inversely associated with hs-CRP, leptin, and IL-6 in children with higher BF% (β=-0.344 to -0.181, 95% CI=-0.477 to -0.033) but not among children with lower BF% (β=-0.007-0.033, 95% CI=-0.183-0.184). In conclusion, PA was inversely and ST directly associated with circulating levels of biomarkers of inflammation among children. Furthermore, we observed that PA was inversely associated with these biomarkers for inflammation in children with a higher BF%. Systemic inflammation, as indicated by increased circulating concentrations of biomarkers for inflammation, may be important in causal pathways leading to insulin resistance, sub-clinical atherosclerosis, and eventually clinical manifestations of cardiovascular diseases.Higher levels of physical activity and lower levels of sedentary time were associated with more favourable inflammatory profile.Body fat percentage modified these associations and especially vigorous intensity physical activity was inversely associated with biomarkers of inflammation on children with higher body fat percentage but not in children with lower body fat percentage.
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http://dx.doi.org/10.1080/17461391.2021.1892830DOI Listing
March 2021

Response.

Med Sci Sports Exerc 2021 02;53(2):454

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http://dx.doi.org/10.1249/MSS.0000000000002485DOI Listing
February 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Oxygen-18 and Carbon-13 isotopes in eCOand erythrocytes carbonic anhydrase activity of Finnish prediabetic population.

J Breath Res 2020 Dec 10. Epub 2020 Dec 10.

VTT Ltd, Espoo, FINLAND.

Complex human physiological processes create the stable isotopic composition of exhaled carbon dioxide (eCO2), measurable with noninvasive breath tests. Recently, isotope-selective breath tests utilizing natural fluctuation in 18O/16O isotope ratio in eCO2 have been proposed for screening prediabetic (PD) individuals. It has been suggested that 18O/16O fractionation patterns reflect shifts in the activity of carbonic anhydrase (CA), an enzyme involved in the metabolic changes in the PD state. To evaluate the applicability of the breath sampling method in Finnish PD individuals, breath delta values (BDVs, ‰) of 18O/16O (δ18O) were monitored for 120 min in real-time with a high-precision optical isotope ratio spectrometer, both in the fasting state and during a 2-hour oral glucose tolerance test (2h OGTT) with non-labelled glucose. In addition, the BDV of 13C/12C (δ13C) was measured, and total erythrocyte CA activity was determined. δ18O and CA did not demonstrate any statistically significant differences between PD and non-diabetic control (NDC) participants. Instead, δ13C was significantly lower in PD patients in comparison to NDCs in the fasting state and at time points 90 and 120 min of the 2h OGTT, thus indicating slightly better potential in identifying Finnish PD individuals. However, overlapping values were measured in PD participants and NDCs, and therefore, δ13C cannot be applied as a sole measure in screening prediabetes at an individual level. Thus, because the combination of environmental and lifestyle factors and anthropometric parameters has a greater effect on glucose metabolism and CA activity in comparison to the PD state, 18O/16O and 13C/12C fractionations or CA activity did not prove to be reliable biomarkers for impaired glucose tolerance in Finnish subjects. This study was conducted under the clinicaltrials.gov ID NCT03156478.
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http://dx.doi.org/10.1088/1752-7163/abd28dDOI Listing
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

A 2 year physical activity and dietary intervention attenuates the increase in insulin resistance in a general population of children: the PANIC study.

Diabetologia 2020 11 20;63(11):2270-2281. Epub 2020 Aug 20.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, P.O. Box 1627, FI-70211, Kuopio, Finland.

Aims/hypothesis: We studied for the first time the long-term effects of a combined physical activity and dietary intervention on insulin resistance and fasting plasma glucose in a general population of predominantly normal-weight children.

Methods: We carried out a 2 year non-randomised controlled trial in a population sample of 504 children aged 6-9 years at baseline. The children were allocated to a combined physical activity and dietary intervention group (306 children at baseline, 261 children at 2-year follow-up) or a control group (198 children, 177 children) without blinding. We measured fasting insulin and fasting glucose, calculated HOMA-IR, assessed physical activity and sedentary time by combined heart rate and body movement monitoring, assessed dietary factors by a 4 day food record, used the Finnish Children Healthy Eating Index (FCHEI) as a measure of overall diet quality, and measured body fat percentage (BF%) and lean body mass by dual-energy x-ray absorptiometry. The intervention effects on insulin, glucose and HOMA-IR were analysed using the intention-to-treat principle and linear mixed-effects models after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The measures of physical activity, sedentary time, diet and body composition at baseline and 2 year follow-up were entered one-by-one as covariates into the models to study whether changes in these variables might partly explain the observed intervention effects.

Results: Compared with the control group, fasting insulin increased 4.65 pmol/l less (absolute change +8.96 vs +13.61 pmol/l) and HOMA-IR increased 0.18 units less (+0.31 vs +0.49 units) over 2 years in the combined physical activity and dietary intervention group. The intervention effects on fasting insulin (regression coefficient β for intervention effect -0.33 [95% CI -0.62, -0.04], p = 0.026) and HOMA-IR (β for intervention effect -0.084 [95% CI -0.156, -0.012], p = 0.023) were statistically significant after adjustment for sex, age at baseline, and pubertal status at baseline and 2 year follow-up. The intervention had no effect on fasting glucose, BF% or lean body mass. Changes in total physical activity energy expenditure, light physical activity, moderate-to-vigorous physical activity, total sedentary time, the reported consumption of high-fat (≥60%) vegetable oil-based spreads, and FCHEI, but not a change in BF% or lean body mass, partly explained the intervention effects on fasting insulin and HOMA-IR.

Conclusions/interpretation: The combined physical activity and dietary intervention attenuated the increase in insulin resistance over 2 years in a general population of predominantly normal-weight children. This beneficial effect was partly mediated by changes in physical activity, sedentary time and diet but not changes in body composition.

Trial Registration: ClinicalTrials.gov NCT01803776 Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05250-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527318PMC
November 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

The effects of a 2-year physical activity and dietary intervention on plasma lipid concentrations in children: the PANIC Study.

Eur J Nutr 2021 Feb 4;60(1):425-434. Epub 2020 May 4.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

Purpose: We studied the effects of a physical activity and dietary intervention on plasma lipids in a general population of children. We also investigated how lifestyle changes contributed to the intervention effects.

Methods: We carried out a 2-year controlled, non-randomized lifestyle intervention study among 504 mainly prepubertal children aged 6-9 years at baseline. We assigned 306 children to the intervention group and 198 children to the control group. We assessed plasma concentrations of total, LDL, HDL, and VLDL cholesterol, triglycerides, HDL triglycerides, and VLDL triglycerides. We evaluated the consumption of foods using 4-day food records and physical activity using a movement and heart rate sensor. We analyzed data using linear mixed-effect models adjusted for age at baseline, sex, and pubertal stage at both time points. Furthermore, specific lifestyle variables were entered in these models.

Results: Plasma LDL cholesterol decreased in the intervention group but did not change in the control group ( - 0.05 vs. 0.00 mmol/L, regression coefficient (β) =  - 0.0385, p = 0.040 for group*time interaction). This effect was mainly explained by the changes in the consumption of high-fat vegetable oil-based spreads (β =  - 0.0203, + 47% change in β) and butter-based spreads (β =  - 0.0294, + 30% change in β), moderate-to-vigorous physical activity (β =  - 0.0268, + 30% change in β), light physical activity (β =  - 0.0274, + 29% change in β) and sedentary time (β =  - 0.0270, + 30% change in β). The intervention had no effect on other plasma lipids.

Conclusion: Lifestyle intervention resulted a small decrease in plasma LDL cholesterol concentration in children. The effect was explained by changes in quality and quantity of dietary fat and physical activity.

Clinical Trial Registry Number: NCT01803776, ClinicalTrials.gov.
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http://dx.doi.org/10.1007/s00394-020-02260-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867543PMC
February 2021

Leisure-time cross-country skiing and the risk of venous thromboembolism: A prospective cohort study.

Eur J Prev Cardiol 2020 Mar 2:2047487320908978. Epub 2020 Mar 2.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Finland.

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http://dx.doi.org/10.1177/2047487320908978DOI Listing
March 2020

Associations of dietary carbohydrate and fatty acid intakes with cognition among children.

Public Health Nutr 2020 Jun 21;23(9):1657-1663. Epub 2020 Feb 21.

Physiology, Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, 70211Kuopio, Finland.

Objective: To investigate the cross-sectional associations of dietary carbohydrate and fatty acid intakes with cognition in mid-childhood.

Design: Dietary carbohydrate and fatty acid intakes were assessed using 4-d food records, and cognition was evaluated using the Raven's Coloured Progressive Matrices (RCPM) score. The cross-sectional associations of dietary carbohydrate and fatty acid intakes with cognition were investigated using linear regression analyses adjusted for age, sex, body fat percentage, household income, parental education and daily energy intake.

Setting: The baseline examinations of the Physical Activity and Nutrition in Children study.

Participants: A population-based sample of 487 children (250 boys, 237 girls) aged 6-8 years living in the city of Kuopio, Finland.

Results: A higher dietary intake of fructose (standardised regression coefficient, β = 0·24, P < 0·001), total fibre (β = 0·16, P = 0·02) and soluble fibre (β = 0·15, P = 0·02) was associated with a higher RCPM score in boys. Other dietary carbohydrates and fatty acids, including total carbohydrates, glucose, sucrose, starch, insoluble fibre, total fat, SFAs, MUFAs, PUFAs, palmitic acid (C16), stearic acid (C18), linoleic acid (C18:2), α-linoleic acid (C18:3), arachidonic acid (C20:4), EPA (C20:5n-3) and DHA (C22:6n-6), were not associated with the RCPM score in boys. Dietary carbohydrates or fatty acids were not associated with the RCPM score in girls.

Conclusions: Higher dietary fructose and fibre intakes were associated with better cognition in boys, but not in girls. Dietary fatty acids were not related to cognition in boys or in girls.
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http://dx.doi.org/10.1017/S1368980019003860DOI Listing
June 2020

Child-related and parental predictors for thelarche in a general population of girls: the PANIC study.

Pediatr Res 2020 10 12;88(4):676-680. Epub 2020 Feb 12.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

Background: Obesity has been associated with earlier thelarche, whereas other predictors for it remain unclear.

Methods: We studied child-related and parental predictors for earlier thelarche in 195 girls aged 6-8 years followed up for 2 years. A physician evaluated breast development by inspection and palpation. Body fat percentage (BF%) was measured by dual-energy X-ray absorptiometry, diet by food records, and physical activity and sedentary time by body movement and heart rate monitors. Parental education, smoking, and alcohol consumption and household income were assessed by questionnaires. Gestational age, birth weight, and maternal prepregnancy BMI were obtained from hospital registers. Predictors for thelarche were examined using logistic regression analysis adjusted for age and follow-up time.

Results: The incidence of thelarche during 2 years increased by 11% (OR 1.11, CI 1.06-1.17, p < 0.001) for 1 unit increase in baseline BF%. Girls with a smoking parent had a 2.64 (95% CI 1.21-5.77, p = 0.015) times higher incidence of thelarche than other girls. The associations of lower parental education and higher maternal prepregnancy BMI with the higher incidence of thelarche were largely explained by BF%. Other possible predictors were not associated with thelarche.

Conclusions: Higher BF% and exposure to tobacco smoke are independent predictors for earlier thelarche.
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http://dx.doi.org/10.1038/s41390-020-0802-0DOI Listing
October 2020

Associations of cardiometabolic risk factors with heart rate variability in 6- to 8-year-old children: The PANIC Study.

Pediatr Diabetes 2020 03 30;21(2):251-258. Epub 2019 Dec 30.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland.

Background: Associations of cardiometabolic risk factors with heart rate variability (HRV) in children are unclear. We examined associations of cardiometabolic risk score (CRS) and individual cardiometabolic risk factors with HRV variables in 6- to 8-year-olds.

Methods: The participants were a population-based sample of 443 children participating in baseline measurements of the Physical Activity and Nutrition in Children trial. Cardiometabolic risk factors included waist circumference (WC), insulin, glucose, triglycerides, HDL cholesterol, systolic blood pressure (SBP), and diastolic blood pressure (DBP). CRS was calculated as WC + insulin + glucose + triglycerides - HDL cholesterol + the mean of SBP and DBP. HRV variables (SDNN, RMSSD, HF, LF, LF/HF, Mean RR) were measured using 5-minute electrocardiography at rest and analyzed using the Kubios HRV software. In this cross-sectional study, associations of CRS and individual cardiometabolic risk factors with HRV were investigated using linear regression analyses adjusted for sex and peak height velocity.

Results: CRS was negatively associated with RMSSD, HF, Mean RR (P value < .05) and positively with LF/HF (P value = .005). Insulin was negatively associated with SDNN, RMSSD, HF, LF, and Mean RR (P value < .05) and positively with LF/HF (P value = .008). SBP was negatively associated with SDNN, RMSSD, HF, LF, and Mean RR (P value < .05). DBP was negatively associated with SDNN, RMSSD, and Mean RR (P value < .05). WC, glucose, triglycerides, or HDL cholesterol were not associated with HRV variables.

Conclusions: Higher CRS, insulin, and blood pressure were associated with smaller HRV, mainly indicating lower parasympathetic activity, in young children. This knowledge may help improving the clinical management of metabolic syndrome and cardiovascular diseases since childhood.
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http://dx.doi.org/10.1111/pedi.12967DOI Listing
March 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Cardiorespiratory Fitness, Physical Activity, and Insulin Resistance in Children.

Med Sci Sports Exerc 2020 05;52(5):1144-1152

MRC Epidemiology Unit, University of Cambridge, Cambridge, UNITED KINGDOM.

Purpose: Few studies have investigated the independent and joint associations of cardiorespiratory fitness (CRF) and body fat percentage (BF%) with insulin resistance in children. We investigated the independent and combined associations of CRF and BF% with fasting glycemia and insulin resistance and their interactions with physical activity (PA) and sedentary time among 452 children age 6 to 8 yr.

Methods: We assessed CRF with a maximal cycle ergometer exercise test and used allometrically scaled maximal power output (Wmax) for lean body mass (LM) and body mass (BM) as measures of CRF. The BF% and LM were measured by dual-energy X-ray absorptiometry, fasting glycemia by fasting plasma glucose, and insulin resistance by fasting serum insulin and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The PA energy expenditure, moderate-to-vigorous PA (MVPA), and sedentary time were assessed by combined movement and heart rate sensor.

Results: Wmax/LM was not associated with glucose (β = 0.065, 95% confidence interval [CI] = -0.031 to 0.161), insulin (β = -0.079, 95% CI = -0.172 to 0.015), or HOMA-IR (β = -0.065, 95% CI = -0.161 to 0.030). Wmax/BM was inversely associated with insulin (β = -0.289, 95% CI = -0.377 to -0.200) and HOMA-IR (β = -0.269, 95% CI = -0.359 to -0.180). The BF% was directly associated with insulin (β = 0.409, 95% CI = 0.325 to 0.494) and HOMA-IR (β = 0.390, 95% CI = 0.304 to 0.475). Higher Wmax/BM, but not Wmax/LM, was associated with lower insulin and HOMA-IR in children with higher BF%. Children with higher BF% and who had lower levels of MVPA or higher levels of sedentary time had the highest insulin and HOMA-IR.

Conclusions: Children with higher BF% together with less MVPA or higher levels of sedentary time had the highest insulin and HOMA-IR. Cardiorespiratory fitness appropriately controlled for body size and composition using LM was not related to insulin resistance among children.
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http://dx.doi.org/10.1249/MSS.0000000000002216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358077PMC
May 2020

Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.

Nat Commun 2019 11 12;10(1):5121. Epub 2019 Nov 12.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
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http://dx.doi.org/10.1038/s41467-019-12958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851116PMC
November 2019

Associations of physical activity, sedentary time, and cardiorespiratory fitness with heart rate variability in 6- to 9-year-old children: the PANIC study.

Eur J Appl Physiol 2019 Dec 18;119(11-12):2487-2498. Epub 2019 Sep 18.

Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, PO Box 1627, 70211, Kuopio, Finland.

Purpose: To study the associations of physical activity (PA), sedentary time (ST), and cardiorespiratory fitness (CRF) with heart rate variability (HRV) in children.

Methods: The participants were a population sample of 377 children aged 6-9 years (49% boys). ST, light PA (LPA), moderate PA (MPA), vigorous PA (VPA), and moderate-to-vigorous PA (MVPA), and PA energy expenditure (PAEE) were assessed using a combined heart rate and movement sensor, maximal power output per kilograms of lean body mass as a measure of CRF by maximal cycle ergometer exercise test, and HRV variables (SDNN, RMSSD, LF, and HF) using 5 min resting electrocardiography. Data were analysed by linear regression adjusted for years from peak height velocity.

Results: In boys, ST was inversely associated (β = - 0.185 to - 0.146, p ≤ 0.049) and MVPA, VPA, PAEE, and CRF were directly associated (β = 0.147 to 0.320, p ≤ 0.048) with HRV variables. CRF was directly associated with all HRV variables and PAEE was directly associated with RMSSD after mutual adjustment for ST, PAEE, and CRF (β = 0.169 to 0.270, p ≤ 0.046). In girls, ST was inversely associated (β = - 0.382 to - 0.294, p < 0.001) and LPA, MPA, VPA, MVPA, and PAEE were directly associated with HRV variables (β = 0.144 to 0.348, p ≤ 0.049). After mutual adjustment for ST, PAEE, and CRF, only the inverse associations of ST with HRV variables remained statistically significant.

Conclusions: Higher ST and lower PA and CRF were associated with poorer cardiac autonomic nervous system function in children. Lower CRF in boys and higher ST in girls were the strongest correlates of poorer cardiac autonomic function.
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http://dx.doi.org/10.1007/s00421-019-04231-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858383PMC
December 2019

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
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http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Abdominal adiposity and cardiometabolic risk factors in children and adolescents: a Mendelian randomization analysis.

Am J Clin Nutr 2019 11;110(5):1079-1087

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear.

Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization.

Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y.

Results: WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal.

Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.
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http://dx.doi.org/10.1093/ajcn/nqz187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904295PMC
November 2019

Cross-country skiing and the risk of acute myocardial infarction: A prospective cohort study.

Eur J Prev Cardiol 2020 07 19;27(10):1108-1111. Epub 2019 Aug 19.

National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, UK.

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http://dx.doi.org/10.1177/2047487319869696DOI Listing
July 2020
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