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The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL’s catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1’s IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1–LPL interactions and the ability of GPIHBP1 to protect LPL against ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1–LPL encounter via electrostatic steering, increasing the association rate constant (k on) for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1’s IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1’s ability to preserve LPL structure and activity.

Background Levels of physical activity and variation in physical activity and sedentary time by place and person in European children and adolescents are largely unknown. The objective of the study was to assess the variations in objectively measured physical activity and sedentary time in children and adolescents across Europe. Methods Six databases were systematically searched to identify pan-European and national data sets on physical activity and sedentary time assessed by the same accelerometer in children (2 to 9.9 years) and adolescents (≥10 to 18 years). We harmonized individual-level data by reprocessing hip-worn raw accelerometer data files from 30 different studies conducted between 1997 and 2014, representing 47,497 individuals (2–18 years) from 18 different European countries. Results Overall, a maximum of 29% (95% CI: 25, 33) of children and 29% (95% CI: 25, 32) of adolescents were categorized as sufficiently physically active. We observed substantial country- and region-specific differences in physical activity and sedentary time, with lower physical activity levels and prevalence estimates in Southern European countries. Boys were more active and less sedentary in all age-categories. The onset of age-related lowering or leveling-off of physical activity and increase in sedentary time seems to become apparent at around 6 to 7 years of age. Conclusions Two third of European children and adolescents are not sufficiently active. Our findings suggest substantial gender-, country- and region-specific differences in physical activity. These results should encourage policymakers, governments, and local and national stakeholders to take action to facilitate an increase in the physical activity levels of young people across Europe.

Near-infrared spectroscopy (NIRS) and intravascular ultrasound are promising imaging modalities to identify non-obstructive plaques likely to cause coronary-related events. We aimed to assess whether combined NIRS and intravascular ultrasound can identify high-risk plaques and patients that are at risk for future major adverse cardiac events (MACEs). PROSPECT II is an investigator-sponsored, multicentre, prospective natural history study done at 14 university hospitals and two community hospitals in Denmark, Norway, and Sweden. We recruited patients of any age with recent (within past 4 weeks) myocardial infarction. After treatment of all flow-limiting coronary lesions, three-vessel imaging was done with a combined NIRS and intravascular ultrasound catheter. Untreated lesions (also known as non-culprit lesions) were identified by intravascular ultrasound and their lipid content was assessed by NIRS. The primary outcome was the covariate-adjusted rate of MACEs (the composite of cardiac death, myocardial infarction, unstable angina, or progressive angina) arising from untreated non-culprit lesions during follow-up. The relations between plaques with high lipid content, large plaque burden, and small lumen areas and patient-level and lesion-level events were determined. This trial is registered with ClinicalTrials.gov, NCT02171065. Between June 10, 2014, and Dec 20, 2017, 3629 non-culprit lesions were characterised in 898 patients (153 [17%] women, 745 [83%] men; median age 63 [IQR 55–70] years). Median follow-up was 3·7 (IQR 3·0–4·4) years. Adverse events within 4 years occurred in 112 (13·2%, 95% CI 11·0–15·6) of 898 patients, with 66 (8·0%, 95% CI 6·2–10·0) arising from 78 untreated non-culprit lesions (mean baseline angiographic diameter stenosis 46·9% [SD 15·9]). Highly lipidic lesions (851 [24%] of 3500 lesions, present in 520 [59%] of 884 patients) were an independent predictor of patient-level non-culprit lesion-related MACEs (adjusted odds ratio 2·27, 95% CI 1·25–4·13) and non-culprit lesion-specific MACEs (7·83, 4·12–14·89). Large plaque burden (787 [22%] of 3629 lesions, present in 530 [59%] of 898 patients) was also an independent predictor of non-culprit lesion-related MACEs. Lesions with both large plaque burden by intravascular ultrasound and large lipid-rich cores by NIRS had a 4-year non-culprit lesion-related MACE rate of 7·0% (95% CI 4·0–10·0). Patients in whom one or more such lesions were identified had a 4-year non-culprit lesion-related MACE rate of 13·2% (95% CI 9·4–17·6). Combined NIRS and intravascular ultrasound detects angiographically non-obstructive lesions with a high lipid content and large plaque burden that are at increased risk for future adverse cardiac outcomes. Abbott Vascular, Infraredx, and The Medicines Company.

The effect of small concentrations of intracrystalline water on the strength of olivine is significant at asthenospheric temperatures but is poorly constrained at lower temperatures applicable to the shallow lithosphere. We examined the effect of water on the yield stress of olivine during low‐temperature plasticity using room‐temperature Berkovich nanoindentation. The presence of water in olivine (1,600 ppm H/Si) does not affect hardness or yield stress relative to dry olivine (≤40 ppm H/Si) outside of uncertainty but may slightly reduce Young’s modulus. Differences between water‐bearing and dry crystals in similar orientations were minor compared to differences between dry crystals in different orientations. These observations suggest water content does not affect the strength of olivine at low homologous temperatures. Thus, intracrystalline water does not play a role in olivine deformation at these temperatures, implying that water does not lead to weakening in the coldest portions of the mantle. Plain Language Summary At high temperatures (>1,000°C), incorporating small amounts of water in a crystalline structure can dramatically affect the strength of that crystal. There are many theories as to why this is the case, and each theory makes a prediction for how water might affect the strength of crystals at low temperatures. Thus, by conducting experiments at room temperature, we can distinguish between some of these theories. Our data indicate that water does not have a significant effect on the strength of olivine at room temperature, and any minor effect that water may have is far outweighed by the effect of crystal orientation. These observations rule out theories in which water causes a decrease in the strength of olivine at all temperatures, implying that water does not lead to weakening in the coldest portions of the mantle. Key Points Room‐temperature nanoindentation tests on wet and dry olivine yield very similar mechanical results Any effect of water incorporation on yield stress is outweighed by the effect of orientation anisotropy Water may only weaken olivine at high temperatures and therefore not influence strength in the coldest portions of the lithosphere

Background There is a scarcity of device measured data on temporal changes in physical activity (PA) in large population-based samples. The purpose of this study is to describe gender and age-group specific temporal trends in device measured PA between 2005, 2011 and 2018 by comparing three nationally representative samples of children and adolescents. Methods Norwegian children and adolescents (6, 9 and 15-year-olds) were invited to participate in 2005 (only 9- and 15-year-olds), 2011 and 2018 through cluster sampling (schools primary sampling units). A combined sample of 9500 individuals participated. Physical activity was assessed by hip worn accelerometers, with PA indices including overall PA (counts per minute), moderate-to-vigorous intensity PA (MVPA), and PA guideline adherence (achieving on average ≥ 60 min/day of moderate-to-vigorous PA). Random-effects linear regressions and logistic regressions adjusted for school-level clusters were used to analyse temporal trends. Findings In total, 8186 of the participating children and adolescents provided valid PA data. Proportions of sufficiently active 6-year-olds were almost identical in 2011 and 2018; boys 95% (95% CI: 92, 97) and 94% (95%CI: 92, 96) and girls 86% (95% CI: 83, 90) and 86% (95% CI: 82, 90). Proportions of sufficiently active 15-year-olds in 2005 and 2018 were 52% (95% CI: 46, 59) and 55% (95% CI: 48, 62) in boys, and 48% (95% CI: 42, 55) and 44% (95% CI: 37, 51) in girls, respectively, resulting from small differences in min/day of MVPA. Among 9-year-old boys and girls, proportions of sufficiently active declined between 2005 and 2018, from 90% (95% CI: 87, 93) to 84% (95% CI: 80, 87)) and 74% (95% CI: 69, 79) to 68% (95% CI: 64, 72), respectively. This resulted from 9.7 min/day less MVPA in boys (95% CI: − 14.8, − 4.7; p  < 0.001) and 3.2 min/day less MVPA (95% CI: − 7.0, 0.7; p  = 0.106) in girls. Conclusions PA levels have been fairly stable between 2005, 2011 and 2018 in Norwegian youth. However, the declining PA level among 9-year-old boys and the low proportion of 15-year-olds sufficiently active is concerning. To evaluate the effect of, and plan for new, PA promoting strategies, it is important to ensure more frequent, systematic, device-based monitoring of population-levels of PA.

Many young people fail to achieve the minimum recommended amount of physical activity to benefit their health. Understanding the nature of age-related changes in behaviour and how this varies for population sub-groups is informative for intervention design. The aim of this study was to describe age-related changes in physical activity and sedentary time and examine variability in patterns of change across demographic sub-groups. Data are from 13 studies in the International Children's Accelerometry Database (ICAD), all of which provided ≥2 waves of waist-worn accelerometer data. Annual change in sedentary time, light intensity physical activity (LPA) and moderate to vigorous intensity physical activity (MVPA) were estimated using three level mixed effects linear regression models, using participant age as the exposure variable. In interaction models, we examined whether changes in behaviour differed by day of the week (weekday/ weekend), age at baseline assessment (<10/ ≥ 10 years), sex, weight category, maternal education and ethnicity. In total, 6567 participants provided two or more waves of valid accelerometer data (44.5% boys, mean (SD) baseline age 10.6 (2.1) years (range 4.1-15.8 years)). Across the week and for all studied sub-groups, sedentary time increased by approximately 25 minutes/day/year of age, LPA decreased by approximately 22 minutes/day/year of age and MVPA decreased by approximately 3 minutes/day/year of age. The annual increase in sedentary time was greater in girls compared to boys (β (95% confidence interval) change (min) for each additional year of age: girls, 25.9 (25.4, 26.4); boys, 23.6 (23.0, 24.2)) and in adolescents compared to children (adolescents, 27.0 (26.5, 27.6); children, (23.5 (22.9, 24.2)). The annual decrease in MVPA was greater in boys compared to girls (boys, -2.7 (-3.0, -2.5); girls, -2.2 (-2.4, -2.0)) and at the weekend compared to during the week (weekend, -3.0 (-3.3, -2.8); weekday -2.3 (-2.5, -2.1)). Accelerometer assessed sedentary time increased whilst LPA and MVPA decreased during childhood and adolescence. This overall pattern was observed across the week and in all studied sub-groups, but small differences in the magnitude of changes can be used to guide the timing and targeting of behaviour change interventions, such as designing physical activity interventions which focus on weekends where a child's time is less structured.

BackgroundPatients with psychiatric disorders have increased all-cause mortality compared with the general population. Previous research has shown that there is a fourfold increased risk of sudden cardiac death (SCD) among the young.ObjectiveTo investigate the incidence of SCD in patients with psychiatric disorders aged 18–90 years in the Danish population by systematically reviewing all deaths in 1 year.MethodsWe examined all deaths in Denmark among residents aged 18–90 years in 2010 by reviewing death certificates and autopsy reports. All deaths were categorised as non-SCD or SCD based on the available information. Psychiatric disorder was defined according to International Classification of Diseases, 10th revision criteria or by redemption of a prescription for psychotropic medication within 1 year.ResultsOf 4.3 million residents in 2010, we observed 45 703 deaths, of which 6002 were due to SCD. Overall, the incidence rate ratio of SCD was 1.79–6.45 times higher among patients with psychiatric disorders than in the general population and was age dependent (p<0.001 across all age groups). When adjusting for age, sex and comorbidities, psychiatric disorders were independently associated with SCD, with a HR of 2.31 (2.19 to 2.43, p<0.001), and HR was highest among patients with schizophrenic disorders, with a HR of 4.51 (3.95 to 5.16, p <0.001). Furthermore, 18-year-old patients with a psychiatric disorder had an expected 10-year excess loss of life. Patients aged 18–40 with a psychiatric disorder had 13% of excess life years lost caused by SCD.ConclusionIn this study, the rate of SCD in patients with psychiatric disorders is higher across all age groups than in the general population. Having a psychiatric disorder is independently associated with SCD. Patients with schizophrenic disease had the highest rates of SCD. Life expectancy for an 18-year old with a psychiatric disorder is estimated to be 10 years shorter in comparison with those without this disorder.

Background The aim of this study was to investigate how sleep, screen time, active school travel and sport and/or exercise participation associates with moderate-to-vigorous physical activity (MVPA) in nationally representative samples of Norwegian 9- and 15-y-olds, and whether these four behaviors at age nine predict change in MVPA from age nine to 15 years. Method We pooled cross-sectional accelerometer and questionnaire data from 9- ( n  = 2366) and 15-y-olds ( n  = 1554) that participated in the first (2005/06) and second (2011/12) wave of the Physical Activity among Norwegian Children Study to investigate cross-sectional associations. To investigate prospective associations, we used data from a sub-sample that participated in both waves (at age nine and 15 years, n  = 517). Results Cross-sectional analyses indicated a modest, inverse association between screen time and MVPA among 9- (− 2.2 min/d (95% CI: -3.1, − 1.3)) and 15-y-olds (− 1.7 min/d (95% CI: -2.7, − 0.8)). Compared to their peers with 0–5 min/d of active travel to school, 9- and 15-y-olds with ≥16 min/d accumulated 7.2 (95% CI: 4.0, 10.4) and 9.0 (95% CI: 3.8, 14.1) more min/d of MVPA, respectively. Nine-y-old boys and 15-y-olds reporting ≥8 h/week of sports and/or exercise participation accumulated 14.7 (95% CI: 8.2, 21.3) and 17.9 (95% CI: 14.0, 21.8) more min/d of MVPA, respectively, than those reporting ≤2 h/week. We found no cross-sectional association between sleep duration and MVPA in either age group. None of the four behaviors predicted change in MVPA from age nine to 15 years ( p  ≥ 0.102). Conclusion Active travel to school and sport/exercise participation may be important targets for future interventions aimed at increasing MVPA in children and adolescents. However, future studies are needed to determine causality.

The performance of elite breath hold divers (BHD) includes static breath hold for more than 11 minutes, swimming as far as 300 m, or going below 250 m in depth, all on a single breath of air. Diving mammals are adapted to sustain oxidative metabolism in hypoxic conditions through several metabolic adaptations, including improved capacity for oxygen transport and mitochondrial oxidative phosphorylation in skeletal muscle. It was hypothesized that similar adaptations characterized human BHD. Hence, the purpose of this study was to examine the capacity for oxidative metabolism in skeletal muscle of BHD compared to matched controls. Biopsies were obtained from the lateral vastus of the femoral muscle from 8 Danish BHD and 8 non-diving controls (Judo athletes) matched for morphometry and whole body VO2max. High resolution respirometry was used to determine mitochondrial respiratory capacity and leak respiration with simultaneous measurement of mitochondrial H2O2 emission. Maximal citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HAD) activity were measured in muscle tissue homogenates. Western Blotting was used to determine protein contents of respiratory complex I-V subunits and myoglobin in muscle tissue lysates. Muscle biopsies of BHD revealed lower mitochondrial leak respiration and electron transfer system (ETS) capacity and higher H2O2 emission during leak respiration than controls, with no differences in enzyme activities (CS and HAD) or protein content of mitochondrial complex subunits myoglobin, myosin heavy chain isoforms, markers of glucose metabolism and antioxidant enzymes. We demonstrated for the first time in humans, that the skeletal muscles of BHD are characterized by lower mitochondrial oxygen consumption both during low leak and high (ETS) respiration than matched controls. This supports previous observations of diving mammals demonstrating a lower aerobic mitochondrial capacity of the skeletal muscles as an oxygen conserving adaptation during prolonged dives.

Background More studies include multiple generations of the Actigraph activity monitor. So far no studies have compared the output including the newest generation and investigated the impact on the output of the activity monitor when enabling the low frequency extension (LFE) option. The aims were to study the responses of four generations (AM7164, GT1M, GT3X and GT3X+) of the Actigraph activity monitor in a mechanical setup and a free living environment with and without enabling the LFE option. Methods The monitors were oscillated in a mechanical setup using two radii in the frequency range 0.25-3.0 Hz. Following the mechanical study a convenience sample (N = 20) wore three monitors (one AM7164 and two GT3X) for 24 hours. Results The AM7164 differed from the newer generations across frequencies (p < 0.05) in the mechanical setup. The AM7164 produced a higher output at the lower and at the highest intensities, whereas the output was lower at the middle intensities in the mid-range compared to the newer generations. The LFE option decreased the differences at the lower frequencies, but increased differences at the higher. In free living, the mean physical activity level (PA) of the GT3X was 18 counts per minute (CPM) (8%) lower compared to the AM7164 (p < 0.001). Time spent in sedentary intensity was 26.6 minutes (95% CI 15.6 to 35.3) higher when assessed by the GT3X compared to the AM7164 (p < 0.001). Time spend in light and vigorous PA were 23.3 minutes (95% CI 31.8 to 14.8) and 11.7 minutes (95% CI 2.8 to 0.7) lower when assessed by the GT3X compared to the AM7164 (p < 0.05). When enabling the LFE the differences in the sedentary and light PA intensity (<333 counts*10 sec -1 ) were attenuated (p > 0.05 for differences between generations) thus attenuated the difference in mean PA (p > 0.05) when the LFE option was enabled. However, it did not attenuate the difference in time spend in vigorous PA and it introduced a difference in time spend in moderate PA (+ 3.0 min (95% CI 0.4 to 5.6)) between the generations. Conclusion We observed significant differences between the AM7164 and the newer Actigraph GT-generations (GT1M, GT3X and GT3X+) in a mechanical setup and in free-living. Enabling the LFE option attenuated the differences in mean PA completely, but induced a bias in the moderate PA intensities.