Determinants of non-alcoholic fatty liver disease in young people: Maternal, neonatal, and adolescent factors.

AIM: To assess the impact of maternal, neonatal, and adolescent factors on the development of non-alcoholic fatty liver disease (NAFLD) in a cohort of 14- to 19-year-old adolescents. METHODS: This study is part of the Early Vascular Ageing in the YOUth study, a single-center cross-sectional study conducted in western Austria. Maternal and neonatal factors were extracted from the mother-child booklet, adolescent factors were evaluated by a face-to-face interview, physical examination, and fasting blood analyses. Liver fat content was assessed by controlled attenuation parameter (CAP) using signals acquired by FibroScan® (Echosense, Paris, France). The association of maternal, neonatal, and adolescent factors with CAP values was analyzed using linear regression models. RESULTS: In total, 595 adolescents (27.2% male) aged 17.0 ± 1.3 years were included. 4.9% (n = 29) showed manifest NAFLD with CAP values above the 90th percentile. Male sex (p < 0.001), adolescent triglyceride levels (p = 0.021), Homeostatic Model Assessment for Insulin Resistance index and BMI z-score (p < 0.001, each) showed a significant association with liver fat content in the multivariable analysis. Maternal pre-pregnancy BMI was associated with CAP values after adjustment for sex, age, and birth weight for gestational age (p < 0.001), but this association was predominantly mediated by adolescent BMI (indirect effect b = 1.18, 95% CI [0.69, 1.77]). CONCLUSION: Components of the metabolic syndrome were the most important predictors of adolescent liver fat content. Therefore, prevention of NAFLD should focus on lifestyle modification in childhood and adolescence.

Association between dysphagia and symptoms of depression and anxiety after ischemic stroke.

BACKGROUND AND PURPOSE: Dysphagia is associated with poor outcome, higher mortality, reduced quality of life, and social isolation. We investigate the relationship between swallowing impairment and symptoms of anxiety and depression after ischemic stroke. METHODS: Consecutive patients with ischemic stroke participating in the prospective STROKE-CARD Registry study from 2020 to 2022 were assessed for dysphagia on hospital admission (clinical swallowing assessment) and for persistence until discharge and 3-month follow-up (SINGER Independency Index). Anxiety and depression symptoms were recorded using Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS) at 3-month follow-up. RESULTS: Of 648 patients, 19.3% had dysphagia on admission, persisting in 14.8% at discharge and 6.8% at 3-month follow-up. With the presence or duration of dysphagia (no dysphagia, dysphagia at baseline, at discharge, at 3 months), score (mean ± SD) increased on the BDI (7.9 ± 6.7, 12.5 ± 8.7, 13.5 ± 9.0, 16.5 ± 10.2), HADS-D (4.4 ± 3.7, 7.1 ± 4.2, 7.7 ± 4.4, 9.8 ± 4.3), and HADS-A (4.4 ± 3.5, 5.4 ± 3.6, 6.0 ± 3.6, 7.0 ± 3.6). In linear regression analysis adjusting for age, sex, diabetes, dementia, and either functional disability or stroke severity, BDI and HADS-D scores were significantly higher in patients with dysphagia across all points in time (admission, discharge, 3-month follow-up). An independent association with HADS-A scores was only evident in patients with persisting dysphagia after 3 months. Patients with dysphagia were more likely to receive antidepressants, antipsychotics, or benzodiazepines at discharge and 3-month follow-up. CONCLUSIONS: Dysphagia after stroke is common and severely affects psychosocial functioning of individuals. Our results highlight swallowing impairment as an independent predictor for poststroke depressive and, to a lesser extent, anxiety symptoms.

Comparison of body mass index and fat mass index to classify body composition in adolescents-The EVA4YOU study.

The objectives of this study were to develop age- and sex-specific reference percentiles for fat mass index (FMI) and fat-free mass index (FFMI) in adolescents aged 14 to 19 years and to determine differences in overweight/obesity classification by FMI and body mass index (BMI). The EVA4YOU study is a single-center cross-sectional study conducted in western Austria. Cardiovascular risks including anthropometric measurements and bioelectrical impedance analysis were assessed in adolescents (mean age 17 years). FMI and FFMI were calculated as the ratio of fat mass (FM) and fat-free mass (FFM) to the square of height and compared to study population-specific BMI percentiles. One thousand four hundred twenty-two adolescents were included in the analysis. Girls had a significantly higher mean FM and FMI and a significantly lower mean FFM, FFMI (p < 0.001, each), and mean BMI (p = 0.020) than boys. Body composition classification by FMI and BMI percentiles shows a concordance for the < 75th and > 97th percentile, but a significant difference in percentile rank classifications between these two cut-off values (all p < 0.05). Based on FMI, 15.5% (221/1422) of the whole population and 29.4% (92/313) of those between the 75th and 97th percentiles are classified one category higher or lower than those assigned by BMI. CONCLUSION:  Classification of normal or pathologic body composition based on BMI and FMI shows good accordance in the clearly normal or pathologic range. In an intermediate range, FMI reclassifies categories based on BMI in more than a quarter of adolescents. Cut-off values to differentiate normal from pathologic FMI values on a biological basis are needed. TRIAL REGISTRATION: The study is registered at www. CLINICALTRIALS: gov  (Identifier: NCT04598685; Date of registration: October 22, 2020). WHAT IS KNOWN: • Chronic non-communicable diseases (NCDs) are the leading cause of morbidity and mortality globally, with major risk factors including unhealthy diets, harmful behaviors, and obesity. Obesity in children and adolescents is a key risk factor for later NCDs, which is commonly measured by Body Mass Index (BMI). • BMI can be misleading as it doesn't distinguish between fat mass (FM) and fat-free mass (FFM), leading to potential misclassification of obesity in children. Previous studies have already suggested the use of the Fat Mass Index (FMI) and Fat-Free Mass Index (FFMI) as a more accurate measures of body composition. WHAT IS NEW: • This study adds the first age- and sex-specific reference values for FMI and FFMI in Austrian adolescents using bioelectrical impedance analysis (BIA) as a safe and secure measurement method of a large representative cohort. • We found percentile misclassification between BMI and FMI when categorizing for obesity, especially in intermediate categories of body composition. Furthermore, when comparing the new reference values for FMI and FFMI to existing ones from the US, UK, and Germany we could show a good alignment within the European cohorts and major differences with American values, indicating and confirming the difference of FMI and FFMI for different populations of different ethnical background, living on different continents.

Sex differences in acute stroke metrics and outcome dependent on COVID status.

BACKGROUND AND PURPOSE: Biological sex is known to have an impact on quality metrics of acute stroke. We aimed to determine whether COVID positivity accentuates this effect and constitutes worse outcome. METHODS: The present analysis was based on the Global COVID-19 Stroke Registry, a retrospective, international, cohort study of consecutive ischemic stroke patients receiving intravenous thrombolysis and/or endovascular thrombectomy between 1 March 2020 and 30 June 2021. We investigated differences between the sexes in patient characteristics, acute stroke metrics as well as post-stroke outcome in COVID-positive and COVID-negative stroke patients undergoing acute revascularization procedures. RESULTS: A total of 15,128 patients from 106 centers were recorded in the Global COVID-19 Stroke Registry, 853 (5.6%) of whom were COVID-positive. Overall, COVID-positive individuals were treated significantly slower according to every acute stroke metric compared to COVID-negative patients. We were able to show that key quality indicators in acute stroke treatment were unfavorable for COVID-negative women compared to men (last-seen-well-to-door time + 11 min in women). Furthermore, COVID-negative women had worse 3-month outcomes (3-month modified Rankin Scale score [interquartile range] 3.0 [4.0] vs. 2.0 [3.0]; p < 0.01), even after adjusting for confounders. In COVID-positive individuals no such difference between the sexes, either in acute management metrics or in 3-month outcome, was seen. CONCLUSION: Known sex-related differences in acute stroke management exist and extend to times of crisis. Nevertheless, if patients were COVID-19-positive at stroke onset, women and men were treated the same, which could be attributed to structured treatment pathways.

Longitudinal Lipidomic Signature of Coronary Heart Disease in American Indian People.

BACKGROUND: Dyslipidemia is an independent risk factor for coronary heart disease (CHD). Standard lipid panel cannot capture the complexity of the blood lipidome (ie, all molecular lipids in the blood). To date, very few large-scale epidemiological studies have assessed the full spectrum of the blood lipidome on risk of CHD, especially in a longitudinal setting. METHODS AND RESULTS: Using an untargeted liquid chromatography-mass spectrometry, we repeatedly measured 1542 lipid species from 1835 unique American Indian participants who attended 2 clinical visits (≈5.5 years apart) and followed up to 17.8 years in the Strong Heart Family Study (SHFS). We first identified baseline lipid species associated with risk of CHD, followed by replication in a European population. The model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, low-density lipoprotein cholesterol, estimated glomerular filtration rate, education, and physical activity at baseline. We then examined the longitudinal association between changes in lipid species and changes in cardiovascular risk factors during follow-up. Multiple testing was controlled by the false discovery rate. We found that baseline levels of multiple lipid species (eg, phosphatidylcholines, phosphatidylethanolamines, and ceramides) were associated with the risk of CHD and improved the prediction accuracy over conventional risk factors in American Indian people. Some identified lipids in American Indian people were replicated in European people. Longitudinal changes in multiple lipid species (eg, acylcarnitines, phosphatidylcholines, and triacylglycerols) were associated with changes in cardiovascular risk factors. CONCLUSIONS: Baseline plasma lipids and their longitudinal changes over time are associated with risk of CHD. These findings provide novel insights into the role of dyslipidemia in CHD.

No association between SARS-CoV-2 vaccination and ischaemic stroke or high-risk transient ischaemic attack.

BACKGROUND: Initiation of SARS-CoV-2 (Severe acute respiratory syndrome coronavirus type 2) vaccinations aroused scepticism within the general-public about risks including stroke. Our aim was to explore temporal associations between vaccination and cerebrovascular events through an analysis of a prospective large-scale cohort of consecutive stroke and high-risk TIA (transitory ischaemic attack) patients. METHODS: We prospectively recruited a cohort of consecutive ischaemic stroke and high-risk TIA (ABCD2-Score ≥ 4) patients treated at the Innsbruck University Hospital (STROKE-CARD Registry Study, NCT04582825) from December 2020 until February 2022. SARS-CoV-2 vaccination status and the time of administration was ascertained by electronic health-data. A Cox model with vaccination status as time-dependent co-variable was employed to examine its association with ischaemic events. RESULTS: Data on 572 participants were available with 355 (62.1%) vaccinated against SARS-CoV-2 before suffering cerebral ischaemia. In our cohort, no temporal association between vaccination and cerebrovascular event was detected (HR 1.06 [0.85-1.34; p = 0.60]) and this also applies to TIA (HR [0.82 0.37-1.85; p = 0.64]) or minor stroke (HR 1.18 [0.89-1.56; p = 0.26]) and subgroups defined by sex and age. Neither vector-based (HR 1.11 [0.79-1.56; p = 0.55]) nor mRNA-based (HR 1.06 [0.84-1.34; p = 0.61]) vaccinations were associated with the occurrence of cerebral ischaemia. CONCLUSION: Among patients with stroke or high-risk TIA, SARS-CoV-2 vaccination was not associated with cerebral ischaemia.

Determinants of Diet Quality in Adolescents: Results from the Prospective Population-Based EVA-Tyrol and EVA4YOU Cohorts.

(1) Background: Unhealthy dietary behaviors are estimated to be one of the leading causes of death globally and are often shaped at a young age. Here, we investigated adolescent diet quality and its predictors, including nutrition knowledge, in two large Central European cohorts. (2) Methods: In 3056 participants of the EVA-Tyrol and EVA4YOU prospective population-based cohort studies aged 14 to 19 years, diet quality was assessed using the AHEI-2010 and DASH scores, and nutrition knowledge was assessed using the questionnaire from Turconi et al. Associations were examined utilizing multivariable linear regression. (3) Results: The mean overall AHEI-2010 score was 42%, and the DASH score was 45%. Female participants (60.6%) had a significantly higher diet quality according to the AHEI-2010 and DASH score. AHEI-2010 and DASH scores were significantly associated (p < 0.001) with sex, school type, smoking, and total daily energy intake. The DASH score was additionally significantly associated (p < 0.001) with age, socioeconomic status, and physical activity. Participants with better nutrition knowledge were more likely to be older, to attend a general high school, to live in a high-income household, to be non-smokers, and to have a higher diet quality according to the AHEI-2010 and DASH score. (4) Conclusions: Predictors of better diet quality included female sex, physical activity, educational level, and nutrition knowledge. These results may aid focused interventions to improve diet quality in adolescents.

Early Vascular Ageing in adolescents with migraine with aura: a community-based study.

BACKGROUND: Migraine with aura is associated with an increased risk of cardiovascular disease, yet the pathophysiology is unknown. Suggested underlying mechanisms of aura formation point into the direction of an abnormal vasoreactivity that also extends to the extracranial vasculature. METHODS: In the Early Vascular Ageing Tyrol study, a community-based non-randomized controlled trial conducted in 45 schools and companies in Tyrol (Austria) and South-Tyrol (Italy) between May 2015 and September 2018 aiming to increase cardiovascular health in adolescents, headache syndromes were classified according to the International Classification of Headache Disorders in a face-to-face interview. Carotid-femoral pulse-wave-velocity was measured by applanation tonometry and carotid intima-media-thickness by high-resolution ultrasound of the distal common carotid arteries. Differences in pulse-wave-velocity and carotid intima-media-thickness in youngsters with migraine with aura were compared respectively to those without headache and with other headaches by multivariable linear regression analysis. RESULTS: Of the 2102 study participants 1589 were aged 14 to 19 (mean 16.8) years and had complete data. 43 (2.7%) reported migraine with aura and 737 (46.4%) other headaches. Mean pulse-wave-velocity was 6.17 m/s (± 0.85) for migraine with aura, 6.06 m/s (± 0.82) for all other headaches and 6.15 (0.95) m/s for participants without headaches. Carotid intima-media-thickness was 411.3 µm (± 43.5) for migraine with aura, 410.9 µm (± 46.0) for all other headaches and 421.6 µm (± 48.4) for participants without headaches. In multivariable linear regression analysis, we found no differences in carotid-femoral pulse-wave-velocity or carotid intima-media-thickness in young subjects with migraine with aura, all other headaches, or no headaches. CONCLUSIONS: In line with previous large-scale studies in adults, we could not demonstrate relevant associations of migraine with aura with markers of arterial stiffness or subclinical atherosclerosis making early vascular ageing an unlikely pathophysiological link between migraine with aura and cardiovascular diseases. TRIAL REGISTRATION: First registered on ClinicalTrials.gov 29/04/2019 (NCT03929692).

Plasma homocysteine levels and associated factors in community-dwelling adolescents: the EVA-TYROL study.

Background: Homocysteine (Hcy) has been associated with an adverse cardiovascular risk profile in adolescents. Assessment of the association between plasma Hcy levels and clinical/laboratory factors might improve our understanding of the pathogenesis of cardiovascular disease. Methods: Hcy was measured in 1,900 14- to 19-year-old participants of prospective population-based EVA-TYROL Study (44.3% males, mean age 16.4 years) between 2015 and 2018. Factors associated with Hcy were assessed by physical examination, standardized interviews, and fasting blood analysis. Results: Mean plasma Hcy was 11.3 ± 4.5 µmol/L. Distribution of Hcy was characterized by extreme right skew. Males exhibited higher Hcy and sex differences increased with increasing age. Univariate associations with Hcy emerged for age, sex, body mass index, high-density lipoprotein cholesterol, and for factors pertaining to blood pressure, glucose metabolism, renal function, and diet quality, whereas the most important multivariate predictors of Hcy were sex and creatinine. Discussion: Clinical and laboratory factors associated with Hcy in adolescents were manifold, with sex and high creatinine identified as strongest independent determinants. These results may aid when interpreting future studies investigating the vascular risk of homocysteine.

Global distributions of age- and sex-related arterial stiffness: systematic review and meta-analysis of 167 studies with 509,743 participants.

BACKGROUND: Arterial stiffening is central to the vascular ageing process and a powerful predictor and cause of diverse vascular pathologies and mortality. We investigated age and sex trajectories, regional differences, and global reference values of arterial stiffness as assessed by pulse wave velocity (PWV). METHODS: Measurements of brachial-ankle or carotid-femoral PWV (baPWV or cfPWV) in generally healthy participants published in three electronic databases between database inception and August 24th, 2020 were included, either as individual participant-level or summary data received from collaborators (n = 248,196) or by extraction from published reports (n = 274,629). Quality was appraised using the Joanna Briggs Instrument. Variation in PWV was estimated using mixed-effects meta-regression and Generalized Additive Models for Location, Scale, and Shape. FINDINGS: The search yielded 8920 studies, and 167 studies with 509,743 participants from 34 countries were included. PWV depended on age, sex, and country. Global age-standardised means were 12.5 m/s (95% confidence interval: 12.1-12.8 m/s) for baPWV and 7.45 m/s (95% CI: 7.11-7.79 m/s) for cfPWV. Males had higher global levels than females of 0.77 m/s for baPWV (95% CI: 0.75-0.78 m/s) and 0.35 m/s for cfPWV (95% CI: 0.33-0.37 m/s), but sex differences in baPWV diminished with advancing age. Compared to Europe, baPWV was substantially higher in the Asian region (+1.83 m/s, P = 0.0014), whereas cfPWV was higher in the African region (+0.41 m/s, P < 0.0001) and differed more by country (highest in Poland, Russia, Iceland, France, and China; lowest in Spain, Belgium, Canada, Finland, and Argentina). High vs. other country income was associated with lower baPWV (-0.55 m/s, P = 0.048) and cfPWV (-0.41 m/s, P < 0.0001). INTERPRETATION: China and other Asian countries featured high PWV, which by known associations with central blood pressure and pulse pressure may partly explain higher Asian risk for intracerebral haemorrhage and small vessel stroke. Reference values provided may facilitate use of PWV as a marker of vascular ageing, for prediction of vascular risk and death, and for designing future therapeutic interventions. FUNDING: This study was supported by the excellence initiative VASCage funded by the Austrian Research Promotion Agency, by the National Science Foundation of China, and the Science and Technology Planning Project of Hunan Province. Detailed funding information is provided as part of the Acknowledgments after the main text.

Apolipoprotein Proteomics for Residual Lipid-Related Risk in Coronary Heart Disease.

BACKGROUND: Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid panels to guide use of emerging treatments for the prevention of coronary heart disease (CHD). This report assessed the relevance of 13 apolipoproteins measured using a single mass-spectrometry assay for risk of CHD in the PROCARDIS case-control study of CHD (941 cases/975 controls). METHODS: The associations of apolipoproteins with CHD were assessed after adjustment for established risk factors and correction for statin use. Apolipoproteins were grouped into 4 lipid-related classes [lipoprotein(a), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides] and their associations with CHD were adjusted for established CHD risk factors and conventional lipids. Analyses of these apolipoproteins in a subset of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) were used to assess their within-person variability and to estimate a correction for statin use. The findings in the PROCARDIS study were compared with those for incident cardiovascular disease in the Bruneck prospective study (n=688), including new measurements of Apo(a). RESULTS: Triglyceride-carrying apolipoproteins (ApoC1, ApoC3, and ApoE) were most strongly associated with the risk of CHD (2- to 3-fold higher odds ratios for top versus bottom quintile) independent of conventional lipid measures. Likewise, ApoB was independently associated with a 2-fold higher odds ratios of CHD. Lipoprotein(a) was measured using peptides from the Apo(a)-kringle repeat and Apo(a)-constant regions, but neither of these associations differed from the association with conventionally measured lipoprotein(a). Among HDL-related apolipoproteins, ApoA4 and ApoM were inversely related to CHD, independent of conventional lipid measures. The disease associations with all apolipoproteins were directionally consistent in the PROCARDIS and Bruneck studies, with the exception of ApoM. CONCLUSIONS: Apolipoproteins were associated with CHD independent of conventional risk factors and lipids, suggesting apolipoproteins could help to identify patients with residual lipid-related risk and guide personalized approaches to CHD risk reduction.

Long-term outcome of a pragmatic trial of multifaceted intervention (STROKE-CARD care) to reduce cardiovascular risk and improve quality-of-life after ischaemic stroke and transient ischaemic attack: study protocol.

BACKGROUND: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of incident cardiovascular events and recurrent stroke. Despite compelling evidence about the efficacy of secondary prevention, a substantial gap exists between risk factor management in real life and that recommended by international guidelines. We conducted the STROKE-CARD trial (NCT02156778), a multifaceted pragmatic disease management program between 2014 and 2018 with follow-up until 2019. This program successfully reduced cardiovascular risk and improved health-related quality of life and functional outcome in patients with acute ischaemic stroke or TIA within 12 months after the index event. To investigate potential long-term effects of STROKE-CARD care compared to standard care, an extension of follow-up is warranted. METHODS: We aim to include all patients from the STROKE-CARD trial (n = 2149) for long-term follow-up between 2019 and 2021 with the study visit scheduled 3-6 years after the stroke/TIA event. The co-primary endpoint is the composite of major recurrent cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) from hospital discharge until the long-term follow-up visit and health-related quality of life measured with the European Quality of Life-5 Dimensions (EQ-5D-3L) at the final visit. Secondary endpoints include overall mortality, long-term functional outcome, and target-level achievement in risk factor management. DISCUSSION: This long-term follow-up will provide evidence on whether the pragmatic post-stroke/TIA intervention program STROKE-CARD is capable of preventing recurrent cardiovascular events and improving quality-of-life in the long run. Trial registration clinicaltrials.gov: NCT04205006 on 19 December 2019.

Mortality of Hemato-Oncologic Patients Admitted to a Pediatric Intensive Care Unit: A Single-Center Experience.

Introduction: Mortality in children with hemato-oncologic disease admitted to a pediatric intensive care unit (PICU) is higher compared to the general population. The reasons for this fact remain unexplored. The aim of this study was to assess outcomes and trends in hemato-oncologic patients admitted to a PICU, with analytical emphasis on emergency admissions. Methods: Patients with a hemato-oncologic diagnosis admitted to a tertiary care university hospital PICU between 1 January 2009 and 31 December 2019 were retrospectively analyzed. Additionally, patient mortality 6 months after PICU admission and follow-up mortality until 31 December 2020 were recorded. Measurements and Main Results: We reviewed a total of 701 PICU admissions of 338 children with hemato-oncologic disease, of which 28.5% were emergency admissions with 200 admissions of 122 patients. Of these, 22 patients died, representing a patient mortality of 18.0% and an admission mortality of 11.0% in this group. Follow-up patient mortality was 25.4% in emergency-admitted children. Multivariable analysis revealed severe neutropenia at admission and invasive mechanical ventilation (IMV) as independent risk factors for PICU death (p = 0.029 and p = 0.002). The total number of PICU admissions of hemato-oncologic patients rose notably over time, from 44 in 2009 to 125 in 2019. Conclusion: Although a high proportion of emergency PICU admissions of hemato-oncologic patients required intensive organ support, mortality seemed to be lower than previously reported. Moreover, in this study, total PICU admissions of the respective children rose notably over time.

Association of desphospho-uncarboxylated matrix gla protein with incident cardiovascular disease and all-cause mortality: Results from the prospective Bruneck Study.

BACKGROUND AND AIMS: Matrix Gla protein (MGP), a vitamin K-dependent protein, is a potent inhibitor of vascular calcification. Desphospho-uncarboxylated MGP (dp-ucMGP), a marker of vitamin K insufficiency, has been shown to predict cardiovascular disease (CVD) and all-cause mortality in high-risk populations. Whether the increased risk associated with dp-ucMGP also applies to the general, and especially, the elderly population has not yet been fully elucidated. METHODS AND RESULTS: Plasma dp-ucMGP was measured in 684 individuals aged 50-89 years of the prospective population-based Bruneck Study (baseline evaluation in 2000). Baseline median dp-ucMGP was 478.4 (IQR 335.0-635.2) pmol/L. Over a median follow-up of 15.5 years, 163 CVD events occurred and 235 participants died. Age-/sex-adjusted hazard ratios (HRs) per 1-SD higher level of loge transformed dp-ucMGP were 1.30 (95%CI: 1.09-1.55; p=0.004) for incident CVD and 1.36 (95%CI: 1.17-1.57; p<0.001) for all-cause mortality. After multivariable adjustment, the associations remained significant with HRs of 1.23 (95%CI: 1.02-1.47, p=0.029) for CVD and 1.40 (95%CI: 1.20-1.64; p<0.001) for all-cause mortality. The associations remained virtually unchanged after additional adjustment for dietary quality as measured with the Alternative Healthy Eating Index. We found no association of dp-ucMGP with myocardial infarction and sudden cardiac deaths, but a strong association with other vascular deaths and non-vascular/non-cancer deaths. CONCLUSIONS: This study shows a significant association of plasma dp-ucMGP with incident CVD and a significant and even stronger association with all-cause mortality. Clinical trials are needed to investigate whether vitamin K substitution results in improved health outcomes.

Association of adolescent lipoprotein subclass profile with carotid intima-media thickness and comparison to adults: Prospective population-based cohort studies.

BACKGROUND AND AIMS: Assessment of comprehensive lipoprotein subclass profiles in adolescents and their relation to vascular disease may enhance our understanding of the development of dyslipidemia in early life and inform early vascular prevention. METHODS: Nuclear magnetic resonance was used to measure lipoprotein profiles, including lipids (cholesterol, free cholesterol, triglycerides, phospholipids) and apolipoproteins (apoB-100, apoA1, apoA2) of 17 lipoprotein subclasses (from least dense to densest: VLDL-1 to -6, IDL, LDL-1 to -6, HDL-1 to -4) in n = 1776 14- to 19-year olds (56.6% female) and n = 3027 25- to 85-year olds (51.5% female), all community-dwelling. Lipoprotein profiles were related to carotid intima-media thickness (cIMT) as ascertained by sonography. RESULTS: Adolescents compared to adults had lower triglycerides, total, LDL, and non-HDL cholesterol, and apoB, and higher HDL cholesterol. They showed 26.6-59.8% lower triglyceride content of all lipoprotein subclasses and 21.9-51.4% lower VLDL lipid content. Concentrations of dense LDL-4 to LDL-6 were 36.7-40.2% lower, with also markedly lower levels of LDL-1 to LDL-3, but 24.2% higher HDL-1 ApoA1. In adolescents, only LDL-3 to LDL-5 subclasses were associated with cIMT (range of differences in cIMT for a 1-SD higher concentration, 4.8-5.9 µm). The same associations emerged in adults, with on average 97 ± 42% (mean ± SD) larger effect sizes, in addition to LDL-1 and LDL-6 (range, 6.9-11.3 µm) and HDL-2 to HDL-4, ApoA1, and ApoA2 (range, -7.0 to -17.7 µm). CONCLUSIONS: Adolescents showed a markedly different and more favorable lipoprotein profile compared to adults. Dense LDL subclasses were the only subclasses associated with cIMT in adolescents, implicating them as the potential preferred therapeutic target for primary prevention of cardiovascular disease at this age. In adults, associations with cIMT were approximately twice as large as in adolescents, and HDL-related measures were additionally associated with cIMT.

Long-term life history predicts current gut microbiome in a population-based cohort study.

Extensive scientific and clinical microbiome studies have explored contemporary variation and dynamics of the gut microbiome in human health and disease1-3, yet the role of long-term life history effects has been underinvestigated. Here, we analyzed the current, quantitative microbiome composition in the older adult Bruneck Study cohort (Italians, Bruneck, n = 304 (male, 154; female, 150); age 65-98 years) with extensive clinical, demographic, lifestyle and nutritional data collected over the past 26 years4. Multivariate analysis of historical variables indicated that medication history, historical physical activity, past dietary habits and specific past laboratory blood parameters explain a significant fraction of current quantitative microbiome variation in older adults, enlarging the explanatory power of contemporary covariates by 33.4%. Prediction of current enterotype by a combination of past and contemporary host variables revealed good levels of predictability (area under the curve (AUC), 0.78-0.83), with Prevotella and dysbiotic Bacteroides 2 being the best predicted enterotypes. These findings demonstrate long-term life history effects on the microbiota and provide insights into lifestyle variables and their role in maintaining a healthy gut microbiota in later life.

Diagnostic Yield of a Systematic Vascular Health Screening Approach in Adolescents at Schools.

PURPOSE: A significant proportion of noncommunicable diseases in adults has its roots in adolescence, and this is particularly true for cardiovascular disease and stroke. Detection of vascular and metabolic risk factors at young ages may aid disease prevention. METHODS: In 2,088 adolescents sampled from the general population of Tyrol, Austria, and South Tyrol, Italy, we systematically assessed the frequency of yet unknown vascular and metabolic risk conditions that require further diagnostic workup or intervention (lifestyle counselling or pharmacotherapy). The health screening included medical history taking, fasting blood analysis, and blood pressure and body measurements and was performed at schools. To recruit a representative sample of adolescents, equal proportions (about 67%) of schools were invited per school type and region. RESULTS: Adolescents were on average 16.4 (standard deviation 1.1) years old, and 56.4% were female. A proportion of 22.8% (95% confidence interval [CI], 19.6-26.3) had previous or current physician-confirmed diseases. The health screening newly detected relevant medical conditions in 45.4% [95% CI, 41.5-49.4] (55.8% [95% CI, 52.7-58.7] in boys and 37.4% [95% CI, 35.0-39.8] in girls, p < .001). The most prevalent were elevated blood pressure and hypertension, metabolic syndrome, hypercholesterolemia, hypertriglyceridemia, hyperuricemia, and subclinical hypothyroidism. Detection of risk conditions did not depend on socioeconomic status but increased with age and body mass index. CONCLUSIONS: Vascular health screening in adolescents at schools has a high diagnostic yield and may aid guideline-recommended prevention in the youth. Implementation should carefully consider national differences in healthcare systems, resources, and existing programs.

PCSK9 Activity Is Potentiated Through HDL Binding.

Rationale: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.

Predictors of Carotid Intima-Media Thickness Progression in Adolescents-The EVA-Tyrol Study.

Background Cardiovascular disease depends on the duration and time course of risk factor exposure. Previous reports on risk factors of progression of carotid intima-media thickness (cIMT) in the young were mostly restricted to high-risk populations or susceptible to certain types of bias. We aimed to unravel a risk factor signature for early vessel pathology based on repeated ultrasound assessments of the carotid arteries in the general population. Methods and Results Risk factors were assessed in 956 adolescents sampled from the general population with a mean age of 15.8±0.9 years, 56.2% of whom were female. cIMT was measured at baseline and on average 22.5±3.4 months later by high-resolution ultrasound. Effects of baseline risk factors on cIMT progression were investigated using linear mixed models with multivariable adjustment for potential confounders, which yielded significant associations (given as increase in cIMT for a 1-SD higher baseline level) for alanine transaminase (5.5 µm; 95% CI: 1.5-9.5), systolic blood pressure (4.7 µm; 0.3-9.2), arterial hypertension (9.5 µm, 0.2-18.7), and non-high-density (4.5 µm; 0.7-8.4) and low-density lipoprotein cholesterol (4.3 µm; 0.5-8.1). Conclusions Systolic blood pressure, arterial hypertension, low-density and non-high-density lipoprotein cholesterol, and alanine transaminase predicted cIMT progression in adolescents, even though risk factor levels were predominantly within established reference ranges. These findings reemphasize the necessity to initiate prevention early in life and challenge the current focus of guideline recommendations on high-risk youngsters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03929692.

Dietary spermidine improves cognitive function.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.