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Abstract Neuroglia critically shape the brain´s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of the cellular composition of the early ischemic lesion. Here we present a single cell resolution transcriptomics dataset of the brain´s acute response to infarction. Oligodendrocyte lineage cells and astrocytes range among the most transcriptionally perturbed populations and exhibit infarction- and subtype-specific molecular signatures. Specifically, we find infarction restricted proliferating oligodendrocyte precursor cells (OPCs), mature oligodendrocytes and reactive astrocytes, exhibiting transcriptional commonalities in response to ischemic injury. OPCs and reactive astrocytes are involved in a shared immuno-glial cross talk with stroke-specific myeloid cells. Within the perilesional zone, osteopontin positive myeloid cells accumulate in close proximity to CD44+ proliferating OPCs and reactive astrocytes. In vitro, osteopontin increases the migratory capacity of OPCs. Collectively, our study highlights molecular cross talk events which might govern the cellular composition of acutely infarcted brain tissue.

Abstract The systemic inflammatory response following acute ischaemic stroke remains incompletely understood. We characterised the circulating inflammatory profile in 173 acute ischaemic stroke patients by measuring 65 cytokines and chemokines in plasma. Participants were grouped based on their inflammatory response, determined by high-sensitivity C-reactive protein levels in the acute phase. We compared stroke patients’ profiles with 42 people experiencing spontaneous cervical artery dissection without stroke. Furthermore, variations in cytokine levels among stroke aetiologies were analysed. Follow-up samples were collected in a subgroup of ischaemic stroke patients at three and twelve months. Ischaemic stroke patients had elevated plasma levels of HGF and SDF-1α, and lower IL-4 levels, compared to spontaneous cervical artery dissection patients without stroke. Aetiology-subgroup analysis revealed reduced levels of nine cytokines/chemokines (HGF, SDF-1α, IL-2R, CD30, TNF-RII, IL-16, MIF, APRIL, SCF), and elevated levels of IL-4 and MIP-1β, in spontaneous cervical artery dissection (with or without ischaemic stroke as levels were comparable between both groups) compared to other aetiologies. The majority of cytokine/chemokine levels remained stable across the study period. Our research indicates that stroke due to large artery atherosclerosis, cardioembolism, and small vessel occlusion triggers a stronger inflammatory response than spontaneous cervical artery dissection.

IntroductionPosterior circulation stroke can lead to ataxia, manifesting in a loss of coordination and balance. Patients experience difficulty in activities of daily living and an increased risk of falling, both profoundly affecting quality of life. In individuals with neurodegenerative diseases, coordination exercises have been shown to lead to a reduction in ataxic symptoms. There is, however, limited evidence on the effect of physical therapy, specifically coordination exercises in patients with stroke-related ataxia. We therefore present a study protocol for a prospective trial.MethodsThe purpose of this trial is to investigate the effects of coordination exercises compared to standard physiotherapy on balance and walking in ataxic stroke patients. Therefore, a prospective, single-blinded randomized controlled trial is currently ongoing at the Clinical Department of Neurology, Medical University of Innsbruck, Austria, in collaboration with two local rehabilitation facilities in Austria, Hochzirl Hospital and the Clinic for Rehabilitation Münster. Balance is the primary outcome of the study as assessed using the Berg Balance Scale. Secondary outcomes are concerned with walking, risk and number of falls, independence in daily life, and quality of life, rated using appropriate scales and scores. Patients are allocated applying a 1:1 ratio and a stratified block randomization. In both groups recruited individuals undergo five 45-min treatment sessions per week, totaling 20 sessions of coordination exercises (IG) or standard physiotherapy (CG) over the course of 4 weeks. Data is collected at the baseline (T0), after the 4-week supervised practice (T1), and after another 8 weeks of independent home-based training (T2).DiscussionThis is the first randomized controlled trial investigating the effects of coordination exercises on balance and walking in people with stroke-related ataxia. As stroke guidelines emphasize the limited evidence of treatment for ataxic symptoms, this study aims to contribute further knowledge regarding tailored interventions for these patients.Clinical Trial RegistrationGerman Clinical Trials Registry (drks.de). Identifier: DRKS00020825.

IntroductionThis study aimed to emphasize the importance of cranial nerve (CN) palsies in spontaneous cervical artery dissection (sCeAD).MethodsA search term-based literature review was conducted on “cervical artery dissection” and “cranial nerve palsy.” English and German articles published until October 2023 were considered.ResultsCranial nerve (CN) palsy in sCeAD is evident in approximately 10% of cases. In the literature, isolated palsies of CN II, III, VII, IX, X, and XII have been reported, while CN XI palsy only occurs in combination with other lower cranial nerve palsies. Dissection type and mural hematoma localization are specific to affected CN as CN palsies of II or III are solely evident in those with steno-occlusive vessel pathologies located at more proximal segments of ICA, while those with CN palsies of IX, X, XI, and XII occur in expansive sCeAD at more distal segments. This dichotomization emphasizes the hypothesis of a different pathomechanism in CN palsy associated with sCeAD, one being hypoperfusion or microembolism (CN II, III, and VII) and the other being a local mass effect on surrounding tissue (CN IX, X, XI, and XII). Clinically, the distinction between peripheral palsies and those caused by brainstem infarction is difficult. This differentiation is key, as, according to the reviewed cases, peripheral cranial nerve palsies in sCeAD patients mostly resolve completely over time, while those due to brainstem stroke do not, making cerebrovascular imaging appraisal essential.DiscussionIt is important to consider dissections as a potential cause of peripheral CN palsies and to be aware of the appropriate diagnostic pathways. This awareness can help clinicians make an early diagnosis, offering the opportunity for primary stroke prevention.

We present a case with prolonged Lorlatinib-related dyslipidemia causing internal carotid artery stenosis, putting the patient at risk of cerebrovascular events. Through intensified lipid-lowering treatment and dose reduction of Lorlatinib, LDL-C levels decreased markedly. Surprisingly, the left sided internal carotid artery stenosis dissolved accordingly. Due to the high efficacy of the new selective tyrosine kinase inhibitors and resulting long-term treatment, it is essential to carefully follow-up and include drug specific side effect monitoring. This case emphasizes that Loraltinib-related dyslipidemia has to be taken seriously and treatment should be initiated as promptly as possible. We conclude that in cases were lipid dysregulation remains and Lorlatinib treatment has to be continued, cerebrovascular appraisal through ultrasound should be considered and, if stenosis is evident, intensified treatment regimen of dyslipidemia or dose reduction of Lorlatinib should be discussed in an interdisciplinary setting.

Ehlers-Danlos syndrome (EDS) belongs to a spectrum of rare heritable connective tissue disorders and is characterised by hyperextensibility, joint hypermobility and tissue fragility. Peripheral blood mononuclear cells (PBMCs) from a vascular EDS (vEDS) patient, known as the rarest EDS subtype, carrying a heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene, which is essential for type III collagen synthesis, were reprogrammed into induced pluripotent stem cells (iPSCs). The generated iPSCs exhibit high expression of pluripotency-associated markers, possess trilineage differentiation capacity and reveal a normal karyotype. This novel patient-specific cell line enables in-depth pathophysiological studies of vEDS.

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.

Abstract 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).

Abstract The aim of our study was to assess whether a well-established federal state-wide Stroke Care Pathway delivering high quality stroke care can cope with the COVID-19 pandemic and associated measures to contain the virus spread. The retrospective analysis is based on a prospective, quality-controlled, population-based registry of all stroke patients in the Tyrol, a federal state of Austria and one of the early hot-spots of COVID-19 in Europe. Patient characteristics, pre-hospital management, intra-hospital management and post-hospital were analysed. All residents of the Tyrol suffering ischemic stroke in 2020 (n = 1160) and four pre-COVID-19 years (n = 4321) were evaluated. In 2020, the annual number of stroke patients was the highest in this population-based registry. When local hospitals were overwhelmed with SARS-CoV-2-patients, stroke subjects were temporarily allocated to the comprehensive stroke centre. Stroke severity, quality metrics of stroke management, serious complications, and post-stroke mortality did not differ between 2020 and the four comparator years. Notably, iv. thrombolysis-rate was similar (19.9% versus 17.4%, P = 0.25) and endovascular stroke treatment even better (5.9% versus 3.9%, P = 0.003) but resources for in-patient rehabilitation were limited (25.8% versus 29.8%, P = 0.009). Concluding, a well-established Stroke Care Pathway was able to maintain high-quality acute stroke care even when challenged by a global pandemic.

Abstract Increasing evidence suggests persistent cognitive dysfunction after COVID‐19. In this cross‐sectional study, frontal lobe function was assessed 12 months after the acute phase of the disease, using tailored eye tracking assessments. Individuals who recovered from COVID‐19 made significantly more errors in all eye tracking tasks compared to age/sex‐matched healthy controls. Furthermore, patients who were treated as inpatients performed worse compared to outpatients and controls. Our results show impaired inhibitory cortical control in individuals who recovered from COVID‐19. The association between disease severity and its sequelae may contribute to a better understanding of post‐COVID‐19 cognitive function.

Abstract 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.

Abstract Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper‐transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single‐nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10−6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10−5; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.

Summary: 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

Abstract Short- to mid-term functional outcome in spontaneous cervical artery dissection is favorable, but the concomitant psychosocial impact is underreported. We aimed to determine these possible sequelae, with a special focus on sex differences, in our cohort of spontaneous cervical artery dissection subjects. During a standardized prospective in-house follow-up visit we, among other values, evaluated functional outcome (modified Rankin Scale [mRS]), psychosocial measures (return to work-, divorce rate) and health-related quality of life (WHO-QoL-BREF and SF-36-questionnaires). 145 patients participated in the long-term prospective follow-up. Median follow-up time was 6.5 years and excellent functional outcome (mRS ≤ 1) was achieved in 89.0% subjects. 87.6% returned to work and 17.6% married patients had a divorce during follow-up. Even though relevant baseline-/discharge characteristics and functional outcome did not differ between the sexes, women were less likely to return to work compared to men (79.7% vs. 93.8%; P = 0.010) and divorce rate was considerably higher in women (30.2% vs. 9.2%; P = 0.022). Health related quality of life did not differ significantly between the sexes, but women consistently reported lower values. Even though functional outcome is beneficial in most patients, measures to prevent poor psychosocial outcome should be considered in the long-term care of patients with spontaneous cervical artery dissection, especially women.

Abstract Background In recent years, there has been increasing evidence that asthma is associated with atherosclerosis and cardiovascular disease. However, data in children and adolescents are scarce and conflicting. We aimed to assess the impact of asthma with and without an allergic component on the carotid intima-media thickness in a large pediatric population. Methods The community-based early vascular ageing-Tyrol cohort study was performed between May 2015 and July 2018 in North, East (Austria) and South Tyrol (Italy) and recruited youngster aged 14 years and above. Medical examinations included anthropometric measurements, fasting blood analysis, measurement of the carotid intima-media thickness by high-resolution ultrasound, and a physician guided interview. Results The mean age of the 1506 participants was 17.8 years (standard deviation 0.90). 851 (56.5%) participants were female. 22 subjects had a physician diagnosis of non-allergic asthma, 268 had inhalative allergies confirmed by a positive radio-allergo-sorbent-test and/or prick test, and 58 had allergic asthma. Compared to healthy controls, participants with non-allergic asthma (411.7 vs. 411.7 µm; p = 0.932) or inhalative allergy (420.0 vs. 411.7 µm; p = 0.118) did not have significantly higher carotid intima-media thickness (cIMT). However, participants with allergic asthma had significantly higher cIMT (430.8 vs. 411.7; p = 0.004) compared to those without and this association remained significant after multivariable adjustment for established cardiovascular risk factors. Conclusion Allergic asthma in the youth is associated with an increased carotid intima-media thickness. Physicians should therefore be aware of allergic asthma as a potential cardiovascular risk factor in children and adolescents. Trial Registration Number The EVA-Tyrol Study has been retrospectively registered at clinicaltrials.gov under NCT03929692 since April 29, 2019.

Purpose: The aim of this article is to examine the extent of structural and inflammatory lesions by ultrasound in elderly subjects with hand osteoarthritis (HOA) fulfilling the ACR classification criteria (Group A), in subjects with painless enlarged finger joints (Group B), and in individuals without clinical abnormalities at hands (Group C). Methods: This study was nested within the population-based, prospective Bruneck study; 293 subjects of ⩾65 years of age were assessed. Clinical and ultrasound assessment was conducted at wrists and finger joints. Gray scale synovitis (GSS), Power Doppler (PD), osteophytes, and erosions were scored semiquantitatively (0–3). The Short Form Score for the Assessment and Quantification of Chronic Rheumatic Affections of the Hands (SF-SACRAH), the Health Assessment Questionnaire (HAQ), and the Functional Index for Hand Osteoarthritis (FIHOA) were retrieved. Results: Most subjects had ⩾1 ultrasound abnormality, of which osteophytes were the most prevalent finding in all groups (Group A: 100%, Group B: 99.4%, and Group C: 93.9%). GSS and PD-signals were more common in Group A than in Group B (94% versus 67% and 33% versus 13%, respectively). In Group C, GSS was observed in 39.4% of subjects. In subjects with HOA, the SF-SACRAH correlated with osteophyte scores (corr coeff = 0.48), and the FIHOA correlated with the osteophyte (corr coeff = 0.42) and PD scores (corr coeff = 0.33). Conclusion: GSS and PD were more frequent in patients with symptomatic HOA than in cases with painless bony enlargements and subjects without clinical joint abnormalities. Functional restriction in HOA is associated with structural and inflammatory ultrasound changes.

BackgroundCoronavirus Disease-19 (COVID-19) convalescents are at risk of developing a de novo mental health disorder or worsening of a pre-existing one. COVID-19 outpatients have been less well characterized than their hospitalized counterparts. The objectives of our study were to identify indicators for poor mental health following COVID-19 outpatient management and to identify high-risk individuals.MethodsWe conducted a binational online survey study with adult non-hospitalized COVID-19 convalescents (Austria/AT: n = 1,157, Italy/IT: n = 893). Primary endpoints were positive screening for depression and anxiety (Patient Health Questionnaire; PHQ-4) and self-perceived overall mental health (OMH) and quality of life (QoL) rated with 4 point Likert scales. Psychosocial stress was surveyed with a modified PHQ stress module. Associations of the mental health and QoL with socio-demographic, COVID-19 course, and recovery variables were assessed by multi-parameter Random Forest and Poisson modeling. Mental health risk subsets were defined by self-organizing maps (SOMs) and hierarchical clustering algorithms. The survey analyses are publicly available (https://im2-ibk.shinyapps.io/mental_health_dashboard/).ResultsDepression and/or anxiety before infection was reported by 4.6% (IT)/6% (AT) of participants. At a median of 79 days (AT)/96 days (IT) post-COVID-19 onset, 12.4% (AT)/19.3% (IT) of subjects were screened positive for anxiety and 17.3% (AT)/23.2% (IT) for depression. Over one-fifth of the respondents rated their OMH (AT: 21.8%, IT: 24.1%) or QoL (AT: 20.3%, IT: 25.9%) as fair or poor. Psychosocial stress, physical performance loss, high numbers of acute and sub-acute COVID-19 complaints, and the presence of acute and sub-acute neurocognitive symptoms (impaired concentration, confusion, and forgetfulness) were the strongest correlates of deteriorating mental health and poor QoL. In clustering analysis, these variables defined subsets with a particularly high propensity of post-COVID-19 mental health impairment and decreased QoL. Pre-existing depression or anxiety (DA) was associated with an increased symptom burden during acute COVID-19 and recovery.ConclusionOur study revealed a bidirectional relationship between COVID-19 symptoms and mental health. We put forward specific acute symptoms of the disease as “red flags” of mental health deterioration, which should prompt general practitioners to identify non-hospitalized COVID-19 patients who may benefit from early psychological and psychiatric intervention.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT04661462].

Abstract Background According to the World Health Organization, cardiovascular diseases (CVDs) are the leading non-communicable cause of death. Awareness of the individual risk profile is crucial to implement a healthy lifestyle and prevent CVDs. Multiple studies demonstrated that atherosclerosis, the main cause of CVDs, begins early in life. Therefore, it may be necessary to start prevention programs already in childhood. Methods The EVA-Tyrol study is a population-based non-randomized controlled trial that will prospectively enroll 2000 participants from high schools and training companies in North- and East-Tyrol (Austria) and South-Tyrol (Italy). Participants will be assigned to either an intervention (n = 1500) or a control (n = 500) group. Intervention group participants will be enrolled at the 10th school grade (mean age 15–16 years), undergo two examinations within a two-year interval, with follow-up at the 12th grade (mean ages 17–18 years). Control group participants will be enrolled at the 12th grade (mean age 17–18 years). Medical examination will include anthropometric measurements, comprehensive lifestyle and dietary questionnaires, a fasting blood sample, high-resolution ultrasound of the carotid arteries, and measurement of carotid-femoral pulse wave velocity. Active intervention will consist of (1) enhancing knowledge about CVDs, (2) individual medical counseling based on the results of the baseline examination, (3) an online health promotion tool and (4) involvement of participants in planning and implementation of health promotion projects. Effectiveness of the intervention will be assessed by comparing the proportion subjects with ideal health metrics as defined by the American Heart Association between study groups. Discussion This study aims to improve cardiovascular health in Tyrolean adolescents by demonstrating the efficacy of a multi-layer health promotion program and may yield novel insights into the prevalence of vascular risk conditions and mechanisms of early vascular pathologies in adolescents. Trial registration EVA-Tyrol has been retrospectively registered at clinicaltrials.gov under NCT03929692 since April 29, 2019.

Abstract Background We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

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.

Summary: 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.

Abstract Background Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of future cardiovascular events. 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. Moreover, stroke is a leading cause of disability and morbidity which partly emerges from post-stroke complications. Methods/design We designed a block-randomised (2:1 ratio) open pragmatic trial [NCT02156778] with blinded outcome assessment comparing STROKE-CARD to usual post-stroke-patient care. STROKE-CARD is a multifaceted post-stroke disease management program with the objective of reducing recurrent cardiovascular events and improving quality of life in ischaemic stroke and TIA-patients. It combines intensified multi-domain secondary prevention, systematic detection and treatment of post-stroke complications, and patient self-empowerment. Enrolment of 2160 patients with acute ischaemic stroke or TIA (ABCD2-Score ≥ 3) is planned at two study centres in Austria. The co-primary efficacy endpoints are (i) the composite of major recurrent cardiovascular events (nonfatal stroke, nonfatal myocardial infarction, and vascular death) occurring within 12 months after the index event and (ii) one-year health-related quality-of-life measured with the European Quality of Life-5 Dimensions (EQ-5D-3 L) questionaire. Secondary endpoints include all-cause mortality, functional outcome, and target-level achievement in risk factor management. Discussion This trial will provide evidence on whether the pragmatic post-stroke intervention program STROKE-CARD can help prevent cardiovascular events and improve quality-of-life within the setting of a high-quality acute stroke care system. In case of success, STROKE-CARD may be implemented in daily clinical routine and serve as a model for other disease management initiatives. Trial registration ClinicalTrials.gov: NCT02156778. (June 5, 2014, retrospectively registered).

Introduction Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue.Research design and methods We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up.Results Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction.Conclusions Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.

Even though cervical artery dissection is one of the main reasons for ischemic stroke in young patients, acute management and post-acute primary or secondary prevention of cerebral ischemia differ significantly in different centers and countries. These discrepancies are reflected by the differences in guideline recommendations of major stroke societies. Our narrative review aims to shed light on the different recommendations in guideline-statements of stroke societies and to give an overview of the current literature concerning acute management and post-acute treatment of cervical artery dissection patients. In general, intravenous thrombolysis and mechanical thrombectomy are recommended, irrespective of stroke etiology, if administered within the label. Secondary prevention of cerebral ischemia can be achieved by antiplatelet intake or anticoagulation, with, to date, neither treatment establishing superiority over the other. Duration of antithrombotic treatment, statin use as well as optimal endovascular approach are still up for debate and need further evaluation. Additionally, it is still unknown, whether the recommendations given in any of the guideline statements are similarly relevant in spontaneous and traumatic cervical artery dissection, as none of the stroke societies differentiates between the two.

Background: Patients with ischaemic stroke or transient ischaemic attack (TIA) are at high risk of recurrent stroke and other cardiovascular diseases and commonly suffer from reduced quality of life. We aimed to determine whether the disease management programme STROKE-CARD can prevent cardiovascular diseases and improve quality of life in these patients. Methods: In this pragmatic open-label two-centre randomised controlled trial with blinded outcome assessment, we randomly assigned patients with acute ischaemic stroke or TIA (ABCD2 score ≥3) in a 2:1 ratio to receive STROKE-CARD care or standard care. STROKE-CARD care is a disease management programme by a multidisciplinary stroke team that comprises a standardised 3-month visit and access to a web-based patient portal targeting risk factor management, post-stroke complications, comorbidities and cardiovascular warning signs, rehabilitation demands, and patient education, counselling, and self-empowerment. Co-primary outcomes were analysed on an intention-to-treat basis and were: (i) major cardiovascular disease events defined as nonfatal ischaemic or haemorrhagic stroke, nonfatal myocardial infarction, or vascular death occurring between hospital discharge and 12 months; and (ii) health-related quality of life at 12 months quantified with the EuroQol-5-Dimensions-3-Levels (EQ-5D-3L) overall utility score. This trial is registered with ClinicalTrials.gov, number NCT02156778. Findings: Of 2149 patients enrolled between January 2014 and December 2017 (mean age 69 years, 41% female, 83% with ischaemic stroke, 17% with TIA), 1438 were assigned to STROKE-CARD care and 711 to standard care. Major cardiovascular disease events occurred in 78 patients in the STROKE-CARD care group (5.4%) and in 59 patients in the standard care group (8.3%) (hazard ratio, 0.63; 95% confidence interval: 0.45-0.88; P=0.007). STROKE-CARD care also led to a better EQ-5D-3L overall utility score at 12 months (P

Background Dickkopf‐1 and sclerostin have been implicated in atherosclerosis and vascular calcification. We aimed to quantify the association of their serum levels with incident cardiovascular disease (CVD) in the general population. Methods and Results Among 706 participants of the prospective, population‐based Bruneck Study, mean±SD of serum levels were 44.5±14.7 pmol/L for dickkopf‐1 and 47.1±17.5 pmol/L for sclerostin. The primary outcome was a composite CVD end point composed of ischemic or hemorrhagic stroke, transient ischemic attack, myocardial infarction, angina pectoris, peripheral vascular disease, and revascularization procedures. Over a median follow‐up duration of 15.6 years, 179 CVD events occurred. For the primary CVD outcome, multivariable‐adjusted hazard ratios (HRs) per SD higher level were 1.20 for dickkopf‐1 (95% CI, 1.02–1.42; P=0.028) and 0.92 for sclerostin (95% CI, 0.78–1.08; P=0.286). Secondary outcome analyses revealed that the association of dickkopf‐1 was primarily driven by ischemic and hemorrhagic stroke (67 events; HR, 1.37; 95% CI, 1.06–1.78; P=0.017), whereas no increase in risk was observed for transient ischemic attack (22 events; HR, 0.87; 95% CI, 0.53–1.44; P=0.593), myocardial infarction (45 events; HR, 1.10; 95% CI, 0.78–1.54; P=0.598), or for other CVD (45 events; HR, 1.25; 95% CI, 0.88–1.76; P=0.209). Conclusions In this prospective, population‐based study, elevated baseline levels of dickkopf‐1, but not sclerostin, were independently associated with incident cardiovascular events, which was mainly driven by stroke. Our findings support the hypothesis of a role of dickkopf‐1 in the pathogenesis of CVD.

Background Genome‐wide association studies have shown an association between the single‐nucleotide polymorphism rs17514846 on chromosome 15q26.1 and coronary artery disease susceptibility. The underlying biological mechanism is, however, not fully understood. rs17514846 is located in the FES Upstream Region (FURIN) gene, which is expressed in vascular endothelial cells (ECs). We investigated whether rs17514846 has an influence on FURIN expression in ECs and whether FURIN affects EC behavior. Methods and Results Quantitative reverse transcription–polymerase chain reaction analysis showed that cultured vascular ECs from individuals carrying the coronary artery disease risk allele of rs17514846 had higher FURIN expression than cells from noncarriers. In support, luciferase reporter analyses in ECs indicated that the risk allele had higher transcriptional activity than the nonrisk allele. Electrophoretic mobility shift assays using EC nuclear protein extracts detected a DNA‐protein complex with allele‐specific differential binding of a nuclear protein. Knockdown of FURIN in ECs reduced endothelin‐1 secretion, nuclear factor‐κB activity, vascular cell adhesion molecule‐1, and MCP1 (monocyte chemotactic protein‐1) expression and monocyte‐endothelial adhesion and transmigration. A population‐based study showed an association of the rs17514846 risk allele with higher circulating MCP1 levels and greater carotid intima‐media thickness. Conclusions The coronary artery disease risk variant at the 15q26.1 locus modulates FURIN expression in vascular ECs. FURIN levels in ECs affect monocyte‐endothelial adhesion and migration.

Background Little is known about plasma apolipoprotein profiles in very preterm‐born and term‐born preschool children compared with the adult population. This is of particular interest because apolipoprotein composition might contribute to cardiometabolic outcome in later life. Methods and Results Children aged 5 to 7 years born at term or with

Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease (CVD) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE, and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow‐up of 4.2 years, 4066 CVD events were recorded. In a random‐effects meta‐analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12–1.50; P

[This corrects the article DOI: 10.1371/journal.pone.0191172.].

AIMS:Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS:From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS:We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.