Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Temperament and character personality profiles and personality disorders in chronic pain patients

In his psychobiological model of personality, Cloninger developed a novel approach concerning the relationships between psychopathological syndromes and personality. We investigated 207 chronic pain patients (CPPs) and compared them to 105 pain-free control subjects. Participants were assessed using the Temperament and Character Inventory (TCI), the Structured-Clinical-Interview-II, the Beck Depression Inventory and the Spielberger Anxiety Inventory. The CPPs scored higher on the depression and state anxiety scales and 41% fulfilled the criteria of having at least one personality disorder (PD). We used a covariance analysis to control for depression and state anxiety and found that the CPPs scored higher on the Harm Avoidance Temperament Dimension and lower on the Self-Directedness and Cooperativeness Character Dimensions. In CPPs, the symptom counts of all PD subtypes were significantly related to low Self-Directedness and, to a lesser degree, low Cooperativeness. The PD symptoms in Cluster A were related to low Reward Dependence, those in Cluster B were related to high Novelty Seeking and the PD symptoms in Cluster C were related to high Harm Avoidance. In multiple hierarchical regression analyses, controlling for age, gender, depression and state anxiety, TCI scales predicted on average 23% in PD symptom counts. The Self-Directedness and Cooperativeness personality traits appeared to be significant predictors in determining the presence or absence of a PD by correctly classifying 75.8% of CPPs. The TCI provides further insight into the mechanisms underlying the development of chronic pain. This useful diagnostic instrument helps to economically and validly facilitate the identification of core PD feature

The 4π4\pi-fragment-spectrometer FOBOS

The 4 π - fragment - spectrometer FOBOS developed for heavy-ion research at beam energies of 10 - 100 AMeV has been commissioned for physical experiments at the Flerov Laboratory of Nuclear Reactions of the Joint Institute for Nuclear Research in Dubna. Based on the logarithmic detector principle, it is able to register charged fragments from Protons up to heavy residual nuclei in a large dynamical range. Position-sensitive avalanche counters, axial ionization chambers and CsI(TI) scintillation detectors are arranged in three concentric detector shells. An array of phoswich detectors is used as a more granular forward detector at narrow polar angles. The modular concept of FOBOS allows for different experimental application in the field of exclusive fragment spectroscopy at medium multiplicities. For illustration the fragment spectroscopy studies concerning the spontaneous fission process and the fragmentation of hot nuclei by means of the FOBOS set-up are considered

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity

Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10-3per year [95% CI, -6.49×10-3to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH

The management of acute venous thromboembolism in clinical practice - study rationale and protocol of the European PREFER in VTE Registry

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS0000479