Interdisciplinary Analyses of Bronze Age Communities from Western Hungary Reveal Complex Population Histories.

In this study, we report 21 ancient shotgun genomes from present-day Western Hungary, from previously understudied Late Copper Age Baden, and Bronze Age Somogyvár-Vinkovci, Kisapostag, and Encrusted Pottery archeological cultures (3,530-1,620 cal Bce). Our results indicate the presence of high steppe ancestry in the Somogyvár-Vinkovci culture. They were then replaced by the Kisapostag group, who exhibit an outstandingly high (up to ∼47%) Mesolithic hunter-gatherer ancestry, despite this component being thought to be highly diluted by the time of the Early Bronze Age. The Kisapostag population contributed the genetic basis for the succeeding community of the Encrusted Pottery culture. We also found an elevated hunter-gatherer component in a local Baden culture-associated individual, but no connections were proven to the Bronze Age individuals. The hunter-gatherer ancestry in Kisapostag is likely derived from two main sources, one from a Funnelbeaker or Globular Amphora culture-related population and one from a previously unrecognized source in Eastern Europe. We show that this ancestry not only appeared in various groups in Bronze Age Central Europe but also made contributions to Baltic populations. The social structure of Kisapostag and Encrusted Pottery cultures is patrilocal, similarly to most contemporaneous groups. Furthermore, we developed new methods and method standards for computational analyses of ancient DNA, implemented to our newly developed and freely available bioinformatic package. By analyzing clinical traits, we found carriers of aneuploidy and inheritable genetic diseases. Finally, based on genetic and anthropological data, we present here the first female facial reconstruction from the Bronze Age Carpathian Basin.

Oral Anticoagulant Treatment in Patients with Atrial Fibrillation and Chronic Kidney Disease.

Over the past few decades, a series of innovative medicines have been developed in order to optimize anticoagulation therapy for atrial fibrillation (AF). As a result, a number of nonvitamin K antagonist oral anticoagulants (NOAC) that directly target the enzymatic activity of factor II and factor Xa have been successfully licensed providing a more predictable effect and better safety profile compared to conventional anticoagulants (heparins and vitamin K antagonists (VKAs)). However, comparative efficacy and safety data is limited in patients with advanced chronic kidney disease (i.e., CKD stage 4/5 and end stage renal disease) because patients with estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 were actively excluded from landmark trials, thus representing a major clinical limitation for the currently available agents. However, the renal function of AF patients can be altered over time. On the other hand, patients with CKD have an increased risk of developing AF. This review article will provide an overview of current concepts and recent evidence guiding the clinical use of NOACs in patients with CKD requiring chronic anticoagulation, and the associated risks and benefits of treatment in this specific patient population.

Factor XI inhibition fulfilling the optimal expectations for ideal anticoagulation.

INTRODUCTION: Thromboembolic diseases are leading cause of mortality accounting for an estimated 1 in 4 deaths all over the world. Anticoagulation remains the mainstay of prevention and treatment of venous thromboembolic disorders. Conventional anticoagulants have been efficiently used over the last decades, but their clinical use encounters safety and convenience issues. To overcome these limitations, research have focused on development of new targets for anticoagulation leading to a relatively new class of drugs, non-vitamin K antagonist oral anticoagulants, specifically targeting activated factor X and thrombin. However, the search for more potent anticoagulant agents with reduced bleeding risk is still continuing. Areas covered: In this review, we provide an overview on emerging investigational anticoagulant drugs targeting factor XI in the coagulation cascade. We review data about the role of intrinsic pathway in thrombosis and haemostasis and the rationale of different pharmacodynamic approaches targeting factor XI. Expert opinion: Recent evidence suggests that the contact pathway plays a significant role in thrombosis by thrombus stabilization and growth without perturbing haemostasis. Factor XI might be a promising drug target to develop highly effective antithrombotic therapy with safety bleeding profile. Most of these investigational agents are in early development phases, only few have reached early phase clinical trials.

No short-term treatment effect of prism adaptation for spatial neglect: An inclusive meta-analysis.

Despite 25 years of research on the topic, there is still no consensus on whether prism adaptation is an effective therapy for visuospatial neglect. We have addressed this question through a meta-analysis of the most well-controlled studies on the topic. Our main meta-analytic model included studies with a placebo/sham/treatment-as-usual control group from which data from right hemisphere stroke patients and left-sided neglect could be aggregated. The short-term treatment effects on the two commonly used standard tests for neglect, the conventional Behavioural Inattention Test (BIT-C) and cancellation test scores were combined into one random effect model justified by the fact that 89% of the BIT-C score is determined by cancellation tasks. With this approach, we were able to obtain a larger and more homogeneous dataset than previous meta-analyses: sixteen studies including 430 patients. No evidence for beneficial effects of prism adaptation was found. The secondary meta-analysis including data from the Catherine Bergego Scale, a functional measure of activities of daily living, also found no evidence for the therapeutic effects of prism adaptation, although half as many studies were available for this analysis. The results were consistent after the removal of influential outliers, after studies with high risk-of-bias were excluded, and when an alternative measure of effect size was considered. These results do not support the routine use of prism adaptation as a therapy for spatial neglect.

High Coverage Mitogenomes and Y-Chromosomal Typing Reveal Ancient Lineages in the Modern-Day Székely Population in Romania.

Here we present 115 whole mitogenomes and 92 Y-chromosomal Short Tandem Repeat (STR) and Single Nucleotide Polymorphism (SNP) profiles from a Hungarian ethnic group, the Székelys (in Romanian: Secuii, in German: Sekler), living in southeast Transylvania (Romania). The Székelys can be traced back to the 12th century in the region, and numerous scientific theories exist as to their origin. We carefully selected sample providers that had local ancestors inhabiting small villages in the area of Odorheiu Secuiesc/Székelyudvarhely in Romania. The results of our research and the reported data signify a qualitative leap compared to previous studies since it presents the first complete mitochondrial DNA sequences and Y-chromosomal profiles of 23 STRs from the region. We evaluated the results with population genetic and phylogenetic methods in the context of the modern and ancient populations that are either geographically or historically related to the Székelys. Our results demonstrate a predominantly local uniparental make-up of the population that also indicates limited admixture with neighboring populations. Phylogenetic analyses confirmed the presumed eastern origin of certain maternal (A, C, D) and paternal (Q, R1a) lineages, and, in some cases, they could also be linked to ancient DNA data from the Migration Period (5th-9th centuries AD) and Hungarian Conquest Period (10th century AD) populations.

Role of Vitamin D in Cognitive Dysfunction: New Molecular Concepts and Discrepancies between Animal and Human Findings.

PURPOSE OF REVIEW: increasing evidence suggests that besides the several metabolic, endocrine, and immune functions of 1alpha,25-dihydroxyvitamin D (1,25(OH)2D), the neuronal effects of 1,25(OH)2D should also be considered an essential contributor to the development of cognition in the early years and its maintenance in aging. The developmental disabilities induced by vitamin D deficiency (VDD) include neurological disorders (e.g., attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia) characterized by cognitive dysfunction. On the other hand, VDD has frequently been associated with dementia of aging and neurodegenerative diseases (e.g., Alzheimer's, Parkinson's disease). RECENT FINDINGS: various cells (i.e., neurons, astrocytes, and microglia) within the central nervous system (CNS) express vitamin D receptors (VDR). Moreover, some of them are capable of synthesizing and catabolizing 1,25(OH)2D via 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1) and 25-hydroxyvitamin D 24-hydroxylase (CYP24A1) enzymes, respectively. Both 1,25(OH)2D and 25-hydroxyvitamin D were determined from different areas of the brain and their uneven distribution suggests that vitamin D signaling might have a paracrine or autocrine nature in the CNS. Although both cholecalciferol and 25-hydroxyvitamin D pass the blood-brain barrier, the influence of supplementation has not yet demonstrated to have a direct impact on neuronal functions. So, this review summarizes the existing evidence for the action of vitamin D on cognitive function in animal models and humans and discusses the possible pitfalls of therapeutic clinical translation.

Atrial high-rate episodes and risk of major adverse cardiovascular events in patients with cardiac implantable electronic devices.

BACKGROUND: Patients with atrial high-rate episodes (AHREs) are at higher risk of thromboembolic events and mortality. The risk of major adverse cardiovascular events (MACE) in these patients is unknown. OBJECTIVE: To investigate the risk of MACE in patients implanted with cardiac implantable electronic devices (CIEDs) developing AHREs METHODS AND RESULTS: We included 852 consecutive patients undergoing CIEDs implantation. Primary outcome was a composite endpoint of MACEs occurring after AHREs ≥ 5 min. AHRE was defined as > 175 bpm and lasting ≥ 5 min. We also performed a subgroup analysis in patients with the longest AHRE lasting ≥ 24 h. Cox regression analysis with time-dependent covariates was used to investigate the relationship between AHREs and MACEs. Mean age was 70.0 ± 13.6 years, and 39.3% were women: 325 patients developed AHREs ≥ 5 min [incidence rate (IR) 13.1% year 95% confidence interval (CI) 11.7-14.6] and 124 patients developed AHREs ≥ 24 h (IR 3.7%/year 95% CI 3.1-4.5). During a median follow-up of 37.0 months (IQR 19.0-64.3, 316,132 patient-years), 152 MACEs occurred (IR 4.85%/year, 95% CI 4.11-5.68). The IR of MACE occurring after AHREs onset was higher in patients developing AHREs ≥ 24 h (IR 1.13%/year) than AHREs ≥ 5 min (IR 0.63%/year, p = 0.030). Multivariable Cox regression analysis showed that AHREs ≥ 5 min (HR 1.788, 95% CI 1.247-2.562, p = 0.002), diabetes (HR 1.909, 95% CI 1.358-2.683, p < 0.001), heart failure (HR 2.203, 95% CI 1.527-3.178, p < 0.001), and coronary artery disease (HR 1.862, 95% CI 1.293-2.681, p = 0.001) were associated to MACE. This association was even stronger for AHREs ≥ 24 h (HR 2.390, 95% CI 1.481-3.857, p < 0.001). CONCLUSIONS: Patients implanted with CIEDs developing AHREs show a significant risk for MACE, which is dependent on AHREs burden. Cardiovascular prevention strategies in this patient population are warranted.

Atrial high rate episodes in patients with cardiac implantable electronic devices: implications for clinical outcomes.

BACKGROUND: Atrial high rate episodes (AHREs) detected by cardiac implantable electronic devices (CIEDs) are associated with an increased risk of stroke. However, the impact of AHRE on improving stroke risk stratification scheme remains uncertain. OBJECTIVE: The purpose of this study was to assess the impact of AHRE on prognosis in relation with cardiovascular events and risk stratification. METHODS: A total of 856 consecutive patients who had dual-chamber CIEDs implanted were retrospectively analyzed. To detect AHREs, they were monitored for 6 months after CIEDs' implantation and were followed for a mean of 4.0 years for clinical outcomes such as thromboembolism or death. RESULTS: Overall, 125 (14.6%) of patients developed AHREs within the first 6 months (median age 72.0 years, 39.3% female). Patients with AHREs had a high rate of thromboembolism (2.6%/year) and mortality (3.0%/year). On multivariate analysis, AHRE was significantly associated with increased risk of thromboembolism [hazard ratio (HR) 3.40; 95% confidence interval (CI) 1.38-8.37, P = 0.01] and death (HR 3.47; 95% CI 1.51-7.95; P < 0.01). The predictive abilities of the CHADS2 and CHA2DS2-VASc scores were modest, with no significant improvements by adding AHRE to those scores. However, the integrated discrimination improvement and net reclassification improvement showed that the addition of AHRE to the CHADS2 and CHA2DS2-VASc scores statistically improved their predictive ability for the composite outcome. CONCLUSIONS: AHRE was an independent factor associated with increased risk of clinical outcomes. The addition of AHRE to the clinical risk scores significantly improved discrimination for thromboembolism or death.

Atrial high-rate episodes and thromboembolism in patients without atrial fibrillation: The West Birmingham Atrial Fibrillation Project.

BACKGROUND: Patients with cardiac implantable electronic device (CIED) developing atrial high-rate episodes (AHRE) have a significant risk of thromboembolic events (TEs), but risk factors have been scarcely investigated. OBJECTIVES: To analyze risk factors for TEs in a contemporary cohort of patients with CIED. METHODS: Consecutive non-AF patients without anticoagulation at baseline were followed up after the CIED implantation. The role of newly-developed AHRE and other risk factors for TEs were analyzed using a time-dependent Cox regression model and Kaplan-Meier analysis with log-rank tests. RESULTS: A total of 594 CIED patients were followed up for a mean of 4.2 years: 175 developed AHRE (29.5%; incident rate [IR] 8.80% per patient-year). Of those, 33 experienced TEs (5.5%; IR 1.38% per patient-year). Incidence of TEs was low in patients with a CHA2DS2-VASc score < 2 (male)/<3 (female) (AHRE vs. no-AHRE, 0.60% vs. 0.00% per patient-year, p = 0.469) and high in those with score ≥ 2 (male)/≥3 (female) (AHRE vs. no-AHRE, 2.12% vs. 1.36% per patient-year, p = 0.209), regardless of the AHRE presence. AHRE was not significantly associated with TEs (hazard ratio [HR], 1.46 [0.64-3.33]). There was no temporal relationship between AHRE and TEs. Baseline CHA2DS2-VASc score was independently associated with TEs (HR, 1.41 [1.13-1.75]) on multivariate analysis, but not AHRE. CONCLUSIONS: Thromboembolic risk in patients with CIED is mainly driven by comorbidity burden, i.e., CHA2DS2-VASc score, rather than AHRE per se. Decision-making on stroke prevention needs to focus on comorbidity burden and not merely on the presence or absence of AHRE in CIED patients.

Current and emerging pharmacotherapy for ischemic stroke prevention in patients with atrial fibrillation.

Introduction: Atrial fibrillation (AF) is associated with high morbidity and mortality rates due to thromboembolic complications, and anticoagulation is central to the management of this common arrhythmia to prevent acute thromboembolic events. The traditional anticoagulants: heparin, fondaparinux, and vitamin K antagonists (VKA, e.g. warfarin, acenocoumarol or phenprocoumin) have long served as pharmacotherapy for ischemic stroke prophylaxis. Areas covered: In this review article, the authors provide an overview on current and emerging pharmacotherapy for ischemic stroke prevention. Furthermore, they review the data from novel therapeutic targets in the coagulation cascade, and investigational anticoagulant drugs currently assessed in preclinical and clinical studies. Expert opinion: The introduction of nonvitamin K antagonist oral anticoagulants (NOACs) was an important milestone, as these drugs show relative efficacy, safety, and convenience compared to the VKAs. Nevertheless, their clinical use still has some limitations with, for example, patients with severe renal impairment and those with mechanical heart valves, high bleeding risks, lack of standard laboratory monitoring and (some) reversal agents. To overcome some of these limitations, various attempts are now underway to discover new strategies and targets via the hemostatic pathway in order to develop new coagulation inhibiting drugs.