State of play and future direction with NOACs: An expert consensus.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice

Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Effects of splint therapy in TMJ dysfunction: a study using magnetic resonance imaging.

This pilot study was undertaken to correlate clinical and MRI diagnoses in seven symptomatic TMJ dysfunction patients and to account, if possible, for the clinical improvement in the signs and symptoms after the use of a maxillary stabilizing splint. The symptomatic TMJs were evaluated by means of MRI prior to splint insertion. Sagittal open/closed, and coronal closed images were obtained with a 0.3 T Fonar MR Scanner. A follow-up MRI was taken after three months of splint therapy for the purposes of a comparative study. All subjects responded positively even at the early phase of splint treatment. By the end of the three month period, six subjects experienced full remission of pain in the TMJ and associated masticatory muscles with one subject experiencing only partial remission following therapy. Baseline MRI study revealed that only three subjects had anterior disc displacement while the other four subjects had normal disc/condyle relationships and morphology. In the follow-up MRI study, there were no signs of recapture of the three anteriorly displaced discs despite there being evidence of improved jaw movement and remission of pain symptoms. The use of MRI in this preliminary study indicates that some but not all TMJ pain dysfunction syndromes are caused by internal derangements of the joint. A larger MRI study using the same clinical parameters is indicated for future research

Bacterial biodiversity in deep-sea sediments from two regions of contrasting surface water productivity near the Crozet Islands, Southern Ocean

The relationship between surface-derived particulate organic matter (POM) and deep-sea sediment bacterial abundance, community structure and composition was investigated in two different sediment layers from two zones of contrasting surface water productivity in the southern Indian Ocean. Bacterial sediment communities from high chlorophyll (HC) and low chlorophyll (LC) sites were characterized and compared using direct counts, clone library construction, denaturing gradient gel electrophoresis (DGGE) and fluorescence in situ hybridization (FISH). Of the 1566 bacterial clones generated from the sediment communities, 1010 matched published 16 S rDNA sequences at ?97% identity. A comparison of surface sediment clone libraries showed that at least one third of all identified operational taxonomic units (OTUs) were common to both HC and LC sites. DGGE community profiles were consistent (82% similar) and evenness of the major phylogenetic groups was 96% similar between surface sediment communities, where gamma- and alpha-Proteobacteria were dominant. Sediment communities shared similarly high biodiversity, while species richness was marginally higher at the LC site. Intra-site shifts in bacterial abundance and composition were observed with increasing sediment depth. Despite the differences in organic matter input between sites, the consistency observed between HC and LC sediment communities pointed to 1) the extent of remineralisation by mega and meio-fauna was a factor affecting the quantity and quality of POM available to sediment bacteria, 2) sampling during the early ‘nutrient assimilation phase’ of the bacterial response to freshly deposited POM or 3) the action of bacteria in the water column could affect the quantity and quality of POM available to sediment bacteria. Although factors other than these may explain the observed similarities, this first comparison of deep-sea sediment communities in relation to surface-derived productivity may be useful in further elucidating the role of sediment bacteria in carbon remineralisation in the deep-sea environment