Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism : a pooled analysis of the EINSTEIN-DVT and PE randomized studies

Background: Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects. Methods: A prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE studies compared the efficacy and safety of rivaroxaban (15 mg twice-daily for 21 days, followed by 20 mg once-daily) with standard-therapy (enoxaparin 1.0 mg/kg twice-daily and warfarin or acenocoumarol). Patients were treated for 3, 6, or 12 months and followed for suspected recurrent VTE and bleeding. The prespecified noninferiority margin was 1.75. Results: 8282 patients were enrolled. 4151 received rivaroxaban and 4131 received standard-therapy. The primary efficacy outcome occurred in 86 rivaroxaban-treated patients (2.1%) compared with 95 (2.3%) standard-therapy-treated patients (hazard ratio, 0.89; 95% confidence interval [CI], 0.66-1.19; pnoninferiority<0.001). Major bleeding was observed in 40 (1.0%) and 72 (1.7%) patients in the rivaroxaban and standard-therapy groups, respectively (hazard ratio, 0.54; 95% CI, 0.37-0.79; p=0.002). In key subgroups, including fragile patients, cancer patients, patients presenting with large clots and those with a history of recurrent VTE, the efficacy and safety of rivaroxaban was similar compared with standard-therapy. Conclusion: The single-drug approach with rivaroxaban resulted in similar efficacy to standard-therapy and was associated with a significantly lower rate of major bleeding. Efficacy and safety results were consistent among key patient subgroups

P-Element Homing Is Facilitated by engrailed Polycomb-Group Response Elements in Drosophila melanogaster

P-element vectors are commonly used to make transgenic Drosophila and generally insert in the genome in a nonselective manner. However, when specific fragments of regulatory DNA from a few Drosophila genes are incorporated into P-transposons, they cause the vectors to be inserted near the gene from which the DNA fragment was derived. This is called P-element homing. We mapped the minimal DNA fragment that could mediate homing to the engrailed/invected region of the genome. A 1.6 kb fragment of engrailed regulatory DNA that contains two Polycomb-group response elements (PREs) was sufficient for homing. We made flies that contain a 1.5kb deletion of engrailed DNA (enΔ1.5) in situ, including the PREs and the majority of the fragment that mediates homing. Remarkably, homing still occurs onto the enΔ1. 5 chromosome. In addition to homing to en, P[en] inserts near Polycomb group target genes at an increased frequency compared to P[EPgy2], a vector used to generate 18,214 insertions for the Drosophila gene disruption project. We suggest that homing is mediated by interactions between multiple proteins bound to the homing fragment and proteins bound to multiple areas of the engrailed/invected chromatin domain. Chromatin structure may also play a role in homing

Model organisms contribute to diagnosis and discovery in the Undiagnosed Diseases Network: Current state and a future vision

Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000-13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support

Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure

Mitochondrial dysfunction and metabolic remodelling are pivotal in the development of cardiomyopathy. Here, we show that myocardial COUP-TFII overexpression causes heart failure in mice, suggesting a causal effect of elevated COUP-TFII levels on development of dilated cardiomyopathy. COUP-TFII represses genes critical for mitochondrial electron transport chain enzyme activity, oxidative stress detoxification and mitochondrial dynamics, resulting in increased levels of reactive oxygen species and lower rates of oxygen consumption in mitochondria. COUP-TFII also suppresses the metabolic regulator PGC-1 network and decreases the expression of key glucose and lipid utilization genes, leading to a reduction in both glucose and oleate oxidation in the hearts. These data suggest that COUP-TFII affects mitochondrial function, impairs metabolic remodelling and has a key role in dilated cardiomyopathy. Last, COUP-TFII haploinsufficiency attenuates the progression of cardiac dilation and improves survival in a calcineurin transgenic mouse model, indicating that COUP-TFII may serve as a therapeutic target for the treatment of dilated cardiomyopathy

Bacteriophage- based tests for the detection of Mycobacterium tuberculosis in clinical specimens: a systematic review and meta- analysis

BACKGROUND: Sputum microscopy, the most important conventional test for tuberculosis, is specific in settings with high burden of tuberculosis and low prevalence of non tuberculous mycobacteria. However, the test lacks sensitivity. Although bacteriophage-based tests for tuberculosis have shown promising results, their overall accuracy has not been systematically evaluated. METHODS: We did a systematic review and meta-analysis of published studies to evaluate the accuracy of phage-based tests for the direct detection of M. tuberculosis in clinical specimens. To identify studies, we searched Medline, EMBASE, Web of science and BIOSIS, and contacted authors, experts and test manufacturers. Thirteen studies, all based on phage amplification method, met our inclusion criteria. Overall accuracy was evaluated using forest plots, summary receiver operating (SROC) curves, and subgroup analyses. RESULTS: The data suggest that phage-based assays have high specificity (range 0.83 to 1.00), but modest and variable sensitivity (range 0.21 to 0.88). The sensitivity ranged between 0.29 and 0.87 among smear-positive, and 0.13 to 0.78 among smear-negative specimens. The specificity ranged between 0.60 and 0.88 among smear-positive and 0.89 to 0.99 among smear-negative specimens. SROC analyses suggest that overall accuracy of phage-based assays is slightly higher than smear microscopy in direct head-to-head comparisons. CONCLUSION: Phage-based assays have high specificity but lower and variable sensitivity. Their performance characteristics are similar to sputum microscopy. Phage assays cannot replace conventional diagnostic tests such as microscopy and culture at this time. Further research is required to identify methods that can enhance the sensitivity of phage-based assays without compromising the high specificity

Drosophila Neuroligin 2 is Required Presynaptically and Postsynaptically for Proper Synaptic Differentiation and Synaptic Transmission

Trans-synaptic adhesion between Neurexins and Neuroligins is thought to be required for proper synapse organization and modulation, and mutations in several human NEUROLIGINS have shown association with autism spectrum disorders (ASD). Here we report the generation and phenotypic characterization of Drosophila neuroligin 2 (dnlg2) mutants. Loss of dnlg2 results in reduced bouton numbers, aberrant pre- and post-synaptic development at neuromuscular junctions (NMJs), and impaired synaptic transmission. In dnlg2 mutants, the evoked responses are decreased in amplitude, whereas the total active zone numbers at the NMJ are comparable to wild type, suggesting a decrease in the release probability. Ultrastructurally, the presynaptic active zone number per bouton area and the postsynaptic density area are both increased in dnlg2 mutants, whereas the subsynaptic reticulum (SSR) is reduced in volume. We show that both pre- and post-synaptic expression of Dnlg2 is required to restore synaptic growth and function in dnlg2 mutants. Post-synaptic expression of Dnlg2 in dnlg2 mutants and wild type leads to reduced bouton growth whereas pre- and post-synaptic overexpression in wild type animals results in synaptic overgrowth. Since Neuroligins have been shown to bind to Neurexins, we created double mutants. These mutants are viable and display phenotypes that closely resemble those of dnlg2 and dnrx single mutants. Our results provide compelling evidence that Dnlg2 functions both pre- and post-synaptically together with Neurexin to determine the proper number of boutons as well as the number of active zones and size of synaptic densities during the development of NMJs

Rivaroxaban or Aspirin for extended treatment of venous thromboembolism

Background: although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. Methods: in this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. Results: a total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. Conclusions: among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439)