Citations

Significance Ebolaviruses belong to the group of nonsegmented negative strand (NNS) RNA viruses. Most members of the Ebolavirus genus cause severe disease in humans. Here, we report that ebolaviruses have evolved a genome replication mechanism that distinguishes them from the other NNS RNA viruses. The ebolavirus replication strategy includes the addition of a nontemplated 3′ nucleotide at the genome ends which may aid in avoiding antiviral recognition. Our data highlight the need for more research on NNS RNA virus replication strategies to reveal commonalities between virus families as well as unique features. Dissecting the replication mechanisms of NNS RNA viruses, including ebolaviruses, paves the way for the development of broad-spectrum antivirals that target the viral replication complexes, thereby preventing virus amplification.

Objectives Compare the effect of apixaban and warfarin on coagulation and primary haemostasis biomarkers in atrial fibrillation (AF). Methods The biomarker substudy from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial included 4850 patients with AF randomised to treatment with apixaban or warfarin. Sixty per cent of patients used vitamin K antagonist (VKA) within 7 days before randomisation. Prothrombin fragment 1+2 (F1+2), D-dimer, soluble CD40 ligand (sCD40L) and von Willebrand factor (vWF) antigen were analysed at randomisation and after 2 months of study treatment. Results In patients not on VKA treatment at randomisation, F1+2 and D-dimer levels were decreased by 25% and 23%, respectively, with apixaban, and by 59% and 38%, respectively, with warfarin (p<0.0001 for treatment differences for both). In patients on VKA at randomisation, F1+2 and D-dimer levels increased by 41% and 10%, respectively, with apixaban and decreased by 37% and 11%, respectively, with warfarin (p<0.0001 for treatment differences for both). sCD40L levels were slightly increased at 2 months, regardless of VKA or randomised treatment. Apixaban and warfarin also both reduced vWF antigen regardless of VKA treatment. The efficacy (stroke) and safety (bleeding) of apixaban compared with warfarin was similar irrespectively of biomarker levels at 2 months. Conclusions Treatment with apixaban compared with warfarin for stroke prevention in patients with AF was associated with less reduction in thrombin generation and fibrin turnover. This effect of apixaban could contribute to the clinical results where apixaban was superior to warfarin both in stroke prevention and in reducing bleeding risk. Trial registration number NCT00412984.

Objectives: Pulmonary arterial hypertension (PAH) is a cardiopulmonary disease without effective cure. The objective of this study is to test the hypothesis that PAH patients have a distinct gut microbiome composition acting as a driving force for the increased PAH metabolic biomarkers, acyl carnitines and urate. Methods: Fecal samples from 18 type 1 PAH patients (mean pulmonary arterial pressure [mPAP] 57.4±16.7 mmHg) and 13 reference subjects in Brazil were collected for comparison of microbiome using shotgun metagenomics. Plasma samples from 33 type I PAH patients (mPAP 51.7± 13.5 mmHg) and 19 reference subjects in the USA were used for untargeted metabolomic analysis. Results: More than 80 bacterial taxa were differentially enriched in the microbiomes of the PAH cohort. Random forest machine-learning algorithm predicted PAH patients with 82.4% accuracy from their gut microbiome composition. The most increased taxa in the PAH microbiome were trimethylamine (TMA) producing bacteria like Collinsella (P=0.0037). The PAH metabolome also showed increases of gut microbiome-derived short chain acyl carnitines like isubutyrylcarnitine (P=0.010) and valerylcarnitine (P=0.030), which are the precursors of TMA. In addition, increased urate (P=0.0004) and allantoin (P=0.027) in PAH plasma correlated with significantly increased enzymes producing urate in the PAH microbiome (purine metabolism (P=0.017) and xanthine oxidase (P<0.05)). Conclusion: These findings suggest that the random forest modeling of the gut microbiome composition can be used for prediction of PAH and that the unique gut microbiome of PAH influences acyl carnitines and urate metabolism to contribute to pathophysiology.

Abstract Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression–based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx’s utility for routine diagnostic purposes and therapeutic decision making.

AbstractObjectiveThe prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1‐42was examined in frontotemporal dementia subtypes.MethodsWe compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits.ResultsNeurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau181predicted faster clinical progression whereas lower amyloid beta1‐42predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau181were of greater predictive value in patients with tau pathology as compared toTDP‐43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia.InterpretationHigh cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau181, and amyloid beta1‐42also predict some measures of disease aggressiveness in frontotemporal dementia.

Background Chronic kidney disease ( CKD ) is a common comorbidity in patients with atrial fibrillation. The presence of CKD complicates drug selection for stroke prevention and rhythm control. Methods and Results Patients enrolled in ORBIT AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) with baseline renal function and follow‐up data were included (N=9019). CKD was defined as an estimated creatinine clearance <60 mL /min. Patient characteristics were compared by CKD status, and Cox proportional hazards modeling was used to examine the association between oral anticoagulant ( OAC ) use and outcomes and antiarrhythmic drug use and outcomes stratified by CKD stages. At enrollment, 3490 (39%) patients had an estimated creatinine clearance <60 mL /min. Patients with CKD were older and had higher CHA 2 DS 2 VAS c and Anticoagulant and Risk Factors in Atrial Fibrillation (ATRIA) scores. A rhythm control strategy was selected less frequently in patients with CKD , while OAC use was lower among Stage IV and V CKD patients. After adjustment, no significant interaction was noted for OAC and CKD on all‐cause mortality ( P =0.5442) or cardiovascular death ( P =0.1233), although a trend for increased major bleeding ( P =0.0608) and stroke, systemic embolism or transient ischemic attack ( P =0.0671) was observed. No interaction was noted for antiarrhythmic drug use and CKD status on all‐cause mortality ( P =0.9706), or stroke, systemic embolism or transient ischemic attack ( P =0.4218). Conclusions Patients with atrial fibrillation and CKD are less likely to be treated with rhythm control. Patients with advanced CKD are less likely to receive OAC . Finally, outcomes with OAC in patients with advanced CKD may be materially different with higher rates of both bleeding and stroke.