Characterization of patients with embolic strokes of undetermined source in the NAVIGATE ESUS randomized trial

Background: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. Aims: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. Methods: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. Results: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. Conclusions: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research

JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection

Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath

Rivaroxaban versus aspirin for secondary prevention of ischaemic stroke in patients with cancer: a subgroup analysis of the NAVIGATE ESUS randomized trial

Background and purpose: Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome events during treatment with aspirin and rivaroxaban were investigated. Methods: Trial participation required a recent embolic stroke of undetermined source. Patients’ history of cancer was recorded at the time of study entry. During a mean follow-up of 11 months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all-cause mortality were compared between patients with cancer and patients without cancer. Results: Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban [254 (7.0%) with cancer] and 3604 patients to aspirin [289 (8.0%) with cancer]. The annual rate of recurrent ischaemic stroke was 4.5% in non-cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm [hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78–1.24]. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71–2.87). Amongst cancer patients, the annual rate of major bleeds was non-significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67–9.96; P for interaction 0.95). All-cause mortality was similar in both groups. Conclusions: Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all-cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. www.clinicaltrials.gov (NCT02313909). © 2020 European Academy of Neurolog

Dabigatran versus warfarin in patients with atrial fibrillation.

BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rat

Per lo studio dei commenti alle opere di Giovanni Boccaccio: una banca dati digitale sulle chiose alle Tre Corone (ante 1500)

BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P <0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P <0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P <0.001) and 0.10% per year with 150 mg of dabigatran (P <0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.

Qualitative histopathologic features of each tissue block.

<p>Qualitative histopathologic features of each tissue block.</p

Model for PML propagation in white matter from this case.

<p>JCV (green dot) infects myelinating oligodendrocytes (blue, with processes ensheathing axons), which progress from early (red, TAg) to late (green, VP1) infection. Some virus spreads intracellularly within oligodendroglial processes toward the myelin sheath. Infected oligodendrocytes lyse and most viral aggregates associate with nearby myelin, leading to extracellular virus dispersion along white matter tracts (large green arrow), demyelination, and propagation by infection of distant oligodendrocytes (small black arrow). Variable amounts of myelin (blue) and virus are seen in association with astrocytes (magenta), microglia (orange), and macrophages (gray).</p

Quantification of JCV DNA and VP1 capsid protein.

<p>Log-log plot of the concentration of JCV genomes vs capsids per microliter tissue for all 9 PML blocks (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155897#pone.0155897.t002" target="_blank">Table 2</a>). Data are means ± standard deviation based on triplicate measurements. Blue dashed line indicates theoretical relationship for one capsid per viral genome. Linear regression reveals a positive relationship with <i>r</i>² = 0.96, <i>p</i><0.0001 (regression line not shown). Asterisk designates the uncertainty of the protein measurement of VP1 in NL3, which was below the assay’s lower limit of quantitation (not shown).</p

Spectrum of PML histopathology.

<p>H&E (A-C) and IHC (brown, with blue hematoxylin counterstain) for NFP to label neuronal processes (D-F), MBP to label myelin (G-I), GFAP to label astrocytes (black arrows) (J-L), and IBA1 to label microglia/macrophages (blue arrowheads) (M-O) from grossly unaffected, actively infected, and end-stage white matter (blocks NL3, PL3, and L3, respectively). NL3 (left column) had largely normal white matter composed of linear axons/myelin throughout the neuropil, oligodendrocytes with characteristic perinuclear “fried egg” halos (green arrowheads), astrocytes with thin and elongated processes, and microglia with short, thick processes. PL3 (middle column) showed active infection with viral nuclear inclusions (red arrows), hypertrophied astrocytes with thickened processes, swollen myelin, and some enlarged macrophages (this section also had foci of demyelination, not shown here). L3 (right column) had end-stage lesions with rare viral inclusions, reduced number and fragmentation of axons, residual axonal myelin (magenta arrowhead), and variable amounts of MBP within engorged macrophages and massively hypertrophied (“bizarre”) astrocytes. Asterisks in B and C designate thinning of neuropil secondary to axonal loss. Scale bar = 30 μm for all panels.</p

White matter “wave” of JCV infection.

<p>(A-D) Top of each panel shows low magnification views of sequential sections of block L1, stained for H&E (A) or indicated IHCs (B-D), with higher magnification of region designated by red box shown in bottom of each panel. Black asterisk designates confluent area of demyelination behind wave; blue asterisks designate two foci of MBP pallor ahead of VP1 wave, indicative of recent demyelination. Panel D is a dual IHC, revealing TAg with alkaline phosphatase/fast red detection (red arrows) and VP1 with HRP/DAB detection (green arrow). (E) Schematic of four zones (1–4) relative to wave front of dispersed virus (blue line demarcated by blue arrowheads at the edge of the section) overlying the tissue image in panel D following manual segmentation of TAg-positive cells (red dots) and VP1-positive cells (green dots). Orange arrows indicate putative direction of wave movement through the section. Graphs show cell counts for TAg (red) and VP1 (green) (bottom left), and ratio of early (TAg positive) to late (VP1 positive) infected cells as a function of zone (bottom right). (F) Magnified area of wave front indicated by black box in panels D and E, with TAg-positive cells false-colored red, VP1-positive cells false-colored green, and wave front (gray line) inferred to be progressing in the direction indicated by orange arrow. G–G"–confocal image at wave front stained for TAg (red), VP1 (green), and DNA (blue), with orange arrow showing direction of wave. (Punctate, non-nuclear red stain represents nonspecific autofluorescence due to endogenous lipofuscin.) Scale bar in G" = 2 mm in top panels of A-E, 50 μm in bottom panels of A–D and in G–G" and 70 μm in F.</p