Personal Protective Equipment and Antiviral Drug Use during Hospitalization for Suspected Avian or Pandemic Influenza1

In a pandemic, many current national stockpiles of PPE and antiviral medications are likely inadequate

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

New insights into the plasticity of the endothelial phenotype

The mammalian vascular system consists of two distinct, but closely related, networks: the blood vasculature (itself divided into arterial and venous networks) and the lymphatic vasculature. EC (endothelial cell) lineage specification has been proposed to be determined during embryonic development, after which the ECs are committed to their fate. However, increasing evidence suggests that ECs retain various degrees of plasticity, and have the ability to express characteristics of alternative cell lineages. Therapeutic control of endothelial plasticity will allow greater understanding of the genesis and treatment of several vascular diseases

Communication disorders in young children with cerebral palsy

Aim: To test the prediction of communication disorder severity at 5 years of age from characteristics at 2 years for children with cerebral palsy (CP) whose communication is giving cause for concern. Method: In this cohort study, 77 children (52 males; 25 females) with communication difficulties and CP were visited at home at 2 (mean 2y 4mo; SD 3mo) and 5 (mean 5y 5mo; SD 4mo) years of age. Information on the type and distribution of motor disorder, seizures, gross and fine motor function, hearing, and vision were collected from medical notes. Non-verbal cognition, language comprehension, language expression, spoken vocabulary, and methods of communication were assessed directly at age 2 years. At 5 years, communication and speech function were rated using the Communication Function Classification System (CFCS), Functional Communication Classification System (FCCS), and Viking Speech Scale (VSS). Results: In multivariable regression models, CP type, Gross Motor Function Classification System level, vision, the amount of speech understood by strangers, non-verbal cognition, and number of consonants produced at age 2 years predicted the CFCS level at age 5 years (R=0.54). CP type, Manual Ability Classification System level, amount of speech understood, vision, and number of consonants predicted the FCCS level (R=0.49). CP type, amount of speech understood by strangers, and number of consonants predicted the VSS level (R=0.50). Interpretation: Characteristics at 2 years of age predict communication and speech performance at 5 years, and should inform referral to speech and language therapy

Computational Modelling of Metastasis Development in Renal Cell Carcinoma

To improve our understanding of the biology of the metastatic colonization process, weconducted a modelling study based on multi-modal data from an orthotopic murine experimentalsystem of metastatic renal cell carcinoma. The standard theory of metastatic colonization usuallyassumes that secondary tumours, once established at a distant site, grow independently from eachother and from the primary tumour. Using a mathematical model describing the metastaticpopulation dynamics under this assumption, we challenged the theory against our data thatincluded: 1) dynamics of primary tumour cells in the kidney and metastatic cells in the lungs,retrieved by green fluorescent protein tracking, and 2) magnetic resonance images (MRI) informingon the number and size of macroscopic lesions. While the model could fit the primary tumour andtotal metastatic burden, the predicted size distribution was not in agreement with the MRIobservations. Moreover, the model was incompatible with the growth rates of individual metastatictumours.To explain the observed metastatic patterns, we hypothesised that metastatic foci derivedfrom one or a few cells could aggregate, resulting in a similar total mass but a smaller number ofmetastases. This was indeed observed in our data and led us to investigate the effect of spatialinteractions on the dynamics of the global metastatic burden. We derived a novel mathematicalmodel for spatial tumour growth, where the intra-tumour increase in pressure is responsible for theslowdown of the growth rate. The model could fit the growth of lung metastasis visualized bymagnetic resonance imaging. As a non-trivial outcome from this analysis, the model predicted thatthe net growth of two neighbouring tumour lesions that enter in contact is considerably impaired (of31% ± 1.5%, mean ± standard deviation), as compared to the growth of two independent tumours.Together, our results have implications for theories of metastatic development and suggest thatglobal dynamics of metastasis development is dependent on spatial interactions between metastaticlesions

A novel subgroup of rhadinoviruses in ruminants

In the course of investigating the malignant catarrhal fever (MCF) subgroup of rhadinoviruses, seven novel rhadinoviruses were identified in a variety of ruminants, including domestic sheep, bighorn sheep, bison, black-tailed deer, mule deer, fallow deer, elk and addax. Based on the DNA polymerase gene sequences, these newly recognized viruses clustered into a second distinct subgroup in ruminants with three members identified previously in cattle, goats and oryx. Phylogenetic analysis revealed that the currently known ruminant rhadinoviruses appear to comprise three distinct genetic lineages: (i) the MCF subgroup, defined by sequence identity and the presence of the 15A antigenic epitope; (ii) a second distinct subgroup, devoid of the 15A epitope, which contains the previously reported bovine lymphotropic herpesvirus and related viruses; and (iii) a third distinct subgroup represented by Bovine herpesvirus 4. Comparison of phylogenetic trees between the rhadinoviruses and their corresponding hosts further supports the gammaherpesvirus and host co-evolution theory

Spatial model fitting.

<p>(A) Top: Coronal MRI data of the lungs at days 19 and 26. Bottom: the simulated growth by the model using the fitted parameters and starting from the real shape of the observed metastasis at day 19 on the coronal MRI slice. Simulations were obtained using Eqs <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004626#pcbi.1004626.e006" target="_blank">4</a>–<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004626#pcbi.1004626.e009" target="_blank">7</a> with the following parameter values: <i>γ</i>₀ = 0.78 day^-1; <i>Π</i>₀ = 0.0026 Pa; Time of simulation: T = 7 days (B) Volumes compared to simulations by the fitted model for the growth of four individual metastasis. The fits were performed on the volume only, considering the metastases as spherical.</p

Time course of the macro-metastases size distribution: standard model versus observations.

<p>(A) Top row: Simulation of the mathematical formalism of the standard theory (i.e. dissemination and independent growth of the resulting tumour foci), using the parameter values inferred from the data of the total metastatic burden (total GFP signal in the lungs). Only tumours larger than the visible threshold at MRI (0.05 mm³) are plotted. Simulations were obtained using Eqs <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004626#pcbi.1004626.e001" target="_blank">1</a> and <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004626#pcbi.1004626.e003" target="_blank">2</a> for the time evolution of the density of secondary tumours, endowed with a lognormal distribution of the parameters for inter-animal variability, with the following values (retrieved from the population mixed-effects fit, median ± standard deviation): λ = 0.679 <i>α</i> = 0.417 ± 0.171 day^-1, <i>β</i> = 0.106 ± 0.0478 day^-1 and <i>μ</i> = 9.72 × 10⁻⁶ ± 0.428 × 10⁻⁶ cell∙day^-1. Shown are the results of 1000 simulations, mean + standard deviation. Bottom row: Observations of macro-metastases numbers and sizes in one mouse on MRI data. (B) Comparison of several metrics derived from the metastatic size distributions. For the model, numbers are represented as mean value and standard deviation in parenthesis. The data corresponds to the mouse presented in the upper histogram. (C) Comparison of the largest metastatic size at day 19 between model (<i>n =</i> 1000 simulated animals) and observations (<i>n =</i> 6 animals), log scale. The observed largest metastases are significantly larger than simulated ones (<i>p</i> < 10^-5 by the z-test).</p