Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia.

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112?151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.Molecular Psychiatry advance online publication, 26 January 2016; doi:10.1038/mp.2015.225

Late Ebola virus relapse causing meningoencephalitis: a case report

Background: There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods: A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings: On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation: Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern

Coherent Photoproduction of pi^+ from 3^He

We have measured the differential cross section for the $\gamma$$^3$He$\rightarrow \pi^+ t$ reaction. This reaction was studied using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Lab. Real photons produced with the Hall-B bremsstrahlung tagging system in the energy range from 0.50 to 1.55 GeV were incident on a cryogenic liquid $^3$He target. The differential cross sections for the $\gamma$$^3$He$\rightarrow \pi^+ t$ reaction were measured as a function of photon-beam energy and pion-scattering angle. Theoretical predictions to date cannot explain the large cross sections except at backward angles, showing that additional components must be added to the model.Comment: 11 pages, 16 figure

Prioritisation of Anti-SARS-Cov-2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics.

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, EC90 values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentrations (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax/EC50 as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8- and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials

Observation of exclusive DVCS in polarized electron beam asymmetry measurements

We report the first results of the beam spin asymmetry measured in the reaction e + p -> e + p + gamma at a beam energy of 4.25 GeV. A large asymmetry with a sin(phi) modulation is observed, as predicted for the interference term of Deeply Virtual Compton Scattering and the Bethe-Heitler process. The amplitude of this modulation is alpha = 0.202 +/- 0.028. In leading-order and leading-twist pQCD, the alpha is directly proportional to the imaginary part of the DVCS amplitude.Comment: 6 pages, 5 figure

Electron Scattering From High-Momentum Neutrons in Deuterium

We report results from an experiment measuring the semi-inclusive reaction $d(e,e'p_s)$ where the proton $p_s$ is moving at a large angle relative to the momentum transfer. If we assume that the proton was a spectator to the reaction taking place on the neutron in deuterium, the initial state of that neutron can be inferred. This method, known as spectator tagging, can be used to study electron scattering from high-momentum (off-shell) neutrons in deuterium. The data were taken with a 5.765 GeV electron beam on a deuterium target in Jefferson Laboratory's Hall B, using the CLAS detector. A reduced cross section was extracted for different values of final-state missing mass $W^{*}$, backward proton momentum $\vec{p}_{s}$ and momentum transfer $Q^{2}$. The data are compared to a simple PWIA spectator model. A strong enhancement in the data observed at transverse kinematics is not reproduced by the PWIA model. This enhancement can likely be associated with the contribution of final state interactions (FSI) that were not incorporated into the model. A ``bound neutron structure function'' $F_{2n}^{eff}$ was extracted as a function of $W^{*}$ and the scaling variable $x^{*}$ at extreme backward kinematics, where effects of FSI appear to be smaller. For $p_{s}>400$ MeV/c, where the neutron is far off-shell, the model overestimates the value of $F_{2n}^{eff}$ in the region of $x^{*}$ between 0.25 and 0.6. A modification of the bound neutron structure function is one of possible effects that can cause the observed deviation.Comment: 33 pages RevTeX, 9 figures, to be submitted to Phys. Rev. C. Fixed 1 Referenc

Complete measurement of three-body photodisintegration of 3He for photon energies between 0.35 and 1.55 GeV

The three-body photodisintegration of 3He has been measured with the CLAS detector at Jefferson Lab, using tagged photons of energies between 0.35 GeV and 1.55 GeV. The large acceptance of the spectrometer allowed us for the first time to cover a wide momentum and angular range for the two outgoing protons. Three kinematic regions dominated by either two- or three-body contributions have been distinguished and analyzed. The measured cross sections have been compared with results of a theoretical model, which, in certain kinematic ranges, have been found to be in reasonable agreement with the data.Comment: 22 pages, 25 eps figures, 2 tables, submitted to PRC. Modifications: removed 2 figures, improvements on others, a few minor modifications to the tex

A Kinematically Complete Measurement of the Proton Structure Function F2 in the Resonance Region and Evaluation of Its Moments

We measured the inclusive electron-proton cross section in the nucleon resonance region (W < 2.5 GeV) at momentum transfers Q**2 below 4.5 (GeV/c)**2 with the CLAS detector. The large acceptance of CLAS allowed for the first time the measurement of the cross section in a large, contiguous two-dimensional range of Q**2 and x, making it possible to perform an integration of the data at fixed Q**2 over the whole significant x-interval. From these data we extracted the structure function F2 and, by including other world data, we studied the Q**2 evolution of its moments, Mn(Q**2), in order to estimate higher twist contributions. The small statistical and systematic uncertainties of the CLAS data allow a precise extraction of the higher twists and demand significant improvements in theoretical predictions for a meaningful comparison with new experimental results.Comment: revtex4 18 pp., 12 figure

eta-prime photoproduction on the proton for photon energies from 1.527 to 2.227 GeV

Differential cross sections for the reaction gamma p -> eta-prime p have been measured with the CLAS spectrometer and a tagged photon beam with energies from 1.527 to 2.227 GeV. The results reported here possess much greater accuracy than previous measurements. Analyses of these data indicate for the first time the coupling of the etaprime N channel to both the S_11(1535) and P_11(1710) resonances, known to couple strongly to the eta N channel in photoproduction on the proton, and the importance of j=3/2 resonances in the process.Comment: 6 pages, 3 figure