Background. Ebolavirus and Marburgvirus cause severe hemorrhagic fever with high mortality and are potential bioterrorism agents. There are no available vaccines or therapeutic agents. Previous ...clinical trials evaluated transmembrane-deleted and point-mutation Ebolavirus glycoproteins (GPs) in candidate vaccines. Constructs evaluated in this trial encode wild-type (WT) GP from Ebolavirus Zaire and Sudan species and the Marburgvirus Angola strain expressed in a DNA vaccine. Methods. The VRC 206 study evaluated the safety and immunogenicity of these DNA vaccines (4 mg administered intramuscularly by Biojector) at weeks 0, 4, and 8, with a homologous boost at or after week 32. Safety evaluations included solicited reactogenicity and coagulation parameters. Primary immune assessment was done by means of GP-specific enzyme-linked immunosorbent assay. Results. The vaccines were well tolerated, with no serious adverse events; 80% of subjects had positive enzymelinked immunosorbent assay results (≥30) at week 12. The fourth DNA vaccination boosted the immune responses. Conclusions. The investigational Ebolavirus and Marburgvirus WT GP DNA vaccines were safe, well tolerated, and immunogenic in this phase I study. These results will further inform filovirus vaccine research toward a goal of inducing protective immunity by using WT GP antigens in candidate vaccine regimens.
Summary
VRC‐HIVMAB060‐00‐AB (VRC01) is a broadly neutralizing HIV‐1 monoclonal antibody (mAb) isolated from the B cells of an HIV‐infected patient. It is directed against the HIV‐1 CD4 binding site ...and is capable of potently neutralizing the majority of diverse HIV‐1 strains. This Phase I dose‐escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose‐limiting toxicities. Mean 28‐day serum trough concentrations after the first infusion were 35 and 57 μg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28‐day trough concentrations after the second infusion were 56 and 89 μg/ml for the same two doses. Over the 5–40 mg/kg i.v. dose range (n = 18), the clearance was 0·016 l/h and terminal half‐life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti‐VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half‐life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV‐1 prevention efficacy studies.
The prototypical genetic autoimmune disease is immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a severe pediatric disease with limited treatment options. IPEX syndrome ...is caused by mutations in the forkhead box protein 3 (
) gene, which plays a critical role in immune regulation. As a monogenic disease, IPEX is an ideal candidate for a therapeutic approach in which autologous hematopoietic stem and progenitor (HSPC) cells or T cells are gene edited ex vivo and reinfused. Here, we describe a CRISPR-based gene correction permitting regulated expression of FOXP3 protein. We demonstrate that gene editing preserves HSPC differentiation potential, and that edited regulatory and effector T cells maintain their in vitro phenotype and function. Additionally, we show that this strategy is suitable for IPEX patient cells with diverse mutations. These results demonstrate the feasibility of gene correction, which will be instrumental for the development of therapeutic approaches for other genetic autoimmune diseases.
Polymorphisms of Th1-Th2 cytokine genes have previously been implicated in the rate of progression to AIDS in seropositive patients. To evaluate further the impact of these genes in the development ...of AIDS, we have performed an extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNgamma. The coding regions and promoters of these genes were sequenced in a Caucasian cohort of 337 HIV-1 seropositive extreme patients (the GRIV cohort) consisting of patients with slow progression and rapid progression, and up to 470 healthy controls. In all, 64 single nucleotide polymorphisms (SNPs) and four deleterious polymorphisms with frequency >1% were identified and evaluated for their association with disease. Statistically significant associations were observed with haplotypes of the IL4 and IL10 genes, but no relation was found with variants of other genes. The catalogue of SNP and haplotypes presented here will facilitate further genetic investigations of Th1-Th2 cytokines in AIDS and other immune-related disorders.
In a companion paper by Koposov et al., RR Lyrae from Gaia Data Release 2 are used to demonstrate that stars in the Orphan stream have velocity vectors significantly misaligned with the stream track, ...suggesting that it has received a large gravitational perturbation from a satellite of the Milky Way. We argue that such a mismatch cannot arise due to any realistic static Milky Way potential and then explore the perturbative effects of the Large Magellanic Cloud (LMC). We find that the LMC can produce precisely, the observed motion-track mismatch and we therefore use the Orphan stream to measure the mass of the Cloud. We simultaneously fit the Milky Way and LMC potentials and infer that a total LMC mass of |$1.38^{+0.27}_{-0.24} \times 10^{11}\, \rm {M_\odot}$| is required to bend the Orphan stream, showing for the first time that the LMC has a large and measurable effect on structures orbiting the Milky Way. This has far-reaching consequences for any technique which assumes that tracers are orbiting a static Milky Way. Furthermore, we measure the Milky Way mass within 50 kpc to be |$3.80^{+0.14}_{-0.11}\times 10^{11} \, \mathrm{M}_\odot$|. Finally, we use these results to predict that, due to the reflex motion of the Milky Way in response to the LMC, the outskirts of the Milky Way’s stellar halo should exhibit a bulk, upwards motion.
A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear ...Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons ACCF Multimodality Appropriate Use Criteria for the Detection and Risk Assessment of Ischemic Heart Disease Writing Group, Technical Panel, Task Force, and Indication Reviewers...Relationships With Industry and Other Entities (Relevant)... .403 Abstract The American College of Cardiology Foundation along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical presentations for stable ischemic heart disease (SIHD) to consider use of stress testing and anatomic diagnostic procedures. The use of some modalities of testing in the initial evaluation of patients with symptoms representing ischemic equivalents, newly diagnosed heart failure, arrhythmias, and syncope was generally found to be Appropriate or May Be Appropriate, except in cases where low pre-test probability or low risk limited the benefit of most testing except exercise electrocardiogram (ECG).
Abstract
We use astrometry, broad-band photometry, and variability information from the Data Release 2 of ESA’s Gaia mission (GDR2) to identify members of the Orphan Stream (OS) across the whole sky. ...The stream is traced above and below the celestial equator and in both Galactic hemispheres, thus increasing its visible length to ∼210° equivalent to ∼150 kpc in physical extent. Taking advantage of the large number of RR Lyrae stars in the OS, we extract accurate distances and proper motions across the entire stretch of the tidal debris studied. As delineated by the GDR2 RR Lyrae, the stream exhibits two prominent twists in its shape on the sky which are accompanied by changes in the tangential motion. We complement the RR Lyrae maps with those created using GDR2 Red Giants and the DECam Legacy Survey Main Sequence Turn-Off stars. The behaviour of the OS track on the sky is consistent across all three tracers employed. We detect a strong non-zero motion in the across-stream direction for a substantial portion of the stream. Such a misalignment between the debris track and the streaming velocity cannot be reproduced in a static gravitational potential and signals an interaction with a massive perturber.
Over the last 20 years, nuclear cardiology has become a mainstay in the evaluation of ischemic heart disease. In the setting of acute coronary syndromes (myocardial infarction or unstable angina), ...myocardial perfusion imaging has emerged as an important tool in assessing the functional significance of angiographic coronary stenoses, evaluating the efficacy of therapeutic interventions, and risk-stratifying patients in the postinfarction period. Recent literature has demonstrated the diagnostic and prognostic value, as well as the cost-effectiveness, of perfusion imaging in acute chest pain syndromes and the diagnostic superiority of perfusion imaging compared with two-dimensional echocardiography. Acute perfusion imaging is now being included in the algorithm for the triage and management of acute chest pain syndromes. Emergency physicians are increasingly using nuclear cardiac imaging modalities for aid in the evaluation of patients who present with chest pain of uncertain origin. Kim SC, Adams SL, Hendel RC: Role of nuclear cardiology in the evaluation of acute coronary syndromes.
Ann Emerg Med August 1997;30:210-218.
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