Aggressive Surveillance Is Needed to Detect Endoleaks and Junctional Separation between Device Components after Zenith Fenestrated Aortic Reconstruction

Background Junctional separation and resulting type IIIa endoleak is a well-known problem after EVAR (endovascular aneurysm repair). This complication results in sac pressurization, enlargement, and eventual rupture. In this manuscript, we review the incidence of this late finding in our experience with the Cook Zenith fenestrated endoprosthesis (ZFEN, Bloomington, IN). Methods A retrospective review was performed of a prospectively maintained institutional ZFEN fenestrated EVAR database capturing all ZFENs implanted at a large-volume, academic hospital system. Patients who experienced junctional separation between the fenestrated main body and distal bifurcated graft (with or without type IIIa endoleak) at any time after initial endoprosthesis implantation were subject to further evaluation of imaging and medical records to abstract clinical courses. Results In 110 ZFENs implanted from October 2012 to December 2017 followed for a mean of 1.5 years, we observed a 4.5% and 2.7% incidence of clinically significant junctional separation and type IIIa endoleak, respectively. Junctional separation was directly related to concurrent type Ib endoleak in all 5 patients. Three patients presented with sac enlargement. One patient did not demonstrate any evidence of clinically significant endoleak and had a decreasing sac size during follow-up imaging. The mean time to diagnosis of modular separation in these patients was 40 months. Junctional separation was captured in surveillance in 2 patients and reintervened upon before manifestation of endoleak. However, the remaining 3 patients completed modular separation resulting in rupture and emergent intervention in 2 and an aortic-related mortality in the other. Conclusions Junctional separation between the fenestrated main and distal bifurcated body with the potential for type IIIa endoleak is an established complication associated with the ZFEN platform. Therefore, we advocate for maximizing aortic overlap during the index procedure followed by aggressive surveillance and treatment of stent overlap loss captured on imaging

Dynamical Synapses Enhance Neural Information Processing: Gracefulness, Accuracy and Mobility

Experimental data have revealed that neuronal connection efficacy exhibits two forms of short-term plasticity, namely, short-term depression (STD) and short-term facilitation (STF). They have time constants residing between fast neural signaling and rapid learning, and may serve as substrates for neural systems manipulating temporal information on relevant time scales. The present study investigates the impact of STD and STF on the dynamics of continuous attractor neural networks (CANNs) and their potential roles in neural information processing. We find that STD endows the network with slow-decaying plateau behaviors-the network that is initially being stimulated to an active state decays to a silent state very slowly on the time scale of STD rather than on the time scale of neural signaling. This provides a mechanism for neural systems to hold sensory memory easily and shut off persistent activities gracefully. With STF, we find that the network can hold a memory trace of external inputs in the facilitated neuronal interactions, which provides a way to stabilize the network response to noisy inputs, leading to improved accuracy in population decoding. Furthermore, we find that STD increases the mobility of the network states. The increased mobility enhances the tracking performance of the network in response to time-varying stimuli, leading to anticipative neural responses. In general, we find that STD and STP tend to have opposite effects on network dynamics and complementary computational advantages, suggesting that the brain may employ a strategy of weighting them differentially depending on the computational purpose.Comment: 40 pages, 17 figure

A library of infectious hepatitis C viruses with engineered mutations in the E2 gene reveals growth-adaptive mutations that modulate interactions with scavenger receptor class B type I

While natural hepatitis C virus (HCV) infection results in highly diverse quasispecies of related viruses over time, mutations accumulate more slowly in tissue culture, in part because of the inefficiency of replication in cells. To create a highly diverse population of HCV particles in cell culture and identify novel growth-enhancing mutations, we engineered a library of infectious HCV with all codons represented at most positions in the ectodomain of the E2 gene. We identified many putative growth-adaptive mutations and selected nine highly represented E2 mutants for further study: Q412R, T416R, S449P, T563V, A579R, L619T, V626S, K632T, and L644I. We evaluated these mutants for changes in particle-to-infectious-unit ratio, sensitivity to neutralizing antibody or CD81 large extracellular loop (CD81-LEL) inhibition, entry factor usage, and buoyant density profiles. Q412R, T416R, S449P, T563V, and L619T were neutralized more efficiently by anti-E2 antibodies and T416R, T563V, and L619T by CD81-LEL. Remarkably, all nine variants showed reduced dependence on scavenger receptor class B type I (SR-BI) for infection. This shift from SR-BI usage did not correlate with a change in the buoyant density profiles of the variants, suggesting an altered E2-SR-BI interaction rather than changes in the virus-associated lipoprotein-E2 interaction. Our results demonstrate that residues influencing SR-BI usage are distributed across E2 and support the development of large-scale mutagenesis studies to identify viral variants with unique functional properties. IMPORTANCE Characterizing variant viruses can reveal new information about the life cycle of HCV and the roles played by different viral genes. However, it is difficult to recapitulate high levels of diversity in the laboratory because of limitations in the HCV culture system. To overcome this limitation, we engineered a library of mutations into the E2 gene in the context of an infectious clone of the virus. We used this library of viruses to identify nine mutations that enhance the growth rate of HCV. These growth-enhancing mutations reduced the dependence on a key entry receptor, SR-BI. By generating a highly diverse library of infectious HCV, we mapped regions of the E2 protein that influence a key virus-host interaction and provide proof of principle for the generation of large-scale mutant libraries for the study of pathogens with great sequence variability

Clustering in mixing flows

We calculate the Lyapunov exponents for particles suspended in a random three-dimensional flow, concentrating on the limit where the viscous damping rate is small compared to the inverse correlation time. In this limit Lyapunov exponents are obtained as a power series in epsilon, a dimensionless measure of the particle inertia. Although the perturbation generates an asymptotic series, we obtain accurate results from a Pade-Borel summation. Our results prove that particles suspended in an incompressible random mixing flow can show pronounced clustering when the Stokes number is large and we characterise two distinct clustering effects which occur in that limit.Comment: 5 pages, 1 figur

Calibration and Irradiation Study of the BGO Background Monitor for the BEAST II Experiment

Beam commissioning of the SuperKEKB collider began in 2016. The Beam Exorcism for A STable experiment II (BEAST II) project is particularly designed to measure the beam backgrounds around the interaction point of the SuperKEKB collider for the Belle II experiment. We develop a system using bismuth germanium oxide (BGO) crystals with optical fibers connecting to a multianode photomultiplier tube (MAPMT) and a field-programmable gate array (FPGA) embedded readout board for monitoring the real-time beam backgrounds in BEAST II. The overall radiation sensitivity of this system is estimated to be $(2.20\pm0.26)\times10^{-12}$ Gy/ADU (analog-to-digital unit) with the standard 10 m fibers for transmission and the MAPMT operating at 700 V. Our $\gamma$-ray irradiation study of the BGO system shows that the exposure of BGO crystals to $^{60}$Co $\gamma$-ray doses of 1 krad has led to immediate light output reductions of 25--40%, and the light outputs further drop by 30--45% after the crystals receive doses of 2--4 krad. Our findings agree with those of the previous studies on the radiation hard (RH) BGO crystals grown by the low thermal gradient Czochralski (LTG Cz) technology. The absolute dose from the BGO system is also consistent with the simulation, and is estimated to be about 1.18 times the equivalent dose. These results prove that the BGO system is able to monitor the background dose rate in real time under extreme high radiation conditions. This study concludes that the BGO system is reliable for the beam background study in BEAST II

Neutralization of Diverse Human Cytomegalovirus Strains Conferred by Antibodies Targeting Viral gH/gL/pUL128-131 Pentameric Complex

Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection, and developing a prophylactic vaccine is of high priority to public health. We recently reported a replication-defective human cytomegalovirus with restored pentameric complex glycoprotein H (gH)/gL/pUL128-131 for prevention of congenital HCMV infection. While the quantity of vaccine-induced antibody responses can be measured in a viral neutralization assay, assessing the quality of such responses, including the ability of vaccine-induced antibodies to cross-neutralize the field strains of HCMV, remains a challenge. In this study, with a panel of neutralizing antibodies from three healthy human donors with natural HCMV infection or a vaccinated animal, we mapped eight sites on the dominant virus-neutralizing antigen-the pentameric complex of glycoprotein H (gH), gL, and pUL128, pUL130, and pUL131. By evaluating the site-specific antibodies in vaccine immune sera, we demonstrated that vaccination elicited functional antiviral antibodies to multiple neutralizing sites in rhesus macaques, with quality attributes comparable to those of CMV hyperimmune globulin. Furthermore, these immune sera showed antiviral activities against a panel of genetically distinct HCMV clinical isolates. These results highlighted the importance of understanding the quality of vaccine-induced antibody responses, which includes not only the neutralizing potency in key cell types but also the ability to protect against the genetically diverse field strains. IMPORTANCE HCMV is the leading cause of congenital viral infection, and development of a preventive vaccine is a high public health priority. To understand the strain coverage of vaccine-induced immune responses in comparison with natural immunity, we used a panel of broadly neutralizing antibodies to identify the immunogenic sites of a dominant viral antigen-the pentameric complex. We further demonstrated that following vaccination of a replication-defective virus with the restored pentameric complex, rhesus macaques can develop broadly neutralizing antibodies targeting multiple immunogenic sites of the pentameric complex. Such analyses of site-specific antibody responses are imperative to our assessment of the quality of vaccine-induced immunity in clinical studies

Therapeutic efficacy of favipiravir against Bourbon virus in mice

Bourbon virus (BRBV) is an emerging tick-borne RNA virus in the orthomyxoviridae family that was discovered in 2014. Although fatal human cases of BRBV have been described, little is known about its pathogenesis, and no antiviral therapies or vaccines exist. We obtained serum from a fatal case in 2017 and successfully recovered the second human infectious isolate of BRBV. Next-generation sequencing of the St. Louis isolate of BRBV (BRBV-STL) showed >99% nucleotide identity to the original reference isolate. Using BRBV-STL, we developed a small animal model to study BRBV-STL tropism in vivo and evaluated the prophylactic and therapeutic efficacy of the experimental antiviral drug favipiravir against BRBV-induced disease. Infection of Ifnar1-/- mice lacking the type I interferon receptor, but not congenic wild-type animals, resulted in uniformly fatal disease 6 to 10 days after infection. RNA in situ hybridization and viral yield assays demonstrated a broad tropism of BRBV-STL with highest levels detected in liver and spleen. In vitro replication and polymerase activity of BRBV-STL were inhibited by favipiravir. Moreover, administration of favipiravir as a prophylaxis or as post-exposure therapy three days after infection prevented BRBV-STL-induced mortality in immunocompromised Ifnar1-/- mice. These results suggest that favipiravir may be a candidate treatment for humans who become infected with BRBV

Ionization near-zones associated with quasars at z ~ 6

We analyze the size evolution of HII regions around 27 quasars between z=5.7 to 6.4 ('quasar near-zones' or NZ). We include more sources than previous studies, and we use more accurate redshifts for the host galaxies, with 8 CO molecular line redshifts and 9 MgII redshifts. We confirm the trend for an increase in NZ size with decreasing redshift, with the luminosity normalized proper size evolving as: R_{NZ,corrected} = (7.4 \pm 0.3) - (8.0 \pm 1.1) \times (z-6) Mpc. While derivation of the absolute neutral fraction remains difficult with this technique, the evolution of the NZ sizes suggests a decrease in the neutral fraction of intergalactic hydrogen by a factor ~ 9.4 from z=6.4 to 5.7, in its simplest interpretation. Alternatively, recent numerical simulations suggest that this rapid increase in near-zone size from z=6.4 to 5.7 is due to the rapid increase in the background photo-ionization rate at the end of the percolation or overlap phase, when the average mean free path of ionizing photons increases dramatically. In either case, the results are consistent with the idea that z ~ 6 to 7 corresponds to the tail end of cosmic reionization. The scatter in the normalized NZ sizes is larger than expected simply from measurement errors, and likely reflects intrinsic differences in the quasars or their environments. We find that the near-zone sizes increase with quasar UV luminosity, as expected for photo-ionization dominated by quasar radiation.Comment: 16 pages, aas format, 4 figures, to appear in the ApJ letter

A simultaneous search for prompt radio emission associated with the short GRB 170112A using the all-sky imaging capability of the OVRO-LWA

We have conducted the most sensitive low frequency (below 100 MHz) search to date for prompt, low-frequency radio emission associated with short-duration gamma-ray bursts (GRBs), using the Owens Valley Radio Observatory Long Wavelength Array (OVRO-LWA). The OVRO-LWA's nearly full-hemisphere field-of-view ($\sim20$,$000$ square degrees) allows us to search for low-frequency (sub-$100$ MHz) counterparts for a large sample of the subset of GRB events for which prompt radio emission has been predicted. Following the detection of short GRB 170112A by Swift, we used all-sky OVRO-LWA images spanning one hour prior to and two hours following the GRB event to search for a transient source coincident with the position of GRB 170112A. We detect no transient source, with our most constraining $1\sigma$ flux density limit of $650~\text{mJy}$ for frequencies spanning $27~\text{MHz}-84~\text{MHz}$. We place constraints on a number of models predicting prompt, low-frequency radio emission accompanying short GRBs and their potential binary neutron star merger progenitors, and place an upper limit of $L_\text{radio}/L_\gamma \lesssim 7\times10^{-16}$ on the fraction of energy released in the prompt radio emission. These observations serve as a pilot effort for a program targeting a wider sample of both short and long GRBs with the OVRO-LWA, including bursts with confirmed redshift measurements which are critical to placing the most constraining limits on prompt radio emission models, as well as a program for the follow-up of gravitational wave compact binary coalescence events detected by advanced LIGO and Virgo.Comment: 14 pages, 5 figures, ApJ submitte

Detection of 1.6×10101.6\times 10^{10} M⊙_\odot of molecular gas in the host galaxy of the z=5.77z=5.77 SDSS quasar J0927+2001

We have detected emission by the CO 5-4 and 6-5 rotational transitions at $z = 5.7722\pm 0.0006$ from the host galaxy of the SDSS quasar J0927+2001 using the Plateau de Bure interferometer. The peak line flux density for the CO 5-4 line is $0.72 \pm 0.09$ mJy, with a line FWHM = $610 \pm 110$ km s$^{-1}$. The implied molecular gas mass is $(1.6 \pm 0.3) \times 10^{10}$ M$_\odot$. We also detect the 90 GHz continuum at $0.12 \pm 0.03$ mJy, consistent with a 47K dust spectrum extrapolated from higher frequencies. J0927+2001 is the second example of a huge molecular gas reservoir within the host galaxy of a quasar within 1 Gyr of the big bang. Observations of J0927+2001 are consistent with a massive starburst coeval with a bright quasar phase in the galaxy, suggesting the rapid formation of both a super-massive black hole through accretion, and the stellar host spheroid, at a time close to the end of cosmic reionization.Comment: 12 pages, 2 figures, to appear in ApJ Letter