A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis.

The efficacy and safety of rivipansel, a predominantly E-selectin antagonist, were studied in a phase 3, randomized, controlled trial for vaso-occlusive crisis (VOC) requiring hospitalization (RESET). A total of 345 subjects (204 adults and 141 children) were randomized and 320 were treated (162 with rivipansel, 158 with placebo) with an IV loading dose, followed by up to 14 additional 12-hourly maintenance doses of rivipansel or placebo, in addition to standard care. Rivipansel was similarly administered during subsequent VOCs in the Open-label Extension (OLE) study. In the full analysis population, the median time to readiness for discharge (TTRFD), the primary end point, was not different between rivipansel and placebo (-5.7 hours, P = .79; hazard ratio, 0.97), nor were differences seen in secondary end points of time to discharge (TTD), time to discontinuation of IV opioids (TTDIVO), and cumulative IV opioid use. Mean soluble E-selectin decreased 61% from baseline after the loading dose in the rivipansel group, while remaining unchanged in the placebo group. In a post hoc analysis, early rivipansel treatment within 26.4 hours of VOC pain onset (earliest quartile of time from VOC onset to treatment) reduced median TTRFD by 56.3 hours, reduced median TTD by 41.5 hours, and reduced median TTDIVO by 50.5 hours, compared with placebo (all P < .05). A similar subgroup analysis comparing OLE early-treatment with early-treatment RESET placebo showed a reduction in TTD of 23.1 hours (P = .062) and in TTDIVO of 30.1 hours (P = .087). Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE).

Hosing of a Long Relativistic Particle Bunch in Plasma.

Experimental results show that hosing of a long particle bunch in plasma can be induced by wakefields driven by a short, misaligned preceding bunch. Hosing develops in the plane of misalignment, self-modulation in the perpendicular plane, at frequencies close to the plasma electron frequency, and are reproducible. Development of hosing depends on misalignment direction, its growth on misalignment extent and on proton bunch charge. Results have the main characteristics of a theoretical model, are relevant to other plasma-based accelerators and represent the first characterization of hosing.

Pharmacokinetics of ivermectin after oral and intravenous administration in Bilgorajska geese (Anser anser domesticus).

AIMS: To assess the pharmacokinetic profile of ivermectin in Bilgorajska geese (Anser anser domesticus) after single I/V or oral administration, in order to compare these routes of administration and assess oral bioavailability. METHODS: Ten healthy male geese were used in a single-dose, two-phase study with a 3-month washout period between phases. In the first phase, all geese were given 0.2 mg/kg I/V ivermectin, while in the second phase they were treated orally with the same dosage. Blood samples were collected at selected time points up to 480 hours after each administration. Samples were purified using protein precipitation and drug concentration was quantified using HPLC. The analytical method was validated on blank goose plasma and was characterised by an optimal linearity and a limit of quantification of 0.025 µg/mL. The pharmacokinetic analysis was carried out using a non-compartmental approach. RESULTS: The drug was quantifiable up to 240 hours after I/V administration, while after oral treatment it was quantifiable up to 144 hours in most of the geese. The elimination half-life of ivermectin was approximately 3.8 (95% CI = 1.98-7.92; p = 0.027) times higher after I/V administration compared to oral administration. Moreover, the area under the curve from zero to the last detectable timepoint was 6.4 (95% CI = 4.65-8.74; p < 0.001) hours greater after I/V than oral administration. This difference led to a bioavailability of 20.38 (SD 5.92) %. CONCLUSIONS: Following oral administration in geese, ivermectin has a bioavailability of approximately 20%. Further research on the action of ivermectin in the gastrointestinal tract is required along with assessment of tissue residues to allow calculation of withdrawal time to ensure consumer safety. ABBREVIATIONS: AUC: Area under the concentration-time curve; AUClast: Area under the curve from zero to the last detectable timepoint; AUMC: Area under the first moment curve; Cmax: Maximum concentration; Tmax: Time at maximum plasma concentration.

Transition between Instability and Seeded Self-Modulation of a Relativistic Particle Bunch in Plasma.

We use a relativistic ionization front to provide various initial transverse wakefield amplitudes for the self-modulation of a long proton bunch in plasma. We show experimentally that, with sufficient initial amplitude [≥(4.1±0.4) MV/m], the phase of the modulation along the bunch is reproducible from event to event, with 3%-7% (of 2π) rms variations all along the bunch. The phase is not reproducible for lower initial amplitudes. We observe the transition between these two regimes. Phase reproducibility is essential for deterministic external injection of particles to be accelerated.

Proton-driven plasma wakefield acceleration in AWAKE.

In this article, we briefly summarize the experiments performed during the first run of the Advanced Wakefield Experiment, AWAKE, at CERN (European Organization for Nuclear Research). The final goal of AWAKE Run 1 (2013-2018) was to demonstrate that 10-20 MeV electrons can be accelerated to GeV energies in a plasma wakefield driven by a highly relativistic self-modulated proton bunch. We describe the experiment, outline the measurement concept and present first results. Last, we outline our plans for the future. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Genomic characterization of key bacteriophages to formulate the potential biocontrol agent to combat enteric pathogenic bacteria.

Combating bacterial pathogens has become a global concern especially when the antibiotics and chemical agents are failing to control the spread due to its resistance. Bacteriophages act as a safe biocontrol agent by selectively lysing the bacterial pathogens without affecting the natural beneficial microflora. The present study describes the screening of prominent enteric pathogens NDK1, NDK2, NDK3, and NDK4 (Escherichia, Klebsiella, Enterobacter, and Serratia) mostly observed in domestic wastewater; against which KNP1, KNP2, KNP3, and KNP4 phages were isolated. To analyze their potential role in eradicating enteric pathogens and toxicity issue, these bacteriophages were sequenced using next-generation sequencing and characterized based on its genomic content. The isolated bacteriophages were homologous to Escherichia phage (KNP1), Klebsiella phage (KNP2), Enterobacter phage (KNP3), Serratia phage (KNP4), and belonged to Myoviridae family of Caudovirales except for the unclassified KNP4 phage. Draft genome analysis revealed the presence of lytic enzymes such as holing and lysozyme in KNP1 phage, endolysin in KNP2 phage, and endopeptidase with holin in KNP3 phage. The absence of any lysogenic and virulent genes makes this bacteriophage suitable candidate for preparation of phage cocktail to combat the pathogens present in wastewater. However, KNP4 contained a virulent gene rendering it unsuitable to be used as a biocontrol agent. These findings make the phages (KNP1-KNP3) as a promising alternative for the biocontrol of pathogens in wastewater which is the main culprit to spread these dominated pathogens in different natural water bodies. This study also necessitates for genomic screening of bacteriophages for lysogenic and virulence genes prior to its use as a biocontrol agent.

Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study.

Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-ß) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-ß treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-ß-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5).

Canards in a minimal piecewise-linear square-wave burster.

We construct a piecewise-linear (PWL) approximation of the Hindmarsh-Rose (HR) neuron model that is minimal, in the sense that the vector field has the least number of linearity zones, in order to reproduce all the dynamics present in the original HR model with classical parameter values. This includes square-wave bursting and also special trajectories called canards, which possess long repelling segments and organise the transitions between stable bursting patterns with n and n + 1 spikes, also referred to as spike-adding canard explosions. We propose a first approximation of the smooth HR model, using a continuous PWL system, and show that its fast subsystem cannot possess a homoclinic bifurcation, which is necessary to obtain proper square-wave bursting. We then relax the assumption of continuity of the vector field across all zones, and we show that we can obtain a homoclinic bifurcation in the fast subsystem. We use the recently developed canard theory for PWL systems in order to reproduce the spike-adding canard explosion feature of the HR model as studied, e.g., in Desroches et al., Chaos 23(4), 046106 (2013).

Filamentation of a relativistic proton bunch in plasma.

We show in experiments that a long, underdense, relativistic proton bunch propagating in plasma undergoes the oblique instability, which we observe as filamentation. We determine a threshold value for the ratio between the bunch transverse size and plasma skin depth for the instability to occur. At the threshold, the outcome of the experiment alternates between filamentation and self-modulation instability (evidenced by longitudinal modulation into microbunches). Time-resolved images of the bunch density distribution reveal that filamentation grows to an observable level late along the bunch, confirming the spatiotemporal nature of the instability. We provide a rough estimate of the amplitude of the magnetic field generated in the plasma by the instability and show that the associated magnetic energy increases with plasma density.

Inflection, canards and excitability threshold in neuronal models.

A technique is presented, based on the differential geometry of planar curves, to evaluate the excitability threshold of neuronal models. The aim is to determine regions of the phase plane where solutions to the model equations have zero local curvature, thereby defining a zero-curvature (inflection) set that discerns between sub-threshold and spiking electrical activity. This transition can arise through a Hopf bifurcation, via the so-called canard explosion that happens in an exponentially small parameter variation, and this is typical for a large class of planar neuronal models (FitzHugh-Nagumo, reduced Hodgkin-Huxley), namely, type II neurons (resonators). This transition can also correspond to the crossing of the stable manifold of a saddle equilibrium, in the case of type I neurons (integrators). We compute inflection sets and study how well they approximate the excitability threshold of these neuron models, that is, both in the canard and in the non-canard regime, using tools from invariant manifold theory and singularity theory. With the latter, we investigate the topological changes that inflection sets undergo upon parameter variation. Finally, we show that the concept of inflection set gives a good approximation of the threshold in both the so-called resonator and integrator neuronal cases.

Interleukin 6-174G>C polymorphism and risk of aneurysmal subarachnoid hemorrhage: case-control study and meta-analysis.

OBJECTIVES: Vascular inflammation contributes to the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH). Interleukin 6 (IL6) is a proinflammatory cytokine involved in many vascular pathologies. Two studies analyzing an association of the functional IL6 gene -174G>C promoter polymorphism with aSAH provided inconsistent results. The aim of this study was to investigate whether this IL6 polymorphism is associated with aSAH in a Polish population. MATERIAL AND METHODS: We genotyped 276 aSAH patients and 581 unrelated control subjects. All were of Caucasian origin. In addition, a meta-analysis combining results of the current and previously published studies was conducted. RESULTS: The distribution of IL6 genotypes and alleles did not differ significantly between aSAH (GG - 29.7%, GC - 50.0%, CC - 20.2%, G - 54.7%) and control subjects (GG - 32.0%, GC - 47.3%, CC - 20.7%, G - 44.3%). In the meta-analysis, the IL6-174G>C polymorphism was not associated with aSAH risk either. CONCLUSIONS: We failed to find an association between the IL6 -174G>C polymorphism and aSAH in analyzed European populations.

Peripheral arterial tonometry in assessing endothelial dysfunction in pediatric sickle cell disease.

BACKGROUND: SCD is characterized by hemolysis and oxidative stress, resulting in endothelial dysfunction (EDF). Peripheral arterial tonometry (PAT), a noninvasive technology for measuring EDF, utilizes reactive hyperemia following mini-ischemic stress (reactive hyperemia index or RHI). METHODS: The authors studied PAT in 36 SCD children to determine the influence of hemoglobin genotype and treatment on EDF. RESULTS AND CONCLUSIONS: Blunted RHI was seen in the majority of children with SCD, especially with increased symptomatology (1.53 and 1.71; p value .032). RHI was not normal in children on chronic transfusion or hydroxyurea. RHI correlated with reticulocyte fraction (Spearman r = -.47, p = .037). PAT merits further exploration as a measure of EDF in SCD.

It Is Not Necessary to Discontinue Seizure Threshold-Lowering Medications Prior to Myelography.

BACKGROUND AND PURPOSE: There is no consensus on whether patients undergoing myelography should discontinue medications that could lower their seizure threshold. The purpose of this study was to document the most commonly prescribed seizure threshold-lowering medications in patients undergoing myelography and determine whether withholding such medications decreases the incidence of seizures. MATERIALS AND METHODS: We performed a retrospective observational study of all the myelograms obtained in 2016 at 2 affiliated hospitals. At hospital A, seizure threshold-lowering medications are discontinued before myelography, and prophylactic diazepam is given for all cervical myelograms. At hospital B, seizure threshold-lowering medications are not withheld before the procedure, and medical seizure prophylaxis is not implemented. The seizure threshold-lowering medications the patients were taking at the time of the procedure and postmyelographic seizure incidence were documented. RESULTS: A total of 311 patients underwent myelography during 2016. One hundred eleven patients (36%) were on at least 1 seizure threshold-lowering medication, and 30 (10%) were on at least 2. The most common medications were duloxetine, sertraline, venlafaxine, bupropion, and trazodone. The most common tricyclic antidepressant was amitriptyline. Three patients across both sites had a controlled seizure disorder and were on antiepileptics. None of the patients at either hospital had seizures during or within 3 hours following any of the myelograms during the study period. CONCLUSIONS: Continuing seizure threshold-lowering medications during myelography does not increase the risk of seizures. Screening for and withholding seizure threshold-lowering medications are not indicated for routine myelography.

High-frequency forced oscillations in neuronlike elements.

We analyzed a generic relaxation oscillator under moderately strong forcing at a frequency much greater that the natural intrinsic frequency of the oscillator. Additionally, the forcing is of the same sign and, thus, has a nonzero average, matching neuroscience applications. We found that, first, the transition to high-frequency synchronous oscillations occurs mostly through periodic solutions with virtually no chaotic regimes present. Second, the amplitude of the high-frequency oscillations is large, suggesting an important role for these oscillations in applications. Third, the 1:1 synchronized solution may lose stability, and, contrary to other cases, this occurs at smaller, but not at higher frequency differences between intrinsic and forcing oscillations. We analytically built a map that gives an explanation of these properties. Thus, we found a way to substantially "overclock" the oscillator with only a moderately strong external force. Interestingly, in application to neuroscience, both excitatory and inhibitory inputs can force the high-frequency oscillations.

Ducks in space: from nonlinear absolute instability to noise-sustained structures in a pattern-forming system.

A subcritical pattern-forming system with nonlinear advection in a bounded domain is recast as a slow-fast system in space and studied using a combination of geometric singular perturbation theory and numerical continuation. Two types of solutions describing the possible location of stationary fronts are identified, whose origin is traced to the onset of convective and absolute instability when the system is unbounded. The former are present only for non-zero upstream boundary conditions and provide a quantitative understanding of noise-sustained structures in systems of this type. The latter correspond to the onset of a global mode and are present even with zero upstream boundary conditions. The role of canard trajectories in the nonlinear transition between these states is clarified and the stability properties of the resulting spatial structures are determined. Front location in the convective regime is highly sensitive to the upstream boundary condition, and its dependence on this boundary condition is studied using a combination of numerical continuation and Monte Carlo simulations of the partial differential equation. Statistical properties of the system subjected to random or stochastic boundary conditions at the inlet are interpreted using the deterministic slow-fast spatial dynamical system.

Control of Multidrug-Resistant Gene Flow in the Environment Through Bacteriophage Intervention.

The spread of multidrug-resistant (MDR) bacteria is an emerging threat to the environment and public wellness. Inappropriate use and indiscriminate release of antibiotics in the environment through un-metabolized form create a scenario for the emergence of virulent pathogens and MDR bugs in the surroundings. Mechanisms underlying the spread of resistance include horizontal and vertical gene transfers causing the transmittance of MDR genes packed in different host, which pass across different food webs. Several controlling agents have been used for combating pathogens; however, the use of lytic bacteriophages proves to be one of the most eco-friendly due to their specificity, killing only target bacteria without damaging the indigenous beneficial flora of the habitat. Phages are part of the natural microflora present in different environmental niches and are remarkably stable in the environment. Diverse range of phage products, such as phage enzymes, phage peptides having antimicrobial properties, and phage cocktails also have been used to eradicate pathogens along with whole phages. Recently, the ability of phages to control pathogens has extended from the different areas of medicine, agriculture, aquaculture, food industry, and into the environment. To avoid the arrival of pre-antibiotic epoch, phage intervention proves to be a potential option to eradicate harmful pathogens generated by the MDR gene flow which are uneasy to cure by conventional treatments.

Intriguing Interaction of Bacteriophage-Host Association: An Understanding in the Era of Omics.

Innovations in next-generation sequencing technology have introduced new avenues in microbial studies through "omics" approaches. This technology has considerably augmented the knowledge of the microbial world without isolation prior to their identification. With an enormous volume of bacterial "omics" data, considerable attempts have been recently invested to improve an insight into virosphere. The interplay between bacteriophages and their host has created a significant influence on the biogeochemical cycles, microbial diversity, and bacterial population regulation. This review highlights various concepts such as genomics, transcriptomics, proteomics, and metabolomics to infer the phylogenetic affiliation and function of bacteriophages and their impact on diverse microbial communities. Omics technologies illuminate the role of bacteriophage in an environment, the influences of phage proteins on the bacterial host and provide information about the genes important for interaction with bacteria. These investigations will reveal some of bio-molecules and biomarkers of the novel phage which demand to be unveiled.

Transient Sensitivity of Rat Cerebellar Purkinje Cells to N-methyl-D-aspartate during Development. A Voltage Clamp Study in in vitro Slices.

In vitro sagittal slices of immature rat cerebellum were used to study the development of the sensitivity of Purkinje cells (PC) to L-glutamate (Glu) and N-methyl-D-aspartate (NMDA). In 8-day-old animals, all PCs recorded in magnesium-free medium responded to iontophoretic applications of both agonists by transient and dose dependent inward currents which, in both cases, were heavily contaminated by a Glu and NMDA-induced synaptic noise. When 5 x 10-6 M tetrodotoxin (TTX) was added to the perfusing medium, this evoked synaptic noise was completely abolished in most cells whereas clear-cut inward currents induced in PCs by Glu and NMDA applications on their dendrites were still visible. These responses were selectively antagonized by the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and by the NMDA receptor antagonist D-2-aminophosphono-5-valeric acid (2APV) respectively. Excitatory responses induced by aspartate in 8 - 10-day-old PCs were also markedly antagonized by CNQX. At this stage, the sensitivity of PCs to NMDA was about one order of magnitude less than that to Glu. In 15 - 20-day-old animals, all PCs were still responsive to Glu whereas only 70% of them were still excited by NMDA in the presence of TTX in the bath. Furthermore, the sensitivity of PCs to Glu was higher than at 8 days of age, whereas that to NMDA was significantly lower, even when considering only those cells which still responded to this agonist. This trend was still accentuated later on since at 2 months of age, only 25% of PCs were excited by NMDA whereas their sensitivity to Glu was similar to that observed in 15 - 20-day-old animals. Therefore, the present results are fully consistent with the view that PCs have a transient expression of NMDA receptors during development.

Differential effects of serotonin on the spontaneous discharge and on the excitatory amino acid-induced responses of deep cerebellar nuclei neurons in rat cerebellar slices.

The effects of steady iontophoretic applications of serotonin on the spontaneous discharge and on the excitatory responses induced in deep cerebellar nuclei neurons by iontophoretic pulse applications of L-glutamate, L-aspartate, N-methyl-D,L-aspartate and quisqualate were studied in rat cerebellar slices maintained in vitro. Serotonin increased the spontaneous firing rate of deep cerebellar nuclei neurons in 91% of the tested cells by 109% on the average and had no effect on the remaining recorded neurons. Conversely, the monoamine induced a depression of the excitatory responses induced by four agonists tested and the depressant potency of serotonin was in the order quisqualate, glutamate, aspartate, N-methyl-D,L-aspartate. These effects persisted in low calcium high magnesium solution, suggesting that the serotonin receptors involved in these phenomena were, at least partially, postsynaptically located. The serotonin-induced increase in the cell firing rate appeared to be methysergide-resistant whereas the serotonin-induced decrease in the responses elicited by excitatory amino acids was depressed by this antagonist, which could indicate that these differential effects of serotonin are mediated via different mechanisms and/or serotonin receptor subtypes.