Long-term Safety of Epoetin Alfa-epbx for the Treatment of Anemia in ESKD: Pooled Analyses of Randomized and Open-label Studies

Rationale & Objective Epoetin alfa-epbx is a biosimilar to the reference product, epoetin alfa. We compare the safety of epoetin alfa-epbx versus epoetin alfa based on a pooled analysis of findings from 2 randomized, double-blind, comparative clinical studies, and report new data for the long-term safety of epoetin alfa-epbx. Study Design Pooled analyses of previously conducted studies. Setting & Participants Hemodialysis patients with anemia. Interventions Data from patients who received 1 or more subcutaneous or intravenous doses of study drug were integrated across route of administration in combined randomized groups (epoetin alfa-epbx, n = 423; epoetin alfa, n = 426). Data from patients who received 1 or more doses of epoetin alfa-epbx in either open-label extension trial were integrated across route of administration in a combined long-term safety studies group (n = 576). Outcomes Adverse events (AEs), immunogenicity, and other outcomes were assessed. Results Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were similar between combined randomized epoetin alfa-epbx and epoetin alfa, which had mean treatment durations of 18.1 and 17.7 weeks, respectively. Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were 86.5%, 39.4%, and 6.6%, respectively, for the combined long-term safety studies group, which had a mean treatment duration of 40.0 weeks. In total, 12 patients across the combined randomized groups (epoetin alfa-epbx, n = 5; epoetin alfa, n = 7) and 9 patients in the combined long-term safety studies group tested anti-recombinant human erythropoietin antibody positive in 1 or more visits during study conduct. No patient in any group developed neutralizing antibodies or pure red blood cell aplasia. Limitations Epoetin alfa comparator not included in the long-term safety studies, greater cumulative exposure to study drug for epoetin alfa-epbx, shorter follow-up in the randomized studies, and potential for selection bias among patients in the open-label long-term safety studies. Conclusions This analysis reinforces previous conclusions of similar safety profiles between epoetin alfa-epbx and epoetin alfa. Furthermore, epoetin alfa-epbx had no unexpected safety signals during long-term treatment

Critical adsorption on curved objects

A systematic fieldtheoretic description of critical adsorption on curved objects such as spherical or rodlike colloidal particles immersed in a fluid near criticality is presented. The temperature dependence of the corresponding order parameter profiles and of the excess adsorption are calculated explicitly. Critical adsorption on elongated rods is substantially more pronounced than on spherical particles. It turns out that, within the context of critical phenomena in confined geometries, critical adsorption on a microscopically thin `needle' represents a distinct universality class of its own. Under favorable conditions the results are relevant for the flocculation of colloidal particles.Comment: 52 pages, 10 figure

Phase behavior and material properties of hollow nanoparticles

Effective pair potentials for hollow nanoparticles like the ones made from carbon (fullerenes) or metal dichalcogenides (inorganic fullerenes) consist of a hard core repulsion and a deep, but short-ranged, van der Waals attraction. We investigate them for single- and multi-walled nanoparticles and show that in both cases, in the limit of large radii the interaction range scales inversely with the radius, $R$, while the well depth scales linearly with $R$. We predict the values of the radius $R$ and the wall thickness $h$ at which the gas-liquid coexistence disappears from the phase diagram. We also discuss unusual material properties of the solid, which include a large heat of sublimation and a small surface energy.Comment: Revtex, 13 pages with 8 Postscript files included, submitted to Phys. Rev.

Influence of solvent granularity on the effective interaction between charged colloidal suspensions

We study the effect of solvent granularity on the effective force between two charged colloidal particles by computer simulations of the primitive model of strongly asymmetric electrolytes with an explicitly added hard sphere solvent. Apart from molecular oscillating forces for nearly touching colloids which arise from solvent and counterion layering, the counterions are attracted towards the colloidal surfaces by solvent depletion providing a simple statistical description of hydration. This, in turn, has an important influence on the effective forces for larger distances which are considerably reduced as compared to the prediction based on the primitive model. When these forces are repulsive, the long-distance behaviour can be described by an effective Yukawa pair potential with a solvent-renormalized charge. As a function of colloidal volume fraction and added salt concentration, this solvent-renormalized charge behaves qualitatively similar to that obtained via the Poisson-Boltzmann cell model but there are quantitative differences. For divalent counterions and nano-sized colloids, on the other hand, the hydration may lead to overscreened colloids with mutual attraction while the primitive model yields repulsive forces. All these new effects can be accounted for through a solvent-averaged primitive model (SPM) which is obtained from the full model by integrating out the solvent degrees of freedom. The SPM was used to access larger colloidal particles without simulating the solvent explicitly.Comment: 14 pages, 16 craphic

Emergence of Variability in Isogenic Escherichia coli Populations Infected by a Filamentous Virus

The spread of epidemics not only depends on the average number of parasites produced per host, but also on the existence of highly infectious individuals. It is widely accepted that infectiousness depends on genetic and environmental determinants. However, even in clonal populations of host and viruses growing in homogeneous conditions, high variability can exist. Here we show that Escherichia coli cells commonly display high differentials in viral burst size, and address the kinetics of emergence of such variability with the non-lytic filamentous virus M13. By single-cell imaging of a virally-encoded fluorescent reporter, we monitor the viral charge distribution in infected bacterial populations at different time following infection. A mathematical model assuming autocatalytic virus replication and inheritance of bacterial growth rates quantitatively reproduces the experimental distributions, demonstrating that deterministic amplification of small host inhomogeneities is a mechanism sufficient to explain large and highly skewed distributions. This mechanism of amplification is general and may occur whenever a parasite has an initial phase of exponential growth within its host. Moreover, it naturally reproduces the shift towards higher virulence when the host is experimenting poor conditions, as observed commonly in host-parasite systems

Multi-Particle Collision Dynamics -- a Particle-Based Mesoscale Simulation Approach to the Hydrodynamics of Complex Fluids

In this review, we describe and analyze a mesoscale simulation method for fluid flow, which was introduced by Malevanets and Kapral in 1999, and is now called multi-particle collision dynamics (MPC) or stochastic rotation dynamics (SRD). The method consists of alternating streaming and collision steps in an ensemble of point particles. The multi-particle collisions are performed by grouping particles in collision cells, and mass, momentum, and energy are locally conserved. This simulation technique captures both full hydrodynamic interactions and thermal fluctuations. The first part of the review begins with a description of several widely used MPC algorithms and then discusses important features of the original SRD algorithm and frequently used variations. Two complementary approaches for deriving the hydrodynamic equations and evaluating the transport coefficients are reviewed. It is then shown how MPC algorithms can be generalized to model non-ideal fluids, and binary mixtures with a consolute point. The importance of angular-momentum conservation for systems like phase-separated liquids with different viscosities is discussed. The second part of the review describes a number of recent applications of MPC algorithms to study colloid and polymer dynamics, the behavior of vesicles and cells in hydrodynamic flows, and the dynamics of viscoelastic fluids

Lattice Boltzmann simulations of soft matter systems

This article concerns numerical simulations of the dynamics of particles immersed in a continuum solvent. As prototypical systems, we consider colloidal dispersions of spherical particles and solutions of uncharged polymers. After a brief explanation of the concept of hydrodynamic interactions, we give a general overview over the various simulation methods that have been developed to cope with the resulting computational problems. We then focus on the approach we have developed, which couples a system of particles to a lattice Boltzmann model representing the solvent degrees of freedom. The standard D3Q19 lattice Boltzmann model is derived and explained in depth, followed by a detailed discussion of complementary methods for the coupling of solvent and solute. Colloidal dispersions are best described in terms of extended particles with appropriate boundary conditions at the surfaces, while particles with internal degrees of freedom are easier to simulate as an arrangement of mass points with frictional coupling to the solvent. In both cases, particular care has been taken to simulate thermal fluctuations in a consistent way. The usefulness of this methodology is illustrated by studies from our own research, where the dynamics of colloidal and polymeric systems has been investigated in both equilibrium and nonequilibrium situations.Comment: Review article, submitted to Advances in Polymer Science. 16 figures, 76 page

GRB 071003: Broadband Follow-up Observations of a Very Bright Gamma-Ray Burst in a Galactic Halo

The optical afterglow of long-duration GRB 071003 is among the brightest yet to be detected from any GRB, with R ~ 12 mag in KAIT observations starting 42 s after the GRB trigger, including filtered detections during prompt emission. However, our high S/N ratio afterglow spectrum displays only extremely weak absorption lines at what we argue is the host redshift of z = 1.60435 - in contrast to the three other, much stronger Mg II absorption systems observed at lower redshifts. Together with Keck adaptive optics observations which fail to reveal a host galaxy coincident with the burst position, our observations suggest a halo progenitor and offer a cautionary tale about the use of Mg II for GRB redshift determination. We present early through late-time observations spanning the electromagnetic spectrum, constrain the connection between the prompt emission and early variations in the light curve (we observe no correlation), and discuss possible origins for an unusual, marked rebrightening that occurs a few hours after the burst: likely either a late-time refreshed shock or a wide-angle secondary jet. Analysis of the late-time afterglow is most consistent with a wind environment, suggesting a massive star progenitor. Together with GRB 070125, this may indicate that a small but significant portion of star formation in the early universe occurred far outside what we consider a normal galactic disk.Comment: 24 pages, 14 figures, 12 tables. Accepted for publication by ApJ. Contains minor revisions and additional author

Quantitative imaging of concentrated suspensions under flow

We review recent advances in imaging the flow of concentrated suspensions, focussing on the use of confocal microscopy to obtain time-resolved information on the single-particle level in these systems. After motivating the need for quantitative (confocal) imaging in suspension rheology, we briefly describe the particles, sample environments, microscopy tools and analysis algorithms needed to perform this kind of experiments. The second part of the review focusses on microscopic aspects of the flow of concentrated model hard-sphere-like suspensions, and the relation to non-linear rheological phenomena such as yielding, shear localization, wall slip and shear-induced ordering. Both Brownian and non-Brownian systems will be described. We show how quantitative imaging can improve our understanding of the connection between microscopic dynamics and bulk flow.Comment: Review on imaging hard-sphere suspensions, incl summary of methodology. Submitted for special volume 'High Solid Dispersions' ed. M. Cloitre, Vol. xx of 'Advances and Polymer Science' (Springer, Berlin, 2009); 22 pages, 16 fig