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Dynamics and active mixing of a droplet in a Stokes trap
- Gesse Roure, Alexander Z. Zinchenko, Robert H. Davis
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- Journal:
- Journal of Fluid Mechanics / Volume 985 / 25 April 2024
- Published online by Cambridge University Press:
- 22 April 2024, A15
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Particle trapping and manipulation have a wide range of applications in biotechnology and engineering. Recently, a flow-based, particle-trapping device called the Stokes trap was developed for trapping and control of small particles in the intersection of multiple branches in a microfluidic channel. This device can also be used to perform rheological experiments to determine the viscoelastic response of an emulsion or suspension. We show that besides these applications, the various flow modes produced by the Stokes trap are able to manipulate drop shapes and induce active mixing inside droplets. To this end, we analyse the dynamics of a droplet in a Stokes trap through boundary-integral simulations. We also explore the dynamic response of drop shape with respect to distinct external flow modes, which allows us to perform numerical experiments such as step strain and oscillatory extension. A linear controller is used to manipulate drop position, and the drop deformation is characterized by a spherical-harmonic decomposition. For small drop deformations, we observe a linear superposition of harmonics, which, surprisingly, seems to hold even for moderate deformations. This result indicates that such a device can be used for shape control of droplets. We also investigate how the different flow modes may be combined to induce mixing inside the droplets. The transient combination of modes produces an effective chaotic mixing, which is characterized by a mixing number. The mixing inside the droplet can be further enhanced for lower viscosity ratios and low, but non-zero capillary number and flow frequencies.
Flow of a concentrated emulsion with surfactant through a periodic porous medium
- Alexander Z. Zinchenko, Jacob R. Gissinger, Robert H. Davis
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- Journal:
- Journal of Fluid Mechanics / Volume 953 / 25 December 2022
- Published online by Cambridge University Press:
- 07 December 2022, A21
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High-resolution, long-time three-dimensional simulations are presented for slow, pressure-driven flow of a periodic emulsion of deformable drops through a dense, simple cubic array of solid spheres (one drop and one particle per periodic cell). The drops, covered with insoluble, non-diffusive surfactant, are large compared with pores, and they squeeze with high resistance, very closely coating the solids to overcome surface tension and lubrication effects. The solid volume fraction is 50 %, the emulsion concentration $c_{em}$ in the pore space is 36 % or 50 %, the drop-to-medium viscosity ratio $\lambda$ is 0.25 to 4. The contamination measure $\beta \leq 0.1$ keeps the linear surfactant model (assumed in most of the work) physically relevant. The boundary-integral solution requires extreme resolutions (tens of thousands of boundary elements per surface) achieved by multipole acceleration with special desingularizations, combined with flow-biased surfactant transport algorithms for numerical stability. The time-periodic regime is typically attained after a few squeezing cycles; the motion period is used in the extrapolation scheme to evaluate critical capillary numbers $Ca_{crit}$ demarcating squeezing from trapping. Due to Marangoni stresses, even light ($\beta =0.05$) to moderate ($\beta =0.1$) contaminations significantly reduce the average drop-phase migration velocity (up to 2.8 times, compared with clean drops), especially at small $\lambda =0.25$. In contrast, $Ca_{crit}$ is weakly sensitive to contamination and levels off completely at $\beta =0.05$. At $\lambda =0.25$ and $c_{em}=0.36$, the average drop-phase velocities are much different for lightly and moderately contaminated emulsions, except for near-critical squeezing when they become the same. Nonlinear surfactant models (Langmuir, Frumkin) are used to validate the linear model.
Particle capture by expanding droplets: effects of inner diffusion
- Gesse A. Roure, Jenna Trost, Robert H. Davis
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- Journal:
- Journal of Fluid Mechanics / Volume 948 / 10 October 2022
- Published online by Cambridge University Press:
- 13 September 2022, A36
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Fast agglomeration by emulsion binders to capture fine, hydrophobic particles has been developed in the past few years as an alternative to froth flotation by small air bubbles. This new method consists of mixing a particle suspension and saltwater-filled droplets covered with semi-permeable oil layers. These droplets expand due to an osmotic flux of water caused by the presence of salt inside the droplets. To better understand the physics underlying this novel particle capture method, we investigate binary interactions between droplets and particles. The current work examines the dynamics of a rigid spherical particle and a semi-permeable spherical drop that expands due to osmosis in an external, pure-extensional flow field. The droplet is governed by an expansion-diffusion problem, which is coupled to the set of dynamical equations governing the relative particle trajectory. By performing multiple trajectory simulations, we calculate transient collision efficiencies, which can be used to determine the collision kernel for population dynamics. We also use these simulations to better understand the evolution of the microstructure by determining the transient behaviour of the pair distribution function. Our results indicate that the presence of drop expansion increases the collision efficiency of the system, especially for very small particles, which are the most difficult to capture by froth flotation. Moreover, although the presence of slow salt diffusion inside the drops can mitigate this improvement, the contribution of expansion to the collision efficiency may still be considerable, even in the absence of hydrophobic or other attractive forces.
Modelling of particle capture by expanding droplets
- Gesse A. Roure, Robert H. Davis
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- Journal:
- Journal of Fluid Mechanics / Volume 912 / 10 April 2021
- Published online by Cambridge University Press:
- 05 February 2021, A11
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Froth flotation by small air bubbles has been traditionally used in industry to capture fine minerals and other hydrophobic particles. This method, however, is not efficient for capturing very small particles. The present work is motivated by a new agglomeration process that overcomes this lack of efficiency. It consists of mixing a particle suspension and saltwater-filled droplets covered with semi-permeable oil layers. This paper investigates the two-particle dynamics of a solid particle and a semi-permeable spherical drop that expands due to osmosis in an external, pure extensional flow field. A dimensionless engulfment parameter measures the relative effects of droplet growth and convective flow. The computational results from numerical integration determine a transient collision efficiency, which describes the influence of hydrodynamic interactions and osmotic flow on particle capture. The results show that drop expansion, which decays slowly with time, greatly increases particle capture rates, especially for small particles. Moreover, as the engulfment parameter increases, there is a transition from flow-dominated capture to expansion-dominated capture. For the case of a non-expanding droplet, we provide a numerical solution for the transient pair distribution function, which enables us to explain the transient particle-capture rate in terms of the microstructure of the suspension. Furthermore, we derive an analytical expression for the initial collision efficiency at zero times, which agrees with our numerical data. The numerical results for non-expanding droplets at long times show increasing collision efficiency as the permeability increases and when the size ratio is near unity, in agreement with previous steady-state calculations.
Drop squeezing between arbitrary smooth obstacles
- Jacob R. Gissinger, Alexander Z. Zinchenko, Robert H. Davis
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- Journal:
- Journal of Fluid Mechanics / Volume 908 / 10 February 2021
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- 10 December 2020, A33
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A fully three-dimensional boundary-integral method (BIM) is developed for the interaction of drops, suspended in a uniform far-field flow at small Reynolds number, with arbitrary Lyapunov surfaces. The close approach of fluid interfaces to solid surfaces poses significant challenges for numerical BIM implementations, due to the highly singular behaviour of single- and double-layer boundary integrals. Two new methods are described that generalize the accurate calculation of the highly singular surface integrals used by high-order desingularization techniques. The first method is semi-analytical, and applies to axisymmetric solid obstacles (in an arbitrary three-dimensional configuration). An axisymmetric particle can be divided into a series of characteristic disks along its axis, for which closed-form expressions for single and double layers are derived in terms of elliptic integrals. To accommodate arbitrary smooth surfaces, a multimesh desingularization method is introduced that calculates surface integrals utilizing a hierarchy of embedded mesh resolutions, together with distance-activated mesh interactions. Several particle shapes, including spherocylinders (capsules) and flat plates, are used to represent major classes characteristic of porous media. A droplet approaching a capsule will break up after forming two lobes, connected by a thin filament, on either side of the capsule. The cross-sectional shape of the filament affects lubrication behaviour. A constriction made of two parallel capsules, even of low aspect ratio, significantly retards drop passage compared to two spheres. Trends in drop squeezing between two capsules are summarized over a range of capillary number, viscosity ratio, drop size and capsule length. A constriction of two coplanar plates results in notably different lubrication and squeezing behaviour. Flow rectification is demonstrated for constrictions that are non-symmetrical with respect to flow reversal, for several non-axisymmetric particles.
Simultaneous and sequential collisions of three wetted spheres
- Robert H. Davis
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- Journal of Fluid Mechanics / Volume 881 / 25 December 2019
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- 25 October 2019, pp. 983-1009
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Rectilinear collisions of three wetted spheres are considered under conditions of high capillary numbers, for which viscous lubrication forces dominate over capillary forces. The viscous forces resist the relative motion, as characterized by the Stokes number (a dimensionless ratio of particle inertia and viscous forces). At high Stokes numbers, the particles penetrate the fluid layers between them with sufficient inertia that they collide and rebound. Both simultaneous and sequential collisions are simulated, and various outcomes are demonstrated: full agglomeration of the three spheres at low Stokes numbers, full separation or Newton’s cradle at large Stokes numbers and even reverse Newton’s cradle at intermediate Stokes numbers when there is a thicker combined fluid layer between the two target spheres than between the striker sphere and the first target sphere. When there is an initial air gap between the two target spheres, even more exotic outcomes are predicted, such as full separation after the initial collisions followed by full agglomeration or reverse Newton’s cradle (intermediate Stokes numbers) or Newton’s cradle (large Stokes numbers) after the subsequent collisions when the striker sphere catches back up to the target spheres. The approach and findings of this work are expected to provide input and guidance to future work on discrete-element modelling of collisions of many wet particles.
Drops with insoluble surfactant squeezing through interparticle constrictions
- Jacob R. Gissinger, Alexander Z. Zinchenko, Robert H. Davis
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- Journal of Fluid Mechanics / Volume 878 / 10 November 2019
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- 10 September 2019, pp. 324-355
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The interfacial behaviour of surfactant-laden drops squeezing through tight constrictions in a uniform far-field flow is modelled with respect to capillary number, drop-to-medium viscosity ratio and surfactant contamination. The surfactant is treated as insoluble and non-diffusive, and drop surface tension is related to surfactant concentration by a linear equation of state. The constriction is formed by three solid spheres held rigidly in space. A characteristic aspect of this confined and contaminated multiphase system is the rapid development of steep surfactant-concentration gradients during the onset of drop squeezing. The interplay between two physical effects of surfactant, namely the greater interface deformability due to decreased surface tension and interface immobilization due to Marangoni stresses, results in particularly rich drop-squeezing dynamics. A three-dimensional boundary-integral algorithm is used to describe drop hydrodynamics, and accurate treatment of close squeezing and trapped states is enabled by advanced singularity subtraction techniques. Surfactant transport and hydrodynamics are coupled via the surface convection equation (or convection–diffusion equation, if artificial diffusion is included), the interfacial stress balance and a solid-particle contribution based on the Hebeker representation. For extreme conditions, such as drop-to-medium viscosity ratios significantly less than unity, it is found that upwind-biased methods are the only stable approaches for modelling surfactant transport. Two distinct schemes, upwind finite volume and flow-biased least squares, are found to provide results in close agreement, indicating negligible numerical diffusion. Surfactant transport is enhanced by low drop-to-medium viscosity ratios, at which extremely sharp concentration gradients form during various stages of the squeezing process. The presence of surfactant, even at low degrees of contamination, significantly decreases the critical capillary number for droplet trapping, due to the accumulation of surfactant at the downwind pole of the drop and its subsequent elongation. Increasing the degree of contamination significantly affects surface mobility and further decreases the critical capillary number as well as drop squeezing times, up to a threshold above which the addition of surfactant negligibly affects squeezing dynamics.
ATLAS probe: Breakthrough science of galaxy evolution, cosmology, Milky Way, and the Solar System
- Yun Wang, Massimo Robberto, Mark Dickinson, Lynne A. Hillenbrand, Wesley Fraser, Peter Behroozi, Jarle Brinchmann, Chia-Hsun Chuang, Andrea Cimatti, Robert Content, Emanuele Daddi, Henry C. Ferguson, Christopher Hirata, Michael J. Hudson, J. Davy Kirkpatrick, Alvaro Orsi, Russell Ryan, Alice Shapley, Mario Ballardini, Robert Barkhouser, James Bartlett, Robert Benjamin, Ranga Chary, Charlie Conroy, Megan Donahue, Olivier Doré, Peter Eisenhardt, Karl Glazebrook, George Helou, Sangeeta Malhotra, Lauro Moscardini, Jeffrey A. Newman, Zoran Ninkov, Michael Ressler, James Rhoads, Jason Rhodes, Daniel Scolnic, Stephen Smee, Francesco Valentino, Risa H. Wechsler
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- Publications of the Astronomical Society of Australia / Volume 36 / 2019
- Published online by Cambridge University Press:
- 08 April 2019, e015
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Astrophysics Telescope for Large Area Spectroscopy Probe is a concept for a National Aeronautics and Space Administration probe-class space mission that will achieve ground-breaking science in the fields of galaxy evolution, cosmology, Milky Way, and the Solar System. It is the follow-up space mission to Wide Field Infrared Survey Telescope (WFIRST), boosting its scientific return by obtaining deep 1–4 μm slit spectroscopy for ∼70% of all galaxies imaged by the ∼2 000 deg2 WFIRST High Latitude Survey at z > 0.5. Astrophysics Telescope for Large Area Spectroscopy will measure accurate and precise redshifts for ∼200 M galaxies out to z < 7, and deliver spectra that enable a wide range of diagnostic studies of the physical properties of galaxies over most of cosmic history. Astrophysics Telescope for Large Area Spectroscopy Probe and WFIRST together will produce a 3D map of the Universe over 2 000 deg2, the definitive data sets for studying galaxy evolution, probing dark matter, dark energy and modifications of General Relativity, and quantifying the 3D structure and stellar content of the Milky Way. Astrophysics Telescope for Large Area Spectroscopy Probe science spans four broad categories: (1) Revolutionising galaxy evolution studies by tracing the relation between galaxies and dark matter from galaxy groups to cosmic voids and filaments, from the epoch of reionisation through the peak era of galaxy assembly; (2) Opening a new window into the dark Universe by weighing the dark matter filaments using 3D weak lensing with spectroscopic redshifts, and obtaining definitive measurements of dark energy and modification of General Relativity using galaxy clustering; (3) Probing the Milky Way’s dust-enshrouded regions, reaching the far side of our Galaxy; and (4) Exploring the formation history of the outer Solar System by characterising Kuiper Belt Objects. Astrophysics Telescope for Large Area Spectroscopy Probe is a 1.5 m telescope with a field of view of 0.4 deg2, and uses digital micro-mirror devices as slit selectors. It has a spectroscopic resolution of R = 1 000, and a wavelength range of 1–4 μm. The lack of slit spectroscopy from space over a wide field of view is the obvious gap in current and planned future space missions; Astrophysics Telescope for Large Area Spectroscopy fills this big gap with an unprecedented spectroscopic capability based on digital micro-mirror devices (with an estimated spectroscopic multiplex factor greater than 5 000). Astrophysics Telescope for Large Area Spectroscopy is designed to fit within the National Aeronautics and Space Administration probe-class space mission cost envelope; it has a single instrument, a telescope aperture that allows for a lighter launch vehicle, and mature technology (we have identified a path for digital micro-mirror devices to reach Technology Readiness Level 6 within 2 yr). Astrophysics Telescope for Large Area Spectroscopy Probe will lead to transformative science over the entire range of astrophysics: from galaxy evolution to the dark Universe, from Solar System objects to the dusty regions of the Milky Way.
Using climate change models to inform the recovery of the western ground parrot Pezoporus flaviventris
- Shaun W. Molloy, Allan H. Burbidge, Sarah Comer, Robert A. Davis
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Translocation of species to areas of former habitat after threats have been mitigated is a common conservation action. However, the long-term success of reintroduction relies on identification of currently available habitat and areas that will remain, or become, habitat in the future. Commonly, a short-term view is taken, focusing on obvious and assumed threats such as predators and habitat degradation. However, in areas subject to significant climate change, challenges include correctly identifying variables that define habitat, and considering probable changes over time. This poses challenges with species such as the western ground parrot Pezoporus flaviventris, which was once relatively common in near-coastal south-western Australia, an area subject to major climate change. This species has declined to one small population, estimated to comprise < 150 individuals. Reasons for the decline include altered fire regimes, introduced predators and habitat clearing. The establishment of new populations is a high priority, but the extent to which a rapidly changing climate has affected, and will continue to affect, this species remains largely conjecture, and understanding probable climate change impacts is essential to the prioritization of potential reintroduction sites. We developed high-resolution species distribution models and used these to investigate climate change impacts on current and historical distributions, and identify locations that will remain, or become, bioclimatically suitable habitat in the future. This information has been given to an expert panel to identify and prioritize areas suitable for site-specific management and/or translocation.
34 Long-Term Deutetrabenazine Treatment Response in Tardive Dyskinesia by Concomitant Dopamine-Receptor Antagonists and Baseline Comorbidities
- Karen E. Anderson, David Stamler, Mat D. Davis, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, Joseph McEvoy, Hubert H. Fernandez
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- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 193
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Background
Tardive dyskinesia (TD) results from exposure to dopamine-receptor antagonists (DRAs), such as typical and atypical antipsychotics. Clinicians commonly manage TD by reducing the dose of or stopping the causative agent; however, this may cause psychiatric relapse and worsen quality of life. In the 12-week ARM-TD and AIM-TD trials, deutetrabenazine demonstrated statistically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores versus placebo and was generally well tolerated, regardless of baseline DRA use or comorbidities.
Study ObjectiveTo evaluate the impact of underlying disease and current DRA use on efficacy and safety of long-term therapy of deutetrabenazine in patients with TD.
MethodPatients with TD who completed ARM-TD or AIM-TD were eligible to enter this open-label, single-arm, long-term extension after completing the 1-week washout period and final evaluation in the blinded portion of the trial. Change in AIMS scores from baseline to Week 54 and patients “Much Improved” or “Very Much Improved” (treatment success) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) at Week 54 were analyzed by baseline psychiatric illness type, including mood disorders (bipolar disorder/depression/other) or psychotic disorders (schizophrenia/schizoaffective disorder), and presence or absence of current DRA use.
ResultsAt Week 54, meaningful improvements from baseline in mean (standard error) AIMS scores were observed for patients with baseline mood disorders (–5.2[0.93]) and psychotic disorders (–5.0[0.63]), and in patients currently using DRAs (–4.6[0.54]) or not using DRAs (–6.4[1.27]). Most patients with mood disorders (73%) and psychotic disorders (71%) were “Much Improved” or “Very Much Improved” on CGIC at Week 54, similar to patients currently using (71%) or not using (74%) DRAs. The majority of patients with mood disorders (62%) and psychotic disorders (57%), as well as patients currently using (58%) or not using (63%) DRAs, were also “Much Improved” or “Very Much Improved” on PGIC at Week 54. Prior treatment in ARM-TD and AIM-TD did not impact the long-term treatment response. Underlying psychiatric disorder and concomitant DRA use did not impact the occurrence of adverse events (AEs). The frequencies of dose reductions, dose suspensions, and withdrawals due to AEs were low, regardless of baseline psychiatric comorbidities and DRAuse.
ConclusionsLong-term deutetrabenazine treatment demonstrated meaningful improvements in abnormal movements in TD patients, which were recognized by clinicians and patients, regardless of underlying psychiatric illness or DRAuse.
Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
45 Long-term Treatment with Deutetrabenazine Is Associated with Continued Improvement in Tardive Dyskinesia: Results from an Open-label Extension Study
- Robert A. Hauser, Hubert H. Fernandez, David Stamler, Mat D. Davis, Stewart A. Factor, Joohi Jimenez-Shahed, William G. Ondo, L. Fredrik Jarskog, Scott W. Woods, Mark S. LeDoux, David R. Shprecher, Karen E. Anderson
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- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 200-201
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Study Objective
To evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.
BackgroundIn the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.
MethodPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.
Results343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.
ConclusionsPatients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.
Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
46 Confirmed Safety of Deutetrabenazine for Tardive Dyskinesia in a 2-Year Open-label Extension Study
- Hubert H. Fernandez, David Stamler, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, Joohi Jimenez-Shahed, William G. Ondo, L. Fredrik Jarskog, Scott W. Woods, Mark S. LeDoux, David R. Shprecher, Karen E. Anderson
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- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, p. 201
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Study Objective
To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
BackgroundIn the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.
MethodPatients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).
Results343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.
ConclusionsThese results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.
Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel
35 Long-term Improvements in Site-Rated Outcomes with Deutetrabenazine Treatment in Patients with Tardive Dyskinesia
- Karen E. Anderson, David Stamler, Mat D. Davis, Nicholas Gross, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, Joseph McEvoy, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 24 / Issue 1 / February 2019
- Published online by Cambridge University Press:
- 12 March 2019, pp. 193-194
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Background
Tardive dyskinesia (TD) is an often-irreversible movement disorder that may intensify the stigma of patients with psychiatric disorders and worsen quality of life. In two randomized, double-blind, placebo (PBO)-controlled, 12-week trials, ARM-TD and AIM-TD (‘parent studies’), deutetrabenazine (DTB) demonstrated statistically significant improvements in centrally read Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with PBO and was generally well tolerated.
Study ObjectiveTo evaluate the long-term efficacy of DTB in an open-label safety study following double-blind treatment using site-rated efficacy measures: AIMS, the Clinical Global Impression of Change (CGIC) and the Patient Global Impression of Change (PGIC), which may be used in real-world clinical practice settings.
MethodPatients with TD who completed the parent studies were eligible to enter this open-label, long-term extension (OLE) after completing the 1-week washout period and final evaluation in the blinded portion of the trial. This extension comprised a 6-week titration period followed by a long-term maintenance phase. Patients began DTB at 12mg/day, titrating up to a maximum total dose of 48mg/day based on dyskinesia control and tolerability. Efficacy endpoints included in this analysis are the change in site-rated AIMS score (items 1–7) from parent study baseline, and the proportion of patients who were “Much Improved” or “Very Much Improved” (treatment success) on the CGIC and PGIC from OLE baseline.
ResultsAt the end of the parent studies (Week 12), patients treated with DTB had experienced greater mean (standard error) improvements in site-rated AIMS score (–5.0[0.40]) than patients given PBO (–3.2[0.47]). With long-term DTB treatment, both groups experienced improvements in site-rated AIMS scores (prior DTB, –7.9[0.62]; prior placebo, –6.6[0.64]) compared with parent study baseline. Similarly, at the end of the parent studies, a greater proportion of patients treated with DTB had treatment success on the CGIC (DTB, 51%; PBO, 32%) and the PGIC (DTB, 46%; PBO: 33%); whereas at Week 54 of the OLE study, treatment success on CGIC and PGIC were similar in both the CGIC (prior DTB: 66%; prior PBO: 68%) and PGIC (prior DTB: 62%; prior PBO: 62%) groups. DTB was generally well tolerated.
ConclusionsPatients treated with DTB showed improvements in abnormal movements, as measured by site-rated AIMS, CGIC, and PGIC scores, which may be used in real-world clinical practice settings. These results corroborate the previously reported efficacy of DTB as observed in the 12-week, double-blind ARM-TD and AIM-TD trials, in which central raters were used to evaluate AIMS scores.
Presented at: American Psychiatric Association Annual Meeting; May 5–9, 2018, New York, New York, USA
Funding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.
158 Long-Term Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
- Karen E. Anderson, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, William G. Ondo, Hubert H. Fernandez
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- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, p. 97
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Introduction
In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
ObjectiveTo evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.
MethodsPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.
Results304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.
ConclusionsLong-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
149 Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
- Karen E. Anderson, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, FRCPC, Stanislaw Ochudlo, William G. Ondo, Hubert H. Fernandez
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, pp. 92-93
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder resulting from exposure to dopamine-receptor antagonists. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.
ObjectiveTo evaluate the efficacy and safety of long-term deutetrabenazine therapy in patients with TD.
MethodsPatients with TD who completed the ARM-TD or AIM-TD studies were eligible to enter this open-label, single-arm, long-term safety study after they completed the 1-week washout period and final evaluation in the blinded portion of the trial. Efficacy endpoints included the change in AIMS score from baseline, and treatment success (defined as “much improved” or “very much improved”) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC). This analysis reports results up to Week 54.
Results304 patients enrolled in the extension study. At Week 54, the mean (standard error) change in AIMS score was –5.1 (0.52). After 6 weeks of deutetrabenazine treatment, the proportion of patients who achieved treatment success was 58% per the CGIC and 53% per the PGIC, and by Week 54 was 72% per the CGIC and 59% per the PGIC, thus demonstrating maintenance or enhancement of benefit over time. Deutetrabenazine was well tolerated for up to 54 weeks, and compared with the ARM-TD and AIM-TD studies, no new safety signals were detected.
Conclusions54 weeks of deutetrabenazine treatment was generally efficacious, safe, and well tolerated in patients with TD.
Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.
Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
134 Improvements in Clinical Global Impression of Change With Deutetrabenazine Treatment in Tardive Dyskinesia From the ARM-TD and AIM-TD Studies
- Hubert H. Fernandez, Mat D. Davis, Stewart A. Factor, Robert A. Hauser, L. Fredrik Jarskog, Joohi Jimenez-Shahed, Rajeev Kumar, Stanislaw Ochudlo, William G. Ondo, Karen E. Anderson
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- Journal:
- CNS Spectrums / Volume 23 / Issue 1 / February 2018
- Published online by Cambridge University Press:
- 15 June 2018, p. 84
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Introduction
Tardive dyskinesia (TD) is an involuntary movement disorder that is often irreversible, can affect any body region, and can be debilitating. In the ARM-TDand AIM-TD studies, deutetrabenazine treatment demonstrated statistically and clinically significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo (primary endpoint).
ObjectiveTo evaluate the efficacy of deutetrabenazine, as measured by the Clinical Global Impression of Change (CGIC) scale, in patients with TD from the pooled ARM-TDand AIM-TD (24 and 36 mg/day doses) data sets, as compared with the pooled placebo cohort.
MethodsARM-TD and AIM-TD were 12-week, randomized, double-blind, placebo-controlled studies that evaluated the safety and efficacy of deutetrabenazine for thetreatment of TD. The key secondary endpoint of each study was the proportion of patients “much improved” or “very much improved” (treatment success) at Week 12 on theCGIC.
ResultsAt Week 12, the odds of treatment success among patients treated with deutetrabenazine (n=152) was more than double that of patients given placebo (n=107; odds ratio: 2.12; P=0.005). In a categorical analysis of CGIC ratings, patients treated with deutetrabenazine showed greater improvement than patients given placebo (P=0.003). Patients treated with deutetrabenazine also had a significantly better treatment response than those given placebo (least-squares mean CGIC score treatment difference: –0.4; P=0.006).
ConclusionsDeutetrabenazine treatment led to statistically and clinically significant improvements in TD symptoms based on the CGIC result, suggesting that clinicians were able to recognize the benefit in patients treated with deutetrabenazine.
Presented at: The International Congress of Parkinson’s Disease and Movement Disorders; June 4–8, 2017; Vancouver, British Columbia, Canada.
Funding AcknowledgementsThese studies were funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
General rheology of highly concentrated emulsions with insoluble surfactant
- Alexander Z. Zinchenko, Robert H. Davis
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- Journal of Fluid Mechanics / Volume 816 / 10 April 2017
- Published online by Cambridge University Press:
- 08 March 2017, pp. 661-704
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A general constitutive model is constructed and validated for highly concentrated monodisperse emulsions of deformable drops with insoluble surfactant through long-time, large-scale and high-resolution multidrop simulations. There is the same amount of surfactant on each drop, and the linear model is assumed for the surface tension versus the surfactant concentration. The surfactant surface transport is coupled to multidrop hydrodynamics through the convective–diffusive equation and the interfacial stress balance. Only the limit of small surfactant diffusivities is addressed, when this parameter does not affect the rheology. An Oldroyd constitutive equation is postulated, with five variable coefficients depending on one instantaneous flow invariant (chosen as the drop-phase contribution to the dissipation rate). These coefficients are found by fitting the model to five precise rheological functions from two steady base flows at arbitrary deformation rates. One base flow is planar extension (PE) ($\dot{\unicode[STIX]{x1D6E4}}x_{1},-\dot{\unicode[STIX]{x1D6E4}}x_{2},0$), the other one is planar mixed flow (PM) ($\dot{\unicode[STIX]{x1D6FE}}x_{2}$, $\dot{\unicode[STIX]{x1D6FE}}\unicode[STIX]{x1D712}x_{1}$, 0) with $\unicode[STIX]{x1D712}=0.16$. A small but finite $\unicode[STIX]{x1D712}$ (a precise choice in the range $\unicode[STIX]{x1D712}\sim 0.1$ is unimportant) provides a necessarily perturbation to exclude severe ergodic difficulties and abnormal, kinked behaviour inherent in simple shear for high drop volume fractions $c$, especially at small capillary numbers $Ca$ and small drop-to-medium viscosity ratios $\unicode[STIX]{x1D706}$. The database rheological functions are obtained for $c=0.45{-}0.6$, $\unicode[STIX]{x1D706}=0.25{-}3$ and surfactant elasticities $\unicode[STIX]{x1D6FD}=0.05{-}0.2$ (based on the equilibrium surfactant concentration) from long-time simulations by a multipole-accelerated boundary-integral code with $N=100{-}200$ drops in a periodic cell and 2000–4000 boundary elements per drop. The code is an extension from Zinchenko & Davis (J. Fluid Mech., vol. 779, 2015, pp. 197–244) to account for surfactant transport and Marangoni stresses. Massive drop cusping or (sometimes) drop break-up limit the range of $Ca$ from above in the base flows, but there is no substantial lower limitation owing to the absence of phase transition difficulties. At small $\unicode[STIX]{x1D706}$, even minimal surface contamination may have a strong effect on the rheology. The simulations remain accurate for quite strong drop interactions, when the PE emulsion viscosity is nine times that for the carrier fluid. The model validation against a steady PM flow with a different $\unicode[STIX]{x1D712}=0.5$ shows a very good agreement for various $Ca$, $c$ and $\unicode[STIX]{x1D706}$. In the three PE and PM time-dependent flow tests, the quasi-steady approximation is found to predict stresses poorly. In contrast, the combination of the steady-state results for PE and PM used in the present method to generate the Oldroyd parameters gives a model with much better predictions for these time-dependent flows.
Shear stress of a monolayer of rough spheres – CORRIGENDUM
- Helen J. Wilson, Robert H. Davis
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- Journal:
- Journal of Fluid Mechanics / Volume 814 / 10 March 2017
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- 09 February 2017, pp. 614-617
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Preservation of Arctic landscapes overridden by cold-based ice sheets
- P. Thompson Davis, Jason P. Briner, Roy D. Coulthard, Robert W. Finkel, Gifford H. Miller
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- Quaternary Research / Volume 65 / Issue 1 / January 2006
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- 20 January 2017, pp. 156-163
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For nearly 40 years, a massive, well-preserved glaciomarine delta more than 54,000 years old and ancillary landforms have formed the cornerstone of models positing limited ice-sheet extent in Arctic Canada during the late Wisconsinan. We present exposure ages for large boulders on the delta surface, which coupled with preservation of relict landforms demonstrate that the region was covered by minimally erosive, cold-based ice during the late Wisconsinan. Our data suggest that surficial features commonly used to define the pattern of late Wisconsinan ice movement cannot be used on their own to constrain late Wisconsinan ice-sheet margins in Arctic regions.
Extensional and shear flows, and general rheology of concentrated emulsions of deformable drops
- Alexander Z. Zinchenko, Robert H. Davis
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- Journal of Fluid Mechanics / Volume 779 / 25 September 2015
- Published online by Cambridge University Press:
- 14 August 2015, pp. 197-244
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The rheology of highly concentrated monodisperse emulsions is studied by rigorous multidrop numerical simulations for three types of steady macroscopic flow, (i) simple shear ($\dot{{\it\gamma}}x_{2}$, 0 0), (ii) planar extension (PE) ($\dot{{\it\Gamma}}x_{1},-\dot{{\it\Gamma}}x_{2},0$) and (iii) mixed ($\dot{{\it\gamma}}x_{2}$, $\dot{{\it\gamma}}{\it\chi}x_{1}$, 0), where $\dot{{\it\gamma}}$ and $\dot{{\it\Gamma}}$ are the deformation rates, and ${\it\chi}\in (-1,1)$ is the flow parameter, in order to construct and validate a general constitutive model for emulsion flows with arbitrary kinematics. The algorithm is a development of the multipole-accelerated boundary-integral (BI) code of Zinchenko & Davis (J. Fluid Mech., vol. 455, 2002, pp. 21–62). It additionally incorporates periodic boundary conditions for (ii) and (iii) (based on the reproducible lattice dynamics of Kraynik–Reinelt for PE), control of surface overlapping, much more robust controllable surface triangulations for long-time simulations, and more efficient acceleration. The emulsion steady-state viscometric functions (shear viscosity and normal stress differences) for (i) and extensiometric functions (extensional viscosity and stress cross-difference) for (ii) are studied in the range of drop volume fractions $c=0.45{-}0.55$, drop-to-medium viscosity ratios ${\it\lambda}=0.25{-}10$ and various capillary numbers $\mathit{Ca}$, with 100–400 drops in a periodic cell and 2000–4000 boundary elements per drop. High surface resolution is important for all three flows at small $\mathit{Ca}$. Large system size and strains $\dot{{\it\gamma}}t$ of up to several thousand are imperative in some shear-flow simulations to identify the onset of phase transition to a partially ordered state, and evaluate (although still not precisely) the viscometric functions in this state. Below the phase transition point, the shear viscosity versus $\mathit{Ca}$ shows a kinked behaviour, with the local minimum most pronounced at ${\it\lambda}=1$ and $c=0.55$. The ${\it\lambda}=0.25$ emulsions flow in a partially ordered manner in a wide range of $\mathit{Ca}$ even when $c=0.45$. Increase of ${\it\lambda}$ to 3–10 shifts the onset of ordering to much smaller $\mathit{Ca}$, often outside the simulation range. In contrast to simple shear, phase transition is never observed in PE or mixed flow. A generalized five-parameter Oldroyd model with variable coefficients is fitted to our extensiometric and viscometric functions at arbitrary flow intensities (but outside the phase transition range). The model predictions compare very well with precise simulation results for strong mixed flows, ${\it\chi}=0.25$. Time-dependent PE flow is also considered. Ways to overcome the phase transition and drop breakup limitations on constitutive modelling are discussed.