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To evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.
In 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.
Patients 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).
343 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.
These 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
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.
In 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.
Patients 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.
343 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.
Patients 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.
The euarthropod Luohuilinella deletres sp. nov. is described from rare material from the Chengjiang biota, Cambrian Series 2, Stage 3, of Yunnan Province, China. Phylogenetic analysis recovers a xandarellid affinity for L. deletres, representing only the fifth described species of this clade. L. deletres possesses a head shield that is about one-fifth of the total body length and a trunk with 30 tergites, the reduced anterior-most tergite and terminal three tergites lacking pleural elongations. Anteriorly situated notches in the head shield are associated with stalked eyes, in contrast to the more posterior, enclosed eye slits present in Xandarella. Posterior to the antennae there are at least 11 pairs of biramous appendages preserved, including three pairs in the head. The morphology of the midline gut of L. deletres, in which lateral, unbranched diverticula are wider towards the front of the body, is a characteristic also found in various trilobites. The dorsoventrally flattened exoskeleton suggests a benthic or nektobenthic mode of life for L. deletres, as for other trilobitomorphs, and it likely used its well-developed anteriorly positioned eyes for searching out food, either to scavenge or to find prey.
Particle image velocimetry and filtered Rayleigh scattering experiments were performed over a range of Reynolds numbers to study the scaling and structure of a smooth, flat-plate turbulent boundary layer with a free stream Mach number of 7.5. The measurements indicate few, if any, dynamic differences due to Mach number. Mean and fluctuating streamwise velocities in the outer layer show strong similarity to incompressible flows at comparable Reynolds numbers when scaled according to van Driest and Morkovin. In addition, correlation lengths and structure angles based on velocity statistics were found to be less sensitive to compressibility than indicated by previous studies based on density fields or mass-weighted statistics, suggesting that the density and velocity fields obey different scaling. Finally, the boundary layer displays uniform momentum zones, with the number of these zones similar to incompressible boundary layers at comparable Reynolds numbers.
We have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival.
This study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike’s information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model.
Genetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011).
These data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype–phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.
As part of a project to investigate the flow of ice at low effective stress, two independent strain-gauge systems were used to measure vertical strain rate as a function of depth and time at Siple Dome, Antarctica. The measurements were made from January 1998 until January 2002 at the ice divide and a site 7km to the northeast on the flank. The strain-rate profiles place constraints on the rheology of ice at low stress, show the expected differences between divide and flank flow (with some structure due to firn compaction and probably ice stratigraphy), and suggest that the flow of the ice sheet has not changed much in the last 8.6 kyr. The strain rates show an unexpected time dependence on scales ranging from several months to hours, including discrete summer events at the divide. Time dependence in strain rate, water pressure, seismicity, velocity and possibly basal motion has been seen previously on the Siple Coast ice streams, but it is especially surprising on Siple Dome because the bed is cold.
As part of a larger program to measure and model vertical strain around Siple Dome on the West Antarctic ice sheet, we developed a new sensor to accurately and stably record displacements. The sensors consist of optical fibers, encased in thin-wall stainless-steel tubes, frozen into holes drilled with hot water, and stretched from the surface to various depths (up to 985 m) in the ice sheet. An optical system, connected annually to the fibers, reads out their absolute lengths with a precision of about 2 mm. Two sets of five sensors were installed in the 1997/98 field season: one set is near the Siple Dome core hole (an ice divide), and a second set is on the flank 7 km to the north (the ice thickness at both sites is approximately 1000 m). The optical-fiber length observations taken in four field seasons spanning a 3 year interval reveal vertical strain rates ranging from −229 ± 4 ppm a−1 to −7 ± 9 ppm a−1. In addition to confirming a non-linear constitutive relationship for deep ice, our analysis of the strain rates indicates the ice sheet is thinning at the flank and is in steady state at the divide.
With >40 14C dates, mainly on bones and charcoal, the site at Son Mas is the only megalithic sanctuary on the Balearic Islands that has been dated by 14C in detail. Although soil erosion made stratigraphy difficult and the monument was cleaned out regularly during its long use, the results demonstrate that the site was occupied from the Pretalayotic (Chalcolithic) until the Roman period. The aim of this study was not only to date the construction and the use of the sanctuary, but also to correlate this monument, by means of dispersion diagrams, with the other prehistoric sites situated within the same valley. The dates were also used to compare the site with the generally accepted chronology of the Balearic archipelago (Mallorca, Menorca, Ibiza and Formentera).
A “giant” outburst of A 0535+262, a transient X-ray binary pulsar, was observed in 1994 February and March with the Burst and Transient Source Experiment (BATSE) onboard the Compton Gamma-Ray Observatory. During the outburst power spectra of the hard X-ray flux contained a QPO-like component with a FWHM of approximately 50% of its center frequency. Over the course of the outburst the center frequency rose smoothly from 35 mHz to 70 mHz and then fell to below 40 mHz. We compare this QPO frequency with the neutron star spin-up rate, and discuss the observed correlation in terms of the beat frequency and Keplerian frequency QPO models in conjunction with the Ghosh-Lamb accretion torque model.
The eruptive variable V838 Mon was discovered on Jan 6, 2002. Due to a subsequent phase of almost constant brightness and a spectral appearance which is unlike classical novae, speculations have been made about its nature. Either it was a very peculiar, slow nova defining a new class, an eruptive event in an evolved star as in the case of Sakurai’s Object but in a much earlier phase, or something completely different.
Down through the years the Constitution has not always included all Americans — especially Blacks and women. No such charges have been leveled against the Religious Liberty clauses, though there have been occasions when their protections have been overridden or imperfectly applied. To remind us — as the Framers knew well — that “nothing human can be perfect,” we hear remarks from a distinguished Baptist pastor, an accomplished lawyer, and an eminent civil rights leader, Dr. Benjamin Hooks.