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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 Laytonville Quarry exotic block contains a series of deep-ocean sediments of varying Fe: Mn, Fe:Al and Fe2+ : Fe3+ contents, but all enriched in Fe-Mn carbonates. These sediments have a complex metamorphic history that has involved the early development of aegirine and garnet, followed by various phases of ‘secondary’ mineral growth, all of which required the addition of water to the metamorphic assemblages under high-P, low-T conditions. During the course of an early hydration episode deerite formed within most of the ironstones, and zussmanite in certain Fe-rich, Mn-poor pelites. At a later, and apparently lower pressure period in the metamorphic history, howieite, riebeckite, stilpnomelane, and a more manganous variety of zussmanite (ZU2) have overtaken much of the earlier mineralogy. Subsequent to this, and contemporaneous with the development of the tremolite-talc exotic block rind assemblage, there is a minor development of minnesotaite and ekmanite. During the course of the metamorphism the ironstones have become enriched in K and Na, necessary to form the blueschist meta-ironstone mineralogy. Such rocks therefore have the potential to reveal details of fluid expulsion within the subduction zone.
Good education requires student experiences that deliver lessons about practice as well as theory and that encourage students to work for the public good—especially in the operation of democratic institutions (Dewey 1923; Dewy 1938). We report on an evaluation of the pedagogical value of a research project involving 23 colleges and universities across the country. Faculty trained and supervised students who observed polling places in the 2016 General Election. Our findings indicate that this was a valuable learning experience in both the short and long terms. Students found their experiences to be valuable and reported learning generally and specifically related to course material. Postelection, they also felt more knowledgeable about election science topics, voting behavior, and research methods. Students reported interest in participating in similar research in the future, would recommend other students to do so, and expressed interest in more learning and research about the topics central to their experience. Our results suggest that participants appreciated the importance of elections and their study. Collectively, the participating students are engaged and efficacious—essential qualities of citizens in a democracy.
We report daptomycin minimum inhibitory concentrations (MICs) for vancomycin-resistant Enterococcus faecium isolated from bloodstream infections over a 4-year period. The daptomycin MIC increased over time hospital-wide for initial isolates and increased over time within patients, culminating in 40% of patients having daptomycin-nonsusceptible isolates in the final year of the study.
The transition from limited-slip conditions at the base of grounded ice to free-slip conditions beneath floating ice occurs across the few-kilometers-wide grounding zone. This region involves either an elastic flexural transition from bedrock to hydrostatically supported elevations (often tidally influenced), a transition from thicker to thinner ice over a flat bed, or some combination of these two processes. In either case, ice must flow across a changing stress field, often resulting in brittle deformation, manifested as basal crevassing. Thus the position and morphology of basal crevasses reveal important information about the stress state across this transition. Our gridded ground-based radar surveys on Whillans Ice Stream, West Antarctica, indicate a complex pattern of basal crevasses, but most are associated with regions where the surface elevation gradient is steepest. Due to the high reflectivity of sea water, we image many off-nadir crevasses from a corner-reflector geometry involving reflections from the ice/sea-water interface and then from the crevasse, producing echoes with an inverted phase that could be misinterpreted as subglacial returns. Our results indicate that basal crevasses offer a rich dataset for diagnosing stress state and salient processes across grounding zones, and that special care is needed when interpreting subglacial returns in radar data.
To develop consensus recommendations for training future clinician educators (CEs) in emergency medicine (EM).
A panel of EM education leaders was assembled from across Canada and met regularly by teleconference over the course of 1 year. Recommendations for CE training were drafted based on the panel’s experience, a literature review, and a survey of current and past EM education leaders in Canada. Feedback was sought from attendees at the Canadian Association of Emergency Physicians (CAEP) annual academic symposium. Recommendations were distributed to the society’s Academic Section for further feedback and updated by a consensus of the expert panel.
Recommendations were categorized for one of three audiences: 1) Future CEs; 2) Academic departments and divisions (AD&D) that support training to fulfill their education leadership goals; and 3) The CAEP Academic Section. Advanced medical education training is recommended for any emergency physician or resident who pursues an education leadership role. Individuals should seek out mentorship in making decisions about career opportunities and training options. AD&D should regularly perform a needs assessment of their future CE needs and identify and encourage potential individuals who fulfill education leadership roles. AD&D should develop training opportunities at their institution, provide support to complete this training, and advocate for the recognition of education scholarship in their institutional promotions process. The CAEP Academic Section should support mentorship of future CEs on a national scale.
These recommendations serve as a framework for training and supporting the next generation of Canadian EM medical educators.
In a time of major medical education transformation, emergency medicine (EM) needs to nurture education scholars who will influence EM education practice. However, the essential ingredients to ensure a career with impact in EM education are not clear.
To describe how to prepare EM educators for a high-impact career.
The Canadian Association of Emergency Physicians (CAEP) Academic Section commissioned an “Education Impact” working group (IWG) to guide the creation of consensus recommendations from the EM community. EM educators from across Canada were initially recruited from the networks of the IWG members, and additional educators were recruited via snowball sampling. “High impact educators” were nominated by this network. The high impact educators were then interviewed using a structured question guide. These interviews were transcribed and coded for themes using qualitative methods. The process continued until no new themes were identified. Proposed themes and recommendations were presented to the EM community at the CAEP 2016 Academic Symposium. Feedback was then incorporated into a final set of recommendations.
Fifty-five (71%) of 77 of identified Canadian EM educators participated, and 170 names of high impact educators were submitted and ranked by frequency. The IWG achieved sufficiency of themes after nine interviews. Five recommendations were made: 1) EM educators can pursue a high impact career by leveraging either traditional or innovative career pathways; 2) EM educators starting their education careers should have multiple senior mentors; 3) Early-career EM educators should immerse themselves in their area of interest and cultivate a community of practice, not limited to EM; 4) Every academic EM department and EM teaching site should have access to an EM educator with protected time and recognition for their EM education scholarship; and 5) Educators at all stages should continuously compile an impact portfolio.
We describe a unique set of recommendations to develop educators who will influence EM, derived from a consensus from the EM community. EM leaders, educators, and aspiring educational scholars should consider how to implement this guide towards enhancing our specialty’s educational mission.
We sought to conduct a major objective of the CAEP Academic Section, an environmental scan of the academic emergency medicine programs across the 17 Canadian medical schools.
We developed an 84-question questionnaire, which was distributed to academic heads. The responses were validated by phone by the lead author to ensure that the questions were answered completely and consistently. Details of pediatric emergency medicine units were excluded from the scan.
At eight of 17 universities, emergency medicine has full departmental status and at two it has no official academic status. Canadian academic emergency medicine is practiced at 46 major teaching hospitals and 13 specialized pediatric hospitals. Another 69 Canadian hospital EDs regularly take clinical clerks and emergency medicine residents. There are 31 full professors of emergency medicine in Canada. Teaching programs are strong with clerkships offered at 16/17 universities, CCFP(EM) programs at 17/17, and RCPSC residency programs at 14/17. Fourteen sites have at least one physician with a Master’s degree in education. There are 55 clinical researchers with salary support at 13 universities. Sixteen sites have published peer-reviewed papers in the past five years, ranging from four to 235 per site. Annual budgets range from $200,000 to $5,900,000.
This comprehensive review of academic activities in emergency medicine across Canada identifies areas of strengths as well as opportunities for improvement. CAEP and the Academic Section hope we can ultimately improve ED patient care by sharing best academic practices and becoming better teachers, educators, and researchers.
We discuss nucleosynthesis within 6 M⊙ models with Z = 0.02, 0.008 and 0.004. The emphasis is on the AGB phase of evolution, with particular reference to thermal pulses and Hot Bottom Burning. We find strong CN cycling, with substantial Al production, especially at low metallicities.
Flapping wings are important in many biological and bioinspired systems. Here, we investigate the fluid mechanics of flapping wings that possess a single flexible hinge allowing passive wing pitch rotation under load. We perform experiments on an insect-scale (
cm wing span) robotic flapper and compare the results with a quasi-steady dynamical model and a coupled fluid–structure computational fluid dynamics model. In experiments we measure the time varying kinematics, lift force and two-dimensional velocity fields of the induced flow from particle image velocimetry. We find that increasing hinge stiffness leads to advanced wing pitching, which is beneficial towards lift force production. The classical quasi-steady model gives an accurate prediction of passive wing pitching if the relative phase difference between the wing stroke and the pitch kinematics,
, is small. However, the quasi-steady model cannot account for the effect of
on leading edge vortex (LEV) growth and lift generation. We further explore the relationships between LEV, lift force, drag force and wing kinematics through experiments and numerical simulations. We show that the wing kinematics and flapping efficiency depend on the stiffness of a passive compliant hinge. Our dual approach of running at-scale experiments and numerical simulations gives useful guidelines for choosing wing hinge stiffnesses that lead to efficient flapping.
At the fall 2001 Social Science History Association convention in Chicago, the Crime and Justice network sponsored a forum on the history of gun ownership, gun use, and gun violence in the United States. Our purpose was to consider how social science historians might contribute nowand in the future to the public debate over gun control and gun rights. To date, we have had little impact on that debate. It has been dominated by mainstream social scientists and historians, especially scholars such as Gary Kleck, John Lott, and Michael Bellesiles, whose work, despite profound flaws, is politically congenial to either opponents or proponents of gun control. Kleck and Mark Gertz (1995), for instance, argue on the basis of their widely cited survey that gun owners prevent numerous crimes each year in theUnited States by using firearms to defend themselves and their property. If their survey respondents are to be believed, American gun owners shot 100,000 criminals in 1994 in selfdefense–a preposterous number (Cook and Ludwig 1996: 57–58; Cook and Moore 1999: 280–81). Lott (2000) claims on the basis of his statistical analysis of recent crime rates that laws allowing private individuals to carry concealed firearms deter murders, rapes, and robberies, because criminals are afraid to attack potentially armed victims. However, he biases his results by confining his analysis to the years between 1977 and 1992, when violent crime rates had peaked and varied little from year to year (ibid.: 44–45). He reports only regression models that support his thesis and neglects to mention that each of those models finds a positive relationship between violent crime and real income, and an inverse relationship between violent crime and unemployment (ibid.: 52–53)–implausible relationships that suggest the presence of multicollinearity, measurement error, or misspecification. Lott then misrepresents his results by claiming falsely that statistical methods can distinguish in a quasi-experimental way the impact of gun laws from the impact of other social, economic, and cultural forces (ibid.: 26, 34–35; Guterl 1996). Had Lott extended his study to the 1930s, the correlation between gun laws and declining homicide rates that dominates his statistical analysis would have disappeared. An unbiased study would include some consideration of alternative explanations and an acknowledgment of the explanatory limits of statistical methods.
Little is currently known about the presence and impact of personality
disorder in adolescents who self-harm.
To evaluate personality disorder in repeated self-harm in adolescence and
its impact on self-harm psychopathology and adaptation outcomes over 1
A clinical referral sample (n = 366) of adolescents
presenting with repeated self-harm aged 12–17 years, as part of a
randomised controlled trial (Assessment of Treatment in Suicidal
Teenagers study, ASSIST). Personality disorder was assessed using the
Structured Clinical Interview for DSM-IV Axis II (SCID-II). One-year
outcomes included frequency and severity of repeat self-harm,
self-reported suicidality, mood and functional impairment.
About 60% of the referred adolescents showed one or more forms of
personality disorder. Personality disorder was associated with
significantly greater severity of self-harm, overall psychopathology and
impairment. There was a complex association with treatment adherence.
Personality disorder predicted worse 1-year outcomes in relation to
self-harm frequency and severity, as well as impairment, suicidality and
Personality disorder can be reliably measured in adolescence and showed
high prevalence in this clinical self-harm sample. Controlling for other
variables, it showed a strong independent association with self-harm
severity at referral and predicted adherence to treatment and clinical
outcomes (independent of treatment) over 1 year. Consideration of
personality disorder diagnosis is indicated in the assessment and
management of adolescents who repeatedly self-harm.
The paper presents findings of a study evaluating the impact of performance appraisal training on rating accuracy and perceived rating ability. 41 supervisors from a telecommunications firm took part in the training evaluated video vignettes and completed a questionnaire measuring self-efficacy beliefs about rating, goal intentions, and feelings about future rating behaviour. Supervisors in a control group (n = 12) also rated the video and completed the questionnaire. Trained supervisors showed increased accuracy on video ratings of work behaviour over the course of the training and an increase in self-efficacy measures. Control group supervisors by comparison decreased their accuracy of rating over the same time period while self-efficacy ratings remained constant. Impact of training on satisfaction and goals of participants is also presented.
To characterize the current state of Canadian emergency medicine (EM) resident research and develop recommendations to promote excellence in this area.
We performed a systematic review of MEDLINE, Embase, and ERIC using search terms relevant to EM resident research. We conducted an online survey of EM residency program directors from the Royal College of Physicians and Surgeons of Canada (RCPSC) and College of Family Physicians of Canada (CFPC). An expert panel reviewed these data, presented recommendations at the Canadian Association of Emergency Physicians 2014 Academic Symposium, and refined them based on feedback received.
Of 654 potentially relevant citations, 35 articles were included. These were categorized into four themes: 1) expectations and requirements, 2) training and assessment, 3) infrastructure and support, and 4) dissemination. We received 31 responses from all 31 RCPSC-EM and CFPC-EM programs. The majority of EM programs reported requiring a resident scholarly project; however, we found wide-ranging expectations for the type of resident research performed and how results were disseminated, as well as the degree of completion expected. Although 93% of RCPSC-EM programs reported providing formal training on how to conduct research, only 53% of CFPC-EM programs reported doing so. Almost all programs (94%) reported having infrastructure in place to support resident research, but the nature of support was highly variable. Finally, there was marked variability regarding the number of resident-published abstracts and manuscripts.
Based on the literature, our national survey, and discussions with stakeholders, we offer 14 recommendations encompassing goals, expectations, training, assessment, infrastructure, and dissemination in order to improve Canadian EM resident research.