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The 12-week ARM-TD and AIM-TD studies in tardive dyskinesia (TD) patients showed statistically significant improvements in TD symptoms with deutetrabenazine. The completed open-label extension (OLE) study (SD-809-C−20) evaluated long-term efficacy and safety of deutetrabenazine in TD.
Patients who completed ARM-TD or AIM-TD enrolled in the OLE study, with deutetrabenazine dose titrated based on dyskinesia control and tolerability. Change from baseline in Abnormal Involuntary Movement Scale (AIMS) score was assessed by local site raters. Treatment success was evaluated locally as patients being “much improved” or “very much improved” on Clinical Global Impression of Change (CGIC).
343 patients enrolled in the OLE study; 6 patients were excluded from analyses. At Week 54 (n=249; dose [mean±SE]: 38.7±0.66mg/day), mean change from baseline in AIMS score was –4.8±0.28; 66% of patients experienced treatment success. At Week 106 (n=194; dose: 39.3±0.75mg/day), mean change from baseline in AIMS score was –5.4±0.33; 65% of patients experienced treatment success. At Week 145 (n=160; dose: 39.4±0.83mg/day), mean change from baseline in AIMS score was –6.6±0.37; 73% of patients experienced treatment success. Treatment was generally well tolerated across 723 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) for akathisia/restlessness were 0.01, somnolence/sedation were 0.07, and symptoms which may represent parkinsonism or depression were 0.08 each.
Patients who received long-term treatment with deutetrabenazine achieved sustained improvement in AIMS scores. Findings from this open-label trial with response-driven dosing suggest the possibility of increasing benefit over time.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
SHEA endorses adhering to the recommendations by the CDC and ACIP for immunizations of all children and adults. All persons providing clinical care should be familiar with these recommendations and should routinely assess immunization compliance of their patients and strongly recommend all routine immunizations to patients. All healthcare personnel (HCP) should be immunized against vaccine-preventable diseases as recommended by the CDC/ACIP (unless immunity is demonstrated by another recommended method). SHEA endorses the policy that immunization should be a condition of employment or functioning (students, contract workers, volunteers, etc) at a healthcare facility. Only recognized medical contraindications should be accepted for not receiving recommended immunizations.
OBJECTIVES/GOALS: Physician-scientists play a vital role in biomedical research but this chosen career path has many challenges, such as long training periods and funding. The University of Rochester (UR) CTSI pipeline programs address this by enabling medical trainees to partake in enriched research experiences. METHODS/STUDY POPULATION: The UR CTSI TL1 is a training grant from the National Center for Advancing Translational Science (NCATS), which funds predoctoral trainees. The TL1-funded physician-scientist pipeline includes the Academic Research Track (ART) year-out program and the Medical Science Training Program (MSTP). We describe the characteristics and training outcomes of TL1-funded trainees. We also obtained testimonials of current and former trainees regarding their career component decision-making, and their perception of programs, in order to identify how best to address the challenges of the physician-scientist workforce, and to facilitate the transition between the clinic and bench. RESULTS/ANTICIPATED RESULTS: From 2006-2019, the UR CTSI has had 56 ART trainees and 17 MSTP trainees complete training; six trainees have transitioned into the MSTP after completing the ART program. As of 2019, 63 of 67 graduated trainees (94%) have continued their engagement in CTS after graduation. Importantly, our programs have facilitated the careers of 31 women (39.7%) and 12 under-represented minorities (15.4%). We will present a breadth of qualitative data to inform which parts of the TL1-related programs have been successful, and which parts could use programmatic improvement to aid the transition into the physician-scientist workforce. DISCUSSION/SIGNIFICANCE OF IMPACT: Physician-scientist training barriers in the US have resulted in a shortage of these professionals in the clinical and translation workforce. Our data show the UR CTSI has been successful in addressing several of these challenges via the TL1-funded ART, MSTP, and ART/MSTP dual program pipeline.
Deutetrabenazine (Austedo) is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The objective of this study was to evaluate the long-term safety and tolerability of deutetrabenazine in patients with TD at 3 years.
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 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. 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 for calculating AE frequencies. This analysis reports results up to Week 158.
A total of 343 patients were enrolled (111 received placebo and 232 received deutetrabenazine in the parent studies). At the time of this analysis, 183 patients were still receiving treatment; 259 completed 1 year, 172 completed 2 years, and 41 completed 3 years. There were 623 patient-years of exposure. More than 40% of patients reached the maximum dose. EAIRs of AEs were comparable to or lower than those observed in the ARM-TD and AIM-TD short-term randomized trials of deutetrabenazine vs. placebo. The frequency of SAEs (EAIR 0.10) was similar to that observed with short-term placebo (0.33) and short-term deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.06), dose reduction (0.10), and dose suspension (0.05) were uncommon.
These results support the safety outcomes observed in the ARM-TD and AIM-TD parent studies and the safety of deutetrabenazine for long-term use in patients with TD.
Funding Acknowledgements: This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel
In the 12-week ARM-TD and AIM-TD studies evaluating deutetrabenazine for the treatment of tardive dyskinesia (TD), the percentage of patients achieving ≥50% response was higher in the deutetrabenazine-treated group than in the placebo group. These studies also showed low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The current open-label study evaluated the long-term efficacy and safety of deutetrabenazine in patients with TD.
Patients with TD who completed ARM-TD or AIM-TD could enroll in this open-label, single-arm extension study, titrating up over 6 weeks to a maximum total daily dose of deutetrabenazine 48 mg/day on the basis of dyskinesia control and tolerability. The proportion of Abnormal Involuntary Movement Scale (AIMS; items 1-7) responders was assessed based on response rates for achieving ≥50% improvement from baseline in the open-label extension study. AlMS score was assessed by local site raters for this analysis.
343 patients enrolled in the extension study. At Week 54 (n=249; total daily dose [mean ± standard error]: 38.6±0.66 mg), the mean percentage change from baseline in AIMS score was –40%; 48% of patients achieved a ≥50% response and 59% of those had already achieved a ≥50% response at Week 15. Further, 34% of those who had not achieved a ≥50% response at Week 15 achieved a ≥50% response at Week 54. At Week 106 (n=169; total daily dose: 39.6±0.77 mg), the mean percentage change from baseline in AIMS score was –45%; 55% of patients achieved a ≥50% response, 59% of those patients had already achieved a ≥50% response at Week 15, and 41% of those who had not achieved a ≥50% response at Week 15 but who reached Week 106 achieved a ≥50% response. At Week 132 (n=109; total daily dose: 39.7±0.97 mg), the mean percentage change from baseline in AIMS score was –61%; 55% of patients achieved a ≥50% response, 61% of those patients had already achieved a ≥50% response at Week 15, and 43% of those who had not achieved a ≥50% response at Week 15 but who reached Week 132 achieved a ≥50% response. Completer analysis suggests that long-term efficacy was not due to dose increases over time. Treatment with deutetrabenazine was generally well tolerated. There were 623 patient-years of exposure through Week 158, and exposure-adjusted incidence rates (incidence/patient-years) of adverse events of special interest were 0.01 for akathisia and restlessness, 0.07 for somnolence and sedation, 0.04 for parkinsonism, and 0.05 for depression.
Patients who received long-term treatment with deutetrabenazine achieved response rates that were indicative of clinically meaningful long-term benefit. Results from this open-label trial suggest the possibility of increasing benefit over time with individual dose titration of deutetrabenazine.
This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel.
To help eliminate perinatal HIV transmission, the US Department of Health and Human Services recommends against breastfeeding for women living with HIV, regardless of viral load or combined antiretroviral therapy (cART) status. However, cART radically improves HIV prognosis and virtually eliminates perinatal transmission, and breastfeeding's health benefits are well-established. In this setting, pregnancy is increasing among American women with HIV, and a harm reduction approach to those who breastfeed despite extensive counseling is suggested. We assess the evidence and ethical justification for current policy, with attention to pertinent racial and health disparities. We first review perinatal transmission and breastfeeding data relevant to US infants. We compare hypothetical risk of HIV transmission from breastmilk to increased mortality from sudden infant death syndrome, necrotizing enterocolitis and sepsis from avoiding breastfeeding, finding that benefits may outweigh risks if mothers maintain undetectable viral load on cART. We then review maternal health considerations. We conclude that avoidance of breastfeeding by women living with HIV may not maximize health outcomes and discuss our recommendation for revising national guidelines in light of autonomy, harm reduction and health inequities.
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.
To 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.
Patients 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.
At 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.
Patients 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.
OBJECTIVES/SPECIFIC AIMS: Deep brain stimulation is currently being evaluated as an experimental therapy for various psychiatric disorders, as well as being investigated as a method for mapping emotional brain functions. This growing area of research requires sensitive measures to quantify effects of stimulation on emotional processing. The current study examined the effects of acute stimulation to 2 limbic regions—the subcallosal cingulate (SCC) and the amygdala—on bias in the perception and evaluation of emotional facial expressions. We hypothesized that transient electrical stimulation to the limbic system would produce acute reductions in negative bias, consistent with its antidepressant effects in patients with severe depression. METHODS/STUDY POPULATION: The current study uses a novel affective bias task, developed to rapidly and covertly quantify emotional state. Over 4–6 minutes, patients rate the intensity and valence of static images of emotional facial expressions. We examined effects of electrical brain stimulation in 2 groups: patients with treatment-refractory depression undergoing SCC DBS therapy, and epilepsy patients undergoing amygdala stimulation via stereo-EEG electrodes during inpatient intracranial monitoring. DBS patients completed the task under stimulation and sham conditions during monthly visits over the first 6 months of therapy, as well as daily during a 1 week, blinded period of DBS discontinuation at the 6-month time point. Epilepsy patients completed the task under stimulation and sham conditions at a single visit. Mixed linear models and paired-samples t-test were used to investigate effects of stimulation as well as depression scale scores on affective bias ratings. RESULTS/ANTICIPATED RESULTS: Four SCC DBS patients showed significant effects of stimulation (p<0.0001) and depressive state (p<0.0001) on affective bias scores across 6 months of chronic DBS therapy, where emotional faces were perceived as less sad with stimulation ON, as well as during visits in which patients were nondepressed (typically later in the treatment course). Furthermore, 2 DBS patients showed rapid negative shifts in bias following acute blinded discontinuation of chronic stimulation, an effect which persisted over the 1-week period of discontinuation (t29=−2.58, p=0.015), in the absence of any self-reported change in mood. Likewise, 6 epilepsy patients showed significant positive shifts in affective bias with acute amygdala stimulation (t5=−4.75, p=0.005). Current analyses are investigating electrophysiological, autonomic and facial motor correlates to affective bias in these patients. DISCUSSION/SIGNIFICANCE OF IMPACT: Affective bias has revealed rapid, significant changes with stimulation at 2 limbic targets—one a white matter hub and one a nuclear subcortical structure—suggesting the task’s utility as an emotional outcome measure in brain stimulation studies. These stimulation-sensitive measures may provide a new metric to track treatment response to deep brain stimulation therapy for affective disorders. Future studies will determine whether affective bias can predict neuropsychiatric complications in patients undergoing stimulation mapping of brain circuitry ahead of resection surgery for epilepsy.
Senior Instructors and Assistant Professors in their first academic appointment may not have all the tools for an efficient start to their careers. Although many institutions provide access to mentoring programs and seminars on faculty development, the timing and format of the offerings often conflict with ongoing responsibilities of the faculty, particularly clinical faculty.
We established a collaboration between the Clinical and Translational Science Institute (CTSI) and the University of Rochester Medical Center Office for Faculty Development with the goal of developing a week-long Junior Faculty Core Curriculum that would better suit faculty schedules. We convened focus groups and with their help, identified themes for inclusion in the course. Speakers were identified from among local senior faculty. University leadership was enlisted in promoting the course. Individual speakers and course content were evaluated daily, at the end of the week-long course, and 6 months later. Planning for subsequent years incorporated the feedback. Yearly evaluations and subsequent course modification continued.
Junior faculty from nearly every department in the Medical Center were represented. There was high learner satisfaction and participation however several limitations were identified and addressed in subsequent years. The focus on principles and available resources, not specific skills or content was appropriate. Daily interactions among participants from a wide variety of departments fostered networking among faculty who may not otherwise have met and discussed common interests
The ultimate value of such an early, intensive faculty development program will depend on whether it equips junior faculty to organize, develop, and achieve their academic goals better than alternative formats. This will require further study.
Overall IDSA/SIS intra-abdominal infection guideline compliance was not associated with improved outcomes; however, there was a longer time to active therapy (P=.024) and higher mortality (P=.077) if empiric therapy was too narrow per guidelines. These findings support the need for the implementation of customized institutional guidelines adapted from the IDSA/SIS guidelines.
Transparent conducting thin-films of SnO2: F were grown on preheated glass, Al2O3 coated glass, and quartz substrates by Streaming Process for Electrodeless Electrochemical Deposition (SPEED). Stannic chloride (SnCl4) and ammonium fluoride (NH4F) dissolved in a mixture of deionized water and organic solvents were used as precursors. The preheated substrate temperature was varied between 440 and 500 °C. High quality SnO2:F films were grown at all the substrate temperatures studied. The resulting typical film thickness was 250 nm. X-ray diffraction shows that the grown films are polycrystalline SnO2 with a tetragonal crystal structure. The average optical transmission of the films was around 93% throughout the wavelength range 400 to 1000 nm. The lowest electrical resistivity achieved was 6 × 10-4 Ω-cm. The Hall measurements showed that the film is an n-type semiconductor, with carrier mobility of 8.3 cm2/V-s, and carrier concentration of 1 × 1021 cm-3. The direct bandgap was determined to be 4.0 eV from the transmittance spectrum.
As in all fields of surgery, the current trend in neurosurgery is towards less-invasive procedures and the shorter hospital stays that result from them. Therefore, stereotactic techniques are an indispensable tool for the modern neurosurgeon and have been dramatically improved by the recent revolution in digital image guidance technology. These techniques provide a relatively straightforward, accurate, and safe method to approach intracranial targets that are defined by either anatomical or functional characteristics. Anatomically defined targets include brain tumors and abscesses, as well as other structural lesions. Targeting for anatomical disorders relies entirely on patient-specific anatomy derived from radiographs (e.g., ventriculography, rarely used today) or tomograms (e.g., CT, MRI) for localization. In addition, functional imaging modalities (e.g., fMRI), metabolic imaging modalities (e.g., positron emission tomography (PET)), and MR spectroscopy can be utilized in conjunction with other imaging modalities to help with target planning and visualization. Functionally defined structures include the various nuclei of the basal ganglia and thalamus that are targeted for pain and movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia), as well as other conditions such as obsessive-compulsive disorder. Targeting for functional disorders typically combines computerized imaging with intraoperative electrophysiological mapping for localization, although anatomical techniques can be used alone as well.
Previously published guidelines are available that provide comprehensive recommendations for detecting and preventing healthcare-associated infections. The intent of this document is to highlight practical recommendations in a concise format designed to assist acute care hospitals in implementing and prioritizing their Clostridium difficile infection (CDI) prevention efforts. Refer to the Society for Healthcare Epidemiology of America/Infectious Diseases Society of America “Compendium of Strategies to Prevent Healthcare-Associated Infections” Executive Summary and Introduction and accompanying editorial for additional discussion.
1. Increasing rates of CDI
C. difficile now rivals methicillin-resistant Staphylococcus aureus (MRSA) as the most common organism to cause healthcare-associated infections in the United States.
a. In the United States, the proportion of hospital discharges in which the patient received the International Classification of Diseases, Ninth Revision discharge diagnosis code for CDI more than doubled between 2000 and 2003, and CDI rates continued to increase in 2004 and 2005 (L. C. McDonald, MD, personal communication, July 2007). These increases have been seen in pediatric and adult populations, but elderly individuals have been disproportionately affected. CDI incidence has also increased in Canada and Europe.
b. There have been numerous reports of an increase in CDI severity.
c. Most reports of increases in the incidence and severity of CDI have been associated with the BI/NAP1/027 strain of C. difficile. This strain produces more toxins A and B in vitro than do many other strains of C. difficile, produces a third toxin (binary toxin), and is highly resistant to fluoroquinolones.