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Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2; Gen2) at 18 years; HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP; quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant’s fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.
There is much research on race and schooling focused on punitive discipline, but little attention is paid to how teachers and administrators use minor policies to coerce students to “willingly” adopt hegemonic ideologies, particularly the ones that correspond to Whiteness. In this work, Whiteness is conceptualized as a social concept in which forms of knowledge, skills, and behavioral traits are cultivated for the sake of maintaining White supremacy as the dominant ideology in the social organization of structures and people. My work explores how teachers and administrators use school dress code policies, specifically the policies regarding hairstyles, to indoctrinate Black students into Whiteness. I argue that schools are sites intended to racialize Black students into White society. I argue that dress codes that regulate hairstyles are a form of White hegemony. I ground my work in Antonio Gramsci and John Gaventa’s theoretical views of hegemony to conceptualize how administrators and teachers invoke forms of domination and coercion to force Black students to transform their appearance for the sake of upholding White ideals of professionalism. I offer a critical race conceptual model that articulates how power is enacted upon Black students to further a White aesthetic. The conceptual model highlights how teachers and administrators assign racialized social meanings to different hairstyles and unconsciously or consciously reinforce the idea that Black hairstyles hinder Black students’ performance in the classroom and reduce their future employment opportunities. Contemporary examples of Black students’ experiences in school are cases that validate this model. I argue that dress code policies about hair that incur minor infractions are destructive to Black students’ sense of identity and reinforce Whiteness as the normative frame of civil society.
There is a critique that investment arbitration undermines or hampers the development of national legal institutions. By providing a forum for foreign investors separate and distinct from local courts, critics argue, ISDS removes any incentive for foreign investors to promote the development of local legal institutions. This chapter sets out an account of how investment arbitration might affect development of local legal institutions, in particular international commercial arbitration and, perhaps, domestic arbitration. The authors find that while both the number of investment agreements and investment arbitration proceedings to which a state is a party is negatively related to the rule of law in the state, the presence of an indicator for support for international commercial arbitration – adoption of the UNCITRAL Model Law on International Commercial Arbitration – essentially offsets that negative relationship.
Recent research has investigated the use of serious games as a form of therapeutic intervention for depression and anxiety in young people.
To conduct a systematic review and meta-analysis into the effectiveness of gaming interventions for treating either depression or anxiety in individuals aged 12–25 years.
An electronic search was conducted on the 30 March 2020, using PsycINFO, ISI Web of Science Core Collection, Medline and EMBASE databases. Standardised effect sizes (Hedge's g) were calculated for between-participant comparisons between experimental (therapeutic intervention) and control conditions, and within-participant comparisons between pre- and post-intervention time points for repeated measures designs.
Twelve studies (seven randomised controlled trials (RCTs) and five non-randomised studies) were included. For RCTs, there was a statistically significant and robust effect (g = −0.54, 95% CI −1.00 to −0.08) favouring the therapeutic intervention when treating youth depression. For non-RCTs, using a repeated measures design, the overall effect was also strong (g = −0.75, 95% CI −1.64 to 0.14) favouring therapeutic intervention, but this was not statistically significant. Interestingly, we found no statistically significant effect for treating youth anxiety.
There is preliminary evidence to suggest that gaming interventions are an effective treatment for youth depression, but not anxiety. Further research is warranted to establish the utility, acceptability and effectiveness of gaming interventions in treating mental health problems in young people.
The National Institute of Mental Health's Research Domain Criteria (RDoC) framework has prompted a paradigm shift from categorical psychiatric disorders to considering multiple levels of vulnerability for probabilistic risk of disorder. However, the lack of neurodevelopmentally based tools for clinical decision making has limited the real-world impact of the RDoC. Integration with developmental psychopathology principles and statistical methods actualize the clinical implementation of RDoC to inform neurodevelopmental risk. In this conceptual paper, we introduce the probabilistic mental health risk calculator as an innovation for such translation and lay out a research agenda for generating an RDoC- and developmentally informed paradigm that could be applied to predict a range of developmental psychopathologies from early childhood to young adulthood. We discuss methods that weigh the incremental utility for prediction based on intensity and burden of assessment, the addition of developmental change patterns, considerations for assessing outcomes, and integrative data approaches. Throughout, we illustrate the risk calculator approach with different neurodevelopmental pathways and phenotypes. Finally, we discuss real-world implementation of these methods for improving early identification and prevention of developmental psychopathology. We propose that mental health risk calculators can build a needed bridge between the RDoC multiple units of analysis and developmental science.
Poverty increases the risk of poorer executive function (EF) in children born full-term (FT). Stressors associated with poverty, including variability in parenting behavior, may explain links between poverty and poorer EF, but this remains unclear for children born very preterm (VPT). We examine socioeconomic and parental psychosocial adversity on parenting behavior, and whether these factors independently or jointly influence EF in children born VPT. At age five years, 154 children (VPT = 88, FT = 66) completed parent-child interaction and EF tasks. Parental sensitivity, intrusiveness, cognitive stimulation, and positive and negative regard were coded with the Parent-Child Interaction Rating Scale. Socioeconomic adversity spanned maternal demographic stressors, Income-to-Needs ratio, and Area Deprivation Index. Parents completed measures of depression, anxiety, inattention/hyperactivity, parenting stress, and social-communication interaction (SCI) problems. Parental SCI problems were associated with parenting behavior in parents of children born VPT, whereas socioeconomic adversity was significant in parents of FT children. Negative parenting behaviors, but not positive parenting behaviors, were related to child EF. This association was explained by parental depression/anxiety symptoms and socioeconomic adversity. Results persisted after adjustment for parent and child IQ. Findings may inform research on dyadic interventions that embed treatment for parental mood/affective symptoms and SCI problems to improve childhood EF.
Jane Manning's death, in March 2021, brought to an end a remarkable life and musical career, and it seems appropriate to celebrate that life with an extended tribute. TEMPO has always had a particularly close relationship with new music in Britain, where the journal is based, and Jane's work as a performer transformed the way in which musicians and audiences in Britain understood the technical and imaginative potential of new music. Her repertoire was enormous, and her interpretations of older music – Dallapiccola, Messiaen, Ravel, Webern – were wonderful, but it was as the creator of new work with living composers that she had such an extraordinary influence. What follows is an attempt to describe how that influence developed and to explain why it was so extraordinary.
The objectives of this study were to develop and refine EMPOWER (Enhancing and Mobilizing the POtential for Wellness and Resilience), a brief manualized cognitive-behavioral, acceptance-based intervention for surrogate decision-makers of critically ill patients and to evaluate its preliminary feasibility, acceptability, and promise in improving surrogates’ mental health and patient outcomes.
Part 1 involved obtaining qualitative stakeholder feedback from 5 bereaved surrogates and 10 critical care and mental health clinicians. Stakeholders were provided with the manual and prompted for feedback on its content, format, and language. Feedback was organized and incorporated into the manual, which was then re-circulated until consensus. In Part 2, surrogates of critically ill patients admitted to an intensive care unit (ICU) reporting moderate anxiety or close attachment were enrolled in an open trial of EMPOWER. Surrogates completed six, 15–20 min modules, totaling 1.5–2 h. Surrogates were administered measures of peritraumatic distress, experiential avoidance, prolonged grief, distress tolerance, anxiety, and depression at pre-intervention, post-intervention, and at 1-month and 3-month follow-up assessments.
Part 1 resulted in changes to the EMPOWER manual, including reducing jargon, improving navigability, making EMPOWER applicable for a range of illness scenarios, rearranging the modules, and adding further instructions and psychoeducation. Part 2 findings suggested that EMPOWER is feasible, with 100% of participants completing all modules. The acceptability of EMPOWER appeared strong, with high ratings of effectiveness and helpfulness (M = 8/10). Results showed immediate post-intervention improvements in anxiety (d = −0.41), peritraumatic distress (d = −0.24), and experiential avoidance (d = −0.23). At the 3-month follow-up assessments, surrogates exhibited improvements in prolonged grief symptoms (d = −0.94), depression (d = −0.23), anxiety (d = −0.29), and experiential avoidance (d = −0.30).
Significance of results
Preliminary data suggest that EMPOWER is feasible, acceptable, and associated with notable improvements in psychological symptoms among surrogates. Future research should examine EMPOWER with a larger sample in a randomized controlled trial.
Replacing tillage with cover crops (CC) for weed management in corn (Zea mays L.)-soybean [Glycine max (L.) Merr.] systems with mechanical weed control has many soil health benefits but in the western Corn Belt, CC establishment after harvest is hampered by cold temperatures, limited labor and few compatible CC species. Spring-planted CC may be an alternative, but information is lacking on suitable CC species. Our objective was to evaluate four spring-planted CC with respect to biomass production and weed suppression, concurrent with CC growth and post-termination. Cover crop species tested were oat (Avena sativa L.), barley (Hordeum vulgare L.), brown mustard [Brassica juncea (L.) Czern.] and yellow mustard (Brassica hirta Moench). They were compared to no-CC treatments that were either tilled pre- and post-planting of soybean (no-CC tilled) or not tilled at all (no-CC weedy). CC were planted in late March to early April, terminated 52–59 days later using an undercutter, and soybean was planted within a week. The experiment had a randomized complete block design with four replications and was repeated for 3 years. Mustards and small grains produced similar amounts of biomass (1.54 Mg ha−1) but mustard biomass production was more consistent (0.85–2.72 Mg ha−1) than that of the small grains (0.35–3.81 Mg ha−1). Relative to the no-CC weedy treatment, mustards suppressed concurrent weed biomass in two out of 3 years, by 31–97%, and small grains suppressed concurrent weed biomass in only 1 year, by 98%.
Six weeks after soybean planting, small grains suppressed weed biomass in one out of 3 years, by 79% relative to the no-CC weedy treatment, but mustards did not provide significant weed suppression. The no-CC tilled treatment suppressed weeds each year relative to the no-CC weedy treatment, on average 87%. The ineffective weed control by CC reduced soybean biomass by about 50% six weeks after planting. While spring-planted CC have the potential for pre-plant weed control, they do not provide adequate early season weed suppression for soybean.
We report infrared reflectance and ultraviolet fluorescence spectra of the surfaces and cleaved side of Beacon Sandstone from Antarctica that harbours a cryptoendolithic microbial community - a photosynthesis-based consortium of algae, lichen and bacteria present a few millimetres below the surface. Chlorophyll absorptions were present in the reflectance spectra of the exposed interior but not on the top or bottom surfaces and their band depths changed < 4% between measurements taken 19 years apart, indicating the stability of the microorganisms when the sample is kept dry. The presence of subsurface organic layers was detected in reflectance at 3.41 μm on the sample's surface. Fluorescence spectra of the cleaved side showed the blue fluorescence peaks expected from chlorophyll but no 0.65–0.80 μm peaks seen in fluorescence measurements of green vegetation. A weak fluorescence signal was detectable at the surface of the sample, presumably due to some light leaking into the subsurface through pores or cracks in the goethite coating the sample's surface. Theoretically, this weak fluorescence signal could possibly be observed in rock surfaces broken by erosion or meteor impacts on Mars. Sandstone outcrops have been reported on Mars and detection of organic layers in sandstones there would be of interest.
The regulation of pesticides in the European Union (EU) relies on a network of hard law (legislation and implementing acts) and soft law (non-legally binding guidance documents and administrative and scientific practices). Both hard and soft laws govern how risk assessments are conducted, but a significant role is left to the latter. Europe’s pesticide regulation is one of the most stringent in the world. Its stated objectives are to ensure an independent, objective and transparent assessment of pesticides and achieve a high level of protection for health and environment. However, a growing body of evidence shows that pesticides that have passed through this process and are authorised for use may harm humans, animals and the environment. The authors of the current paper – experts in toxicology, law and policy – identified shortcomings in the authorisation process, focusing on the EU assessment of the pesticide active substance glyphosate. The shortcomings mostly consist of failures to implement the hard or soft laws. But in some instances the law itself is responsible, as some provisions can only fail to achieve its objectives. Ways to improve the system are proposed, requiring changes in hard and soft laws as well as in administrative and scientific practices.
Compliance with college emergency notifications can minimize injury; however, time is often wasted in alert verification. Building on prior research, this study assesses using health-behavior theory to predict rapid compliance to emergency notifications across a range of scenarios and within a diverse college population.
Cross-sectional, student data were collected in 2017-2018 (n = 1529). The Theory of Planned Behavior and Protection Motivation Theory were used to explain intention to comply with emergency notifications in scenarios: robbery, shooter, fire, chemical spill, protest, health emergency, and air quality. Regression models assessed associations between constructs and intention to rapidly comply with each notification.
The most consistent predictors of rapid compliance were attitudes and subjective norms (adjusted odds ratio [AOR]: 1.057-1.118; 95% CI: 1.009-1.168). Scenarios prone to rapid developments such as robbery, shooter, and fire were associated with increased perceived threat and response efficacy (AOR: 1.024-1.082; 95% CI: 1.003-1.132) Slower developing situations such as air quality and health hazards were associated with increased perceived control (AOR: 1.027-1.073; 95% CI: 1.031-1.117).
This study identified attitude and subjective norms as consistent predictors of rapid compliance and improves understanding of additional constructs across scenarios. Campuses may benefit from leveraging concepts from health-behavior theory to provide targeted intervention focusing on factors associated with rapid compliance.
Natural disasters are increasing in frequency and impact; they cause widespread disruption and adversity throughout the world. The Canterbury earthquakes of 2010–2011 were devastating for the people of Christchurch, New Zealand. It is important to understand the impact of this disaster on the mental health of children and adolescents.
To report psychiatric medication use for children and adolescents following the Canterbury earthquakes.
Dispensing data from community pharmacies for the medication classes antidepressants, antipsychotics, anxiolytics, sedatives/hypnotics and methylphenidate are routinely recorded in a national database. Longitudinal data are available for residents of the Canterbury District Health Board (DHB) and nationally. We compared dispensing data for children and adolescents residing in Canterbury DHB with national dispensing data to assess the impact of the Canterbury earthquakes on psychotropic prescribing for children and adolescents.
After longer-term trends and population adjustments are considered, a subtle adverse effect of the Canterbury earthquakes on dispensing of antidepressants was detected. However, the Canterbury earthquakes were not associated with higher dispensing rates for antipsychotics, anxiolytics, sedatives/hypnotics or methylphenidate.
Mental disorders or psychological distress of a sufficient severity to result in treatment of children and adolescents with psychiatric medication were not substantially affected by the Canterbury earthquakes.
Thermal infrared data collected by the Thermal Emission Spectrometer (TES) and Thermal Emission Imaging System (THEMIS) instruments have significantly impacted the understanding of martian surface mineralogy. Spatial/temporal variations in igneous lithologies; the discovery of quartz, carbonates, and chlorides; and the widespread identification of amorphous, silica-enriched materials reveal a planet that has experienced a diversity of primary and secondary geo-logic processes including igneous crustal evolution, regional sedimentation, aqueous alteration, and glacial/periglacial activity.
Meat sharing is common in chimpanzees. While being well-studied, it is still unclear what drives meat owners to relinquish nutritional benefits in favour of group members. The topic is rich in theoretical models, with support for different hypotheses coming from various chimpanzee populations. Few studies have considered several alternative hypotheses simultaneously, which provides insight into how multiple mechanisms interact to enable meat sharing. We investigated whether Reciprocal Altruism, Sharing-under-pressure, Mutualism, or Costly Signalling can explain meat sharing in Taï chimpanzees. We found evidence that chimpanzees exchange meat for support in aggressive interactions, supporting Reciprocal Altruism. We found partial support for Mutualism, as individuals who caught the prey ate more than others, and hunters who begged were more likely to receive meat than others. Finally, we found that begging led to sharing, possibly supporting the Sharing-under-pressure hypothesis. Various mechanisms can lead to meat sharing; the prevalence of one mechanism over another might result from their ability to adapt to the specific environmental and social conditions of the population.
Across Africa, chimpanzee communities exhibit large behavioural diversity not exclusively explained by ecological or genetic variation. However, excluding subtle environmental factors is difficult when comparing far-apart populations. Taï National Park offers a unique opportunity to explore the impact of social learning on behavioural diversity. The Taï South and Djouroutou communities live only 60 km apart in a continuous ecosystem. However, these groups apply semi-different techniques when nut-cracking. Djouroutou chimpanzees crack five species of nuts, exclusively using stone tools. Taï South only cracks four of those species, using stone and wooden tools, and does not exploit abundant Sacoglottis gabonensis nuts. Moreover, this group uses stone and wooden tools. Here, we compared tool material availability and tool choice. Our results showed that both groups did not differ in available nut trees and access to different materials. The communities responded to these ecological conditions differently than predicted if availability was the only factor responsible for shaping behaviour. This highlights the potential role of cultural behaviour in wild chimpanzee feeding ecology.
We longitudinally observed and assessed the impact of the operating room (OR) staff movements and door openings on surrogates of the exogenous infectious risk using a new technology system.
Design and setting:
This multicenter observational study included 13 ORs from 10 hospitals, performing planned cardiac and orthopedic surgery (total hip or knee replacement). Door openings during the surgical procedure were obtained from data collected by inertial sensors fixed on the doors. Intraoperative staff movements were captured by a network of 8 infrared cameras. For each surgical procedure, 3 microbiological air counts, longitudinal particles counts, and 1 bacteriological sample of the wound before skin closure were performed. Statistics were performed using a linear mixed model for longitudinal data.
We included 34 orthopedic and 25 cardiac procedures. The median frequency of door openings from incision to closure was independently associated with an increased log10 0.3 µm particle (ß, 0.03; standard deviation [SD], 0.01; P = .01) and air microbial count (ß, 0.07; SD, 0.03; P = .03) but was not significantly correlated with the wound contamination before closure (r = 0.13; P = .32). The number of persons (ß, −0.08; SD, 0.03; P < .01), and the cumulated movements by the surgical team (ß, 0.0004; SD, 0.0005; P < .01) were associated with log10 0.3 µm particle counts.
This study has demonstrated a previously missing association between intraoperative staff movements and surrogates of the exogenous risk of surgical site infection. Restriction of staff movements and door openings should be considered for the control of the intraoperative exogenous infectious risk.
OBJECTIVES/SPECIFIC AIMS: The objective of this study is to assess the efficacy of combined AF and NP repairs to prevent degenerative changes and restore native disc morphology in an in vivo large animal model. We hypothesize that combined repairs will prevent disc degeneration following injury to a greater extent than the individual repairs after 6 weeks in vivo, as demonstrated through disc height measurements and disc morphology. METHODS/STUDY POPULATION: A total of 8 skeletally mature female Finn sheep were used in this study. Following a previously described method, IVDs from L1 to L6 of the lumbar spine were exposed using a lateral access, extraperitoneal approach5. IVDs were randomized into 5 treatment groups: 1) intact discs, 2) discs injured via a 3 cm x 1 cm box annulotomy and partial nucleotomy, 3) injury followed by a high density collagen (HDC) AF patch, 4) injury followed by injection of a modified hyaluronic acid (HA) into the NP, and 5) injury followed by both the HDC AF patch and HA NP injection. The HDC treatment was 15 mg/mL type-I collagen mixed with 0.06mM riboflavin, injected at the defect site and crosslinked in situ with blue light. The NP injection was HA modified with C16 side chains to increase the viscosity of the hydrogel (HYADD 4®)6. At 6 weeks post-operatively, sheep were sacrificed and had 3T magnetic resonance images (MRI) taken of their lumbar spine. Disc height analysis and Pfirrmann grading were performed on each segment using MR images. Additionally, quantitative MRI analyses were performed using a custom MATLAB algorithm that segments NP from the surrounding tissue and directly measures the NP volume. ANOVA with Tukey’s HSD was used to determine statistical significance between groups for disc height and quantitative MRI analyses, and the Kruskal-Wallis test with Mann-Whitney tests was used to statistically analyze Pfirrmann Grades. All animal use followed approved IACUC protocol. RESULTS/ANTICIPATED RESULTS: As shown in axial MR images (Figure 1A), intact discs had hyperintense NP with a distinct border to the AF. The discs receiving injury with no treatment had hypointense NP with no distinct border between the AF and NP. Individual and combined treatment with the HA NP injection and HDC AF patch appeared to preserve the hyperintense NP signal and AF/NP border. Intact control discs were not degenerated and had an average Pfirrmann grade of 1 (Figure 1B), while injured, untreated discs had significant degeneration with an average Pfirrmann grade of 3. Discs receiving the HA NP injection and collagen AF patch individually showed fewer signs of degeneration than the injured alone, and the combined treatment resulted in the least amount of degeneration with Pfirrmann grades not significantly different than the intact controls. Disc height index confirmed the trends seen in the Pfirrmann grades (Figure 1C), where injured discs lost 20% of the intact disc height, the individual NP and AF repairs restored 5-10% of intact disc height, and the combined repairs preserved 90% of the intact disc height. The NP voxel count of all treatment groups were similar to the intact controls (Figure 1D). DISCUSSION/SIGNIFICANCE OF IMPACT: The objective of this study was to determine how combined AF and NP can prevent degenerative changes to the disc in a large animal in vivo model. Pfirrmann grading and disc height index results show that the greatest preservation of disc morphology was seen with combined AF and NP repairs, while the individual strategies prevented degenerative changes better than injury with no treatment. It appears the HA NP injection restores lost water content to the disc following injury, and the AF collagen patch plays a role in maintaining the NP repair within the disc. This is the first study to our knowledge to attempt combined AF and NP repairs in an in vivo large animal model. Combining NP and AF repairs leads to significantly improved outcomes following disc injury, which warrants the translation of combined repairs into the clinic to improve patient outcomes with degenerative disc disease involving NP and AF.
Valbenazine is approved for tardive dyskinesia (TD) in adults based on clinical trials that included patients with mood disorders (e.g., bipolar disorder, major depressive disorder). In two long-termphase 3 trials, KINECT 3 (NCT02274558) and KINECT 4 (NCT02405091), sustained TD improvements were found in participants who received once-daily treatment with valbenazine (40 or 80mg). Data from these studies were analyzed post hoc to evaluate changes in psychiatric status of patients with a primary mood disorder.
Data were pooled from participants with mood disorders in KINECT 3 (6-week double-blind, placebo-controlled period; 42-week double-blind extension period; 4-week drug-free washout) and KINECT 4 (48week open-label treatment; 4-week drug-free washout). At screening, patients must have had a Brief Psychiatric Rating Scale total score <50. Mood changes were evaluated after long-term treatment (Week 48) and washout (Week 52) using the Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS). For each scale, mean changes from baseline in the total score and individual item scores were analyzed descriptively.
Of the 95 participants with a primary mood disorder (40mg , n=32; 80mg , n=63), 59 (62.1%) were diagnosed with bipolar disorder, 32 (33.7%) with major depressive disorder, and 4 (4.2%) with another mood disorder. A majority of all mood participants received concomitant antidepressants (84.2%) and/or antipsychotics (76.8%) during treatment; other common concomitant medications included antiepileptics (47.4%), anxiolytics (38.9%), and anticholinergics (22.1%). Mean YMRS and MADRS total scores in all mood participants indicated mood symptom stability at baseline (YMRS, 2.7; MADRS, 5.9). This stability was maintained during the studies, as indicated by minimal changes from baseline in mean total scores (YMRS: Week 48, 1.0; Week 52, –1.0; MADRS: Week 48, 0.3; Week52,0.9). Changes in individual items on both scales were also small (<±0.3), indicating no clinically significant changes or worsening in specific mood symptoms or domains.
Mood symptom stability was maintained in patients with TD and a primary mood disorder who received up to 48 weeks of treatment with once-daily valbenazine in addition to their psychiatric medication(s).
Funding Acknowledgements: Neurocrine Biosciences, Inc.