bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of vortex lattice method for supersonic aircraft design
Authors: Joshi H. , Thomas P.
Published: April 2023

There has been a renewed interest in developing environmentally friendly, economically viable, and technologically feasible supersonic transport aircraft and reduced order modeling methods can play an important contribution in accelerating the design process of these future aircraft. This paper reviews the use of the vortex lattice method (VLM) in modeling the general aerodynamics of subsonic and supersonic aircraft. The historical overview of the vortex lattice method is reviewed which indicates the use of this method for over a century for development and advancements in the aerodynamic analysis of subsonic and supersonic aircraft. The preference of VLM over other potential flow-solvers is because of its low order highly efficient computational analysis which is quick and efficient. Developments in VLM covering steady, unsteady state, linear and non-linear aerodynamic characteristics for different wing planform for the purpose of several different types of design optimisation is reviewed. For over a decade classical vortex lattice method has been used for multi-objective optimisation studies for commercial aircraft and unmanned aerial vehicle’s aerodynamic performance optimisation. VLM was one of the major potential flow solvers for studying the aerodynamic and aeroelastic characteristics of many wings and aircraft for NASA’s supersonic transport mission (SST). VLM is a preferred means for solving large numbers of computational design parameters in less time, more efficiently, and cheaper when compared to conventional CFD analysis which lends itself more to detailed study and solving the more challenging configuration and aerodynamic features of civil supersonic transport.
Indexing Philosophy in a Fair and Inclusive Key
Authors: FOKT SIMON , PHARR QUENTIN , TORREGROSSA CLOTILDE
Published: April 2023

Existing indexing systems used to arrange philosophical works have been shown to misrepresent the discipline in ways that reflect and perpetuate exclusionary attitudes within it. In recent years, there has been a great deal of effort to challenge those attitudes and to revise them. But as the discipline moves toward greater equality and inclusivity, the way it has indexed its work has unfortunately not. To course correct, we identify in this article some of the specific changes that are needed within current indexing systems and propose a new model that could embody them. We use the Diversity Reading List in Philosophy as a case study and PhilPapers as a basis for comparison. The model we propose not only represents the discipline in a more inclusive and fair way, but it is also efficient, easy to use or implement, and adaptable for a variety of contexts.
Computerized-adaptive testing versus short forms for pediatric inflammatory bowel disease patient-reported outcome assessment
Authors: Brenner Erica J. , Lin Li , Bahnson Kirsten M. , Long Millie D. , Chen Wenli , Kappelman Michael D. , Reeve Bryce B.
Published: April 2023

Introduction:

Computerized-adaptive testing (CAT) may increase reliability or reduce respondent burden for assessing patient-reported outcomes compared with static short forms (SFs). We compared CAT versus SF administration of the Patient-Reported Outcomes Measurement Information System® (PROMIS®) Pediatric measures in pediatric inflammatory bowel disease (IBD).

Methods:

Participants completed 4-item CAT, 5- or 6-item CAT, and 4-item SF versions of the PROMIS Pediatric measures. We compared average T-scores, intra-class correlations (ICCs), floor and ceiling effects, and standard error of measurement (SEM) across forms, along with mean effect sizes between active versus quiescent IBD disease activity groups.

Results:

Average PROMIS T-scores across forms were <3 points (minimally important difference) of each other. All forms correlated highly with each other (ICCs ≥0.90) and had similar ceiling effects, but the CAT-5/6 had lower floor effects. The CAT-5/6 had lower SEM than the CAT-4 and SF-4, and the CAT-4 had a lower SEM than the SF-4. Mean effect sizes were similar across forms when contrasting disease activity groups.

Conclusions:

The CAT and SF forms produced similar score results, but the CAT had better precision and lower floor effects. Researchers should consider PROMIS pediatric CAT if they anticipate that their sample will skew toward symptom extremes.
Euro as the currency of the EU’s green transition
Authors: Smoleńska Agnieszka
Published: April 2023

Stefan Eich’s The Currency of Politics offers us a new way of looking at the EU’s sustainable finance trend, one that allows us to see how the ‘greening’ financial transactions creates “green money” and thus intertwines with questions of justice and democracy. In this contribution I explore how The Currency of Politics can help us understand the significance and the constitutional implications of the transformation of the euro into the ‘currency of the green transition’ as it has been referred to by Eurogroup’s President in 2021. I show how the three trends of EU green bond issuance, granular sustainable finance regulation and the progressive greening of monetary policy are moulding the euro in a political sense as the ‘currency of the green transition’ as much as the legal tender. Euro currency becomes in this sense ‘a governance project’ for the sustainable transition. This perspective offers multiple points of engagement with the themes of Stefan Eich’s important book. For example, the claim of privatisation of money creation must be qualified to reflect on the implications of the granular way in which EU law defines what green money is. At the same time, while a ‘green currency’ creates spaces for engagement and new forms of organising a polity, it still remains largely removed from ordinary citizens as ‘technocratic’ rather than ‘democratic’ self-government.
Value extraction and institutions in digital capitalism: Towards a law and political economy synthesis for competition law
Authors: Lianos Ioannis
Published: April 2023

The rise of digital capitalism was marked by significant changes in the processes of value generation and capture in the economy. However, its impact on competition has only been recently explored. Taking a Law and Political Economy perspective we analyse four central developments challenging the traditional competition law framework and raising important questions regarding the broader institutional environment for the protection of competition: the transition towards financialisation and the logic of futurity, in particular in the digital economy, which gives rise to new competitive strategies of undertakings, structured around the ‘shareholder value’ principle; the extraction of economic value through new types of labour, which fall outside traditional employment relationships and hence affect the scope of competition law in the digital economy; the emergence of digital value chains that rely on multi-sided platforms and the formation of digital ecosystems, which challenge the usual focus of competition law on markets; the generation and extraction of value in the digital economy through new types of commodities and natural and artificial scarcities, that shape new social relations of production in accordance with the logic of futurity and lead to the emergence of competitive bottlenecks. Based on this analysis, we emphasize the need for a comprehensive theory-building for competition law and regulation that engages with these new processes of value generation and capture. We highlight how the underlying theories of ‘value’ and the institutional set-up have led to inequality and reduced competition. Existing institutions could not respond to these changes, which led to the initiation of significant institutional reforms. The prevailing conception of competition law had to evolve in congruence with different regulatory alternatives (a ‘toolkit’ approach). The article concludes by analysing how the emerging competition and regulatory compass for the digital economy in the European Union (EU) contributes to this dialectic between value generation/capture and institutional choice.
Towards the imaginary of collective prosperity in the European Union (EU): reorienting the corporation
Authors: Bartl Marija
Published: April 2023

In February 2022, the European Commission published the ‘Proposal for a Directive on Sustainable Due Diligence’. This proposal appears a first tentative step to move the European Union (EU) away from a neoliberal conception of corporation. It replaces the wholesale trust in shareholders as the drivers of social progress with a greater reliance on public intervention that, via law, should expand the purposes pursued by corporations and set more sustainable rules for their action. This intended shift towards a more socially responsible, ‘collectivist’ understanding of corporation, I argue, should be seen as part of a broader change in perception of the desirable relationship between the market, government and law in the EU, forced by the many unfolding crises.

In this paper I develop the concept of ‘imaginaries of prosperity’ as an analytical category that should enable us to grasp deep changes in the conception of political economy that the EU is currently undergoing. I use the Commission’s attempt to transform one of the core institutions of the deeply entrenched imaginary of privatised prosperity – the neoliberal corporation – to identify shifts in our background understanding of the economy, politics, government, nature and law which are pointing to the emergence of a more collective imaginary of prosperity in the EU. However, even if Commission’s due diligence proposal represents a visible shift toward such a collective imaginary of prosperity, in the last part of the paper I will argue that a more serious engagement with the question of power and the role of profit is both necessary, and imaginable, if we are to change course from what has led us to the current polycrisis.
On the Torelli Lie algebra
Authors: Kupers Alexander , Randal-Williams Oscar
Published: April 2023

We prove two theorems about the Malcev Lie algebra associated to the Torelli group of a surface of genus g: Stably, it is Koszul and the kernel of the Johnson homomorphism consists only of trivial

$\mathrm {Sp}_{2g}(\mathbb {Z})$

-representations lying in the centre.
Deformations of arcs and comparison of formal neighborhoods for a curve singularity
Authors: Bourqui David , Morán Cañón Mario
Published: April 2023

Let

$ {\mathcal C} $

be an algebraic curve and c be an analytically irreducible singular point of

${\mathcal C}$

. The set

${\mathscr {L}_{\infty }}({\mathcal C})^c$

of arcs with origin c is an irreducible closed subset of the space of arcs on

${\mathcal C}$

. We obtain a presentation of the formal neighborhood of the generic point of this set which can be interpreted in terms of deformations of the generic arc defined by this point. This allows us to deduce a strong connection between the aforementioned formal neighborhood and the formal neighborhood in the arc space of any primitive parametrization of the singularity c. This may be interpreted as the fact that analytically along

${\mathscr {L}_{\infty }}({\mathcal C})^c$

the arc space is a product of a finite dimensional singularity and an infinite dimensional affine space.
Upscale transfer of waves in one-dimensional rotating shallow water
Authors: Thomas Jim , Ding Lingyun
Published: April 2023

We study the inverse flux of waves in one of the simplest geophysical fluid dynamics models: one-dimensional rotating shallow water equations. Based on direct numerical integration of the governing equations, we find that waves injected at small scales get transferred upscale predominantly via resonant quartic interactions between wave modes. The waves’ upscale transfer is non-local and involves turbulent transfer between disparate scales of the flow. Our analysis reveals that the upscale transfer of waves is extremely intermittent and is a result of localized-in-time bursts in wave action flux. These intermittent events of flux bursts lead to shallower waves’ spectrum and relatively higher amplitude wave fields in physical space. On examining statistics of the flow fields, we find that low-energy high wavenumbers more or less comply with the assumptions used in wave turbulence theory, such as uniformly distributed wave phases and the Gaussian distribution of fields, while non-uniform distribution of wave phases and non-Gaussian statistics dominate at large scales or low wavenumbers that contain a major share of the flow energy. Our findings point out that the one-dimensional rotating shallow water equations, despite being a simple geophysical fluid dynamic model, harbour complex and intricate features associated with the upscale transfer of waves that have not been recognized in the past.
Does Austerity Cause Polarization?
Authors: Hübscher Evelyne , Sattler Thomas , Wagner Markus
Published: April 2023

In recent decades, governments in many Western democracies have shown a remarkable consensus in pursuing fiscal austerity measures during periods of strained public finances. In this article, we show that these decisions have consequences for political polarization. Our macro-level analysis of 166 elections since 1980 finds that austerity measures increase both electoral abstention and votes for non-mainstream parties, thereby boosting party system polarization. A detailed analysis of selected austerity episodes also shows that new, small and radical parties benefit most from austerity policies. Finally, survey experiments with a total of 8,800 respondents in Germany, Portugal, Spain and the UK indicate that the effects of austerity on polarization are particularly pronounced when the mainstream right and left parties both stand for fiscal restraint. Austerity is a substantial cause of political polarization and hence political instability in industrialized democracies.
SISTERHOOD, AFFECTION AND ENSLAVEMENT IN HYPERIDES’AGAINST TIMANDRUS
Authors: Backler Katherine
Published: April 2023

A recently published fragment of the fourth-century speechwriter Hyperides contains a speech for the prosecution of Timandrus, accused of mistreating four orphans in his care. This article draws out from the fragment three important contributions to our understanding of Athenian conceptions of family relationships, particularly the relationships of marginalized groups: girls and enslaved people. First, the fragment constitutes a rare portrayal of a relationship between two sisters. Second, the fragment clearly articulates the idea that affective family relationships are not a biological inevitability but arise from socialization, a departure from other fourth-century thinking. Third, the speaker applies this statement to enslaved people, claiming that the separation of children from close family members is so cruel that even slave-traders avoid it in their sale of human beings. Though this claim seems to have been untrue except in a very limited sense, its place in the argumentation of the speech assumes broad recognition of the existence and value of family relationships between enslaved people, vivid evidence of the paradox that slave societies recognized the humanity of people they simultaneously insisted were subhuman.
The syntactic flexibility of German and English idioms: Evidence from acceptability rating experiments
Authors: WIERZBA MARTA , BROWN J.M.M. , FANSELOW GISBERT
Published: April 2023

It is controversial which idioms can occur with which syntactic structures. For example, can Mary kicked the bucket (figurative meaning: ‘Mary died’) be passivized to The bucket was kicked by Mary? We present a series of experiments in which we test which structures are compatible with which idioms in German (for which there are few experimental data so far) and English, using acceptability judgments. For some of the tested structures – including German left dislocation, scrambling, and prefield fronting – it is particularly contested to what extent they are restricted by semantic factors and, as a consequence, to what extent they are compatible with idioms. In our data, these structures consistently showed similar limitations: they were fully compatible with one subset of our test idioms (those categorized as semantically compositional) and degraded with another (those categorized as non-compositional). Our findings only partly align with previously proposed hierarchies of structures with respect to their compatibility with idioms.
A fast, accurate and easy to implement Kapur–Rokhlin quadrature scheme for singular integrals in axisymmetric geometries
Authors: Toler Evan , Cerfon A.J. , Malhotra D.
Published: April 2023

Many applications in magnetic confinement fusion require the efficient calculation of surface integrals with singular integrands. The singularity subtraction approaches typically used to handle such singularities are complicated to implement and low-order accurate. In contrast, we demonstrate that the Kapur–Rokhlin quadrature scheme is well-suited for the logarithmically singular integrals encountered for a toroidally axisymmetric confinement system, is easy to implement and is high-order accurate. As an illustration, we show how to apply this quadrature scheme for the efficient and accurate calculation of the normal component of the magnetic field due to the plasma current on the plasma boundary, via the virtual-casing principle.
Disenchanted: Thailand's indigenisation of the American Cold War, seen through the experience of Gordon Young
Authors: Hyun Sinae
Published: April 2023

Oliver Gordon Young was a third-generation American Baptist missionary who served with the Central Intelligence Agency during the 1950s and the United States Agency for International Development during the 1960s. He left Southeast Asia in 1974 disenchanted with his missions in the border areas of Thailand, Burma, and Laos. His ‘disenchantments’ with these two preeminent American Cold War agencies illustrated what the United States had increasingly failed to grasp, which was the ‘indigenising’ nature of the Cold War in Thailand. This essay examines Young's career in Thailand and bordering regions to better understand the limitations of American foreign policymaking establishments and their Cold War policies.
Cystic echinococcosis in Iceland: a brief history and genetic analysis of a 46-year-old Echinococcus isolate collected prior to the eradication of this zoonotic disease
Authors: Saarma Urmas , Skirnisson Karl , Björnsdottir Thorunn Soley , Laurimäe Teivi , Kinkar Liina
Published: April 2023

Cystic echinococcosis (CE) is considered the most severe parasitic disease that ever affected the human population in Iceland. Before the start of eradication campaign in the 1860s, Iceland was a country with very high prevalence of human CE, with approximately every fifth person infected. Eradication of CE from Iceland by 1979 was a huge success story and served as a leading example for other countries on how to combat such a severe One Health problem. However, there is no genetic information on Echinococcus parasites before eradication. Here, we reveal the genetic identity for one of the last Echinococcus isolates in Iceland, obtained from a sheep 46 years ago (1977). We sequenced a large portion of the mitochondrial genome (8141 bp) and identified the isolate as Echinococcus granulosus sensu stricto genotype G1. As G1 is known to be highly infective genotype to humans, it may partly explain why such a large proportion of human population in Iceland was infected at a time . The study demonstrates that decades-old samples hold significant potential to uncover genetic identities of parasites in the past.
The doctrine of participation in Augustine'stotus Christusecclesiology
Authors: Fogleman Alex
Published: April 2023

Augustine's understanding of the church as part of thetotus Christus– the ‘whole Christ’ – has become an important resource in contemporary theology, offering a robust vision of the church's union with God. Yet a key critique maintains that it threatens to elide the distinction between the perfected Christ and the created church. This article addresses this issue by asking how thetotus Christusdoctrine relates to the doctrine of participation. For Augustine, participation is a metaphysical category that expresses the creature's dependent, non-divine status, its essential being out of nothing. Thetotus Christusdoctrine is most explicitly an exegetical, not metaphysical doctrine. Nevertheless, by putting these two facets of Augustine's thought together, we can see the way in which they mutually reinforce the view that the astonishing claims of unity in thetotus Christusare structured by a larger theological grammar that distinguishes God and creature.
A POWERFUL SUBVECTOR ANDERSON–RUBIN TEST IN LINEAR INSTRUMENTAL VARIABLES REGRESSION WITH CONDITIONAL HETEROSKEDASTICITY
Authors: Guggenberger Patrik , Kleibergen Frank , Mavroeidis Sophocles
Published: April 2023

We introduce a new test for a two-sided hypothesis involving a subset of the structural parameter vector in the linear instrumental variables (IVs) model. Guggenberger, Kleibergen, and Mavroeidis (2019, Quantitative Economics, 10, 487–526; hereafter GKM19) introduce a subvector Anderson–Rubin (AR) test with data-dependent critical values that has asymptotic size equal to nominal size for a parameter space that allows for arbitrary strength or weakness of the IVs and has uniformly nonsmaller power than the projected AR test studied in Guggenberger et al. (2012, Econometrica, 80(6), 2649–2666). However, GKM19 imposes the restrictive assumption of conditional homoskedasticity (CHOM). The main contribution here is to robustify the procedure in GKM19 to arbitrary forms of conditional heteroskedasticity. We first adapt the method in GKM19 to a setup where a certain covariance matrix has an approximate Kronecker product (AKP) structure which nests CHOM. The new test equals this adaptation when the data are consistent with AKP structure as decided by a model selection procedure. Otherwise, the test equals the AR/AR test in Andrews (2017, Identification-Robust Subvector Inference, Cowles Foundation Discussion Papers 3005, Yale University) that is fully robust to conditional heteroskedasticity but less powerful than the adapted method. We show theoretically that the new test has asymptotic size bounded by the nominal size and document improved power relative to the AR/AR test in a wide array of Monte Carlo simulations when the covariance matrix is not too far from AKP.
Problématiques d’accumulation chez les aînés : l’expérience de proches aidants québécois au sein des services communautaires et publics
Authors: Moreau Annik , Dallaire Bernadette
Published: April 2023

Cette recherche qualitative traite de la situation des proches aidants des aînés composant avec une problématique d’accumulation (trouble d’accumulation compulsive, autonégligence, syndrome de Diogène). Il s’agit d’un contexte de la proche aidance qui a été jusqu’à maintenant peu étudié, où les réalités du vieillissement et de la santé mentale sont en interaction. Onze proches aidants et huit intervenants sociaux des régions de la Capitale-Nationale et de Chaudière-Appalaches ont participé à des entretiens semi-dirigés, lesquels ont été soumis à une analyse thématique de contenu. Nos résultats indiquent que malgré l’interaction du vieillissement et de problématiques de santé mentale, ce sont les enjeux liés au vieillissement qui déclenchent le début de la proche aidance, puis le maintien de cet engagement dans la durée. Ils nous montrent aussi que des efforts de concertation et de coordination devraient être déployés afin que les différents acteurs interpellés prévoient des trajectoires de services pour la personne âgée et les proches avant que le problème d’accumulation engendre des enjeux de sécurité importants. Dans ces trajectoires, les organisations sociosanitaires gagneraient à davantage reconnaître les savoirs des proches et à mettre à leur disposition les services requis pour répondre à leurs besoins spécifiques.
Impact of Cariprazine on Weight and Blood Pressure in Bipolar I Depression: A Real-World Study Using Electronic Medical Records
Authors: Correll Christoph U. , Laliberté François , Germain Guillaume , MacKnight Sean D. , Nguyen Huy-Binh , Parikh Mousam , Wade Sally W. , Cutler Andrew J.
Published: April 2023

Introduction

Patients with a severe mental illness such as bipolar I disorder (BP-I) have a higher prevalence of obesity and related metabolic comorbidities than the general population. This study evaluated the impact of cariprazine on weight and blood pressure in patients with BP-I depression using electronic medical records (EMRs) from a nationally representative database.

Methods

Analyses were based on data from EMRs in the Symphony Health’s Integrated Dataverse® from March 2015 to October 2018. Patients ≥18 years of age with ≥2 cariprazine fills (first dispensing=index date) and clinical activity for ≥12 months pre-index (baseline) and ≥1 month post-index were included. Patients also had a diagnosis of BP-I depression at their most recent episode prior to cariprazine initiation. The on-treatment period spanned from the index date to the earliest of cariprazine discontinuation, a switch to another atypical or long-acting injectable antipsychotic, end of clinical activity, or end of data. Metabolic outcomes of interest were weight and blood pressure (systolic and diastolic). For each outcome, patients were required to have ≥1 measurement in both the baseline and on-treatment periods. Linear trajectories during those periods were estimated using mixed-effects models; 95% confidence intervals (CIs) were calculated using non-parametric bootstrap procedures.

Results

In total, 1702 patients who met study eligibility criteria had ≥1 weight measurement recorded in the baseline and on-treatment periods; of these patients, 178 had bipolar I depression as their most recent episode. Patients gained an average of 2.43 kg/year during the baseline period and 0.60 (95% CI: -1.97, 3.70) kg/year during the on-treatment period. Analyses of blood pressure change (n=179) showed that cariprazine had neutral effects over the on-treatment period. Patients’ systolic blood pressure increased at 1.12 mmHg/year during baseline and decreased at -0.63 (95% CI: -3.59, 2.25) mmHg/year during the on-treatment period. For diastolic blood pressure, increases of 0.25 mmHg/year during baseline and 0.44 (95% CI: -1.65, 2.16) mmHg/year during the on-treatment period were observed.

Conclusions

Although patient weight was increasing prior to cariprazine initiation, a neutral weight trajectory was seen with long-term cariprazine treatment among those with a most recent BP-I depression episode. Cariprazine also had minimal impact on systolic or diastolic blood pressure. Overall, these findings are consistent with prior short- and long-term studies showing that cariprazine has a neutral weight and metabolic profile.

Funding

AbbVie
Anticholinergics Should Not Be Used to Treat Tardive Dyskinesia: Insights From an Expert Panel of Psychiatry and Neurology Healthcare Professionals
Authors: Vanegas-Arroyave Nora , Vanderhoef Dawn , Manahan Rachel , Cicero Samantha
Published: April 2023

Introduction

Tardive dyskinesia (TD) is a persistent and often disabling hyperkinetic movement disorder associated with prolonged exposure to dopamine receptor blocking agents (e.g., antipsychotics, antiemetics). The use of anticholinergics for the treatment of movement disorders including TD is a common practice, despite a lack of supportive evidence and the potential to worsen TD. Moreover, there are now FDA-approved medications specifically indicated for TD. Two virtual meetings were held with movement disorder experts from neurology and psychiatry to better understand the real-world use of anticholinergics for TD.

Methods

In November 2020, a panel of eight experts was convened to gather insights on the challenges of differentiating TD from other drug-induced movement disorders (DIMDs) and to discuss appropriate treatments for TD and other DIMDs. A follow-up meeting was held in June 2021 to consolidate these insights. Key recommendations based on the panel discussions are presented.

Results

The panel emphasized that while anticholinergics can help with managing some DIMDs, current evidence indicates that they are not effective in TD and may even worsen symptoms. Therefore, FDA-approved vesicular monoamine transporter 2 (VMAT2) inhibitors like valbenazine were recommended by the panel as first-line TD therapies. The panel noted that TD is often grouped under the term “extrapyramidal symptoms,” which leads to difficulty in differentiating TD from other DIMDs and the inappropriate treatment of TD with anticholinergics. The panel agreed that prophylaxis with anticholinergics is only appropriate in patients at high risk of acute dystonia. However, chronic anticholinergic use should be avoided whenever possible due to potentially serious adverse effects (e.g., cognitive difficulties) and anticholinergic burden, particularly in older patients. The potential for abuse, addiction, and diversion should also be considered when prescribing anticholinergics. Abrupt anticholinergic discontinuation can result in cholinergic rebound, which is characterized by sleep disturbances, gastrointestinal problems, urinary urgency, and manifestations of DIMDs. Thus, when used appropriately (e.g., for acute dystonia), anticholinergics should be prescribed at minimally effective doses and slowly tapered for successful discontinuation.

Conclusions

These findings align with the current TD treatment guidelines, including the lack of evidence for anticholinergic use and recommended first-line treatment with approved VMAT2 inhibitors. Conclusions from this panel highlight educational needs across HCPs on the phenomenology of DIMDs, the inappropriate use of anticholinergics for TD, TD risks and assessment, and treatment strategies for TD.

Funding

Neurocrine Biosciences, Inc.
Complete in vitro Dissolution of Valbenazine as Either Whole Capsules or Crushed Capsule Contents
Authors: Hebert Mello , Moore Richard , Jen Eric , Siegert Scott
Published: April 2023

Introduction

Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Three valbenazine capsule strengths (40 mg, 60 mg, 80 mg) are approved for the once-daily treatment of TD. However, some patients with TD, especially in elderly populations, have trouble swallowing due to orolingual movements. This study was conducted to evaluate two different dissolution methods for valbenazine: whole intact capsules versus crushed capsule contents.

Methods

Samples were prepared using two commercial lots (Lot-A, Lot-B) for two doses (40 mg, 80 mg), with six replicate samples per lot and dose. The whole capsules were weighed, put into a sinker, and added to a dissolution bath containing 900 mL of 0.1N HCl at 37±0.5° Celsius. Testing on the crushed capsule contents commenced after opening the capsules, weighing and crushing the contents, and transferring the contents to the dissolution bath. Samples were collected (at 10, 15, 20, 30, 45, and 60 min) with a paddle speed of 50 rpm and analyzed using high performance liquid chromatography. Standards were prepared at nominal concentrations of 0.044 mg/mL (for 40 mg) and 0.089 mg/mL (for 80 mg).

Results

Capsules were opened easily by manual manipulation, and contents were crushed easily between spoons. Very rapid (>85% in 15 min) and complete drug release was observed in all samples, independent of capsule strength (40 mg, 80 mg) or preparation (whole intact capsule or crushed capsule contents). For 40-mg capsules, average percent release at first and last collection timepoints were as follows (whole vs crushed): 10 min (98.4% vs 98.6% [A], 93.7% vs 97.6% [B]); 60 min (102.3% vs 100.5% [A], 100.9% vs 100.6% [B]). Results for 80-mg capsules were as follows: 10 min (98.2% vs 99.6% [A], 99.4% vs 97.9% [B]); 60 min (102.0% vs 101.6% [A], 103.2% vs 100.9% [B]).

Conclusions

Crushing the capsule contents did not impact the in vitro dissolution performance of valbenazine. Many patients with TD, particularly elderly patients, have difficulty swallowing and may benefit from alternative delivery methods for valbenazine, especially if other TD medications cannot be crushed. More research is needed to better understand if and how crushing the capsule contents of valbenazine affects their stability when mixed with food or delivered through a feeding tube.

Funding

Neurocrine Biosciences, Inc.
Genetic Behavioral Trait Assessment Paired With Personalized Recommendations and Coaching to Support Mental Health and Wellness
Authors: Krause David , VanDorn Daniel , Nguyen Harris , Amato Russel
Published: April 2023

Background

Genetics, environment, and lifestyle each contribute to human behaviors. We have developed a direct-to-consumer genetic assay (Mental Health Map) that allows users to explore their genetic behavioral predispositions and potential interventions that may positively influence mental health and wellness. Based on preliminary consumer feedback suggesting increased desire to take action on their mental health and wellness, we initiated a pilot study to assess several measures of mental health and self-care in individuals both before and after reviewing their Mental Health Map.

Methods

This was a virtual case series in adults who purchased a Mental Health Map. Subjects served as their own control based on survey responses leading up to genetic testing and up to 7 weeks after an introductory coaching session. Coaching included a demonstration of how to navigate the interactive online report, discussion of key results, and provision of additional external resources as appropriate. The co-primary measures were changes in quality of life as measured by WHO-5, report of initiating a discussion or seeking mental health care with a health care provider, report of initiating and sustaining positive lifestyle changes, and subjective improvements in stress management, sleep quality, mood, focus, and social interactions. Secondary measures were changes in GAD-7 and PHQ-9.

Results

Twenty-seven individuals completed the study. Average WHO-5 at baseline was 41.2 which numerically increased to 48.3 at week 7, suggesting improved quality of life, but this effect was not statistically significant. 42.3% of individuals were in treatment with a mental health provider at the time of survey. Of those not in treatment, 33.3% were actively seeking professional mental healthcare prompted by the coaching session. At week 6, 87% of survey respondents (n=15) asserted that they continued to make lifestyle changes that improved stress; 74% made changes to improve mood and 80% made changes that improved their habits. Percentage of respondents who reported lifestyle changes to improve sleep, focus, and social interactions were all less than 70%. In secondary outcomes, average GAD-7 at baseline was 8.9 and decreased to 6.7 at week 7, while PHQ-9 averaged 10.3 at baseline and decreased to 7.5 at week 7. Neither of the secondary outcome measures achieved a statistically significant difference.

Conclusion

Despite the small patient population, this pilot study provides proof-of-concept that Mental Health Map and the accompanying coaching session encourages participants to make positive lifestyle changes and prompts pursuit of a healthcare professional. We also saw numerical trends toward modest improvements in quality of life, anxiety, and depression symptoms, although these differences were not statistically significant, and may require larger sample sizes.

Funding

Genomind
Long-Term Lumateperone Treatment in Bipolar Disorder: Six-Month Open-Label Extension Study
Authors: Tohen Mauricio , Durgam Suresh , Kozauer Susan , D’Souza Ian , Chen Richard , Mates Sharon
Published: April 2023

Introduction

Approved therapeutics for bipolar depression are associated with a range of undesirable side effects. Lumateperone (LUMA), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. The efficacy of LUMA in bipolar depression was previously established in two Phase 3 trials, as monotherapy (NCT03249376) and as adjunctive to lithium or valproate (NCT02600507).

A recent Phase 3 multi-center trial, Study 401 (NCT02600494) investigated the efficacy and safety of LUMA in bipolar depression and comprised a 6-week, randomized, double-blind, placebo-controlled period and a 6-month open-label extension (OLE) period. Here, we report the results of the OLE period, examining long-term safety.

Methods

Patients, aged 18–75 years, with a clinical diagnosis of bipolar I or II disorder who were experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and a Clinical Global Impression Scale-Bipolar Version, Severity [CGI-BP-S] score ≥4) were eligible for Study 401. Patients who completed the double-blind study were eligible for direct rollover into the OLE or were re-screened if completing the double-blind period prior to the initiation of the OLE. During the OLE, LUMA 42 mg was administered once-daily in the evening for 25 weeks.

The primary objective was safety and tolerability of LUMA as measured by incidences of adverse events (AEs) and changes in laboratory parameters, cardiometabolic measurements, electrocardiogram (ECG), and vital signs. The secondary objective was improvement/maintenance of symptoms of depression as measured MADRS and CGI-BP-S Total scores.

Results

A total of 127 patients were enrolled in the OLE, with 74 (58.3%) completing the study. Treatment-emergent AEs (TEAEs) occurred in 73 patients (57.5%) with 54 (42.5%) experiencing a drug-related TEAE. TEAEs that occurred in ≥5% of patients were headache, dry mouth, dizziness, nausea, somnolence, anxiety, and irritability. Most TEAEs were mild or moderate in severity. Extrapyramidal-symptom-related TEAEs were rare. Most patients who had normal metabolic laboratory values at baseline remained normal during the treatment period. Mean changes in blood pressure, pulse rate, ECG, and body morphology were minimal. Symptoms of depression improved as measured by the mean change from baseline to Day 175 in MADRS Total score (−8.9) and CGI-BP-S Total score (−2.3).

Conclusion

In patients with bipolar depression, long-term LUMA treatment was generally well tolerated with low risk of extrapyramidal symptoms, weight gain, and cardiometabolic effects. These data further support the safety, tolerability, and effectiveness of LUMA in patients with bipolar depression.

Funding

Intra-Cellular Therapies, Inc.
Effect of Lumateperone (ITI-007) on Quality of Life and Functional Disability in the Treatment of Bipolar Depression
Authors: Edwards John B , Durgam Suresh , Kozauer Susan G , Jain Rakesh , McIntyre Roger S
Published: April 2023

Introduction

In patients with bipolar disorder, depression symptoms are associated with greater reduction in function and quality of life than hypomania/mania symptoms. Lumateperone (LUMA), is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder.

In a recent phase 3 clinical trial (Study 404, NCT03249376) in people with bipolar depression, LUMA 42 mg monotherapy significantly improved symptoms of depression compared with placebo (PBO). This analysis of Study 404 investigated the effects of LUMA on functional disability and quality of life as measured using the secondary outcome measure, the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF).

Methods

Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4) were randomized to LUMA 42 mg or PBO orally, once daily in the evening for 6 weeks. The primary endpoint was the change from baseline to Day 43 in MADRS Total score, analyzed using a mixed-effects model for repeated measures (MMRM) approach in the intent-to-treat population (ITT). This post hoc analysis evaluated the mean change from baseline to Day 43 in the Q-LES-Q-SF individual item scores using an analysis of covariance with last observation carried forward (ANCOVA-LOCF) in the ITT. Categorical shifts in individual items were also analyzed.

Results

The ITT comprised 376 patients (LUMA 42 mg, 188; PBO, 188). Patients in the LUMA 42 mg group had significantly greater improvement on MADRS Total score change from baseline to Day 43 compared with PBO (least squares mean difference vs PBO [LSMD], −4.585; 95% CI, −6.344 to −2.826; effect size vs PBO [ES], −0.56; P<.0001). LUMA 42 mg treatment significantly improved Q-LES-Q-SF Total score from baseline to Day 43 compared with PBO (LSMD, 2.9; 95% CI, 1.15 to 4.59; P=.001).

The Q-LES-Q-SF items with the lowest mean scores at baseline in both groups were mood, leisure time activities, and sexual drive, interest, and/or performance. By Day 43, LUMA 42 mg treatment significantly improved 8 of the 14 items in the Q-LES-Q-SF (P<0.05). Overall life satisfaction also significantly improved with LUMA treatment (P=.0016). The largest improvements with LUMA 42 mg compared with PBO (ES>0.3,) were seen for the ability to function in daily life, family relationships, household activities, leisure time activities, and mood (all LSMD=0.3; all P<.01).

Conclusion

In patients with bipolar depression, treatment with LUMA 42 mg compared with PBO significantly improved patient quality of life and functional impairment. These results support LUMA 42 mg as treatment of MDEs associated with bipolar I or bipolar II disorder in adults.

Funding

Intra-Cellular Therapies, Inc.
A 16-Week Open-Label Study of the Effects of Treatment With Pimavanserin on Activities of Daily Living in Subjects With Parkinson’s Disease Psychosis
Authors: Evidente Virgilio G. H. , DeKarske Daryl , Coate Bruce , Naujoks Karla , Abler Victor
Published: April 2023

Introduction

Accurate assessment of disability associated with Parkinson’s Disease Psychosis (PDP) is essential and has been poorly studied. Patients often have poor insight on impact of PDP on daily function. This phase 4 study is the first to evaluate the impact of pimavanserin on activities of daily living (ADL) in PDP patients.

Methods

Eligible PDP patients entered a 16-week single-arm, open-label study of oral pimavanserin (34 mg) taken once daily. Primary endpoint (modified Functional Status Questionnaire [mFSQ]) and secondary endpoints (MDS-UPDRS I & II; Schwab and England ADL; CGI-S, CGI-I, and PGI-I) were measured as change from baseline to Week 16 using mixed-effects model for repeated measures (MMRM) and least-squares means (LSM).

Results

29 patients were treated with pimavanserin, of which 24 (82.8%) completed the study. Treated patients demonstrated significant improvements in LSM (SE) mFSQ score change from baseline to Week 12 (11.5 [2.44]) and Week 16 (14.0 [2.50]; both p<0.0001). Significant improvements (p<0.05) were also observed for all secondary outcomes at Week 16 (MDS-UPDRS Part I: -6.3 [0.97]; MDS-UPDRS Part II: -2.6 [0.98]; CGI-S: -1.5 [0.25]; CGI-I: 1.9 [0.17]; PGI-I: 2.0 [0.22], except for Schwab and England ADL. No new safety signals were observed.

Conclusion

Functional outcomes and psychosis measures improved in PDP patients treated with pimavanserin, with safety findings consistent with previous studies. Our findings highlight the positive effect of pimavanserin in improving ADLs in patients with PDP.

Funding

Acadia Pharmaceuticals Inc.
Safety And Efficacy of Aripiprazole 2-Month Ready-to-Use 960 mg in Adult Patients With Schizophrenia
Authors: Such Pedro , Yildirim Murat , Madera-McDonough Jessica , Citrome Leslie
Published: April 2023

Background

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I), versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with schizophrenia are reported here.

Methods

Patients with schizophrenia were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale [VAS] scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was evaluated at Week 32 using mean (standard deviation [SD]) Clinical Global Impression – Improvement (CGI-I) score, and mean (SD) change from baseline in Clinical Global Impression – Severity (CGI-S) score, Subjective Well-being under Neuroleptic Treatment – Short Form [SWN-S] Total score, and Positive and Negative Syndrome Scale (PANSS) Total score.

Results

Study completion rate was 79.3% (73/92 patients) in the Ari 2MRTU 960 group and 67.7% (63/93 patients) in the AOM 400 group. Demographics and disease characteristics were well balanced between groups at baseline (mean [SD] PANSS Total score: Ari 2MRTU 960, 62.0 [13.5]; AOM 400, 61.8 [13.5]; mean (SD) CGI-S score: Ari 2MRTU 960, 3.3 [0.9]; AOM 400, 3.1 [0.9]). Treatment-emergent AE (TEAE) incidence was 66.3% with Ari 2MRTU 960 and 63.4% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 21.7%; AOM 400, 18.3%) and injection site pain (Ari 2MRTU 960, 15.2%; AOM 400, 9.7%). Mean (SD) VAS score for pain after last injection was 1.5 (4.58) with Ari 2MRTU 960 and 1.3 (2.79) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was similar between groups (Ari 2MRTU 960, 3.5 [1.0]; AOM 400, 3.6 [0.9]). Minimal change from baseline was seen at Week 32 in CGI-S score and SWN-S Total score. There was no clinically meaningful difference between the groups for PANSS Total score (difference of least squares mean change from baseline [95% confidence interval]: -0.9 [-3.5, 1.8]; p=0.5154).

Conclusions

In patients with schizophrenia, administration of Ari 2MRTU 960, as compared with AOM 400, was generally well tolerated, and clinical stability was maintained during the study.

Funding

Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).