bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Executive Function on Word Recognition: Comparison Between Native Chinese and Learners with Chinese as A Second Language (CSL)
Authors: Mingjia Cai , Xian Liao
Published: January 2025

Word recognition is a fundamental reading skill that relies on various linguistic and cognitive abilities. While executive functions (EF) have gained attention for their importance in developing literacy skills, their interaction with domain-specific skills in facilitating reading among different learner groups remains understudied. This study examines the relationship between EF, orthographic awareness, morphological awareness, and Chinese word recognition in 204 Chinese as a second language (CSL) students and 419 native Chinese primary students. Our findings reveal that EF indirectly influences word recognition through orthographic awareness, but not through morphological awareness. The result of group comparison indicates that direct and indirect effects of EF on word recognition are evident in both native and CSL groups. Nevertheless, EF plays a more prominent role in CSL learners. These results contribute to our understanding of cognitive skills in reading and offer significant implications for instructional practices.
A systematic review of the blockchain application in healthcare research domain: toward a unified conceptual model
Authors: Cihan Seyma , Yılmaz Nebi , Ozsoy Adnan , Beyan Oya Deniz
Published: January 2025

Recently, research on blockchain applications in the healthcare research domain has attracted increasing attention due to its strong potential. However, the existing literature reveals limited studies on defining use cases of blockchain in clinical research, categorizing and comparing available studies. Therefore, this study aims to explore the significant potential and use cases of blockchain in clinical research through a comprehensive systematic literature review (SLR). To thoroughly investigate all aspects of the subject, we analyzed primary studies based on research questions (RQs) and developed a unified conceptual model using step-based model creation. Studies from 2015 to 2023 were reviewed, and 34 primary studies were comprehensively analyzed by using the PICO template. In our findings, privacy emerged as the most frequently cited requirement in clinical research. The most mentioned use cases for blockchain are ensuring data immutability and security. A significant issue identified beyond the common blockchain limitations of capacity and scalability is the lack of standards for compliance with legal frameworks like GDPR and HIPAA. After all these efforts, we developed a conceptual model, which, to our best knowledge, is the first in the literature to support software developers and clinical researchers in developing and using blockchain-based research platforms efficiently.

Graphical abstract
Case report. Het sarcomatoïde carcinoom van de ureter
Authors: Tijans Aline M. , Bakker Dirk , Stomps Saskia P. , Vink Robert , Duijn Matthijs
Published: January 2025

Samenvatting

Het sarcomatoïde carcinoom van de ureter is een uiterst zeldzame en zeer agressieve maligniteit van de urinewegen. In de literatuur is deze aandoening slechts sporadisch beschreven. Hierdoor ontbreken specifieke richtlijnen voor de bepaling van een behandelstrategie. Primaire behandeling lijkt te berusten op radicale chirurgische excisie. Wij presenteren een casus van een 73-jarige man met een sarcomatoïde carcinoom uitgaande van de linker ureter, waarbij zowel chondro- als osteosarcoomcomponenten aanwezig zijn.
Dynamic analysis of water-rich heavy haul railway tunnels considering basement defects evolution and train effects
Authors: Peng Zhu , Shi Chenghua , Zhu Zixu , Xu Lei , Liu Cong , Lei Mingfeng
Published: January 2025

With the rapid development of heavy haul railway transportation technology, tunnel foundation defects and their effects on structural performance have attracted wide attention. This paper systematically investigates the evolution mechanism of tunnel foundation defects in heavy haul railway tunnels and their impact on structural stiffness degradation through experiments and numerical simulations. A heavy haul train–ballasted track–tunnel basement–surround rock dynamic interaction model (TTTR model) is constructed. Firstly, the study reveals the four-stage evolution process of initial defects in the tunnel basement under complex environmental conditions. Experiments were conducted to measure the load-bearing capacity and stiffness degradation of the tunnel basement structure under different defect states. It is found that foundation defects, especially under the coupling of loose fill in the basement with the water-rich environment of the surrounding rock, significantly reduce the stiffness of the tunnel bottom structure and increase the risk of structural damage. Then, based on refined simulation of wheel–rail interaction and multi-scale coupled modeling technology, the TTTR dynamic interaction model was successfully constructed, and its validity was proven through numerical validation. A time-varying coupling technique of constrained boundary substructures (CBS technique) was adopted, significantly improving computational efficiency while ensuring calculation accuracy. The study also analyzes the effects of different degrees of void defects on the dynamic behavior of the train and the dynamic characteristics of the tunnel structure. It finds that foundation defects have a significant impact on the train’s operational state, track vibration displacement, and vibration stress of the tunnel lining structure, especially under the coupling effect of basement voids and the water-rich environment, which has the greatest impact. The research results of this paper provide a theoretical basis and technical support for the maintenance and reinforcement of tunnel foundation structures.
Full-scale performances of the slab track subgrade filled with basalt fiber-reinforced foamed concrete
Authors: Huang Zhichao , Su Qian , Zhao Wenhui , Zhang Zongyu , Huang Junjie , Kaewunruen Sakdirat
Published: January 2025

Foamed concrete has been used to address the issue of differential settlement in high-speed railway subgrades in China. However, to enhance crack resistance, reinforcement is still necessary, and further research is required to better understand the performance of foamed concrete in subgrade applications. To this end, a series of tests—including uniaxial compressive and dynamic triaxial tests—were conducted to comprehensively examine the effects of basalt fiber reinforcement on the mechanical properties of foamed concrete with densities of 700 and 1000 kg/m3. Additionally, a full-scale model of the foamed concrete subgrade was established, and simulated loading was applied. The diffusion patterns of dynamic stress and dynamic acceleration within the subgrade were explored, leading to the development of experimental formulas to calculate the attenuation coefficients of these two parameters along the depth and width of the subgrade. Furthermore, the dynamic displacement and cumulative settlement were analyzed to evaluate the stability of the subgrade. These findings provide valuable insights for the design and construction of foamed concrete subgrades in high-speed rail systems. The outcomes are currently under consideration for inclusion in the code of practice for high-speed rail restoration.
Comparison of GFR estimation in patients with diabetes mellitus using the EKFC and CKD-EPI equations
Authors: Eisinger Felix , Neumann Mareike , Wörn Matthias , Fritsche Andreas , Heyne Nils , Peter Andreas , Birkenfeld Andreas L. , von Schwartzenberg Reiner Jumpertz , Artunc Ferruh
Published: January 2025

Background

The estimation of glomerular filtration rate (eGFR) is essential in the early detection of diabetic nephropathy. We herein compare the performance of common eGFR formulas against a gold standard measurement of GFR in patients with diabetes mellitus.

Methods

GFR was measured in 93 patients with diabetes mellitus using iohexol clearance as the reference standard. The performance of the creatinine- and cystatin C-based EKFC formulas (2021, 2023) and the CKD-EPI formulas (2009, 2012) was compared against measured GFR.

Results

Sixty patients with type 2 diabetes mellitus and 33 patients with type 1 diabetes mellitus were included. The creatinine-based EKFC formula showed lower bias and higher accuracy than the CKD-EPI formula. No significant difference was observed between the cystatin C-based formulas. The combined creatinine- and cystatin C-based formulas had the highest accuracy and lowest bias. Body fat or diabetes type did not significantly influence the accuracy of the cystatin C-based formulas.

Conclusions

Our study demonstrated a slight advantage of the creatinine-based EKFC formula over the CKD-EPI formula in patients with diabetes. However, both for the CKD-EPI and the EKFC formula, the best performance was achieved by the combined creatinine- and cystatin C-based formulas.

Graphical abstract
Entgrenzte Wehrhaftigkeit? Der deutsche Anti-Terror-Diskurs und die Bundestagsdebatten zum Umgang mit der „Letzten Generation“
Authors: Stephanblome Isabelle
Published: January 2025

Der vorliegende Beitrag untersucht weniger den politischen Umgang mit dem Islamismus selbst, sondern dessen breitere Auswirkungen auf den (sicherheits-)politischen Diskurs in Deutschland. Anhand der Bundestagsdebatte zum Umgang mit der „Letzten Generation“ wird nachgezeichnet, wie (Un)Sicherheitsnarrative, die über die letzten zwei Jahrzehnte mit dem (islamistischen) Terrorismus verbunden waren, in andere Themenfelder übernommen worden sind. Er nimmt die Beobachtung einer ‚diskursiven Schieflage‘ in der aktuellen gesellschaftspolitischen Debatte zum Ausgangspunkt und untersucht, wo und wie sich im Diskurs über die „Letzte Generation“ narrative Parallelen zum „Kampf gegen den Terrorismus“ zeigen. Hierzu werden Erkenntnisse zum deutschen Anti-Terror-Diskurs zusammengetragen und mit einer Narrativanalyse der bundespolitischen Debatte über die „Letzte Generation“ in Beziehung gesetzt. Es zeigt sich eine Übertragung von Erzählmustern, die ursprünglich aus der Terrorismusbekämpfung stammen, und wie versucht wird, deren etablierte legitimatorische Kraft nun in einem anderen Kontext politisch nutzbar zu machen.
A Five-Year Analysis of Market Share and Sales Growth for Original Drugs after Patent Expiration in Korea
Authors: Bae Minyoung , Shim Sung Ryul , Yang Dong-Wook , Son Kyung-Bok , Lee Sang-Won
Published: January 2025

Introduction

The sales patterns of original drugs after patent expiration in Korea show a relatively high market share and continuous sales growth differently from those in the U.S. and European countries. This study aims to investigates a five-year sales pattern of original drugs after patent expiration in Korea using empirical data.

Methods

Using data from the Ministry of Food and Drug Safety, original drugs whose patents expired in 2012–2018 were extracted. And we used IQVIA data to determine the market share and sales growth rate of 48 original drugs, whose generic drug launched for the first time in the same molecule market, and whose sales data over five years after first generic entry were available. We analyzed the differences by the attribute of variables.

Results

The sales volume of original drugs in the fifth year (Q 20) had an average growth rate of 150.6% compared with that before the first generic drug launched, indicating a continuous growth. The average market share of original drugs in the fifth year (Q 20) decreased to 70.6%, but it was higher than previously reported research results in Korea and other countries. Differences were observed across the category of attribute.

Conclusion

This study demonstrated that while market share of original drugs is decreasing, the sales volume increased continuously until the fifth year, differently from those of other countries. Variations in sales patterns by attributes reflect unique dynamics in Korea.
On the suspension and deposition within turbidity currents
Authors: Tsai Yao-Hung , Chou Yi-Ju
Published: January 2025

Numerical simulations are conducted to investigate particle suspension and deposition within turbidity currents. Utilizing Lagrangian particle tracking and a discrete element model, our numerical approach enables a detailed examination of autosuspension, deposition and bulk behaviours of turbidity current. We specifically focus on flow regimes where particle settling and buoyancy-induced hydrodynamics play equally important roles. Our discussion is divided into three parts. Firstly, we examine the main body of the current formed by suspended particles, revealing a temporal evolution consisting of initial slumping, propagation and dissipation stages. Our particle calculation allows for the tracking of autosuspended particles, enabling a deeper understanding of the connection between autosuspension and current propagation through energy budget analysis. In the second part, we delve into particle deposition, highlighting transverse and longitudinal variations. Transverse variations arise from lobe-and-cleft (LC) flow features, while longitudinal variations result from vortex detachment, particularly notable with large-sized particles. We observe that as particle size increases, leading to a particle Stokes number greater than 0.1, rapid particle settling suppresses the LC flow structure, resulting in wider lobes at the deposition height. Lastly, we propose a new scaling law for the propagation speed and current length. Our simulation results demonstrate close agreement with this new scaling law, providing valuable insights into turbidity current dynamics.
GENERALIZED TOWER SPECTRA
Authors: FISCHER VERA , HORVATH SILVAN
Published: January 2025

We investigate the tower spectrum in the generalized Baire space, i.e., the set of lengths of towers in

$\kappa ^\kappa $

. We show that both small and large tower spectra at all regular cardinals simultaneously are consistent. Furthermore, based on previous work by Bağ, the first author and Friedman, we prove that globally, a small tower spectrum is consistent with an arbitrarily large spectrum of maximal almost disjoint families. Finally, we show that any non-trivial upper bound on the tower spectrum in

$\kappa ^\kappa $

is consistent.
Motherese Directed at Prelinguistic Infants at Risk for Neurological Disorders: An Exploratory Study
Authors: Räsänen Okko , Airaksinen Manu , Marchi Viviana , Chorna Olena , Guzzetta Andrea , Festante Fabrizia
Published: January 2025

To investigate how a high risk for infant neurological impairment affects the quality of infant verbal interactions, and in particular properties of infant-directed speech, spontaneous interactions between 14 mothers and their 4.5-month-old infants at high risk for neurological disorders (7 female) were recorded and acoustically compared with those of 14 dyads with typically developing infants (8 female). Mothers of at-risk infants had proportionally less voicing, and the proportion of voicing decreased with increasing severity of the infants’ long-term outcome. Follow-up analysis based on manual annotation of phonation style revealed breathy phonation as more common toward infants with more severe long-term outcomes (N=7; 44.7% of speech) than controls (N=14; 22.0%; p=0.005) or at-risk infants with typical or mildly abnormal long-term outcomes (N=7; 16.5%; p=0.002). The results indicate that maternal phonation style during early dyadic interactions is affected by the infant’s neurological condition.
More than just a happy talk? Evidence for functional pitch and utterance length modifications in infant-, spouse-, and dog-directed communication
Authors: Koós-Hutás Édua , Afrin Shanjida , Kovács Alexandra Barbara , Faragó Tamás , Filep Lőrinc András , Topál József , Gergely Anna
Published: January 2025

By comparing infant-directed speech to spouse- and dog-directed talk, we aimed to investigate how pitch and utterance length are modulated by speakers considering the speech context and the partner’s expected needs and capabilities. We found that mean pitch was modulated in line with the partner’s attentional needs, while pitch range and utterance length were modulated according to the partner’s expected linguistic competence. In a situation with a nursery rhyme, speakers used the highest pitch and widest pitch range with all partners suggesting that infant-directed context greatly influences these acoustic features. Recent findings showed that these speakers expressed more intense positive emotions towards their infants and spouses than towards their dogs. Our results revealed different patterns, leading us to conclude that these acoustic features are not simple by-products of emotional speech. Instead, they are dynamically and functionally used in accordance with the speech context and the audience’s expected needs and capabilities.
Sex Differences in Attention Improvements Across Two Clinical Trials of AKL-T01, A Novel Digital Therapeutic for Inattentive Symptoms in Children and Adolescents with ADHD
Authors: Savarese Antonia , Maple Amanda M. , Stamatis Caitlin A. , Mercaldi Catherine , Hinshaw Stephen , Kollins Scott H.
Published: January 2025

Objectives

Attention-deficit/hyperactivity disorder (ADHD) remains underdiagnosed and undertreated in girls. One important contributor is the predominance of inattentive symptoms in girls relative to boys. Though less “visible,” inattentive symptoms represent a key driver of impairment, often persisting into adulthood. EndeavorRx (AKL-T01) is a game-based, FDA-authorized digital therapeutic directly targeting inattention. This analysis sought to examine potential sex differences in the efficacy of AKL-T01.

Methods

We conducted a secondary analysis of clinical outcomes by sex in 326 children and adolescents from two trials of AKL-T01 (n1 = 180 children; 30.6% female, M age = 9.71; n2 = 146 adolescents; 41.1% female, M age = 14.34). All participants had high inattention per a baseline score ≤ -1.8 on the Test of Variables of Attention (TOVA), a computerized, FDA-cleared continuous performance task objectively measuring attention. Participants used AKL-T01 for 25 minutes/day over 4 weeks. Primary outcomes included change in attention on the TOVA Attention Comparison Score (ACS) and sub-metrics, and change in symptoms on clinician-rated ADHD Rating Scale (ADHD-RS). To evaluate study hypotheses, we conducted a series of t-tests of TOVA and ADHD-RS change scores by sex.

Results

Across the pooled sample, girls using AKL-T01 demonstrated significantly greater improvements in attention on the TOVA ACS (MΔ = 2.44) compared to boys (MΔ = 1.32; t[211.77]) = 2.62, d = .31, p = .009), as well as TOVA reaction time standard score (girls’ MΔ = 13.22; boys’ MΔ = 3.54; t[229.12] = 3.93, d = .46, p <.001). We did not observe sex differences in the 2 other TOVA sub-metrics, nor in ADHD-RS (ps >.05). There were sex differences in compliance (t[207.99] = 2.17, d = .26, p = .031), with girls completing more sessions on average (M = 90.22) compared to boys (M = 80.19).

Conclusions

Results suggest that AKL-T01 may be associated with particularly strong improvements to attentional functioning in girls relative to boys. That there were no significant sex differences in ADHD symptom change over the course of treatment in either sex underscores the specificity of these effects to inattention processes rather than broad ADHD symptoms. Limitations include categorization based on binary sex, which may not capture nuances of gender identity.

Funding

Akili Interactive
Centanafadine Sustained Release Is Efficacious in the Treatment of Adult ADHD Across Disease Severities
Authors: Cutler Andrew J , Zhang Alan , Ward Caroline , McDonough Jessica , Mattingly Greg W
Published: January 2025

Introduction

Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI). The efficacy, safety, and tolerability of CTN sustained release (SR) for adults with ADHD was demonstrated in 2 pivotal phase 3 trials (Adler LA, et al. J Clin Psychopharmacol. 2022;42:429-39).

Methods

Adults (18–55 years) meeting DSM-5 criteria for ADHD enrolled in these double-blind, multicenter, placebo-controlled trials and randomized to treatment if ADHD Investigator Symptom Rating Scale (AISRS) score was ≥28 at screening (if not receiving pharmacologic treatment for ADHD) or ≥22 at screening and ≥28 at baseline (BL) (if receiving treatment). Having had no prior benefit from ≥2 ADHD therapies of 2 different classes, taking prohibited medications, and positive alcohol/drug screen were exclusionary. Trials had 4 periods: (1) screening and washout (≤28 days), (2) single-blind placebo run-in (1 week), (3) double-blind treatment (6 weeks), and (4) follow-up (10 days after last dose). Patients with ≥30% improvement in the Adult ADHD Self-report Scale (ASRS) from start to end of screening were screen failures; those with ≥30% ASRS improvement from start to end of placebo run-in were terminated early. Patients were randomized 1:1:1 to twice-daily CTN SR (200 or 400 mg total daily dose [TDD]) or matching placebo. The 200 mg/d group received CTN SR 200 mg TDD from days 1–42; the 400 mg/d group received 200 mg TDD on days 1–7, and increased to 400 mg TDD on day 8. This analysis assessed CTN SR effects based on median BL AISRS severity score (<38 or ≥38) using a mixed model for repeated measures analysis. Least squares mean (LSM) differences (95% CI) from BL at day 42 were compared between individual CTN SR dose groups and placebo, tested at a 2-sided significance level of 0.05.

Results

In total, 859 patients were randomized (200 mg TDD, n=287; 400 mg TDD, n=287; placebo, n=285). Significant LSM differences on the AISRS were observed vs placebo in the overall population (200 mg TDD and 400 mg TDD, P<0.0001 for each), in the low BL severity (200 mg TDD [P=0.016]; 400 mg TDD [P=0.019]), and in the high BL severity (200 mg TDD [P=0.005]; 400 mg TDD [P=0.003]) populations at day 42. Significant LSM differences vs placebo (P<0.01) began at day 7 (200 mg) and day 14 (400 mg) overall, remaining significant to day 42. Significant LSM differences were observed vs placebo (P<0.05) from day 14 (400 mg TDD) and day 21 (200 mg) in the low severity populations, and from day 21 (400 mg TDD) and day 7 (200 mg TDD) in the high severity population, remaining significant (P<0.05) to day 42.

Conclusions

CTN SR, a potential first-in-class NDSRI, is efficacious for patients with adult ADHD of low or high BL symptom severity, with significant improvements observed vs placebo within the first 3 weeks.

Study Registration: NCT03605680, NCT03605836

Funding

Otsuka
Using Patient iPSC-Derived Neurons to Uncover Mechanisms Associated with Response to Antidepressant Drugs: A Framework for Precision Medicine in Depression
Authors: Kugel Aleksandra , Kroitorou Dana , Albeldas Claudia , Solal Talia Cohen , Laifenfeld Daphna
Published: January 2025

Introduction

Depression is a leading cause of disability worldwide affecting over 300 million individuals globally. Despite the abundance of approved antidepressants, the majority of depressed patients do not respond to their first prescribed antidepressant, with over 30% not responding to subsequent drugs. This is largely attributed to individual differences in the underlying pathophysiology of the disease, which make some medications efficacious for some patients while ineffective for others. Multiple studies have been conducted with the aim of identifying patient subgroups associated with drug response, with a large focus on variations in genetic and gene expression levels that may underlie response to specific drugs. However, these studies yielded mostly inconsistent results, with robust genetic effects largely related to drug pharmacokinetics and gene expression level associations poorly reproducible. In this study, we assessed gene expression levels in iPSC-derived neurons from depressed patients with a known response profile to various medications, alongside genetic variations. iPSC-derived neurons have the potential to unravel mechanisms that are neuronal specific and thus not observed in patient whole blood molecular analysis.

Methods

Patient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study with known response to Citalopram or Bupropion were reprogrammed and then differentiated to cortical neurons. Analysis of genetic variants and differential gene expression was performed on the derived neurons to identify variants and gene expression levels that are associated with drug response.

Results

Significant differential gene expression was shown between Bupropion responders and non-responders as well as between Citalopram responders and non-responders. Functional enrichment analysis revealed biologically relevant pathways that differ between responders and non-responders in Bupropion and in Citalopram. In addition, we found an interplay between genetics and neuronal gene expression, that is associated with patient drug response. This was specifically observed in genes implicated in drug mechanism of action, including COMT and BDNF.

Conclusions

Patient-derived neurons have utility in mechanistic disease and drug modeling, and can elucidate mechanisms that cannot be read out from systemic whole blood analysis. In addition, combining genetics and target organ gene expression levels has the potential to be used as biomarkers for drug response. Together, these findings support a novel framework for precision medicine in depression.

Funding

Genetika+
A Review of the Delivery Technologies used in Attention-Deficit/Hyperactivity Disorder Stimulant Medications
Authors: Cutler Andrew J , Hanaie Jacob
Published: January 2025

Introduction

Multiple pharmaceutical technologies have been developed over the years and applied in the Attention-Deficit/Hyperactivity Disorder (ADHD) treatment space. While the base drugs are either the same or similar, these technologies lead to differences in the medications’ properties – including mechanism of release, timing of active drug release, and pharmacokinetic profiles. The technology differences also bring up clinical considerations applicable to patients, including delayed- or extended-release properties so that once daily dosing can be achieved.

This review seeks to make side-by-side comparisons of the technical features of the different technologies used in ADHD medications, not an efficacy comparison. The publication will focus on stimulant medications that use methylphenidate or amphetamine formulations. Gaining an understanding of the technologies’ properties and their implications will help clinicians to make more informed decisions when developing their patients’ treatment plans to fit their individual needs, and potentially improve adherence.

Methods

Sources including published literature, company websites, filed patents, and prescribing information were reviewed to extract data on the technology used for different ADHD medications. The comparison of the technology in ADHD medications included the drug delivery system, mechanism of drug release, and technology components such as use of resins, beads, complexes, coating or layers. Special considerations that come from these properties were elucidated and framed into a broader clinical context.

Results

Although the medications evaluated were all stimulants containing methylphenidate or amphetamine as the active ingredient, they vary significantly in the technology used to deliver medication to patients. Differences in the technologies used to deliver the stimulants are significant and provide the platform to meet individual patient needs. This side-by-side comparison, describing the specific features and benefits of each technology, will better inform prescribers, leading to better treatment of patients’ ADHD.

Conclusions

Clarifying the technologies available among ADHD pharmacotherapies and discussing their implications on patient care may help healthcare professionals better understand the treatment landscape and assist them in clinical decision-making for appropriate ADHD treatment. Knowledge of the mechanism of the technology could improve patients’ medication adherence. Additionally, understanding the applications of the technology could also benefit research and clinical programs.

Funding

Tris Pharma
Drug-Drug Interactions with Vesicular Monoamine Transporter 2 Inhibitors: Population Estimate of Patients With Tardive Dyskinesia at Risk in Real-World Clinical Practice
Authors: Mychaskiw Marko , Ghibellini Giulia , Dotiwala Zenobia , Konings Martijn , Gandhi Pooja , Casciano Julian
Published: January 2025

Introduction

Valbenazine and deutetrabenazine (vesicular monoamine transporter 2 inhibitors) are approved for tardive dyskinesia (TD) treatment in adults. To prevent potential drug-drug interactions (DDIs), valbenazine labeling recommends doses 40 mg/day when taking strong CYP3A4 or CYP2D6 inhibitors and avoidance of strong CYP3A4 inducers and monoamine oxidase inhibitors (MAOIs). Deutetrabenazine labeling recommends doses ≤36-mg/day when taking strong CYP2D6 inhibitors and avoidance of MAOIs. This study estimated proportions of patients with TD at risk of DDIs with valbenazine/deutetrabenazine in real-world practice.

Methods

Patients aged ≥18 years with TD and ≥1 antipsychotic claim(s) and no valbenazine/ deutetrabenazine claims ≥3 months prior and ≥12 months after diagnosis were identified in the Symphony Health Sciences database (US-based medical, hospital, and pharmacy claims database). Proportions of patients meeting valbenazine/deutetrabenazine concomitant medication labeling restrictions were summarized descriptively.

Results

14,264/66,046 patients with TD met inclusion criteria. Proportions of patients at potential risk of DDIs were lower with deutetrabenazine ≤36 mg/day (0.2%) and >36 mg/day (21%) versus valbenazine 40 mg/day (4.4%; 22-times difference) and >40 mg/day (28%; 1.3-times difference). Across age groups, underlying conditions (major depressive, mood, and bipolar disorders; schizophrenia), and payer types, proportions of patients at potential risk of DDIs were lower with deutetrabenazine ≤36 mg/day (0.0%– 0.5%) and >36 mg/day (14%– 30%) versus valbenazine 40 mg/day (3%– 5%; 8.0- to >40.0times difference) and >40 mg/day (22%– 35%; 1.2- to >1.5-times difference).

Conclusions

Estimated proportions of patients with TD at potential risk of DDIs was lower with deutetrabenazine versus valbenazine overall and across age, underlying conditions, and payer types.

Funding

Teva Branded Pharmaceutical Products R&D, Inc.
d-Amphetamine Transdermal System (d-ATS) in Treatment of Children and Adolescents With ADHD: SKAMP Score Analysis From a Pivotal Trial
Authors: Cutler Andrew J. , Komaroff Marina , Castelli Mariacristina , Meeves Suzanne , Balakrishnan Kanan , Khan Mawish
Published: January 2025

Background

The dextroamphetamine transdermal system (d-ATS) was developed as an alternative to current oral formulations of amphetamine, which is a first-line treatment for ADHD. In a randomized controlled trial of d-ATS in children and adolescents with ADHD, the primary endpoint (SKAMP total score) and secondary endpoints were met. This analysis evaluated the efficacy of d-ATS using SKAMP total score by optimized dose, gender, age group, ADHD type, and baseline ADHD severity.

Methods

This study comprised a 5-week, open-label dose-optimization period (DOP) followed by a 2-week, randomized, cross-over double-blind treatment period (DBP). All eligible patients received d-ATS 5 mg/9hr, with weekly evaluation for dose increase to 10 mg/9hr, 15 mg/9hr, and 20 mg/9hr. Once reached, the optimal dose was maintained for the DOP and used during the DBP. Preplanned subgroup analyses of mean SKAMP total score by optimized dose, gender, age group, ADHD type, and baseline ADHD severity were conducted. Efficacy was assessed by difference (d-ATS vs placebo) in least-squares (LS) mean SKAMP total score from a mixed-model repeated-measures (MMRM) analysis and is reported throughout as LS mean (95% confidence interval [CI]).

Results

In total, 110 patients were enrolled in the DOP, and 106 patients were randomized in the DBP. During the DOP, three patients reported 3 TEAEs that led to study discontinuation (irritability, appetite loss, abdominal pain). The difference (d-ATS vs placebo) in LS mean SKAMP total score was -5.9 (-6.8, -5.0), with differences in attention, deportment, and quality of work sub-scores of -1.4 (-1.7, -1.1), -1.9 (-2.2, -1.5), and -1.3 (-1.5, -1.0), respectively. Patients receiving d-ATS at each optimized dose demonstrated improvements vs placebo in LS mean SKAMP total score (-7.3 [-10.8, -3.7], -4.5 [-6.0, -3.0], -5.9 [-7.4, -4.5], -7.6 [-9.6, -5.6] at 5, 10, 15, and 20 mg/9hr, respectively). Both male and female patients experienced improvements vs placebo in SKAMP total score. The observed difference was greater in males (-6.3 [-7.3, -5.2]) vs females (-5.0 [-6.6, -3.4]). Similarly, improvements vs placebo were seen in patients with combined type ADHD and in those with predominantly inattentive type ADHD, with an observed LS mean difference of -8.0 (-9.2, -6.8) for the combined type and -3.3 (-4.6, -2.1) for the inattentive type. In addition, patients demonstrated improvement during the DBP regardless of baseline ADHD severity. The difference in LS mean SKAMP total score was -4.5 (-5.9, -3.1) for patients with a baseline SKAMP total score of 0-36 and -6.7 (-7.9, -5.6) for those with a baseline SKAMP score of 37-54.

Conclusions

d-ATS was effective and generally well-tolerated in treating ADHD in children and adolescents regardless of optimized dose, gender, age group, ADHD type, or baseline ADHD severity.

Funding

Noven Pharmaceuticals, Inc.
Assessment of Underdiagnosis of Tardive Dyskinesia by Geographic Region, Social Determinants, and Other Patient Characteristics
Authors: Gandhi Pooja , Zhang Su , Patel Ayush , Ayyagari Rajeev
Published: January 2025

Introduction

Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotics (APs).

Objective

To estimate TD diagnosis rates across geographic regions of the United States (US) among adults who use APs.

Methods

In this retrospective cohort study, patients with ≥1 AP claim (≥30-day supply) followed by TD diagnosis (index date) aged ≥18 years at index date with ≥12 months of continuous insurance eligibility after index date and geographic location information were identified in the IBM MarketScan© commercial insurance database (2012– 2019). Additional information was collected from the US census, the Internal Revenue Service, and the Centers for Medicare & Medicaid Services. . Observed TD diagnosis rates were estimated by metropolitan statistical area (MSA; ie, a major city and surrounding geographic areas linked by socioeconomic factors with ≥50,000 individuals). A weighted multivariable linear regression model was used to calculate expected TD diagnosis rates per 1000 patients with an AP prescription at the MSA level. Estimated and expected TD diagnosis rates were aggregated at the state level. Underdiagnosis of TD was defined as the observed TD diagnosis rate being lower than the expected TD diagnosis rate.

Results

Among 572,314 people who met inclusion criteria, the mean observed TD diagnosis rate across 341 MSAs was 3.10 per 1000 patients with an AP prescription; 86 (25.2%) MSAs had no patients with a TD diagnosis. Over 50% of MSAs and states had an underdiagnosis of TD. MSAs with the highest expected TD diagnosis rates were Missoula, MT (5.47), Billings, MT (5.39), and Madison, WI (5.16). MSAs with the highest observed TD rates were Chambersburg-Waynesboro, PA (18.52), Napa, CA (13.70), and San Angelo, TX (13.07). MSAs with the largest negative differences between observed and expected TD diagnosis rates (ie, highest underdiagnosis rates) were Missoula, MT (−5.47), Billings, MT (−5.39), and Gainesville, FL (−4.39). States with the highest expected TD rates were Montana (5.28), Idaho (4.52), and Alaska (4.32). States with the highest observed TD rates were North Dakota (7.09), Idaho (5.85), and New Mexico (5.67). States with the highest underdiagnosis rates were South Dakota (−3.72), Vermont (−3.57), and Montana (−3.21).

Conclusions

Overall, this study showed that TD was underdiagnosed in >50% of US geographic regions. This research highlights opportunities for improved TD recognition in areas with TD underdiagnosis.

Funding

Teva Branded Pharmaceutical Products R&D, Inc.
Valbenazine Improves Tardive Dyskinesia with or Without Concomitant Antipsychotic Therapy: A Meta-Analysis of Three Long-Term Valbenazine Trials
Authors: Dunayevich Eduardo , Marder Stephen R. , Hinton Sean C. , Factor Stewart A. , Watanabe Yumi , Nakanishi Arline
Published: January 2025

Introduction

Valbenazine is a highly selective vesicular monoamine transporter 2 inhibitor indicated for tardive dyskinesia (TD), a persistent and potentially debilitating movement disorder associated with prolonged antipsychotic exposure. Given the paucity of data regarding the course of TD in patients no longer taking antipsychotics, a meta-analysis of 3 long-term valbenazine studies was conducted in subgroups with and without concomitant antipsychotic use at baseline.

Methods

KINECTTM-3 (NCT02274558), KINECTTM-4 (NCT02405091), and JKINECT (NCT03176771) data were analyzed in study completers taking antipsychotics at baseline (AP+) and those who were not (AP-). The Abnormal Involuntary Movement Scale (AIMS) total score was used to measure TD severity at baseline, Wk48 (end of valbenazine treatment), and Wk52 (4 weeks after valbenazine withdrawal). The meta-analysis implemented a random-effects model that weighted each study based on inverse variance, adjusted for between-study variance.

Results

Of 576 enrolled patients, 336 (58.3%) were study completers and included for analysis: AP+ (n=269); AP- (n=67). Mean baseline AIMS scores ranged from 7.9–14.9 (AP+) and 10.9–14.5 (AP-). Mean changes from baseline in AIMS scores indicated substantial TD improvements with valbenazine at Wk48 (AP+, 6.1; AP-, -6.5) and return towards baseline severity at Wk52 (AP+, -2.1; AP-, -1.4).

Conclusions

Once-daily valbenazine treatment resulted in substantial and sustained TD improvement through Wk48, with no meaningful differences between AP+ and AP- subgroups. The return towards baseline severity after valbenazine withdrawal shows TD is chronic and often irreversible, even in patients no longer taking antipsychotics. Continuous treatment with valbenazine may be warranted irrespective of antipsychotic therapy.

Funding

Neurocrine Biosciences, Inc.
Safety and Tolerability of KarXT (Xanomeline Trospium): Pooled Results From the Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials
Authors: Brannan Stephen K. , Cutler Andrew J. , Sawchak Sharon , Kando Judith , Miller Andrew C. , Claxton Amy , Paul Steven M. , Kaul Inder
Published: January 2025

Introduction

In prior studies, the dual M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic activity in people with schizophrenia and Alzheimer’s disease, but its further clinical development was limited primarily by gastrointestinal side effects. KarXT combines xanomeline and the peripherally restricted muscarinic receptor antagonist trospium chloride. KarXT is designed to preserve xanomeline’s beneficial central nervous system effects while mitigating adverse events (AEs) due to peripheral muscarinic receptor activation. The efficacy and safety of KarXT in schizophrenia was demonstrated in the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials.

Methods

The EMERGENT trials enrolled people with a recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale total score ≥80, and Clinical Global Impression–Severity score ≥4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (xanomeline/trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. Safety was assessed by monitoring for spontaneous AEs after administration of the first dose of trial drug until the time of discharge on day 35. Data from the EMERGENT trials were pooled, and all safety analyses were conducted in the safety population, defined as all participants who received ≥1 dose of trial drug.

Results

A total of 683 participants (KarXT, n=340; placebo, n=343) were included in the pooled safety analyses. Across the EMERGENT trials, 51.8% of people in the KarXT group compared with 29.4% in the placebo group reported ≥1 treatment-related AE. The most common treatment-relatedAEs occurring in ≥5% of participants receiving KarXT and at a rate at least twice that observed in the placebo group were nausea (17.1% vs 3.2%), constipation (15.0% vs 5.2%), dyspepsia (11.5% vs 2.3%), vomiting (10.9% vs 0.9%), and dry mouth (5.0% vs 1.5%). The most common treatment-related AEs in the KarXT group were all mild or moderate in severity.

Conclusions

In pooled analyses from the EMERGENT trials, KarXT was generally well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the efficacy results showing a clinically meaningful reduction in the symptoms of schizophrenia, support the potential of KarXT to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics.

Funding

Karuna Therapeutics
Long-Acting Injectable Antipsychotic Treatment: Calculating Cost Offsets From Real-World Data
Authors: Kane John M. , Hollenbeak Christopher S. , Kotak Sameer , Thompson Stephen
Published: January 2025

Background

Long-acting injectable antipsychotics (LAIs) have demonstrated better rates of adherence among patients with schizophrenia than oral antipsychotics (OAs). While LAIs often cost more than OAs, better adherence can lead to cost offsets in other areas.

Objective

The purpose of this LAI Cost-Offset Value Calculator (LCVC) model is to provide an evidence-based model that estimates total costs and total cost offsets for a hypothetical population of adult patients with schizophrenia treated with atypical LAIs relative to second-generation oral antipsychotics (SGOAs) in the United States.

Methods

The model was derived based on studies included in a recent meta-analysis of patients who relapsed while taking an SGOA and were either switched to an atypical LAI or continued an SGOA. User inputs to the model include population size and payer archetype. The model then estimates the difference in adherence rates, relapse rates, hospitalizations, hospital days, hospital costs, emergency department (ED) visits, ED costs, and pharmacy costs, as well as cost offsets overall and by source (ie, hospitalization, ED, pharmacy).

Results

In the base case, representing a hypothetical cohort of 1000 adult patients with schizophrenia in the United States and a composite payer archetype, 1-year pharmacy costs were higher for patients who switched to an LAI relative to patients who continued taking an SGOA ($14,561,971 vs $7,203,142). However, cost offsets were observed for other dimensions of direct costs, including lower ED costs ($1,664,808 vs $2,241,483) and substantially lower hospital costs ($23,623,612 vs $44,195,100) due to fewer relapses (409 vs 508). For some payer archetypes (ie, Medicare and Veteran Affairs), the cost offsets completely covered the higher pharmacy costs for LAIs; for others (ie, Commercial and Medicaid), the cost offsets partially covered the higher pharmacy costs for LAIs, though sometimes substantially.

Conclusion

Despite potential higher pharmacy costs for LAIs, this model supports the conclusion that those costs could be mitigated by cost offsets in other areas, with varying results depending on payer archetype. The LCVC model, parameterized using real-world data extracted from a recent systematic review and meta-analysis, may be helpful for payers in understanding the potential cost offsets of switching patients with schizophrenia who have relapsed while taking OAs to LAIs. To our knowledge, there are no similar studies for schizophrenia that calculate cost offsets based solely on empirical evidence of patients who failed on OAs.

Funding

Teva Branded Pharmaceutical Products R&D, Inc.
Capital Backed Funding Arrangements
Authors: Steeden Derek , Aponte Adolfo , Barnett David , Carr Vicky , Pearce Iain , Reid Andrew , Repp Jonathan , Stone Ben , van Rees Claire , Vigneswaran Ragulan , Xu Kelvin
Published: January 2025

The rise in interest rates globally in 2022–23 led to improved scheme funding for many defined-benefit pension schemes. Many schemes in the UK now find themselves closer to, or at, a fully funded position on a low-risk basis (annuity buyout or self-sufficiency). Finishing the journey while managing the risk of losses on that journey is highly desirable, but may be difficult to achieve in practice.

However many schemes are not yet sufficiently funded to buy out liabilities in full with an insurer. Others may not wish to, and many who can afford to do so are not yet able to for investment reasons (such as holding illiquid assets) or operational reasons (such as the time needed to resolve member data issues). For schemes that instead look to adopt self-sufficient ongoing management with low dependency on the sponsoring employer, this may be difficult to maintain in practice. In short, there remains a risk that benefits will not be secured in full, which with hindsight could have been avoided.

The addition of capital to pension scheme assets has long been deployed to enhance the security of member benefits e.g., capital from insurers in the case of a buyout or capital from sponsors in the form of contingent assets.

More recently, providers have developed a diverse set of arrangements that draw on external capital to aid trustees and corporates to meet scheme funding ambitions. Capital Backed Funding Arrangements (“CBFA”) are in this context an additional tool in the trustee toolkit for delivering funding strategies.

This paper focusses on the UK-defined benefit market but the dynamics are applicable to other jurisdictions, with CBFAs being developed for wider markets (e.g., Ireland).

In this paper we:

survey the current scheme funding landscape and consider the need in this environment for arrangements to support scheme funding journeys to deliver benefits in full

summarise the key features of arrangements in the market that may support these objectives

set out considerations for trustees and sponsoring companies when assessing these arrangements.

The aim of this paper is educational – to increase awareness of the key issues and potential solutions. Professional advice will always be required prior to any transaction. We welcome feedback from readers on further material that would be beneficial to support consideration of these arrangements.