bluuebunny/crossref_metadata_2025 huggingface dataset:
The Social Determinants of Loneliness During COVID-19: Personal, Community, and Societal Predictors and Implications for Treatment
Authors: Bower Marlee , Lauria Eleisha , Green Olivia , Smout Scarlett , Boyle Julia , Donohoe-Bales Amarina , Dingle Genevieve , Barrett Emma , Fearn-Smith Erin , Gournay Kevin , Teesson Maree
Published: April 2023

Objective

The COVID-19 pandemic dramatically altered social determinants of health including work, education, social connections, movement, and perceived control; and loneliness was commonly experienced. This longitudinal study examined how social determinants at the personal (micro), community (meso), and societal (macro) levels predicted loneliness during the pandemic.

Methods

Participants were 2056 Australian adults surveyed up to three times over 18 months in 2020 and 2021. Multi-level mixed-effect regressions were conducted predicting loneliness from social determinants at baseline and two follow-ups.

Results

Loneliness was associated with numerous micro determinants: male gender, lifetime diagnosis of a mental health disorder, experience of recent stressful event(s), low income, living alone or couples with children, living in housing with low natural light, noise, and major building defects. Lower resilience and perceived control over health and life were also associated with greater loneliness. At the meso level, reduced engagement with social groups, living in inner regional areas, and living in neighbourhoods with low levels of belongingness and collective resilience was associated with increased loneliness. At the macro level, increased loneliness was associated with State/Territory of residence.

Conclusions

Therapeutic initiatives must go beyond psychological intervention, and must recognise the social determinants of loneliness at the meso and macro levels.
Use of population health data to promote equitable recruitment for a primary care practice implementation trial addressing unhealthy alcohol use
Authors: Krist Alex H. , Huffstetler Alison N. , Villalobos Gabriela , Rockwell Michelle S. , Richards Alicia , Funk Adam , Sabo Roy T. , Bortz Beth , Webel Ben , Lee Jong Hyung , Russel Kyle , Kuzel Anton , Britz Jaqueline B. , Moeller F. Gerard
Published: April 2023

Background:

Recruiting underrepresented people and communities in research is essential for generalizable findings. Ensuring representative participants can be particularly challenging for practice-level dissemination and implementation trials. Novel use of real-world data about practices and the communities they serve could promote more equitable and inclusive recruitment.

Methods:

We used a comprehensive primary care clinician and practice database, the Virginia All-Payers Claims Database, and the HealthLandscape Virginia mapping tool with community-level socio-ecological information to prospectively inform practice recruitment for a study to help primary care better screen and counsel for unhealthy alcohol use. Throughout recruitment, we measured how similar study practices were to primary care on average, mapped where practices’ patients lived, and iteratively adapted our recruitment strategies.

Results:

In response to practice and community data, we adapted our recruitment strategy three times; first leveraging relationships with residency graduates, then a health system and professional organization approach, followed by a community-targeted approach, and a concluding approach using all three approaches. We enrolled 76 practices whose patients live in 97.3% (1844 of 1907) of Virginia’s census tracts. Our overall patient sample had similar demographics to the state for race (21.7% vs 20.0% Black), ethnicity (9.5% vs 10.2% Hispanic), insurance status (6.4% vs 8.0% uninsured), and education (26.0% vs 32.5% high school graduate or less). Each practice recruitment approach uniquely included different communities and patients.

Discussion:

Data about primary care practices and the communities they serve can prospectively inform research recruitment of practices to yield more representative and inclusive patient cohorts for participation.
‘Creabimus!’ Creatively re-thinking the corporation and the social contract
Authors: Moncrieff Lilian
Published: April 2023

This article rethinks the corporation and ‘the social contract with business’ for the post-pandemic era. It uses a double historical orientation centred on the turbulence of the 1930s in Europe and America to insist on the company’s relationship with government, and to explore transformations in the social contract now needed to socialise and ecologise global business. One part of this history looks forward, from Adolf Berle’s modern corporation to the neoliberal corporation and regulatory governance. The article criticises a transformation of regulatory priorities in this era, closely analysing the shift to procedural mandates and questioning the corporate law tactic of ‘enlightening’ companies. The second part looks backwards to industrial modernism and Walter Rathenau in Germany in the interwar era, and also earlier (the late 1890s), to salvage a different understanding of the company and social contract, built around more constructivist visions of law, government and social consciousness. This part of the article is insistent about the metaphysical aspects of law and about developing law’s equalising powers around corporate impactfulness and injustice. It promotes ‘thought’ about collectivism (John Keynes) and the legal and regulatory recalibration that is needed to confront certain amassing challenges of the present. The article makes institutional transformation about shifting onto a different historical axis, whereby we might re-learn collectivist ambitions around the company that co-evolves with law and government, live to the public interest. It proposes a new social contract with business and a new regulatory modus involving law’s ‘Creabimus’ and ‘regulating dangerously’ for situations of widely adverse corporate impactfulness.
Robust transitivity and domination for endomorphisms displaying critical points
Authors: LIZANA C. , POTRIE R. , PUJALS E. R. , RANTER W.
Published: April 2023

We show that robustly transitive endomorphisms of a closed manifold must have a non-trivial dominated splitting or be a local diffeomorphism. This allows to get some topological obstructions for the existence of robustly transitive endomorphisms. To obtain the result, we must understand the structure of the kernel of the differential and the recurrence to the critical set of the endomorphism after perturbation.
Uncertain veracity judgments: Does the framing of the question influence deception detection?
Authors: Zloteanu Mircea
Published: April 2023

In deception research, little consideration is given to how the framing of the question might impact the decision-making process used to reach a veracity judgment. People use terms such as “sure” to describe their uncertainty about an event (i.e., aleatory) and terms such as “chance” to describe their uncertainty about the world (i.e., epistemic). Presently, the effect of such uncertainty framing on veracity judgments was considered. By manipulating the veracity question wording the effect of uncertainty framing on deception detection was measured. The data show no difference in veracity judgments between the two uncertainty framing conditions, suggesting that these may operate on a robust and invariant cognitive process.
Updates of precision medicine in type 2 diabetes
Authors: Xia Mingfeng , Li Xiaoying
Published: April 2023

Diabetes mellitus is prevalent worldwide and affects 1 in 10 adults. Despite the successful development of glucose-lowering drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors recently, the proportion of patients achieving satisfactory glucose control has not risen as expected. The heterogeneity of diabetes determines that a one-size-fits-all strategy is not suitable for people with diabetes. Diabetes is undoubtedly more heterogeneous than the conventional subclassification, such as type 1, type 2, monogenic and gestational diabetes. The recent progress in genetics and epigenetics of diabetes has gradually unveiled the mechanisms underlying the heterogeneity of diabetes, and cluster analysis has shown promising results in the substratification of type 2 diabetes, which accounts for 95% of diabetic patients. More recently, the rapid development of sophisticated glucose monitoring and artificial intelligence technologies further enabled comprehensive consideration of the complex individual genetic and clinical information and might ultimately realize a precision diagnosis and treatment in diabetics.
EMENDATIONS IN THE DIRAE AND THE LYDIA
Authors: Kayachev Boris
Published: April 2023

This article argues that the text of the Dirae and the Lydia is even more corrupt than current editions give reason to believe, and attempts to emend about a dozen passages.
Introduction: Arabic as a South Asian Language
Authors: Green Nile
Published: April 2023

In recent decades, the ascent of the “Persianate world” paradigm has prompted a major revival in the study of Persian sources in and on South Asia, while at the same time building on Marshall Hodgson's capacious original conception of the Persianate as being more than Persianper seby including “more local languages of high culture that … depended upon Persian wholly or in part for their prime literary inspiration.” While this has been an extraordinarily productive cycle of scholarship, it has also coincided and perhaps contributed to the longstanding occlusion of South Asia's Arabic tradition. A single bibliographical citation may serve to illustrate the stark contrast to the Persianate publishing boom: the last English-language book-length survey of “the contribution of India to Arabic” was completed as long ago as 1929.
Al-Ghazali and his Interpreters: The Case of the Emperor Aurangzeb
Authors: Shah Hinesh
Published: April 2023

The integration of South Asia into a Persianate world or “Persianate cosmopolis” has proven to be a particularly popular framing of the study of South Asian history. In Venture of Islam, Marshall Hodgson describes the Persianate as follows:

The rise of Persian had more than purely literary consequences: it served to carry a new overall cultural orientation within Islamdom. Henceforth, while Arabic held its own as the primary language of the religious disciplines and even, largely, of natural science and philosophy, Persian became, in an increasingly large part of Islamdom, the language of polite culture; it even invaded the realm of scholarship with increasing effect. It was to form the chief model for the rise of still other languages to the literary level … Most of the more local languages of high culture that later emerged among Muslims likewise depended upon Persian wholly or in part for their prime literary inspiration. We may call all these cultural traditions, carried in Persian or reflecting Persian inspiration, “Persianate” by extension.

Much of the subsequent theorization and conceptualization of the “Persianate” owes a significant debt to Hodgson's framing. Scholars have emphasized different aspects of the “Persianate,” with some choosing to frame it as a cultural milieu and others as a linguistically connected region. Here, “Persianate cosmopolis” refers to a geographical area whose major cultural foundation are the stories, ideas, and motifs expressed in New Persian literature. The circulation of such New Persian texts has supplied the primary content of the “Persianate cosmopolis.”
Right to Peaceful Protest in Nigeria and the Recurrent Syndrome of Brutalization: The #EndSARS Protest Debacle
Authors: Ekeke Alex Cyril
Published: April 2023

Protests play a significant role in the political, economic, social and cultural life of our societies. Protests have repeatedly motivated positive social change. Through protesting, individuals and groups express disagreement, opinions and objections to government actions or inactions. Protests bring attention to errors in governance and demand their rectification. The right to peaceful protest is protected under the international and African regional human rights frameworks, including the Nigerian Constitution. In Nigeria, the Public Order Act is designed to support the appropriate and peaceful conduct of peaceful assemblies (protests), meetings and processions. Yet the Nigerian government does not respect the right to peaceful protest, particularly in the case of protests against the government. This can be seen in recent protests against Nigeria's notorious Special Anti-Robbery Squad. This article examines the context of the application of the right to peaceful protest in Nigeria in view of the recent #EndSARS protests.
China’s and Japan’s winding path to the Refugee Convention: State identity transformations and the evolving international refugee regime
Authors: Chiavacci David , Soboleva Elena
Published: April 2023

In the early 1980s, the People’s Republic of China (PRC) and Japan joined the international refugee regime. This timing similarity is puzzling due to the stark differences between the PRC as a communist and authoritarian state versus Japan as a prime example of capitalist development and democratization. Moreover, although both signed the 1951 Refugee Convention and the 1967 Refugee Protocol without major reservations, neither of them has fully implemented these treaties. Discussions regarding the PRC’s and Japan’s engagement with the international refugee regime tend to start with the beginning of the Indochina refugee crisis in 1975. However, this article shows that the early decades of their interaction with the international refugee regime are of crucial importance for a full understanding of the timing and form of accession to the international refugee regime. Although the Southeast Asian refugee crisis played an important role as a trigger, it was the changing character of the international refugee regime and the transformations of state identity in both countries that set the ground for the signing of the refugee-related conventions.
Context and domain matter: the error-related negativity in peer presence predicts fear of negative evaluation, not global social anxiety, in adolescents
Authors: Niu Yanbin , Li Zixuan , Pettit Jeremy W. , Buzzell George A. , Zhao Jingjing
Published: April 2023

Background

Social anxiety symptoms are most likely to emerge during adolescence, a developmental window marked by heightened concern over peer evaluation. However, the neurocognitive mechanism(s) underlying adolescent social anxiety remain unclear. Emerging work points to the error-related negativity (ERN) as a potential neural marker of exaggerated self/error-monitoring in social anxiety, particularly for errors committed in front of peers. However, social anxiety symptoms are marked by heterogeneity and it remains unclear exactly what domain(s) of social anxiety symptoms are associated with ERN variation in peer presence, particularly within the adolescent period.

Methods

To advance and deepen the mechanistic understanding of the ERN's putative role as a neural marker for social anxiety in adolescence, we leveraged a social manipulation procedure and assessed a developmentally salient domain of social anxiety during adolescence – fear of negative evaluation (FNE). Adolescents residing in Hanzhong, a small city in the southwestern region of mainland China, had EEG recorded while performing a flanker task, twice (peer presence/absence); FNE, as well as global social anxiety symptoms, was assessed.

Results

Overall ERN increases in peer presence. FNE specifically, but not global levels of social anxiety symptoms, predicted ERN in peer presence.

Conclusions

These data are the first demonstration that the ERN relates to a specific domain of social anxiety in adolescents, as well as the first evidence of such relations within a non-WEIRD (Western, Educated, Industrialized, Rich and Democratic) sample. Results have important implications for theory and research into adolescent social anxiety.
Game of Scipios: Habsburg Interpretations, Adaptations, and Uses of Scipio Africanus in Early Modern Europe
Authors: Grudnicka Anastazja Maria
Published: April 2023

At the turn of the sixteenth century, the Habsburgs formulated a distinct dynastic identity that centered around their claims of ancient ancestry. They promoted this identity through an elaborate symbolic apparatus that extensively evoked historical and mythological figures from antiquity. This article identifies one such strand in the Habsburgs’ symbolic repertoires that centered upon their identification with Scipio Africanus (236/235–183 BC), the famous Roman general celebrated for his campaigns against Carthage. By tracing the Habsburgs’ uses of Scipio, this article offers a reassessment of the dynasty's relationship with these images. Traditionally, the Habsburgs’ shared symbolic repertoires have been understood to be a source of strength, providing a degree of unity and uniformity to the dynasty scattered across early modern Europe. This article argues that this dynastic uniformity ought not to be taken for granted. While the Habsburgs shared an attachment to Scipio, their interpretations of this Roman hero differed from each other in ways that were revealing of their individual needs, ambitions, and struggles as well as rivalries and animosities within the dynasty. The Habsburgs’ different—ultimately competing—uses of Scipio demonstrate that while their reliance on shared symbolic repertoires presented a significant advantage, it also rendered them uniquely vulnerable.
Dynamic eye-tracking evaluation of responding joint attention abilities and face scanning patterns in children with attention deficit hyperactivity disorder
Authors: Temeltürk Rahime Duygu , Aydın Özgür , Üstün Güllü Belgin , Kılıç Birim Günay
Published: April 2023

There has been growing evidence that autistic traits are more represented in children with attention-deficit hyperactivity disorder (ADHD). The purpose of this study was to investigate autistic traits associated with responding joint attention (RJA) abilities and face scanning patterns using eye-tracking in children with ADHD, and to compare with typically developing peers (TDs). All child participants viewed a series of videos related to male and female children under congruent and incongruent conditions during eye-tracking evaluation. The object and face regions of the models within the videos were determined as areas of interest (AOIs). Children with ADHD had significantly elevated ratings of autistic traits than TDs. Time course analysis of the proportion of fixations (PoF) on object region determined that children with ADHD tended to show more interest in the objects and had higher PoF on face interest area, including eyes and mouth compared to TD children in the videos when the male/female model shifts his/her gaze to the corner. Higher SRS scores were associated with higher PoF on the Face AOI in both groups. Given these findings, social skill interventions directly targeting the core deficits of RJA and problems in facial scanning appears to be beneficial in children with ADHD.
Mini-States and Micro-Sovereignty: Local Democracies in East Central Europe, 1918–1923
Authors: Mazur Zachary
Published: April 2023

As recent scholarship has shown, most of East Central Europe remained at war for several years after the official armistice in November 1918, complicating the transition from empires into nation-states. This article addresses another aspect of the state-building process. As opposed to centralising power emanating from capitals such as Prague, Warsaw and Budapest, I argue that local politicians and village leaders made their own territorial and sovereignty claims. Rather than whole nations, it was small communities that first defined self-determination. Here I present a loose typology of such localities (ethno-linguistic republics, non-Bolshevik workers’ councils, and radical agrarians), and show that conflicts between mini-states and burgeoning nation-states shaped the development of the latter.
STARS Adjunct Trial: Evidence for the Effectiveness of a Digital Therapeutic as Adjunct to Treatment With Medication in Pediatric ADHD
Authors: Maple Amanda , Palko Lisa , Cañadas Elena , Jina Anil
Published: April 2023

Background

Treatment of attention deficit hyperactivity disorder (ADHD) includes pharmacological and non-pharmacological interventions, both of which have demonstrated short-term efficacy. While efficacious, there are limitations to both modalities of treatment. Due partly to these limitations, there has been considerable interest in additional approaches to augmenting ADHD management. Digital therapeutics may offer improved access, minimal side effects, and low potential for abuse, while providing targeted treatment options for improving cognitive functions such as attention. AKL-T01 (EndeavorRx®) is the first and only FDA-cleared nonpharmacological prescription digital therapeutic delivered through a video game interface for the treatment of ADHD.

Objective

The objective is to summarize the data from a clinical trial in support of FDA clearance using AKL-T01 adjunctively in children currently taking stimulant medication for ADHD.

Methods

The STARS-Adjunct Trial was a multicenter, 12-week, open-label study of AKL-T01 in 206 children aged 8 to 14 years with a confirmed diagnosis of primarily inattentive or combined-type ADHD. The study included two cohorts: (1) subjects currently treated with ADHD medication (n=130) and (2) subjects not on any ADHD medication (n=76). Subjects had an ADHD Impairment Rating Scale (IRS) score ≥3 at baseline, and both cohorts used AKL-T01 for approximately 25 minutes per day, 5 days per week, over two 4-week treatment periods separated by a 4-week treatment pause.

Results

AKL-T01 significantly improved (lowered) ADHD-related impairment as measured with the IRS (clinician rated) after the first 4-week treatment in both cohorts (P< 0.001). Results show that effects persist during a 4-week treatment pause and further improve with a second 4-week treatment period. A majority of parents and children indicated a perceived improvement in ability to pay attention after the trial. Most common device-related adverse events were decreased frustration tolerance, headache, and irritability which ranged from mild to moderate. No serious adverse events were reported.

Conclusions

This study adds to and extends the clinical evidence base for AKL-T01, a video game-based treatment for improving attentional functioning in 8–12-year-old children with ADHD. Continued evaluation of the effects of AKL-T01 on other important aspects of functioning, like academic and social functioning, health utilization, and health outcomes, would continue to add to the evidence base that the effects observed in this and previous studies have substantial clinical and functional impact.

Funding

Akili Interactive
Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion
Authors: Gursahani Hema , Jolas Thierry , Martin Maryse , Cotier Sandrine , Hughes Sandrine , Macfadden Wayne , Parks Gregory , Chepke Craig
Published: April 2023

Introduction

Solriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The wake-promoting mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to further elucidate the molecular targets activated by solriamfetol and compare them to that of known WPAs and traditional stimulants.

Methods

In vitro binding and functional studies were conducted in a panel of cell lines or membrane preparations expressing transmembrane receptors and monoamine transporters to measure the activity of solriamfetol, comparator WPAs, and traditional stimulants. Electrophysiology studies were conducted in slice preparations from mouse ventral tegmental area (VTA). Studies to measure locomotor activity and wake-promoting effects were conducted in mice.

Results

In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity. Solriamfetol (1–10 μM) dose-dependently inhibited the firing frequency of dopaminergic VTA neurons in mouse brain slices, similar to known TAAR1 agonists; however, these effects were inhibited by a D2 antagonist, suggesting a DAT-mediated effect. Unlike traditional stimulants, solriamfetol did not increase locomotor activity in naive mice, but inhibited the increase in locomotor activity in DAT knockout mice.

Conclusions

Preclinical studies have identified agonist activity at the TAAR1 receptor and, possibly, lower potency agonist activity at 5-HT1A receptors as potential pharmacological targets for solriamfetol, in addition to its activity as a DAT/NET inhibitor. Given the current understanding of TAAR1 agonists as modulators of monoamine transmission with potential wake-promoting effects in multiple preclinical species, agonist activity at the hTAAR1 receptor may represent an additional pharmacological target underlying the wake-promoting effects for solriamfetol, in addition to its DNRI activity.

Funding

Axsome Therapeutics, Jazz Pharmaceuticals
Digital CBT-I Treatment Improves Sleep and Reduces Anxiety and Depression Symptoms in Adults With Chronic Insomnia: Interim Analysis of DREAM Study
Authors: Morin Charles , Thorndike Frances P , Ojile Joseph M. , Gerwien Robert , Wendorf Angela , Maricich Yuri A
Published: April 2023

Introduction

Chronic insomnia (CI) often co-occurs with depression and anxiety, and treatment may positively impact mood. This ongoing study collected real-world data on changes in insomnia, depression, and anxiety symptoms among adults with CI treated with a prescription digital therapeutic (PDT) delivering cognitive-behavioral therapy for insomnia (CBT-I; Somryst®, previously SHUTi).

Methods

This prospective, single-arm, pragmatic clinical study enrolled adults (≥18 years) in the US with CI and mobile device access. The PDT consists of six core modules completed over 6–9 weeks. In this interim analysis, participants completed the Insomnia Severity Index (ISI), 8-item Patient Health Questionnaire (PHQ-8), and Generalized Anxiety Disorder-7 scale (GAD-7) and other self-reported outcomes—at screening (baseline/prior to Core 1), end of treatment (Day 63), and 6-month follow-up (Day 243).

Results

Mean ISI scores decreased (p<0.0001) from baseline (n=991) to post-treatment (n=777;18.8 vs 11.3) and to Day 243 (n=193; 18.8 vs 12.1). Mean GAD-7 scores improved from baseline to Day 63 (n=744; p<0.0001, Cohen’s d = 0.48) and to Day 243 (n=186; p<0.0001, d = 0.45). Similarly, PHQ-8 scores improved from baseline to Day 63 (n=747; p<0.001, d = 0.76) and to Day 243 (n=186; p<0.0001, d = 0.60). These patterns persisted across baseline anxiety and depressive severity levels among people with any baseline depressive or anxiety symptoms (all p<0.05 for depression, all p<0.0001 for anxiety), with large effect sizes observed for severe anxiety (d=1.43 Day 63, d=1.55 Day 243) and for moderate to severe depression (d range = 0.96-1.51).

Conclusion

In this study, treatment with digital CBT-I was associated with significant reductions in ISI, anxiety, and depression at posttreatment and at 6 months. The largest observed decreases in GAD-7 and PHQ-8 scores were among people with more severe baseline mood symptoms.

Funding

Pear Therapeutics (US), Inc.
Reduced Healthcare Resource Utilization in Patients With Chronic Insomnia 24 Months After Treatment With Digital CBT-I: A Matched-Control Study
Authors: Forma Felicia , Knight Tyler , Baik Rebecca , Wallace Matthew , Malone Dan , Xiong Xiaorui , Velez Fulton , Thorndike Frances , Maricich Yuri
Published: April 2023

Introduction

This analysis examined the impact of a digital therapeutic for treating chronic insomnia (currently marketed as Somryst®, at the time called Sleep Healthy Using The internet [SHUTi]) on healthcare resource use (HCRU) by comparing patients treated with the digital cognitive behavioral therapy for insomnia (dCBTi) to patients not treated with dCBTi, but with insomnia medications.

Methods

A retrospective observational study using health claims data was conducted in two cohorts across the United States: patients who registered for dCBTi (cases) between June 1, 2016 and October 31, 2018 (index date) vs. patients who did not register for dCBTi but initiated a second prescription for an insomnia medication in the same time period (controls). Observation period was 16–24 months. No other inclusion/exclusion criteria were used. Control patients were matched using a nearest neighbor within-caliper matching without replacement approach. Incidence rates for HCRU encounter type were calculated using a negative binomial model for both cohorts. Costs were estimated by multiplying HCRU by published average costs for each medical resource.

Results

Evaluated were 248 cases (median age 56.5 years, 57.3% female, 52.4% treated with sleep-related medications) and 248 matched controls (median age 55.0 years, 56.0% female, 100.0% treated with sleep-related medications). Over the course of 24 months post-initiation, cases had significantly lower incidences of inpatient stays (55% lower, IRR: 0.45; 95% CI: 0.28–0.73; P=0.001), significantly fewer emergency department (ED) visits without inpatient admission (59% lower; IRR: 0.41; 95% CI: 0.27–0.63; P<0.001), and significantly fewer hospital outpatient visits (36% lower; IRR: 0.64; 95% CI: 0.49–0.82; P<0.001). There was also a trend for fewer ambulatory surgical center visits (23% lower; IRR: 0.77; 95% CI: 0.52–1.14; P=0.197) and fewer office visits (7% lower; IRR: 0.93; 95% CI: 0.81–1.07; P=0.302) with the use of SHUTi. Use of sleep medications was more than four times greater in controls vs. cases, with 9.6 (95% CI: 7.88–11.76) and 2.4 (95% CI: 1.91–2.95) prescriptions/patient, respectively (P<0.001). All-cause per-patient HCRU costs were $8,202 lower over 24 months for cases vs. controls, driven primarily by a lower incidence of hospitalizations (-$4,996 per patient) and hospital outpatient visits (-$2,003 per patient).

Conclusions

Patients with chronic insomnia who used a digital CBTi treatment had significant and durable real-world reductions in hospital inpatient stays, ED visits, hospital outpatient visits, and office visits compared to matched controls treated with medications.

Funding

Pear Therapeutics (US), Inc.
Sustained Treatment Response With Long-Term Valbenazine in Patients With Tardive Dyskinesia
Authors: Correll Christoph U. , Lindenmayer Jean-Pierre , Farahmand Khody , Jen Eric , Siegert Scott , Dunayevich Eduardo
Published: April 2023

Background

Valbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.

Methods

Data from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.

Results

Of the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with <50% AIMS improvement at Week 8, 81% achieved the ≥50% response threshold by end of treatment at Week 48. The proportion of participants meeting the threshold for CGI-TD response also increased over time, from 50% at Week 8 to 92% at Week 48. PGIC results were similar, with response rates of 53% and 88% at Weeks 8 and 48, respectively.

Conclusions

Post hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, >80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).

Funding

Neurocrine Biosciences, Inc.
Unique Considerations in the Treatment of Psychosis in DiGeorge Syndrome: A Case Report
Authors: Williams Laura , Jadapalle Sree , Lamm Kevin
Published: April 2023

Introduction

DiGeorge Syndrome is a microdeletion of chromosome 22q11.2 and is most commonly de novo. Manifestations of DiGeorge are wide-spread including cardiac malformations, palatal abnormalities, intellectual disability, hypocalcemia, dysmorphic facial features, and psychiatric disorders (psychotic disorders, Autism, ADHD, etc). This case report highlights difficulties with diagnosis and treatment of psychosis in DiGeorge. This 29 yo male with history of DiGeorge and associated cardiac anomalies presented to the outpatient clinic with prior diagnoses of schizoaffective disorder, bipolar disorder, DMDD, autism, and ADHD. Patient denied all symptoms, though mother noted hallucinations for 5–6 years. He was previously on aripiprazole and divalproex and developed a resting tremor. With family history of Parkinson’s disease (PD), increased risk of PD in DiGeorge, and no improvement in tremor with dose reduction of aripiprazole or discontinuation of divalproex, neurology diagnosed PD, which was later negated when tremor resolved with complete discontinuation of aripiprazole. In our clinic we slowly increased divalproex and olanzapine, though parent concern of sedation limited higher doses. Patient had moderate improvement in symptoms per parents, but after several months on moderate-dose olanzapine, he developed a tremor. Sensitivity to extrapyramidal symptoms limits medication selection. Furthermore, QT prolongation in a population with cardiac abnormalities poses a unique risk. Given complexity and poor response, we researched pathogenesis and treatment of psychosis in DiGeorge.

Methods

We reviewed literature on PubMed with keywords including “DiGeorge,” “treatment,” “psychosis.” Specifically, we looked at articles addressing treatment response, efficacy, side effects, novel treatments, and the pathogenesis as it relates to treatment.

Results

Literature indicates that psychotic symptoms are more treatment resistant compared to psychotic disorders not associated with DiGeorge and there is little consensus on which antipsychotics are more effective. The 22q11.2 deletion contains the gene segment for catechol-O-methyltransferase (COMT) and the resulting COMT deficiency leads to excess catecholamines. The presence of the low activity COMT variant on the remaining allele is associated with possibly more severe psychiatric symptoms. Metyrosine may be a potential medication in the treatment of psychosis in DiGeorge by interfering with dopamine synthesis. Overall there is sparse research on treatment of psychosis in DiGeorge and a lack of firm recommendations.

Conclusion

This case study exemplifies the need for further research on DiGeorge Syndrome and treatment of psychosis. Treatment is complicated by cardiac abnormalities, comorbid neuropsychiatric conditions confounding diagnosis, and little research on treatments that target the unique pathogenesis. Research is inconsistent concerning recommendations and novel treatments are primarily anecdotal.

Funding

No Funding
Digital Health Technologies in Mental Health Care: Changing Perspectives of Health Care Professionals from 2019 to 2021
Authors: Tacelosky Mark , Sadat Fatima , Meyer Chip , McKinley Tara , Pikul Dana , Carlton Tarolyn , Rohman Patricia , Singh Surinder , Moghadam Reza
Published: April 2023

Introduction

Demand for digital mental health tools has risen since the start of the COVID-19 pandemic; however, their evolving use in mental health care is not well understood. We surveyed mental health care professionals (HCPs) before and after the onset of the pandemic and assessed how use of and attitudes about digital technology changed.

Methods

We distributed a digital health survey to HCPs in the United States in 2019 (pre-pandemic; N = 141) and in 2021 (during the pandemic; N = 151). Both surveys recorded the respondents’ perceived barriers to integrating new digital health technologies and the tools they currently used in their practice.

Results

HCP use of telemedicine increased from 47% of respondents in 2019 to 81% in 2021, as did the use of mHealth sensors (2% vs 10%). Patient comfort with technology remained one of the biggest barriers to implementing new digital tools (40% vs 43%), while difficulty integrating digital tools into clinical practice became less common (40% vs 32%). Data management (19% vs 10%) and patient acceptability (19% vs 13%) were cited less often as barriers in 2021. Respondents’ thoughts on what can be most improved by digital technology shifted substantially, with increased access to care rising from 27% of responses in 2019 to 46% in 2021.

Conclusions

The pandemic has changed how HCPs perceive digital health technologies and how they implement these tools in clinical practice. A growing number of HCPs believe increased access to care is the outcome that technology can most improve.

Funding

Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA
Long-Term Safety and Effectiveness of Lurasidone in Adolescents and Young Adults With Schizophrenia: Pooled Post-hoc Analyses of Two 12-month Extension Studies
Authors: Calisti Fabrizio , Tocco Michael , Mao Yongcai , Pikalov Andrei , Goldman Robert
Published: April 2023

Introduction

Earlier onset of schizophrenia, which occurs more commonly in males, is characterized by greater illness severity, chronicity, and functional impairment with a less favorable prognosis than later-onset schizophrenia. The aim of this pooled analysis was to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia in adolescents (13–17 years) and young adults (18–25 years).

Methods

The 2 pooled studies used similar designs and outcome measures. Patients (13–25 years) with schizophrenia completed an initial double-blind 6-week trial of lurasidone (40 and 80 mg/d), and (80 and 160 mg/d) in the young adult trial. In the open-label long-term trials, adolescent patients were treated with 20-80 mg/d of lurasidone, and adults were treated with 40–160 mg/d of lurasidone. Efficacy was evaluated based on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity Scale (CGI-S).

Results

The safety population consisted of 306 patients (mean age, 16.2 years; 208 patients (68.0%) who completed 12 months of treatment; 8.2% discontinued by 12 months due to an adverse event. Mean (SD) change in the PANSS total score from extension Baseline to Months 6 and 12 was -11.8 (13.9) and -15.3 (15.0), respectively (OC); and mean (SD) change in the CGI-S score was -0.8 (1.0) and -1.0 (1.1), respectively (OC). The most frequent adverse events were headache (17.6%), anxiety (11.4%), schizophrenia (9.8%), and nausea (9.8). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin.

Conclusions

In adolescents and young adults with schizophrenia, treatment with lurasidone was generally well-tolerated and effective. Long-term treatment was associated with continued reduction in symptoms of schizophrenia. Long-term treatment was associated with minimal effects on weight, metabolic parameters, and prolactin.

Funding

Angelini Pharma S.p.A. and Sunovion Pharmaceuticals Inc.
Hyperammonemia and First-Degree Atrio-Ventricular Block in Adult Male from Valproic Acid Toxicity
Authors: Wilson Nicholas
Published: April 2023

Introduction

The purpose of this case study is to review the clinical presentation and medical work of an adult male who experienced symptomatic hyperammonemia and first-degree atrio-ventricular block in the setting of valproic acid toxicity.

Method

This case involves a 28-year-old African American male with a past psychiatric history of bipolar 1 disorder with psychotic features, antisocial personality disorder, PTSD, and ASD, who was psychiatrically hospitalized for mania and psychosis at a large midwestern university hospital. At the time of evaluation in the emergency department, the patient endorsed suicidal ideation, religious/persecutory delusions, and auditory hallucinations of demons. Zyprexa Zydis was started and titrated to 20 mg every 12 hours, which did not sufficiently improve symptoms. Depakote EC/DR 1000 mg every 12 hours was then added for treatment of mania. Approximately 1 week later, the patient was observed to be somnolent and complained of malaise, nausea, and vomiting.

Results

Labs were collected which showed an elevated ammonia level of 336 umol/L and free valproic acid level of 13.3 mcg/ml. An EKG was performed which showed first-degree atrio-ventricular block with fusion complexes. The patient’s baseline EKG displayed sinus bradycardia with no evidence of atrio-ventricular block. The patient’s CMP was unremarkable except total bilirubin of 1.5 mg/dL and glucose of 104 mg/dL. His lactate was elevated at 1.95 mmol/L. The patient’s troponin and CRP were unremarkable. The patient was medically transferred for management of hyperammonemia and EKG changes. Depakote was discontinued and lactulose 20 g TID was initiated. Patient was placed on telemetry and the first-degree atrio-ventricular block resolved within 24 hours after discontinuation of Depakote. Daily ammonia level, chem 7, and magnesium were collected. Ammonia decreased to 79 and 59 umol/L on consecutive days. Sodium was mildly elevated at 144 on day 2 of medical admission. Poison control was contacted and L-carnitine 990 TID was started for suspected carnitine deficiency. The patient medically recovered after several days and was readmitted to the psychiatric hospital for further psychiatric management.

Conclusions

The patient’s presentation of hyperammonemia and first-degree atrio-ventricular block were likely due to valproic acid toxicity. We suspect that carnitine deficiency contributed to the patient’s valproic acid toxicity at lower-than-expected blood levels. Although antipsychotics can cause prolonged QTc interval, conduction disorders are not typical abnormalities. Caution should be taken when prescribing Depakote to individuals at higher risk of developing toxicity, including those with potential nutritional deficiencies as well as those with limited self-advocacy abilities secondary to psychiatric illness. Rapid identification of side effects, such as valproic acid toxicity, remain crucial for favorable patient outcomes.

Funding

No Funding
Safety and Tolerability of Cariprazine for the Adjunctive Treatment of Major Depressive Disorder: A Pooled Analysis of Phase 2B and 3 Clinical Trials
Authors: Thase Michael E. , Yeung Paul P. , Hankinson Arlene , Liu Meng , Rekeda Ludmyla , Earley Willie R.
Published: April 2023

Background

Cariprazine has been shown to be efficacious in placebo-controlled clinical trials. In this pooled analysis, the safety of cariprazine in patients with major depressive disorder (MDD) with inadequate response to antidepressants was evaluated using data from placebo-controlled studies of up to 8 weeks’ duration and a long-term open-label safety study.

Methods

The safety, tolerability, and efficacy of cariprazine as an adjunctive treatment for patients with MDD with inadequate response to antidepressant alone was assessed in five placebo-controlled studies (two 6-week fixed-dose studies [NCT03738215; NCT03739203] and three 8-week flexible-dose studies [NCT00854100; NCT01715805; NCT01469377]) and one 26-week open-label flexible-dose study (NCT01838876). Fixed doses of cariprazine 1.5 and 3 mg/d and flexible doses of 0.1-4.5 mg/d were evaluated. Safety assessments included adverse event (AE) reporting, clinical laboratory tests, weight and other vital signs, and suicide evaluation with Columbia-Suicide Severity Rating Scale (C-SSRS). Pooled analyses of the incidence of safety endpoints overall and within each treatment arm were performed using the most frequent (modal) daily dose taken by patients during the study.

Results

A total of 2,222 MDD patients with an ongoing antidepressant received treatment with cariprazine, representing 370 patient-years of exposure in placebo-controlled and open-label studies. In the placebo-controlled studies, 1,969 patients were randomized to cariprazine (dose range, 0.1–4.5 mg/d) and 1,108 patients were randomized to placebo. Overall, treatment-emergent AEs occurred in 61% of cariprazine- and 48% of placebo-treated patients; discontinuation due to an AE occurred with 6% of cariprazine- and 2% of placebo-treated patients. The 2 AEs that occurred in at least 5% of cariprazine-treated patients and at a rate at least twice the rate in placebo-treated patients were akathisia (cariprazine=11%; placebo=2%) and restlessness (cariprazine=6%; placebo=2%). Changes in metabolic parameters, including shifts in fasting glucose and lipid parameters, were similar in cariprazine- and placebo-treated patients. In the long-term safety study, mean weight change was 1.6 kg over 6 months. In the placebo-controlled and long-term studies, other safety endpoints including laboratory and C-SSRS assessments of suicidality were generally consistent with the safety profile of cariprazine in approved indications of bipolar disorder and schizophrenia.

Conclusion

Cariprazine is generally safe and well-tolerated in MDD patients with inadequate response to antidepressant monotherapy. Safety analysis of 2,222 cariprazine-treated patients with MDD revealed no new safety signals, and the data is consistent with the currently approved prescribing information.

Funding

AbbVie