bluuebunny/crossref_metadata_2025 huggingface dataset:
Is the timing of eating relevant for weight loss?
Authors: Flanagan Alan
Published: January 2025

The potential influence of the timing of eating on body weight regulation in humans has attracted substantial research interest. This review aims to critically evaluate the evidence on timed eating for weight loss, considering energetic and behavioural components of the timing of eating in humans. It has been hypothesised that timed eating interventions may alter energy balance in favour of weight loss by enhancing energy expenditure, specifically the thermic effect of food. This energetic effect has been suggested to explain greater weight loss which has been observed with certain timed eating interventions, despite comparable self-reported energy intakes to control diets. However, timed eating interventions have little impact on total daily energy expenditure, and the apparent effect of time of day on the thermic effect of food largely represents an artefact of measurement methods that fail to account for underlying circadian variation in RMR. Differences in weight loss observed in free-living interventions are more likely explainable by real differences in energy intake, notwithstanding similar self-reported energy intakes. In addition, the energetic focus tends to overlook the role of behavioural factors influencing the timing of eating, such as appetite regulation chronotype-environment interactions, which may influence energy intake under free-living conditions. Overall, there is scant evidence that timed eating interventions are superior to general energy restriction for weight loss in humans. However, the role of behavioural factors in influencing energy intake may be relevant for adherence to energy-restricted diets, and this aspect remains understudied in human intervention trials.
Persecution and the Art of Demonstration
Authors: Shaw Beau
Published: January 2025

Rasoul Namazi's Leo Strauss and Islamic Political Thought contains patient and perceptive readings of four texts Strauss devoted to Islamic political philosophy. My comments are limited to just one of those readings, that of “Fârâbî's Plato,” and to a single issue within it—the question of the identity of the philosopher or of philosophy. Namazi rightly recognizes the centrality of this question in “Fârâbî's Plato.” As Strauss writes in explaining Alfarabi's view of Plato's philosophy, “the central question concerns . . . the precise meaning of the philosopher” (361), and Namazi claims that it is “one of the main themes or even the theme of ‘Fârâbî's Plato’” (148, emphasis original).
Bergson and the Mechanics of the Bedroom Farce
Authors: Senelick Laurence
Published: January 2025

Whereas the earliest farces deal with human appetites on the most basic level, by the mid-nineteenth century these had been sublimated and incorporated into a newly mechanical format. Inaugurated by Eugène Labiche, and perfected by Alfred Hennequin and Georges Feydeau, these masterpieces of clockwork ingenuity would appear to be the inspiration for Henri Bergson’s theory of comedy. This article explores the evolution of this style of farce, and demonstrates how Bergson’s influential ideas were themselves influenced not only by the popularity of the boulevard theatre, but also by prevailing concepts of clinical psychology and a Symbolist aesthetic. It is further argued, however, that Bergson’s reduction of the comic butt to an automaton fails to account for the empathetic element: the heavy quantum of anxiety conveyed from character to spectator.
Burning Hope: Staging Queer Ecology in a Time of Wildfire
Authors: Barclay Kari
Published: January 2025

This article analyzes three contemporary plays by trans and gender-non-conforming artists from the United States that engage with forest fires and queer ecology. These three plays – MJ Kaufman’s Sagittarius Ponderosa, Agnes Borinsky’s The Trees, and Kari Barclay’s How to Live in a House on Fire – tie wildfire to colonial histories of fire suppression and imagine a just climate transition as linked to queer and trans self-reinvention. The article describes this dramaturgical tactic as ‘burning hope’ – letting go of straight, settler desire and gesturing toward reciprocal obligation with the non-human world. Building on Kim TallBear’s call to attend to organic matter and Stephen Pyne’s study of fire history in the ‘Pyrocene’, the article imagines theatre as a prescribed burn that can re-orient audience relations to futurity. Burning hope does not abandon hope; it recognizes grief as mobilization for environmentalist solidarities.
Outbreak of Pseudomonas aeruginosa perichondritis associated with ear piercings and a contaminated water system
Authors: Brown Claire E. , Ready Derren , Willis Caroline , Sims Ben , Young Nick , Sheridan Elizabeth , Osbourne Helen , Jones Louise , Landy Yvette , Long Naomi , Walkden Amy , Turton Jane F. , Staniforth Karren , Moore Ginny , Parks Simon , Barkoci Patricia , Bird Sarah
Published: January 2025

In September 2023, the UK Health Security Agency’s (UKHSA) South West Health Protection Team received notification of patients with Pseudomonas aeruginosa perichondritis. All five cases had attended the same cosmetic piercing studio and a multi-disciplinary outbreak control investigation was subsequently initiated. An additional five cases attending the same studio were found. Seven of the ten cases had isolates available for Variable Number Tandem Repeat (VNTR) typing at the UKHSA national reference laboratory. Clinical and environmental P. aeruginosa isolates from the patients, handwash sink, tap water and throughout the wall-mounted point-of-use water heater (including outlet water) were indistinguishable by VNTR typing (11,6,2,2,1,3,6,3,11). No additional cases were identified after control measures were implemented, which included replacing the sink and point-of-use heater.

The lack of specific recommendations to control for P. aeruginosa within Council-adopted ear-piercing byelaws or national guidance means that a cosmetic piercing artist could inadvertently overlook the risks from this bacterial pathogen despite every intention to comply with the law and follow industry best practice advice. Clinicians, Environmental Health Officers and public health professionals should remain alert for single cases of Pseudomonas perichondritis infections associated with piercings and have a low threshold for notification to local health protection teams.
Mosses (Bryophyta) of the north-western region of Marambio (Seymour) Island, Antarctica
Authors: Cottet Agustina Celeste , Messuti María Inés , Ansaldo Martín , Dopchiz Laura Patricia
Published: January 2025

Marambio (Seymour) Island is located in the James Ross Archipelago east of the Antarctic Peninsula. Although several research groups have carried out studies on the biodiversity on the island for decades, surveys of bryophytes have not been developed. That is why there are currently only six species of mosses recorded in the northern part of the island. During the 2021–2022 summer Antarctic field trip, 15 mosses species were surveyed in Marambio Island. Of the total number of collected species, nine are reported for the first time for Marambio Island. For the remaining four species, their distributions are now expanded to Marambio Island.
Evaluating Viloxazine ER (Qelbree) Administered with Psychostimulants For Pediatric ADHD: Analysis of a Phase 4 Safety Trial
Authors: Childress Ann , Hayman Kimberley , Asubonteng Kobby , Yarullina Ilmiya , Earnest Jami , Rubin Jonathan
Published: January 2025

Introduction

Viloxazine extended-release (ER) is an FDA-approved, nonstimulant medication for pediatric (≥6 years) and adult ADHD. Apart from use as monotherapy, nonstimulants may be combined with stimulants when patients experience inadequate response or difficulties with medication tolerability. This phase IV, open-label trial (NCT04786990) evaluated the safety and tolerability of viloxazine ER administration with psychostimulants in children and adolescents with ADHD. Differences between morning and evening use of viloxazine ER were also assessed.

Methods

Children and adolescents (6 – 17 years) experiencing inadequate response (ADHDRS-5 ≥24 and CGI-S ≥3) to psychostimulant treatment (methylphenidate or amphetamine) were enrolled. Subjects maintained stable stimulant use throughout the trial. Following an up to 4-week screening period, subjects continuing to show inadequate response received flexibly dosed viloxazine ER (100-400 mg/day children; 200-600 mg/day adolescents) each morning during Weeks 1-4 and each evening during Weeks 5-8. Safety, tolerability, and efficacy were assessed relative to Baseline, and for change from baseline for morning vs. evening dosing.

Results

56 subjects received viloxazine ER with 85.7% of these completing the study. Adverse events were reported by 55.4% of subjects, most commonly headache (17.9%), decreased appetite (12.5%), and upper respiratory tract infection (10.7%); onset was more common during AM dosing trial weeks [50% of subjects reported AEs during Weeks 1-4 and 36% during Weeks 5-8]. AEs were largely mild (32.1%) or moderate (21.4%) and led to discontinuation for 2 (3.6%) subjects. Baseline mean (SD) Investigator Rated-ADHD-Rating Scale 5th ed. (IR-ADHD-RS-5) score was 37.2 (8.35), n=56. Significant improvement in IR-ADHD-RS-5 was seen by Week 1[ -6.9 (8.16), n=56; P<.0001)] and continued through Weeks 4 and 8 [-13.5 (9.70) p<.0001 and -18.2 (9.99) p<.0001, respectively]. Over 50% of subjects were rated much or very much improved on CGI-I at endpoint. Scores on the sleep disturbance Scale for Children (SDSC) scale also improved at both Weeks 4 and 8 [-8.8 (14.03) P<.0001 and -10.3(17.39) P=.0002, respectively], as did Parent-ratings of morning and evening ADHD symptoms and behavior, suggesting that morning and evening administration of viloxazine ER were both efficacious.

Conclusions

Viloxazine ER showed acceptable safety and tolerability when administered with stimulant medications in this Phase IV open-label trial. Administration of viloxazine ER in the evening instead of the morning did not appear to affect safety, nor the trajectory of drug response or sleep improvement.

Funding

Supernus Pharmaceuticals, Inc.
Psychosis of Epilepsy: A Review of Diagnosis and Management
Authors: Booker Brittany , Rangoonwala Saqib , Imtiaz Ayyub , Chamoun Karla , Duffy Samuel , Zaidi Muhammad
Published: January 2025

Introduction

Neurology and psychiatry have been linked together for a long period of time. One overlap demonstrated in the literature is the correlation between epilepsy with mood and psychosis. There is a big group of psychoses called the psychosis of epilepsy (POE); however, there is not much evidence about the diagnosis and management. Differentiation between POEs is difficult and is compounded by a lack of evidence-based guidelines on appropriate management. Even if you arrive at the diagnosis, POE can be difficult to manage. Some antiepileptic drugs (AEDs) cause psychiatric side effects and some antipsychotics may be epileptogenic. In this poster, we will discuss ways to diagnose and treat POE, as well as how to optimize certain AEDs in patients with POE.

Methods

Articles were chosen from multiple databases, such as MEDLINE, Google Scholar, and PsychInfo, to gather evidence about the diagnosis and management of POE. Specific keywords, such as Psychosis, Epilepsy, Antipsychotic, Antiepileptic, and Electroencephalogram (EEG) were used. Articles talking about recommendations regarding the use of AEDs and antipsychotics in POE were extracted from these databases.

Results

POE includes preictal, ictal, postictal, and interictal psychosis. Preictal psychosis is very rare and tends to present with dissociation and déjà vu. This is correlated with temporal lobe epilepsy and resolves after the seizure. Ictal psychosis will correspond with epileptic activity on EEG and can manifest as aggression, delusions, or hallucinations. Antipsychotics are contraindicated in this POE. Postictal psychosis usually presents as a combination of mood symptoms and grandiose delusions seen with interictal sharp epileptiform discharges on EEG. Interictal psychosis can be subtyped into brief and chronic, with brief occurring during periods of increasing seizure frequency and chronic having no association with seizures. They both present similar to symptoms seen in classic schizophrenia and antipsychotics are often utilized.

Clozapine and chlorpromazine were found to have the highest seizure prevalence from second- and first-generation antipsychotics respectively, and the lowest was found with risperidone. AEDs that are commonly used in psychiatry, such as oxcarbazepine, carbamazepine, valproic acid, and lamotrigine are discussed in detail regarding their optimal dosing strategy for patients presenting with POE.

Conclusions

Diagnosis and management of the various types of POE can be challenging due to the lack of literature. We recommend using the antipsychotic, risperidone, as it has shown to have the lowest seizure prevalence among all antipsychotics. Both neurologists and psychiatrists should keep POE on their differential when dealing with seizure patients with psychosis. It is crucial for psychiatrists to understand how to optimize AEDs in the management of POE as these patients are often seen on the consult service.

Funding

No Funding
Impact of a Virtual Patient Simulation on Clinical Decision Making for Pediatric Patients with ADHD
Authors: Guevara Natalie , Lubarda Jovana , Wright Clinton , Mattingly Gregory
Published: January 2025

Objectives

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood disorder that can persist into adulthood in up to two-thirds of patients. ADHD is a heterogeneous disease, with a wide spectrum of symptoms and severity. Thus, ADHD presents diagnostic and treatment challenges for clinicians. This study utilized an online, virtual patient simulation (VPS)-based continuing medical education intervention to improve the ability of psychiatrists to diagnose, assess, and treat pediatric patients with ADHD.

Methods

A cohort of US-practicing psychiatrists who participated in the simulation-based education was evaluated. The simulation consisted of 2 patient cases that allowed learners to order lab tests, make diagnoses, and prescribe treatments in a manner matching the scope and depth of actual practice. Tailored clinical guidance (CG), based on current evidence and expert recommendation, was provided following each decision, followed by the opportunity for the learner to modify their decisions. Decisions were collected post-CG and compared with each user’s baseline (pre-CG) decisions using a McNemar’s test to determine P values (5% significance level, P <0.05). Data were collected from February 2022 through May 2022.

Results

The assessment sample consisted of psychiatrists (n=420 for case 1, n=358 for case 2) who made clinical decisions within the simulation and proceeded to the concluding debrief section. As a result of clinical guidance provided through simulation, significant improvements (P<0.001) were observed in several areas of clinical care:

•

Assessing symptoms of ADHD using evidence-based tools/scales (70% relative improvement case 1; 100% relative improvement case 2)

•

Diagnosing ADHD and comorbidities across ages (162% relative improvement case 1; 370% relative improvement case 2))

•

Ordering evidence-based treatments for ADHD based on individual patient presentation (71% relative improvement case 1; 53% relative improvement case 2)

Conclusion

VPS that immerses and engages specialists in an authentic, patient-based, practical learning environment can significantly improve evidence-based clinical decision making for the assessment and appropriate management of patients with ADHD to improve patient outcomes.

Funding

Medscape Education, Supernus
EMPOWERing the Next-Generation: A Phase 2 Program to Evaluate Emraclidine, a Selective M4 Positive Allosteric Modulator (PAM), for the Treatment of Schizophrenia
Authors: Konis George , Koenig Erica , Takahashi Koji , Iredale Philip , Tugnait Meera , Waksman Javier , Chang Ih , Blackmon Shauna , Perry Pamela , Leoni Matt , Sanchez Raymond
Published: January 2025

Background

Emraclidine is a novel, highly selective positive allosteric modulator of M4 muscarinic acetylcholine receptors currently in development for the treatment of schizophrenia and Alzheimer’s disease psychosis. By selectively activating M4 receptors, emraclidine may reduce excess dopamine signaling in the
striatum, potentially leading to a reduction in psychotic symptoms. Unlike current antipsychotics, emraclidine does not interfere with signaling at dopamine, serotonin, or histamine receptors, which can lead to adverse events. A previous phase 1b study supports further investigation of emraclidine. The phase 2 EMPOWER program will fully evaluate the efficacy, safety, tolerability, and dose-range of once-daily (QD) emraclidine in schizophrenia.

Methods

EMPOWER-1 and EMPOWER-2 are two adequately powered, multicenter, randomized, double-blind, placebo-controlled, parallel group, 6-week inpatient studies of emraclidine monotherapy (10 mg QD, 15 mg QD, 30 mg QD). The trials are enrolling adult participants with schizophrenia who are experiencing an acute exacerbation of psychosis. Eligible participants will have a Positive and Negative Syndrome Scale (PANSS) Total Score between ≥85 and ≤120 and a Clinical Global Impression – Severity (CGI-S) score ≥4 at baseline. Both de novo participants and those who complete EMPOWER-1 or EMPOWER-2 will be eligible to participate in EMPOWER-3, a 52-week open label extension trial to evaluate the long-term safety and tolerability of emraclidine in adult participants with stable schizophrenia.

Results

Detailed study designs for the EMPOWER program will be presented. Primary outcome measure for EMPOWER 1 and 2 is change from baseline in PANSS total score at week 6. Other outcome measures include change from baseline in CGI-S score at week 6. Data from EMPOWER-3 will contribute to the overall evaluation of safety and tolerability of emraclidine in adult participants with schizophrenia.

Conclusions

The development of emraclidine is promising, as it selectively activates M4, a novel target that has been implicated in reducing psychotic symptoms while potentially avoiding many of the side effects currently associated with antipsychotics. The EMPOWER program aims to establish the efficacy, safety, tolerability, and appropriate dose-range of emraclidine in the treatment of schizophrenia.

Funding

Cerevel Therapeutics
Phase 2A Efficacy, Safety, and Tolerability Study of PH80 Nasal Spray for Acute Management of Menopausal Vasomotor Symptoms (Hot Flashes) in Women
Authors: Monti Louis , Baker Ross A , Salmán Ester , Hanover Rita
Published: January 2025

Introduction

Vasomotor symptoms (hot flashes) are the most common symptom of menopause, affecting about 75% of menopausal women and about 40% of perimenopausal women. PH80, an investigational neuroactive nasal spray, is hypothesized to be a potential treatment for moderate to severe hot flashes due to menopause given that it rapidly activates olfactory to limbic-hypothalamic neural circuits that control autonomic activity, including body temperature and sweating. The primary objective of this Phase 2A clinical study was to explore the efficacy, safety, and tolerability of intranasal administration of PH80 for the acute management of hot flashes due to menopause.

Methods

The study was a randomized, double-blind, placebo-controlled, exploratory Phase 2A clinical study. PH80 nasal spray containing epoxyestrenolone 0.8 μg per 50 μL was self-administered intranasally; two sprays in each nostril (total dose = 3.2 μg) up to four times daily as needed for 4 consecutive weeks. One additional dose was allowed at night if subjects were awakened by hot flashes. During the study period, subjects recorded the number and severity of hot flashes, disruption in function, and sweating related to hot flashes. Patient global impression of change (PGI-C) and clinician global impression of severity (CGI-S) were also assessed.

Results

At baseline, subjects reported a daily mean of 7.7 hot flashes in the PH80 group (n = 18) and 8.0 in the placebo group (n = 18). After 1 week of treatment, the number of hot flashes dropped to 2.8 for PH80 and 6.4 for placebo (P <.001), and after 4 weeks of treatment, the number of hot flashes dropped to 1.5 for PH80 and 5.1 for placebo (P <.001). Treatment with PH80 significantly reduced the severity, disruption in function, and sweating associated with hot flashes during the treatment period as compared with subjects in the placebo group. There was a significant improvement in PGI-C for PH80 vs placebo at endpoint (P = .015) and a strong trend for improvement on CGI-S (P
= .053). PH80 was well-tolerated with no serious adverse events (AEs); the AE profiles of PH80 and placebo were comparable. All 36 subjects completed 4 weeks of treatment and with no study discontinuations due to AEs.

Conclusions

The rapid onset, significant reduction in symptoms, and improved function induced by intranasal PH80 in menopausal women with hot flashes compared with placebo, observed as early as the end of week 1 of treatment, provide a strong signal for continued development of PH80 for the acute treatment of hot flashes due to menopause. The safety data further suggest that, if approved, PH80 will provide a substantial safety benefit over all currently available agents.

Funding

Vistagen Therapeutics, Inc. Editorial assistance was provided by Peloton Advantage, an OPEN Health company, funded by Vistagen Therapeutics, Inc.
S.C.O.P.E. : Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement Platform The Interactive Long-Acting Injectable Antipsychotics Selector
Authors: Correll Christoph U. , Rubio Jose M. , Citrome Leslie , Kane John M. , Mychaskiw Marko A. , Thompson Stephen , Franzenburg Kelli R. , Suett Mark , Kotak Sameer
Published: January 2025

Introduction

Healthcare professionals (HCPs) face unique challenges when managing patients with schizophrenia. Educational initiatives targeting common clinical dilemmas encountered by clinicians, such as unfamiliarity with prescribing information for long-acting injectable antipsychotics (LAIs), may assist clinicians when treating patients with schizophrenia.

Methods

Four experts in schizophrenia management used empirical evidence to identify 11 key clinical dilemmas where LAIs may be useful. These experts then developed a heuristic, educational tool (S.C.O.P.E.™: Schizophrenia Clinical Outcome Scenarios and Patient-Provider Engagement) based on empirical evidence and expert opinion for clinicians to use when encountering similar scenarios to optimize schizophrenia care. S.C.O.P.E.™ also includes supportive elements such as an LAI selector.

Results

S.C.O.P.E.™ is a freely available resource comprising an interactive digital platform providing educational materials for HCPs involved in continued care for patients with schizophrenia. To acquaint HCPs with characteristics of common LAIs used in schizophrenia treatment, S.C.O.P.E.™ offers a selector that filters LAIs by approved indication(s), initiation regimen, reconstitution, dosing strengths and frequency, injection volumes and routes, and supply and storage information based on approved product labels. The LAI selector does not provide LAI safety and efficacy data, so HCPs should visit individual product websites for this information. Therefore, S.C.O.P.E.™ will not replace clinical judgment, guidelines, or continuing medical education, and is not a platform for recording patient-level data, nor intended for payer negotiations or access-related questions by HCPs.

Conclusions

S.C.O.P.E.™ is an educational tool for HCPs to use alongside standard psychiatric evaluations to improve understanding of how to manage common clinical dilemmas when treating patients with schizophrenia, the role of LAIs in schizophrenia management, and the product characteristics of available LAIs.

Funding

Teva Branded Pharmaceutical Products R&D, Inc.
Centanafadine Sustained Release in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: Secondary Outcomes From a Phase 2a Study
Authors: Zhang Zhen , McDonough Jessica
Published: January 2025

Introduction

Centanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) being investigated for the treatment of attention-deficit/hyperactivity disorder (ADHD). In a phase 2a study in adult males with ADHD, CTN sustained release (CTN SR) treatment significantly improved ADHD Rating Scale-IV (ADHD-RS-IV) total and subscale scores and was well tolerated. Additional efficacy outcomes from this study are reported.

Methods

This flexible-dose (CTN SR 200–500 mg/d), single-blind, exploratory study enrolled males aged 18–55 years who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for ADHD and had a baseline ADHD-RS-IV total score ≥28 and Clinical Global Impression-Severity score of ≥4. The study had a screening period, a 1-week placebo run-in, and a 4-week CTN SR treatment phase. Previously unreported secondary outcomes of ADHD-RS-IV change from end of the single-blind placebo run-in and ADHD-RS-IV response (≥30% and ≥50% score reductions) at weeks 1, 2, 3 (on-treatment), and 6 (follow-up) are presented. Analyses were based on observed results using descriptive statistics.

Results

Of 45 patients enrolled, 41 received ≥1 dose of study medication and 37 completed the 4-week treatment phase (mean [SD] age, 38.24 [11.88] years; 91.9% White). At baseline, mean (SD) ADHD-RS-IV total, Inattentive subscale, and Hyperactive/Impulsive subscale scores were 38.7 (6.19), 22.81 (2.55), and 15.89 (4.8), respectively. Mean (SD) changes in ADHD-RS-IV total scores were −11.14 (8.64), −16.14 (11.08), and −20.86 (11.11) at weeks 1, 2, and 3, and −11.53 (8.78) at week 6. Correspondingly, mean (SD) changes in Inattentive subscale scores were −6.32 (4.99), −9.76 (6.4), and −12.16 (6.61) at weeks 1, 2, and 3, and −6.36 (5.7) at week 6, and in Hyperactive/Impulsive subscale scores were −4.81 (4.74), −6.38 (5.94), and −8.7 (5.81) at weeks 1, 2, and 3, and −5.17 (4.33) at week 6. ADHD-RS-IV ≥30% response was observed in 13 (35.14%), 23 (62.16%), and 28 (75.68%) patients at weeks 1, 2, and 3, and in 12 (33.33%) patients at week 6. ADHD-RS-IV ≥50% response was observed in 6 (16.22%), 16 (43.24%), and 23 (62.16%) patients at weeks 1, 2, and 3, and in 8 (22.22%) patients at week 6. The pattern of ≥30% and ≥50% response in Inattentive and Hyperactive/Impulsive subscale scores was similar to that observed with ADHD-RS-IV total score response.

Conclusions

These secondary outcomes support published primary results showing that CTN SR improved ADHD-RS-IV total and subscale scores. CTN SR treatment improved total ADHD symptoms within the first 2 weeks and was well tolerated. These findings support the usefulness of CTN SR, a potential first-in-class NDSRI, in providing rapid treatment benefit to adults with ADHD.

Study Registration: NCT01939353

Previous presentation: ASCP 2023, May 30–June 2, 2023, Miami Beach, FL

Funding

Otsuka
Cost Efficiency of Esketamine Nasal Spray Versus Quetiapine for Treatment Resistant Depression
Authors: Clemens Kristin , Teeple Amanda , Rive Benoit , Kirson Noam , Desai Urvi , Doran Jason , Eid Dody , Qu Alice , Bowrey Hannah , Joshi Kruti
Published: January 2025

Objective

To compare the per-patient direct and indirect costs associated with achieving remission with esketamine nasal spray plus oral antidepressants (ESK NS+OAD) versus quetiapine extended release plus oral antidepressants (QTP XR+OAD) among patients with treatment-resistant depression (TRD). This comparison was based on a subanalysis of results from the ESCAPE-TRD Phase 3b trial (ex-US) comparing response and remission rates for ESK NS+OAD vs QTP XR+OAD in TRD patients over 32 weeks.

Methods

An Excel-based model was developed to estimate the cost-per-remitter for ESK NS+OAD and QTP XR+OAD from the perspective of a commercial insurance plan in the US. Remission rates, response rates, and relapse rates (among patients remitting or responding during the first 8 weeks of treatment) were estimated in 4-week intervals over 32 weeks using data from the ESCAPE-TRD Phase 3b clinical trial comparing ESK NS+OAD versus QTP XR+OAD in patients with TRD. Patients not remitting/responding (non-responders) or experiencing a relapse either stayed on current treatment (i.e., ESK NS+OAD or QTP XR+OAD) or discontinued current treatment and initiated either augmented therapy with antipsychotics (APS) or recurring transcranial magnetic stimulation (rTMS). For basecase analysis, equal proportions of non-responders off-treatment initiated rTMS or augmented therapy with APS. In a scenario analysis, all non-responders off-treatment initiated rTMS. Direct costs, including medical and drug costs, were derived from health economic literature and the RED BOOK® drug pricing database. Indirect costs attributed to work productivity loss from presenteeism and absenteeism were derived from a separate analysis of ESCAPE-TRD patients using the Work Productivity and Activity Impairment: Depression (WPAI:D) questionnaire and US Bureau of Labor Statistics survey results.

Results

The cumulative relapse-free remission rate at 32 weeks was 50% for patients receiving ESK NS+OAD and 33% for patients receiving QTP XR+OAD. In the basecase analysis, the cost-per-remitter (including direct and indirect costs) for ESK NS+OAD was $3,102.17 lower than that of QTP XR+OAD. In the scenario where 100% of non-responders off-treatment were assumed to initiate rTMS, the cost-per-remitter (including direct and indirect costs) for ESK NS+OAD was $15,133.66 lower than that of QTP XR+OAD.

Conclusion

These findings suggest that esketamine nasal spray in conjunction with oral antidepressants is a cost-efficient alternative compared with quetiapine extended release for treatment of TRD for commercial insurance plans. The comparative benefits associated with ESK NS+OAD treatment are driven primarily by better short- and long-term efficacy observed in the trial and particularly pronounced when considering the costs associated with lost productivity.

Funding

Janssen Scientific Affairs, LLC
Money supply and the yield curve
Authors: Xu Libo
Published: January 2025

This paper studies the dynamic interactions between the money supply and the shape of the yield curve in the context of a regime-switching latent factor model. Estimates show that the money supply has important implications for the level, slope, and curvature of the yield curve. Moreover, the Divisia aggregates can provide more information than simple-sum aggregates based on parameter estimates and impulse response functions in understanding the dynamics of the yield curve. The favored broad Divisia aggregate could especially be associated with changes in the yield curve’s level, slope, and curvature over the business cycle. Therefore, this paper highlights the important role of Divisia aggregates in the linkage between financial markets and monetary policy.
Normative Realignment in Domestic Trade Barriers Procedures: Driving Unilateralism in the EU, US, and China
Authors: Chaisse Julien , Su Xueji
Published: January 2025

This article critically examines the evolution and potential of domestic trade barrier procedures in the US, EU, and China. Emblematic of this mechanism is US Section 301. Aimed at facilitating market access, these procedures function as tools of unilateralism and strategic leverage. Employing qualitative and comparative methods, the analysis explores their use in handling private complaints and combating adverse trade practices, highlighting a trend of ‘normative realignment’ in the deployment of these procedures. Once focused on resolving private grievances, such procedures are now increasingly playing a role in securing national interests. This shift marks a departure from traditional international cooperation, reflecting a recalibration of trade policies. Against the backgroup of growing encystment of unilateralism, the article argues that domestic trade barrier procedures could be adapted to address the demands of the current global economic environment. The article posits that, if executed properly, domestic trade barrier procedures may serve as a buffer mechanism vis-a-vis the tectonic shifts in economic order. In doing so, the article envisions a new generation of domestic trade barrier procedural frameworks.
Representations of Metaphysical Temporality in the Libretto of Einojuhani Rautavaara's Vincent with a Corresponding Resemblance to Alban Berg's Wozzeck
Authors: LJUBIBRATIĆ VANJA
Published: January 2025

In his early serialist composition style, Einojuhani Rautavaara expressed indebtedness to the flexible usage of the twelve-tone system that was adapted by Alban Berg. The trace of Berg's influence becomes dramaturgically reminiscent when investigating the philosophical impact that Berg's opera Wozzeck had on Rautavaara's opera Vincent. This study aims to analyse the symbolic content of the Vincent libretto, with a secondary depiction of parallel attributes found in the libretto of Wozzeck. This examination demonstrates how the operas share a philosophical foundation that is based on an expression of metaphysical temporality inherent within the plots of both operas, which juxtapose the duality of the two temporal planes of empirical reality and metaphysical illusion. The outcome of such a comparison illustrates how Rautavaara's opera can be interpreted in a new framework of understanding that is based on the Finnish composer's mirroring of Berg's operatic and dramatic style as seen in Wozzeck.
‘Monster’ Street Organs and Audiovisual Culture in Pre-Cinematic Italy
Authors: Ladd Marco
Published: January 2025

Studies of cinema's emergence from nineteenth-century cultural forms have historically privileged its visual attributes over its sonic ones. This article redresses the balance by examining a musical device commonly associated with early film exhibition across Europe: the fairground organ, whose spectacular audiovisual appeal was exploited in public squares and fairgrounds long before the invention of cinema. Drawing on insights from the field of media archaeology, I ask whether we can locate an archaeological layer of cinematic prehistory in the fairground organ itself. In so doing, what emerges is the critical importance of Italy in the cultural history of the mechanical organ. Partly this is because the individual widely acknowledged as the ‘father of the fairground organ’, Ludovico Gavioli, was an Italian. Yet the Italianness of mechanical organs was also rooted in the stereotypical repertoire of such instruments (well-known excerpts from Italian opera), and on discursive tropes that emphasized an affinity between portative barrel organs – said to have been invented in Italy – and the itinerant operators of such instruments, often perceived to be Italian. Ultimately, I suggest that instead of treating fairground organs as the backing-track to early film exhibition, we might profitably conceive of early cinema as the latest visual enhancement to grace the exhibition of the mechanical organ.
Geochemistry and Geochronology of A‐Type Intermediate‐Felsic Rocks in NW Himalaya, Pakistan: Implications for Petrogenesis and Tectonic Evolution of Northern Gondwana
Authors: Khan Musa , Li Huan , Algeo Thomas J. , Khan Asad , Förster Michael W. , Ullah Zaheen
Published: January 2025

Igneous intrusives in northern Pakistan can provide valuable insights into pre‐Himalayan metaluminous to peraluminous magmatism along the northern boundary of the supercontinent Gondwana and its potential tectonic significance. This study generates new geochronologic, petrographic and geochemical data for intermediate (monzonite, syenite, and foid syenite) and felsic (granite and quartz monzonite) rocks within the NW Himalayan region of Pakistan. Both the intermediate and felsic rocks have values of A/NK > 1.1, implying a metaluminous to peraluminous composition, and are distinguished by high FeOT/(MgO + FeOT) (0.81–1.0), high 10,000 × Ga/Al ratio (2.1–5.1), elevated Nb + Zr + Y + Ce contents (122–1,204 ppm), and negative anomalies of P and Ti, consistent with aluminous A‐type magmatic affinity. These rocks are classified as A1‐type, which is linked to anorogenic intraplate extensional setting. Both rock groups yield high calculated average whole‐rock Zr saturation temperatures (i.e., TZr; 790–823°C), which suggests formation from high‐temperature magmas. Whole‐rock geochemistry, including variable (87Sr/86Sr)i values (0.7034–0.7086), positive εNd(t) (+0.1 to +3.9), high Pb isotopic values (that is, (206Pb/204Pb)i = 18.68 to 19.31, (207Pb/204Pb)i = 15.64 to 15.74, and (208Pb/204Pb)i = 38.93 to 39.78), and variation in zircon εHf(t) values (+0.8 to +7.0), indicates diverse magma sources for the intermediate‐felsic rocks and provide evidence of partial melting of metasomatized lithospheric mantle, producing a primary magma of foid to quartz syenitic composition. Subsequently, this magma was responsible for the partial melting of the overlying juvenile crust, producing granitic, quartz monzonitic and monzonitic magmas. During the magma evolution process of these rocks, this process was primarily determined by partial melting that followed fractionation of K‐feldspar, ilmenite and apatite. TDM2 ages indicate that the parent materials of intermediate‐felsic rocks were generated during the Mesoproterozoic‐Neoproterozoic. LA‐ICP–MS U‐Pb dating of magmatic zircons documents their formation in the Late Paleozoic at ∼278‐268 Ma. The intermediate‐felsic rocks are correlatable with alkaline igneous rocks of the Peshawar Plain, which record the breakup of the supercontinent Gondwana and the subsequent opening of Neo‐Tethys during a Late Paleozoic rifting event. The nepheline syenite records a younger episode during the Cenozoic (37 Ma), corresponding to the collision of the Indian‐Eurasian tectonic plates.
A Study on the Potential Mechanisms Underlying the Seasonal Dependence of 15MLT‐PCA
Authors: Wang Yu , Han De‐Sheng , Feng Hui‐Ting , Xiong Ya‐Ting , Qiu Hui‐Xuan , Zhang Yong‐Liang
Published: January 2025

Specific polar cap auroras, such as 15MLT‐PCA, linked to lobe reconnection due to the influence of the interplanetary magnetic field (IMF) By component, were only observed in the summer. Although the variance in ionospheric conductivity between winter and summer has been proposed as a potential explanation for this seasonal dependency, it has also been argued that the differences in lobe reconnection between the winter and summer hemispheres could be the cause. To address this debate, we examined two data periods with similar IMF conditions when the northern hemisphere was in summer and winter, respectively. Using DMSP/SSUSI and AMPERE observations, we detected clear 15MLT‐PCA and associated field‐aligned currents in the summer, but not in the winter. These observations were compared with global MHD simulations from OpenGGCM. Lobe reconnection signatures were identified for both winter and summer in the simulation results. However, a detailed analysis showed that the pattern of lobe reconnection in the winter hemisphere was different from that in the summer. Based on the combined observation and simulation results, we suggest that particular lobe reconnection in summer is critical for generating 15MLT‐PCA, while the winter's reconnection may lead to transient or small‐scale auroral responses that were not easily identified by DMSP/SSUSI observations as a 15MLT‐PCA event.
Climate Impact of Marine Cloud Brightening Solar Climate Intervention Under a Susceptibility‐Based Strategy Simulated by CESM2
Authors: Chen C.‐C. , Richter J. H. , Lee Walker R. , Tye Mari , MacMartin Douglas G. , Kravitz Ben
Published: January 2025

The efficiency of marine cloud brightening in cooling Earth's surface temperature is investigated using an ensemble of simulations with the Community Earth System Model version 2 (CESM2). We employ a susceptibility‐based cloud seeding strategy, previously developed under the Community Climate System Model version 3 (CCSM3) to counteract the warming of CO2 doubling, in which we target the regions of the ocean most easily brightened, to determine what area extent will be required to induce 1°C cooling under SSP2‐4.5. The results indicate that cloud seeding over 5% of the ocean area is capable of achieving this goal in CESM2. Under this seeding scheme, cloud seeding is mainly deployed over lower latitudes which leads to a La Niña‐like pattern of response which is a major unintended consequence. Potential mechanisms behind such side effects are presented and discussed. The simulations also reveal that the 5% cloud seeding scheme induces an overall reduction in global precipitation, with an increase over land and a decrease over the ocean.
Bias Analysis and Correction of ERA5 Reanalysis in the Context of Tropical Cyclones
Authors: Wei Chunshan , Zhao Xiaofeng , Liu Yudi , Yang Pinglv , Zhou Zeming , Chen Yibin
Published: January 2025

A detailed analysis of temperature and relative humidity biases in ERA5 reanalysis under tropical cyclone (TC) conditions is conducted using a composite analysis method based on more than 17,000 dropsonde observations. The statistical results indicate that ERA5 underestimates the warm‐core intensity of TCs. It shows a moist bias at the tropopause and a cold‐moist bias in the boundary layer beyond four times the radius of maximum winds (RMW). In contrast, within 4 RMW, a warm‐dry bias in the boundary layer was observed. The temperature bias is more pronounced at the TC center, and relative humidity exhibits a similar pattern, primarily in the mid and upper troposphere. The bias distribution is asymmetric, most prominent in the right front quadrant of the TC's motion direction. Besides, bias correction is performed using an eXtreme Gradient Boosting (XGBoost) model and the biases can be reduced by approximately 60%. The dependence relationships between relative humidity and the influencing factors are investigated through SHapley Additive exPlanations (SHAP) values. The results indicate that low‐level relative humidity increases and instability intensifies in TCs at night. Additionally, the findings suggest that ERA5 may inadequately capture the diurnal variation of relative humidity in TCs. The SHAP analysis also shows that relative humidity tends to be stronger in TC's motion direction.
Linking Changes in Plant Growth and Nutrient Stoichiometry With Nitrogen Enrichment in a Meadow Steppe
Authors: Wang Yinliu , Niu Guoxiang , Yang Guojiao , Hasi Muqier , Li Ang , Xue Jianguo , Lü Xiaotao , Han Xingguo , Huang Jianhui
Published: January 2025

Exogenous nitrogen (N) inputs can significantly influence the availability of N and other nutrients in terrestrial ecosystems. However, the connections between soil nutrient dynamics following N enrichment and plant nutrient uptake as well as plant growth responses within a community remain underexplored. Here, we examined the effects of N addition on the dynamics of several macro and micronutrients in soil and three dominant plants on a meadow steppe in China. The results showed that (a) the exchangeable Ca and Mg in the soil initially increased when the N addition rate was lower than 10 g N m−2 yr−1 and then decreased at higher N addition rates (10–50 g N m−2 yr−1), whereas the available P and extractable Fe, Mn, and Cu remained relatively stable at low N addition rates but increased at high N addition rates. (b) The response of plant nutrient concentrations and the stoichiometry of these nutrients to N addition was not only species‐specific but also showed marked differences especially for those micronutrients. (c) Species with lower variation in nutrient concentrations, such as Leymus chinensis (Lc) and Thermopsis lanceolata (Tl), exhibited increased (for Lc) or stable (for Tl) biomass after N addition, whereas species such as Carex duriuscula, with greater nutrient variability, experienced reduced biomass. These findings suggest that soil acidification induced by exogenous N inputs alters soil nutrient availability and further results in imbalanced plant nutrient uptake and stoichiometries, which will affect the dynamics and structures of plant communities under global change scenarios.
Electrophysiology-based screening identifies neuronal HtrA serine peptidase 2 (HTRA2) as a synaptic plasticity regulator participating in tauopathy
Authors: Zheng Naizhen , Li Kun , Cao Jing , Wang Zijie , Zhang Liang , Zhao Zihao , He Jiawei , Wang Yong , Zhu Xiang , Chen Yiqing , Meng Jian , Zhao Dongdong , Niu Mengxi , Luo Hong , Zhang Xian , Sun Hao , Zhang Yun-wu
Published: January 2025

Long-term potentiation (LTP) and long-term depression (LTD) are widely used to study synaptic plasticity. However, whether proteins regulating LTP and LTD are altered in cognitive disorders and contribute to disease onset remains to be determined. Herein, we induced LTP and LTD in the hippocampal CA3-CA1 Schaffer collateral pathway, respectively, and then performed proteomic analysis of the CA1 region. We identified 20 differentially expressed proteins (DEPs) shared by the LTP and the LTD processes. Among them, we found that HtrA serine peptidase 2 (HTRA2) was mainly expressed in neurons and that HTRA2 levels were increased in both the LTP and the LTD processes in C57BL/6 mice. HTRA2 downregulation impaired synapses and reduced ATP production in cultured primary neurons. Furthermore, adeno-associated virus (AAV)-mediated HTRA2 downregulation in the hippocampus impaired synaptic plasticity and cognitive function in C57BL/6 mice. Moreover, we found that HTRA2 expression decreased in the brains of Alzheimer’s disease patients, frontotemporal lobar degeneration with ubiquitin inclusions patients, and tauopathy model mice. Finally, we showed that lentivirus-mediated HTRA2 overexpression in the hippocampus rescued PP2B reduction, alleviated tau hyperphosphorylation, and partially attenuated synaptic plasticity and cognitive deficits in the PS19 tauopathy model mice. Our study not only indicates that HTRA2 in neurons plays an important role in regulating synaptic plasticity under both physiological and pathological conditions, but also provides a novel, electrophysiology-based strategy to identify proteins regulating synaptic plasticity systematically.