Enhanced signaling of dopamine and/or serotonin during highly arousing situations can be reduced in part by monoamine transporters, such as plasma membrane monoamine transporter (PMAT, Slc29a4). An absence of selective pharmacological inhibitors means genetically modified mice constitutively deficient in PMAT remain the best tool for studying PMAT’s organism-level functional effects. Fear conditioning is a high arousal process. Generalization of fear is evolutionarily advantageous, whereby information learned from one experience is applied to other new but similar encounters. Pathological fear generalization, in contrast, is a core feature of most anxiety disorders. Given our previous findings indicating PMAT function reduces male mice’s context fear and enhances extinction of female mice’s cued fear, we hypothesized PMAT would similarly reduce generalization (i.e., enhance discrimination) of context and cued fear in male and female mice, respectively. Our context and cued fear conditioning experiments in adult PMAT wildtype (+/+) and heterozygous (+/−) male and female mice partially supported our hypotheses. We discovered PMAT facilitates extinction of contextually generalized fear, plus subsequent extinction of context-specific fear, selectively in females. Moreover, when specific fear cues or contexts were temporally presented before cues or contexts that were similar enough to make generalization possible, PMAT enhanced biological sex differences. Growing evidence reports common PMAT polymorphisms elicit measurable effects when PMAT function is reduced. Thus, we suspect future experiments may reveal positive associations between PMAT polymorphisms and risk for anxiety disorder symptoms, particularly in people assigned female at birth. Inclusion of these genetic variations in pharmacogenomic analyses may prove therapeutically beneficial.
Serum hypocretin, neurofilament heavy chain, and interleukin-1β as combined predictors of sleep disorders following acute ischemic stroke
BackgroundSleep disorders represent a common and impactful complication following acute ischemic stroke (AIS). This study aimed to identify clinical risk factors and evaluate the predictive value of serum hypocretin (Hcrt), neurofilament heavy chain (NfH), and interleukin-1 beta (IL-1β) for post-stroke sleep disorders.MethodsWe conducted a retrospective observational study of 256 patients with AIS. Patients were classified into sleep disorder (n = 161) and non-sleep disorder (n = 95) groups based on their Pittsburgh Sleep Quality Index scores 7 days after stroke onset. Fasting serum levels of Hcrt, NfH, and IL-1β were measured upon admission. We utilized multivariate logistic regression and receiver operating characteristic (ROC) curves to evaluate predictive performance. The combined model was internally validated using 1,000 bootstrap resamples to assess optimism-corrected discriminative performance.ResultsSleep disorders were present in 62.9% of patients. Nine independent risk factors were identified: age ≥ 65 years (OR = 2.059), snoring history (OR = 1.980), prior stroke (OR = 2.036), lower ADL scores (OR = 1.839), higher HAMD (OR = 1.726) and NIHSS scores (OR = 1.677), decreased serum Hcrt (OR = 1.863), elevated NfH (OR = 2.020), and elevated IL-1β (OR = 1.793; all p < 0.05). Individual biomarker AUCs ranged from 0.742 to 0.781, whereas the combined three-biomarker model achieved a significantly superior AUC of 0.874 (sensitivity 88.82%, specificity 71.58%). Bootstrap internal validation yielded a mean optimism-corrected AUC of 0.861 (95% CI: 0.812–0.903), indicating robust model performance with minimal overfitting.ConclusionClinical variables alongside altered levels of Hcrt, NfH, and IL-1β serve as independent predictors of post-stroke sleep disorders. The combined three-biomarker panel, reflecting neuroendocrine dysregulation, axonal injury, and systemic inflammation, demonstrates substantially superior predictive accuracy over individual biomarkers and offers a clinically practical tool for early identification of high-risk patients.
Introducing a translationally relevant mouse model of radiosurgery-induced unilateral hearing loss
BackgroundStereotactic radiosurgery (SRS) is widely used to treat vestibular schwannomas but may cause irreversible hearing loss due to cochlear toxicity. The underlying mechanisms are not fully understood, and no effective otoprotective therapies exist. We aimed to establish a mouse model that replicates the clinical pattern of radiation-induced hearing loss.MethodsC57BL/6J mice (n = 31) received 8 Gy (n = 3), 16 Gy (n = 5), 24 Gy (n = 8), or 32 Gy (n = 15) using the Leksell Gamma Knife ICON system. Targeting was based on the built-in cone-beam CT, co-registered with MRI and CT-based mouse atlases, to guide unilateral cochlea targeting. A single isocenter was placed lateral to the right cochlea, with the 80% isodose line traversing its medial edge. Auditory brainstem response (ABR) was measured at baseline and at 1 and 4 weeks post-SRS. A 32 Gy subgroup (n = 7) was evaluated at 16 weeks. Histological analysis of cochleae was performed at 4 weeks in all groups and at 16 weeks in the long-term 32 Gy group.ResultsSRS was well tolerated, and the contralateral cochlea received a very low radiation dose. No ABR shifts were observed at 8 or 16 Gy, with only minimal histological changes. At 32 Gy, ABR threshold shifts at 22.6 and 32 kHz were evident by week 1 and worsened by week 4. Similar but milder effects occurred at 24 Gy. In the 32 Gy long-term subgroup, hearing loss progressed across all frequencies, most severely at high frequencies, alongside a sustained wave I amplitude decline. At 32 Gy, outer hair cells were reduced by 14 and 44% at 32 and 45.2 kHz, respectively, at 4 weeks, and by 38 and 80% at 16 weeks. Ribbon synapses were mildly reduced at 4 weeks and more markedly at 16 weeks in corresponding high-frequency regions. Spiral ganglion neuron density was mildly reduced at the basal and middle turns. All reported changes were statistically significant when compared to the contralateral ear.ConclusionThis new model reproduces key features of SRS-induced cochlear toxicity, including unilateral, dose-dependent, and progressive hearing loss. It thus provides a valuable platform for investigating mechanisms and testing otoprotective strategies.
Beyond distress relief: the Anhedonic Subtype of nonsuicidal self-injury and the imperative for Positive Affect Treatment
This perspective article argues that the theoretical landscape of nonsuicidal self-injury (NSSI) has long been stabilized by the “hydraulic” model of Automatic Negative Reinforcement, which conceptualizes self-harm primarily as a mechanism to down-regulate aversive hyper-arousal. While this framework successfully elucidates the etiology of self-injury driven by high-intensity negative affect, it fails to account for a substantial, treatment-resistant phenotype: adolescents driven by profound anhedonia and ventral striatal hypofunction. This perspective article argues for the formal recognition of an “Anhedonic Subtype” of NSSI. Synthesizing recent epidemiological data identifying “emptiness” as a central symptom network bridge, alongside neurobiological evidence of reward blunting, we posit that for this subtype, NSSI functions not as a sedative, but as a mechanism of “forced activation.” We propose a preliminary differential diagnostic framework distinguishing defensive dissociation from anhedonic deficit and outline the theoretical rationale for exploring a shift in clinical intervention from distress tolerance toward positive affect up-regulation. The clinical utility of this framework remains to be evaluated in future empirical research.
Resonance across cultures and faiths: examining the violin music’s role in emotional, psychological, and spiritual well-being for sustainable societies
Music is a decisive factor of the everyday life and the core focus of human being of any culture. People of all ages, races and ethnicities prefer to listen to it and play it. But music is not only entertainment because scientific research has shown that it can also create an impact on the physiological processes that can be used to enhance physical and mental illnesses. The current study analyzes the ways in which the violin may be employed in enhancing emotional, psychological and spiritual well-being of different cultures and religions. It relies on secondary data to examine the emotional appeal of the instrument, the psychological resilience benefits, and the spiritual meaning of the instrument particularly in the intercultural and interfaith context. The sound of the violin that is very flexible and familiar in various cultural and religious practices is also a channel of emotional expression, psychological healing, and spiritual intercourse. Therapeutic interventions and educational environments have been linked to it, as a means of improving emotional control, decreasing stress and increasing resilience. Also, the violin can be used as a significant instrument of spiritual reflection in other religious practices, in the Christian church service as well as in Hindu devotional music. Findings indicate that the violin facilitates interfaith communication and social integration by way of sharing of emotions and spirituality. It is a cultural preservation and common good, that promotes inclusivity and comprehension of the multicultural societies and results in sustainable communities. The paper shows that the field of special role of the violin in promoting resilience, empathy and sustainable development of society needs more empirical studies to advance the knowledge on the topic.
Identifying clinical features associated with electroconvulsive therapy response in adolescents with major depressive disorder using machine learning
BackgroundElectroconvulsive therapy (ECT) is an effective treatment for adolescent major depressive disorder (MDD), but its efficacy varies. This study utilized machine learning (ML) to identify baseline clinical factors associated with poor ECT response.MethodsWe retrospectively enrolled 503 adolescent MDD patients. A poor response was defined as a <50% reduction on the Hamilton Depression Scale (HAMD-24). The optimal ML algorithm (Random Forest, RF) was selected from nine candidates and then simplified using recursive feature elimination (RFE) and interpreted via Shapley Additive Explanations (SHAP).ResultsA simplified model using two baseline features—the neutrophil-to-platelet ratio (NPR) and pre-treatment HAMD score—achieved an AUC of 0.731 on the testing set, comparable to the full-feature model (AUC: 0.751). SHAP analysis revealed that a lower baseline NPR and a lower pre-treatment HAMD score were associated with a poor response. Furthermore, retrospective statistical comparisons revealed that patients in the poor response group completed significantly fewer ECT sessions than those in the good response group.ConclusionsWe developed a concise explanatory model demonstrating that routine clinical data available at admission (blood NPR and HAMD score) can effectively stratify the risk of poor ECT efficacy. Crucially, identifying these high-risk patients early empowers clinicians to implement targeted management, ensuring they complete a full and adequate course of ECT to maximize therapeutic benefits and prevent premature termination.
A two-decade bibliometric analysis (2004–2024) of parental factors in the context of internet gaming disorder research
ObjectiveThis is the first targeted bibliometric analysis which explores the development of scientific production on the relationship between parenting and Internet Gaming Disorder (IGD) over twenty years, emphasizing the central role of the family context in the etiology and maintenance of IGD.MethodsPapers indexed in Scopus and Web of Science databases from 2004 to December 31, 2024, were analyzed using the PRISMA guidelines, the R package Bibliometrix, and VOSviewer. A comprehensive search strategy was developed using Boolean operators to capture variations of parental and gaming-related terminology. Records were exported in BibTeX format and were merged and cleaned to remove duplicates before the analysis. A descriptive bibliometric analysis, bibliometric mapping, and content analysis were conducted to identify trends and thematic clusters. The analysis included 389 publications.ResultsThe most cited papers confirm the association of low parental warmth, family dysfunction, and comorbid psychiatric symptoms with a higher risk of IGD. Thematic mapping reveals six dominant clusters covering the conceptualization and diagnosis of IGD, parental mediation and virtual environment, psychological vulnerability and mental health, parenting and attachment, parenting styles and self-control, and problematic screen-related behaviors, and a strong concentration of publications in China, Germany, and the USA. The analysis also revealed an increase in publication output after 2013, with a notable acceleration following the inclusion of gaming disorder in the International Classification of Diseases 11th Revision (ICD-11).ConclusionThe bibliometric analysis reveals the rapid growth of research on parenting and IGD, highlighting the multifactorial nature of the disorder where dysfunctional family relationships increase risk, while supportive ones reduce it. Despite progress, longitudinal studies are needed for better understanding of causality and interventions.
Trends of incident stimulant use disorder diagnoses before and after the COVID-19 pandemic in British Columbia (2013-2024): a population-based study
BackgroundThere is rising detection of unregulated stimulants (e.g. cocaine and methamphetamine) in toxicology results among people who died of unregulated drug poisoning. Nevertheless, little research describes the population-level trends of incident (new) stimulant use disorder (StUD) diagnoses. This study reports on trends of incident StUD diagnoses pre- and post-Covid-19 public health emergency in British Columbia (BC), Canada.MethodsInterrupted time series analyses were conducted with BC’s COVID-19 public health emergency declaration on March 16, 2020 as the interruption point. Descriptive statistics on demographic and health service contact were conducted for the population diagnosed before (January 1, 2013 – March 16, 2020) and after (March 17, 2020 – December 31, 2024) the COVID-19 pandemic emergency declaration. Seasonal autoregressive integrated moving average (sARIMA) models were used to .estimate changes to incident StuD diagnoses rates before and after the COVID-19 pandemic declaration.Results38, 217 people were identified with incident StUD diagnoses between January 1, 2013 and March 31, 2024. The average diagnosis rate of incident StUD was 5.18 per 100, 000 in the pre-pandemic period and increased by 19.9% to 6.21 per 100, 000 in the post-pandemic period. The estimated increase in slope (ramp) of incident StUD was 0.0315 cases per 100, 000 population per month (95% CI: -0.00182, 0.06482).ConclusionsWe identified a rate of increase in incident StUD diagnoses since the COVID-19 pandemic declaration in BC that was not statistically significant. Our study highlights the need for more comprehensive linked data -including, administrative health data, surveys, and other services/program data (e.g., community services, private sector) to better disentangle StUD incidence and prevalence to inform services to meet the needs of people with StUD. Stimulant use, Stimulant use disorder, pandemic, Covid-19, methamphetamines, cocaine, interrupted time series.
Newcomer anti-IL-33 makes strides in COPD
Nature Biotechnology, Published online: 07 May 2026; doi:10.1038/s41587-026-03136-x
AstraZeneca’s IL-33 antibody tozorakimab targets two distinct signaling pathways engaged in COPD: inflammation and epithelial dysfunction.
STAT+: FDA to reconsider treatment for rare cancer after its surprise rejection
Two companies developing a therapy for a rare blood cancer have reached an agreement with the Food and Drug Administration that walked back the agency’s main reason for rejecting the drug in January.
Pierre Fabre Pharmaceuticals and Atara Biotherapeutics, makers of the drug called Ebvallo, said Thursday that a meeting held in late April with FDA officials ended with the agency agreeing that their already completed, single-arm clinical trial was sufficient to support a review and potential approval.
When the FDA rejected Ebvallo, the agency said the same study was flawed and the data produced from it was “insufficient” to support the drug’s approval. The drug’s review was conducted by the FDA’s Center for Biologics Evaluation and Research, led at the time by Vinay Prasad. He departed the agency at the end of April.