Depression is a common difficulty among adolescents with epilepsy (AWE). Compassion-focused therapy (CFT) has demonstrated potential benefits for adults with epilepsy. This study was a preliminary investigation evaluating whether an eight-session online group intervention based on CFT could reduce symptoms of depression and enhance self-compassion in AWE. Sixteen AWE aged 13-17 took part, completing measures for depression and self-compassion before the intervention (pre-CFT), immediately afterwards (post-CFT), and again six months later (follow-up). Results showed significant reductions in depression and increases in self-compassion from pre- to post-CFT, with these improvements sustained at follow-up. By both post-CFT and six-month follow-up, three-quarters of AWE were below clinical threshold for depression. Overall, these findings offer preliminary, tentative evidence that CFT may be a beneficial approach for supporting AWE who are experiencing depression, though further robust research is required to propose such recommendations.

Gender incongruence in trans and nonbinary ("trans") populations is often associated with psychological distress and increased demand for mental healthcare. Gender-affirming hormone therapy (GAHT) is a key component of care for many trans people, yet long-term evidence around its cost implications remains limited despite increasing uptake and policy attention worldwide. We provide the first population-based evidence on the healthcare costs of GAHT initiation using longitudinal administrative data from 32,313 trans Australians who initiated testosterone-based GAHT (tGAHT) or estradiol-based GAHT (eGAHT) between 2013 and 2024. Employing a dynamic difference-in-differences design, we estimate the impacts on government expenditure and patient out-of-pocket costs in the 6 years after initiation, using future initiators as controls. We find that initiating tGAHT leads to an additional AUD$3119 (USD$2246) in government expenditure and AUD$143 (USD$103) in out-of-pocket costs over 6 years; corresponding estimates were AUD$8348 (USD$6011) and AUD$1269 (USD$914) for eGAHT recipients. For tGAHT recipients, both government and out-of-pocket costs declined after initiation, with mental healthcare reductions exceeding ongoing hormone therapy expenditure after 6 years. For eGAHT recipients, costs also fell but remained above baseline, driven by sustained prescription spending. Taken together with quality-of-life benefits, our results suggest GAHT is likely to be cost-effective.

Previous research has established determinants of young child feeding (IYCF) practices in the general child population, but determinants of these practices in children with severe acute malnutrition (SAM) are unknown. This study assessed the determinants of IYCF practices among children aged 6-23 months with SAM and under SAM treatment in a pastoralist and a predominantly agrarian setting in Ethiopia. As part of the baseline survey for the R-SWITCH cluster randomized control trial, we screened ~28,000 under-fives and included 486 children aged 6-23 months with SAM and under SAM treatment. Multivariable regression analysis was used to identify determinants on household, caregiver and child levels. Minimum meal frequency (MMF) was similar between children from the agrarian (53.9%) and pastoralist (51.9%) setting. The prevalence of children with minimum dietary diversity (MDD) was low overall but higher among pastoralist children (31.5%) than children from the agrarian setting (19.0%; p = 0.012). The consumption of egg/flesh foods was lower among pastoralist children (5.6%) than agrarian children (16.9%, p = 0.085). Caregiver literacy was positively associated with a higher likelihood of MMF (IRR = 1.21; 95% CI:1.02-1.43; p = 0.030), while caregiver depression was associated with a lower likelihood of MMF (RR = 0.97; 95% CI:0.95-0.99; p = 0.003). Improved water source (RR = 1.59; 95% CI:1.06-2.38; p = 0.037), caregiver literacy (RR = 2.04; 95% CI:1.25-3.34; p = 0.002), caregiver MDD (RR = 2.21; 95% CI:1.60-3.05; p ≤ 0.001), older children(RR = 1.05; 95% CI: 1.02-1.08;p ≤ 0.001), and pastoralist setting (RR = 1.62; 95% CI:1.07-2.44; p = 0.014) were associated with a significantly higher likelihood of meeting MDD. Conversely, caregiver depression (RR = 0.94; 95% CI:0.90-0.97; p < 0.001), caregiver mobility restriction (IRR = 0.94; 95% CI:0.89-1.00; p = 0.025), and food insecurity (RR = 0.64; 95% CI:0.41-1.01; p = 0.05) were associated with reduced MDD likelihood. Caregiver community involvement (IRR = 1.12; 95% CI:1.00-1.26; p = 0.038), caregiver MDD (RR = 1.67; 95% CI:1.10-2.53; p = 0.043), and older children (RR = 1.08; 95% CI:1.05-1.12; p < 0.001) were associated with increased egg/flesh-food consumption among children, while living in a pastoralist setting was associated with reduced it (RR = 0.36; 95% CI:0.13-0.97; p = 0.038). Integrated and Targeted interventions recommended: caregiver literacy/depression support to improve IYCF; livelihood-specific foods (eggs/flesh, fruits/vegetables); WaSH enhancements; community engagement; and IYCF counseling within CMAM programs.

OBJECTIVES: To (1) identify cardiac arrest (CA) survivors' and their caregivers' stressors and coping and compensation strategies related to brain health and (2) gather feedback on a proposed brain health lifestyle intervention for this population. METHODS: We conducted two focus groups with dyads of CA survivors and their caregivers ( = 9 dyads) and ten interviews ( = 10 dyads), recruited from the Sudden Cardiac Arrest Foundation's Cardiac Arrest Survivor Alliance, BuildClinical, and provider referrals between 9/2024 and 5/2025. We purposefully sampled to include populations at-risk for cognitive decline based on race and ethnicity. We conducted rapid qualitative data analysis of our focus groups and interview transcripts. RESULTS: Dyads described several sources of brain health stress including survivors' cognitive changes, fear of further decline, and concerns about caregiver stress. Dyads reported using coping strategies including peer support, professional mental health treatment, acceptance strategies, and physical activity, and compensation strategies including delegating more tasks to the caregiver, using organizational aids, visual aids, and pacing strategies. Dyads endorsed proposed program content and recommended additional content on nutrition and diet, managing emotional distress, and psychoeducation on the impact of CA on the brain. CONCLUSION: Survivors and caregivers experience ongoing stressors related to brain health, though they develop coping and compensation strategies that merit further study.

Sport fans can experience a variety of dysfunctional emotions and maladaptive behaviors, including anger, hatred, depression, anxiety, and violence. For many years, rational emotive behavioural therapy (REBT) has used the concepts of rational and irrational beliefs to explain the emotions and behaviours exhibited by different groups, such as athletes, students and employees. The current study examines the relationships between rational and irrational fan beliefs, and psychological distress (depression, anxiety, and stress), in football fans. It also investigates the moderating role of gender, marital status, and match outcomes in these relationships. The study involved 256 football fans, aged between 23 and 48 (M = 26.34). Moderator effect analysis was performed using PROCESS Macro. The analyses revealed that psychological distress was negatively correlated with rational fan beliefs and positively correlated with irrational fan beliefs. The moderating role of gender, marital status and match outcome was not significant. Male gender, single status, and losing a match were risk factors for mental health. Overall, the findings indicate that psychological distress is positively associated with irrational beliefs and negatively associated with rational beliefs, regardless of gender, marital status, or match outcome. The results are discussed in relation to REBT and fan studies.

OBJECTIVES: Patients with tinnitus often have somatic complaints, a reality that is understudied in the broader literature on tinnitus. This study aims to characterize tinnitus patients with somatic complaints, investigate associations between somatic complaints and tinnitus, hyperacusis, and symptoms of anxiety and depression, and to compare patient profiles across genders and healthcare services. DESIGN: A cross-sectional study with a digital questionnaire consisting of Tinnitus Sample Case History Questionnaire (TSCHQ), Tinnitus Handicap Inventory (THI), Hyperacusis Questionnaire (HQ), Hospital Anxiety and Depression Scale (HADS) and Generalized Anxiety Disorder-7 (GAD-7). The somatic complaints investigated were Headaches, Dizziness, Temporomandibular Dysfunction (TMD), Neck pain and Pain Syndromes, as measured using the TSCHQ. STUDY SAMPLE: A total of 144 participants with tinnitus were sampled, from four hearing clinics and two rehabilitation centres in Norway. RESULTS: Several positive associations were observed between somatic complaints and higher levels of tinnitus, hyperacusis, depression and anxiety. Moreover, somatic complaints were more common among women, and those recruited from rehabilitation centres. CONCLUSIONS: Tinnitus patients, with or without comorbid hyperacusis, have several psychological and somatic complaints that need to be mapped thoroughly. An interdisciplinary approach should be considered for patients with tinnitus and comorbid somatic symptoms.

PURPOSE: This study aimed to validate and adapt the Turkish version of the Illness Identity Questionnaire (IIQ) for cultural use. The IIQ was developed by Oris et al. to assess the integration of illness into identity. METHODS AND MATERIALS: This psychometric validation investigation used a sample of young adults with chronic illness (n = 166) to evaluate a questionnaire. The questionnaire underwent forward and back translation procedures, and content and language validity was approved by experts. RESULTS: Confirmatory factor analysis supported a four-factor structure (engulfment, rejection, acceptance and enrichment) and demonstrated good model fit ( = 1.963, RMSEA = 0.076, GFI = 0.940 and CFI = 0.934). Convergent validity analyses revealed significant relationships between dimensions of illness identity, depression and life satisfaction. Engulfment, rejection and acceptance were positively related to depression and negatively related to life satisfaction, while enrichment exhibited the opposite pattern. Reliability analyses showed internal consistency ranging from acceptable to excellent, with Cronbach's alpha coefficients ranging from 0.719 to 0.907. Item-total correlations (0.380-0.799,  < 0.01) confirmed homogeneity in measuring illness identity. CONCLUSIONS: The Turkish version of the IIQ demonstrated acceptable psychometric properties, thus supporting its use as a reliable and valid tool for assessing illness identity.

BACKGROUND: Patients who survive critical illness and intensive care unit (ICU) admission often experience long-lasting physical, psychological, and cognitive impairments. Cognitive impairments are common and may persist well beyond ICU discharge. Few structured interventions address these impairments across the care continuum, from the ICU to post-discharge recovery. This gap informed the development of a stakeholder-driven cognitive rehabilitation intervention. The aim was to develop a cognitive rehabilitation intervention for critically ill patients that bridges the period from ICU admission to post-discharge recovery. METHODS: The intervention was developed using a multiphase process guided by the 2021 Medical Research Council (MRC) framework for complex interventions and reported in line with the GUIDED and TIDieR checklists. Stakeholder input was gathered through: (1) a workshop (n = 11) to identify end-user needs; (2) a three-round Delphi process (n = 39) to prioritise interventions using a seven-point Likert scale; and (3) expert consultations to refine selected components. Qualitative data from the workshop and open-ended Delphi responses were analysed thematically, while quantitative analysis identified consensus, defined a priori as ≥80% agreement on importance. RESULTS: The process generated a range of proposed interventions, including both novel and established elements. Interventions reaching stakeholder consensus were further reviewed by experts for clinical relevance and feasibility. Two prototype interventions were selected: (1) a Mindfulness-based intervention and (2) a Brain Training intervention. CONCLUSION: This study outlines a stakeholder-informed process for developing a cognitive rehabilitation intervention tailored to ICU patients across the care continuum. The co-design approach improved contextual fit and clinical applicability. These findings support the planned feasibility evaluation of the proposed interventions. TRIAL REGISTRATION: The overall research study received ethics approval, while formal ethics committee approval was not required for the workshop and Delphi activities under Danish legislation (osf.io/5a4xq).

BACKGROUND: Standing sedation is frequently required in donkeys for minor surgical and diagnostic procedures, yet information on the cardiac safety of α2-adrenoceptor agonists and opioid combinations in this species is limited. This study evaluated the echocardiographic effects of intravenous medetomidine, butorphanol, and their combination in clinically healthy donkeys. MATERIALS AND METHODS: Sixty donkeys were randomly assigned to four groups (n = 15/group) to receive intravenous saline (control group, CG), medetomidine group (10 µg/kg, MG), butorphanol group (50 µg/kg, BG), or medetomidine-butorphanol group (10 µg/kg + 50 µg/kg, MBG). Butorphanol was administered 5 min after medetomidine in the MBG. M-mode echocardiography was performed from a right parasternal short-axis view at baseline and at 5, 15, 30, 45, 60, 90, and 120 min after treatment. Left ventricular internal diameter (LVID), interventricular septal thickness (IVST), and left ventricular posterior wall thickness (LVPW) were measured at end-diastole (d) and end-systole (s). Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke volume (SV), ejection fraction (EF%), and fractional shortening (FS%) were calculated. Data were analyzed using a repeated-measures general linear model. RESULTS: Medetomidine alone was associated with significant reductions in EF% and FS%, together with significant changes in LVIDs and LVIDd. SV was also significantly lower in the medetomidine group than in the control group during the main post-treatment period; however, SV and the calculated LV volumes were interpreted cautiously because they are load-dependent variables derived from linear M-mode measurements. These changes were accompanied by an increase in LVIDs and a reduction in IVSs, indicating transient depression of conventional left ventricular systolic indices and altered loading conditions. Butorphanol alone produced only minor, parameter-specific changes in LVID, IVST, and most echocardiographic indices, with no consistent clinically relevant deterioration compared with baseline or the CG. In contrast, the MBG showed marked changes in ventricular dimensions and calculated indices from 15 to 60 min; however, these findings were interpreted cautiously because the calculated systolic indices are load-dependent. CONCLUSIONS: Intravenous medetomidine, butorphanol, and their combination exert distinct and protocol-dependent effects on left ventricular dimensions and systolic function in donkeys. Medetomidine alone substantially and transiently depresses systolic performance, whereas butorphanol alone is comparatively cardiovascular-sparing. The medetomidine-butorphanol combination may be considered for standing sedation in clinically healthy donkeys; however, its echocardiographic effects should be interpreted cautiously as load-dependent changes, and cardiovascular monitoring remains advisable.

BACKGROUND: Maternal morbidity and mortality remain major global health challenges, with substantial variation in maternity care delivery across health systems. Although clinical guidelines are widely available, there is limited systematic, multi-country mapping of maternity care systems as integrated architectures. Evidence linking system design and implementation to population outcomes is also limited. This study aims to compare maternity care systems across countries for gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, and uncomplicated pregnancy using a structured, multi-layered care architecture framework. METHODS: This is a multi-country, cross-sectional, mixed-methods comparative study including twenty countries across all World Health Organization regions and income groups, selected using purposive sampling. Data will be collected using a standardised instrument with more than 140 items mapped to a nine-layer care architecture framework, covering policy, clinical standards, guidelines, models of care, care pathways, clinical protocols, digital systems, patient experience, and financing. Data sources will include structured country submissions, systematic document review, and validation interviews with clinicians and policymakers. Each domain will be independently scored by two reviewers using a four-point ordinal scale, with assessment of inter-rater reliability. Country profiles will be validated through member checking and triangulation of documentary and interview data. Comparative analyses will include descriptive profiling, cross-country comparisons, clustering to identify system typologies, and gap analysis against international benchmarks. Implementation and equity dimensions will be assessed using established frameworks, and physical activity guidance will be examined as a cross-cutting domain. Exploratory ecological analyses will assess associations between system characteristics and publicly available outcomes, including maternal mortality, preterm birth, stillbirth, and caesarean section rates, using regression models. A structured consensus process will be used to develop minimum care architecture standards and harmonisation recommendations. DISCUSSION: This study will provide a structured and reproducible approach to characterising and comparing maternity care systems globally. By identifying variation in system design, implementation, and equity considerations, the findings will inform policy, support harmonisation of care, and guide improvements in maternal and perinatal outcomes across diverse settings. REGISTRATION: Open Science Framework.

BACKGROUND: Pregnancy-related anxiety can adversely affect maternal and fetal health; therefore, understanding its related factors is essential. This study aimed to determine the cognitive-psychological predictors of pregnancy-related anxiety among pregnant women. METHODS: This cross-sectional study was conducted on 400 pregnant women who were covered by urban comprehensive health service centers in Urmia. Data were collected using a demographic questionnaire; the Pregnancy-Related Anxiety Questionnaire-Revised (PRAQ-R2); the Edinburgh Postnatal Depression Scale (EPDS); the Multidimensional Scale of Perceived Social Support (MSPSS); the Childbirth Self-Efficacy Inventory (CBSEI); and the Maternal Health Literacy and Pregnancy Outcome Questionnaire (MHLAPQ). The data were analyzed using SPSS version 16. A p-value of less than 0.05 was considered statistically significant. RESULTS: The mean age of participants was 26.53 ± 4.87 years. The mean pregnancy-related anxiety score was 28.03 ± 9.08. Among the subscales of pregnancy-related anxiety, the lowest mean score was associated with concerns about own appearance, while the highest mean score was linked to fear of childbirth. Depression during pregnancy (B = 0.821, β = 0.523, p < 0.001) and childbirth self-efficacy (B = - 0.048, β = -0.176, p < 0.001) were significant predictors of pregnancy-related anxiety, whereas perceived social support and maternal health literacy were not significant predictors. The cognitive-psychological variables examined explained approximately 34% of the variance in pregnancy-related anxiety. CONCLUSIONS: The results showed a moderate level of pregnancy-related anxiety in the study population. Therefore, it is recommended to incorporate early screening for pregnancy-related anxiety and its related factors into routine care. Furthermore, appropriate interventions should be implemented to reduce pregnancy-related anxiety by addressing its predictors.

BACKGROUND: Mental health conditions such as depression, anxiety, and stress are commonly assessed using self-reported questionnaires and limited wearable physiological measures. However, reliance on subjective reporting, restricted sensor modalities such as heart rate variability and electrodermal activity, and small or homogeneous datasets may limit generalizability. We aimed to evaluate whether wearable optical sensing of microcirculation and tissue metabolism enables objective assessment of stress-related mental health states. METHODS: We conducted a prospective observational study including 132 adults aged 18 to 94 years (58% female) from 19 countries. Participants underwent repeated fingertip measurements using a non-invasive wearable device combining laser Doppler flowmetry and fluorescence spectroscopy to capture microvascular perfusion and metabolic signals. Frequency-domain features were extracted using wavelet analysis. Depression, anxiety, and stress levels were assessed using a standardized 21-item questionnaire. Multiple machine learning models were evaluated under subject-wise validation, and model interpretability was assessed using Shapley-based feature attribution. RESULTS: Here we show that ensemble-based models distinguish individuals with stress-related symptoms from those without with a receiver operating characteristic area under the curve of 0.72 and a precision-recall area under the curve of 0.89 under subject-wise validation. Microcirculatory variability and metabolic fluorescence features contribute substantially to prediction performance. Demographic variables, including sex, age, body mass index, and heart rate, are associated with increased stress-related risk. CONCLUSIONS: Wearable optical sensing combined with interpretable machine learning provides physiological signatures associated with stress-related mental health conditions. This framework supports development of scalable and data-driven tools for objective mental health monitoring.

Psoriasis is a chronic immune-mediated inflammatory disease associated not only with cutaneous manifestations but also with substantial psychosocial burden, including impaired quality of life, depression, anxiety, stigmatization, fatigue, and sexual dysfunction. While cyclosporine A (CsA) is an established systemic therapy for moderate-to-severe psoriasis, its broader psychosocial effects remain insufficiently characterized. This prospective study enrolled 37 patients (20 men, 17 women; mean age 47.8 ± 4.9 years) with moderate-to-severe plaque psoriasis treated with oral CsA for 12 weeks. Therapy was initiated at 5 mg/kg/day for the first 42 days and subsequently reduced to 2.5 mg/kg/day until Day 84. Clinical severity was assessed using the Psoriasis Area and Severity Index (PASI) and Body Surface Area (BSA). Patient-reported outcomes included assessments of quality of life, illness acceptance, life satisfaction, depression, anxiety, fatigue, sexual satisfaction, stigmatization, disability, stress, and pruritus using validated psychometric instruments. Sociodemographic and metabolic determinants were additionally analyzed. CsA therapy resulted in rapid and marked clinical improvement, with PASI scores decreasing from 20.3 ± 4.2 at baseline to 0.9 ± 0.9 at week 12 (p < 0.001) and BSA involvement declining from 41.9% to 1.9% (p < 0.001). Significant improvements were additionally observed across multiple psychosocial domains, including dermatology-related quality of life, depressive and anxiety symptoms, fatigue, sexual satisfaction, illness acceptance, stigmatization, disability, stress, and pruritus (all p < 0.05). Younger age, single marital status, urban residence, longer disease duration, and metabolic comorbidity burden were associated with greater baseline psychosocial impairment. CsA therapy provides multidimensional benefits in patients with moderate-to-severe plaque psoriasis, improving not only clinical disease severity but also psychological well-being, social functioning, fatigue, illness acceptance, and overall quality of life. These findings support the integration of psychosocial assessment into routine therapeutic evaluation and reinforce the continued role of CsA as a multidimensional therapeutic approach in contemporary psoriasis management.

Brain maintenance - the preservation of brain structure or function relevant to cognitive performance - remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer's cognitive composite (PACC5) using latent growth curve modelling. We demonstrate its utility in 543 cognitively unimpaired older adults from the DELCODE cohort, followed annually over four years. We show that changes in MTLV-ratio and WMH additively predict cognitive change. We further show that higher neuroticism, depressive symptoms, lower openness, and faster biological ageing are related to unfavourable domain-specific trajectories and poorer brain maintenance. Our findings highlight the combined relevance of WMH and ageing-related atrophy dynamics for brain maintenance. Maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia.

Our understanding of the influence of ancestral background on genetically determined expression remains limited, especially when gene expression models are applied to studies from different or multiple populations. We perform transcriptome-wide association studies of 6 psychiatric conditions, leveraging gene expression models trained in cohorts with different proportions of African, European, and Indigenous American genetic ancestries. For comparison, we repeat each transcriptome-wide association study using a model trained in individuals of predominantly European ancestry. We identify 1416 statistically significant gene-level associations (false discovery rate adjusted p < 0.05) across the 6 diagnoses, of which 62% are uniquely detected by the admixed gene models. Notably, we observe high correlation () in the gene-level effects on disease risk across ancestries, a statistic that remains robust for results that only reach statistical significance in one population. The genes identified by the admixed models implicate more neurophysiological features (as measured by brain imaging) associated with diagnostic symptoms. Overall, admixed gene expression models greatly extend the yield of transcriptome-wide association studies and substantially enhance validation, enabling more precise mapping of genetic effects to underlying pathophysiological mechanisms and highlighting potential avenues for therapeutic development.

Identifying neural networks that infer safety versus danger is of great interest across multiple disciplines. Recent research has started to elucidate the brain networks mediating fear discrimination and generalization. Here, we focus on the contribution of the auditory cortices to auditory fear memory and discrimination processes. We first review studies showing that the primary auditory cortex (Te1) is involved in fear memory for tones with complex perceptual features only. Conversely, Te1 is essential for fear discrimination across all types of acoustic stimuli. These studies support the idea that Te1 plays a key role in the precision of auditory fear memory and in discriminating between aversive sounds and other, non-aversive sounds. We also discuss potential neuronal mechanisms within Te1 that may support these functions. Next, we review studies showing that higher-order auditory cortices, particularly those located in the posterior auditory field, constitute a critical hub for the encoding of auditory fear memories, regardless of the physical characteristics of the tones. We present evidence suggesting that these cortices may be involved in encoding the emotional and motivational significance that sounds acquire through experience. We also summarize studies suggesting that these areas might contribute to fear discrimination, although more compelling evidence is needed. We then discuss how descending pathways from auditory cortices may influence neuronal processes within the basolateral amygdala that participate in fear discrimination. We conclude by proposing that a better understanding of these sensory cortical mechanisms may inform novel strategies to address pathological fear generalization in fear- and anxiety-disorders.

Ketamine is a fast-acting intervention for treatment-resistant depression (TRD), yet only a subset of patients show robust clinical response, and the underlying neural mechanisms remain unclear. High-order interactions (HOI) derived from multivariate information theory provide a framework for examining nonlinear dependencies among brain regions beyond pairwise connectivity. One such metric, the O-information, captures the balance between synergistic and redundant interactions across three or more variables. In this secondary analysis of a randomized, double-blind, midazolam-controlled trial (NCT02556606), we examined EEG-derived HOI in 30 late-life veterans with TRD following a single 40-minute intravenous infusion of ketamine (0.1, 0.25, 0.5 mg/kg; n = 18) or midazolam (0.03 mg/kg; n = 12). Resting state and mismatch negativity data were analyzed at baseline, 1 h, 24 h, and 7 d post-infusion. Ketamine induced temporally dynamic alterations in redundancy-dominant O-info, with maximal effects in the alpha-band at 1 h (Cohen's d = 2.57), attenuation at 24 h that shifted toward the theta-band, and partial resurgence in beta and gamma by Day 7. Linear mixed-effects modeling identified significant group effects across most band x metric families, with the strongest effects in alpha, beta, and gamma redundancy. Greater increases in 24-hour alpha-band redundancy were associated with greater improvement in depressive symptoms at Day 7 (β = 69.31, q = 0.05). HOI metrics also tracked acute dissociative states, with several 24-hour alpha and beta features remaining positively associated with symptom severity after correction. These findings extend prior HOI work in healthy samples to a controlled TRD cohort and suggest that ketamine induces temporally structured reorganization of higher-order brain interactions, with exploratory associations to clinical outcomes.

BACKGROUND: Alcohol use disorder (AUD) remains difficult to treat with lasting success, leading to growing interest in alternative therapeutic approaches. Psychedelic compounds such as Ayahuasca, a traditional brew used in Indigenous Amazonian ceremonies containing N,N-dimethyltryptamine (DMT) along with monoamine oxidase-inhibiting β-carbolines, have shown promise in reducing addictive behaviors. METHODS: Alcohol dependence was induced in Wistar rats through a voluntary ethanol-consumption paradigm (15% and 30% v/v) of 35 days, followed by a deprivation period of 9 days. Subsequently, rats received a single administration of Ayahuasca containing 2.72 mg/kg N,N-dimethyltryptamine, 3.98 mg/kg harmine, 0.20 mg/kg harmaline, and 3.72 mg/kg tetrahydroharmine or water by gavage, and a relapse protocol of 9 days evaluated relapse-like ethanol intake. Subsequently, rats underwent behavioral testing to assess anxiety- and depressive-like behavior using the elevated plus maze, open field test, splash test, and forced swim test. The levels of dopamine (DA), serotonin (5-HT), brain-derived neurotrophic factor (BDNF), antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR)) activities, and oxidative stress biomarkers (2',7'-dichlorodihydrofluorescein (DCFH) oxidation and thiobarbituric acid reactive substances (TBARS) levels) were assessed in the frontal cortex, hippocampus and striatum 15 days after Ayahuasca administration. RESULTS: A single Ayahuasca administration reduced relapse-like ethanol intake in a sex- and concentration-dependent manner; attenuated alcohol-induced anxiety- and depressive-like behavioral alterations, despite limited evidence of locomotor/exploratory changes; increased striatal DA levels in alcohol-exposed males and females and restored cortical 5-HT levels primarily in males; and partially mitigated alcohol-associated reductions in BDNF levels in a region- and sex-dependent manner. Antioxidant enzyme activities did not show consistent treatment-related modulation, whereas oxidative stress markers (DCFH and TBARS) were reduced in the frontal cortex, hippocampus, and striatum following Ayahuasca administration. However, some oxidative stress and BDNF outcomes showed partial rather than complete normalization. Sex-dependent effects were observed for selected ethanol-intake, neurochemical, BDNF, and oxidative-stress outcomes. CONCLUSION: Ayahuasca reduced alcohol intake during relapse and attenuated several alcohol-induced behavioral, neurochemical, neurotrophic, and oxidative disturbances in a preclinical model of alcohol dependence, withdrawal, and relapse. These findings suggest modulation of neurobiological pathways disrupted by chronic alcohol exposure, while highlighting region- and sex-dependent effects and incomplete normalization for selected outcomes. Dose-response, longitudinal, and mechanistic studies are warranted, alongside controlled clinical studies evaluating safety and efficacy in AUD.

INTRODUCTION: First episode psychosis (FEP) refers to a variable clinical presentation of the onset of psychotic symptoms and represents a key point in time to ensure prompt treatment of affected patients. Clustering techniques based on unsupervised machine learning (ML) allow the stratification of heterogeneous patient groups to improve diagnostic and prognostic accuracy. This systematic review focuses on the application of unsupervised ML clustering to patients affected by FEP, assessing its potential in clinical decision making and its current limitations. METHODS: A bibliographic search was conducted from inception through December 31, 2025 on PubMed, Embase, Psycinfo and Scopus, following the PRISMA guidelines. RESULTS: 48 studies met the inclusion criteria by showing a partitioning of the sample into clusters according to a cognitive and functional, immune and genetic, clinical, or imaging and neurophysiological dimension and by using one or more unsupervised ML techniques. The immune and genetic and imaging and neurophysiological studies suggest a two-cluster classification, with one subgroup showing a higher inflammatory state or pre-existing brain damage. Overall, no consensus emerged regarding the number or characteristics of clusters identified across cognitive and functional, and clinical domains, due to differences in analysed features and methodological approaches. Nevertheless, a recurring finding is the identification of a subgroup characterized by greater cognitive, functional or clinical impairment already at the onset of psychosis. This suggests that, despite the lack of a consistent classification framework, unsupervised clustering may help identify patients who need a higher therapeutic commitment. CONCLUSIONS: Unsupervised ML clustering for classification of FEP-affected patients has significant potential to improve diagnostic workflow and individualized treatment strategies, but lack of reproducibility remains a major limitation. Future larger studies integrating multi-omics and longitudinal data are warranted.

Anxiety-related disorders are highly prevalent and persistently difficult to treat, largely due to insufficient understanding of peripheral-central regulatory mechanisms governing emotional behaviors. Irisin, an exercise-dependent myokine, serves as a critical peripheral-to-central signaling mediator modulating brain function and anxiety-like behavioral phenotypes. This review systematically integrates current preclinical evidence illustrating how irisin regulates anxiety through multi-level neural mechanisms. Irisin suppresses microglial NF-κB/STAT3-mediated neuroinflammation, enhances prefrontal-hippocampal synaptic plasticity via BDNF upregulation and AMPK/mTOR-related autophagy, and improves gut-brain axis homeostasis by stabilizing intestinal barrier integrity and reshaping microbial composition. Crucially, we propose a context-dependent therapeutic window model to reconcile contradictory pro-anxiogenic and anxiolytic findings across stress severity and pathological stages, resolving existing controversies in this field. We further summarize key unresolved limitations, including ambiguous central receptor identity, peripheral-central dissociation and sex-dependent heterogeneity. This work provides an integrated mechanistic framework linking muscular metabolic signals to affective circuit regulation, offering novel translational perspectives for anxiety behavioral modulation and targeted therapeutic development.

BACKGROUND: This study examined the long-term effects of polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA and Toll-like receptor 3 (TLR3) agonist, on behavioral and immune outcomes in chronically stressed mice. METHODS: Male C57BL/6J mice were exposed to 21 days of wet bedding stress followed by a poly I:C injection. Post viral fatigue syndrome (PVFS)-like symptoms were evaluated over 7 days post-injection using grip strength testing, the forced swim test, von Frey filament testing, the Morris water maze, the open field test, and the social interaction test. Body temperature and locomotor activity were continuously monitored via intraperitoneally implanted dataloggers. Serum concentrations of interleukin-6 (IL-6), IL-10, and C-X-C motif chemokine ligand 10 (CXCL10) were quantified. In separate cohorts, minocycline (a microglial activation inhibitor) or RU486 (a glucocorticoid receptor antagonist) was administered prior to poly I:C injection. RESULTS: Following IP injection of poly I:C, body temperatures in both stressed and unstressed mice were significantly elevated, indicating a polyphasic febrile response. At 7 days post-injection, stressed mice treated with poly I:C exhibited persistent fatigue, mechanical allodynia, depressive-like behavior, impaired spatial memory, increased anxiety-like behavior, and reduced social interaction. Serum levels of IL-6 and CXCL10 remained elevated and correlated with behavioral outcomes. Pretreatment with minocycline partially attenuated both the behavioral and immune responses, whereas RU486 pretreatment did not. CONCLUSION: These findings demonstrate that TLR3-mediated systemic inflammation induced by poly I:C produces persistent, multi-domain PVFS-like symptoms in chronically stressed mice. The attenuation by minocycline implicates neuroinflammation as a possible mechanism.

OBJECTIVE: This study aimed to evaluate the impact of perioperative respiratory muscle training on respiratory muscle strength, pulmonary function, functional capacity and prognostic outcomes in patients undergoing surgery. DESIGN: A randomized controlled trial. SETTING(S): Cardiac surgery ward and cardiac surgery intensive care unit of a tertiary Grade A hospital in Fuzhou, China. PARTICIPANTS: Eighty-two participants. INTERVENTIONS: Perioperative respiratory muscle exercise. MAIN OUTCOME MEASURES: Eighty-two patients were randomly assigned to either the intervention group (n = 42), who performed perioperative respiratory muscle training, or the control group (n = 40). Patients completed one session per day from admission to discharge (except during mechanical ventilation). Respiratory muscle strength was assessed upon admission, the day before surgery, on the third day post-intensive care unit transfer, and at discharge. Each patient underwent a lung function test, six-minute walk test, self-efficacy for exercise scale, anxiety and depression test, and quality of life questionnaire, before and after intervention. RESULTS: The intervention group showed significantly greater improvements in maximal inspiratory pressure (57.69 ± 10.85 cmHO vs. 48.28 ± 10.30 cmHO), pulmonary function, functional capacity, postoperative pulmonary complications (38.1% vs. 65.0%), inspiratory muscle weakness (42.9% vs. 85.0%), duration of mechanical ventilation and intensive care unit stay, level of anxiety and depression, quality of life, and length of post-operative hospitalization. Additionally, the incidence of postoperative pulmonary (9.5% vs. 22.5%) and re-hospitalization within six months (9.5% vs. 17.5%) was reduced, though not statistically significant. CONCLUSIONS: Perioperative respiratory muscle training could contribute to improved respiratory muscle strength, pulmonary function, functional capacity, prognostic outcome, and quality of life in elderly cardiac surgery patients. Continuous activation of the respiratory muscles could provide multiple benefits for these individuals.

Illigera aromatica, a traditional Chinese medicinal herb, has been historically utilized for treating depression. Although several phytochemical and pharmacological studies on Illigera aromatica have been reported, its antidepressant-like effects and the related mechanisms have not yet been systematically investigated.This study investigated the chemical profile, preliminary antidepressant-like activity, and short-term tolerability of the ethanol extract of Illigera aromatica (EEIA) in rodent models. LC-MS identified 21 constituents in EEIA, including 12 alkaloids. In normal mice, EEIA reduced immobility in the forced swimming and tail suspension tests; however, these findings should be interpreted as preliminary because locomotor control was not performed in the same mouse cohorts. In a reserpine-induced monoamine-depletion rat model, EEIA partially reversed behavioral and biochemical alterations, including ptosis, reduced locomotor activity, anhedonia, and decreased serum 5-HT and DA levels. Western blot analysis of hippocampal tissues suggested modulation of synaptic plasticity-related proteins, although these data should be regarded as pilot findings due to the small sample size. Acute oral toxicity evaluation showed that EEIA extract was tolerated at doses substantially higher than those used in the pharmacodynamic experiments. Overall, these results provide preliminary pharmacological evidence supporting further investigation of Illigera aromatica, while additional chronic stress models, chemical standardization, and subchronic toxicity studies are required.

Health disparities facing American Indian and Alaska Native (AI/AN) populations warrant effective behavioral health interventions that are grounded in culture and Indigenous worldviews, but AI/AN people remain underrepresented in clinical trials. Rigorous scientific methods are needed to determine the efficacy of new interventions, particularly in small rural communities with high treatment need and low access to care. However, many AI/AN communities prefer study designs that ensure all participants receive an intervention, and logistical constraints, such as small population sizes and limited staffing, can impede fully powered randomized controlled trials. This manuscript presents the Sequential Cohort Randomized Clinical Trial (SC-RCT), a study design developed through an academic-community partnership to test the efficacy of a behavioral intervention for substance use disorders in a rural AI reservation community. The SC-RCT differs from existing staggered rollout designs (e.g., stepped wedge, dynamic wait-listed) by using sequential cohort enrollment with individual-level randomization, allowing sample size to accrue over time while standardizing waitlist duration and intervention dosage across participants. This approach preserves a randomized comparison between immediate and delayed treatment conditions while accommodating staffing and recruitment constraints. The SC-RCT offers a feasible and culturally responsive option when traditional designs are not practical, and may be especially useful in small or under-resourced populations where equitable access and limited implementation capacity are key considerations. In AI/AN and other communities, this design may help overcome logistical barriers to research and support ethical and effective interventions in community settings. Clinicaltrials.gov ID number: NCT05612061.

BACKGROUND: The relationship between cannabis use and psychotic-like experiences (PLEs) remains a crucial area of investigation, particularly regarding different consumption patterns. METHODS: This cross-sectional study examined 150 participants divided into three groups: heavy cannabis users (n = 43), occasional users (n = 47), and non-users (n = 60). Participants were classified using CUDIT-R scores combined with self-reported frequency of use. Assessments included the Community Assessment of Psychic Experiences (CAPE) scale, Global Assessment of Functioning (GAF), and Clinical Global Impression (CGI) scales. Cannabis use patterns, age of onset, and duration were documented. RESULTS: Heavy users (mean age 23.6 ± 4.9 years) showed significantly higher scores on positive symptoms (38.4 ± 6.2) compared to occasional users (28.6 ± 5.4) and non-users (18.2 ± 4.2; p < 0.01; ηp = 0.24). Depressive symptoms were also elevated in heavy users (18.6 ± 3.8) versus occasional users (15.4 ± 3.2) and non-users (12.2 ± 2.8; p < 0.01; ηp = 0.19). No significant differences were found in negative symptoms across groups (p = 0.24; ηp = 0.02). Earlier age of onset (<16.4 years) correlated with increased PLEs (r = 0.27, p < 0.05) and poorer functioning. Heavy users demonstrated strong correlations between cannabis use frequency and both positive symptoms (r = 0.58, p < 0.01) and depressive symptoms (r = 0.52, p < 0.01). CONCLUSIONS: The findings suggest a frequency-related association between cannabis use and PLEs, particularly for positive and depressive symptoms. Early onset of use appears to be a significant risk factor for developing psychotic-like experiences, while negative symptoms remain largely unaffected. These results highlight the importance of considering consumption patterns when assessing the psychological impact of cannabis use.