The study aimed to investigate the neurocognitive characteristics of Chinese patients with melancholic depression (MEL) versus non-melancholic depression (NMEL).

Data were derived from a multicenter, multiphase prospective study conducted across nine top-tier hospitals in six provinces of China. A total of 287 healthy controls (HCs), 643 patients with major depressive disorder (MDD) were included. Melancholic traits were assessed using the Chinese version of the Mini-International Neuropsychiatric Interview (MINI). Cognitive function, encompassing processing speed, attention, verbal learning, visual learning, and executive function, was evaluated in both HCs and MDD patients.

Among all MDD patients, 457 (71.07%) were classified as MEL. Both MEL and NMEL subgroups exhibited multi-domain cognitive impairment compared with HCs, including processing speed, attention, verbal learning, visual learning, and executive function (all P < 0.05). After Bonferroni correction, MEL patients showed significantly poorer performance on processing speed (Auditory Verbal Fluency, AVF) compared with NMEL patients (corrected P = 0.011). In contrast, no significant differences were observed between MEL and NMEL patients for executive function (Stroop Color-Word Test, SCWT, corrected P = 0.671) or any other cognitive domains (attention, verbal learning, visual learning). Multiple linear regression analysis confirmed that melancholic features were independently associated with poorer performance on both AVF test (B = -2.807, SE = 1.098, t = -2.556, P = 0.011, 95% CI = [-4.964, -0.651]) and SCWT (B = -2.360, SE = 1.039, t = -2.272, P = 0.023, 95% CI = [-4.400, -0.320]), after adjusting for potential confounders.

Both MEL and NMEL patients demonstrate multi-domain cognitive impairment, with more severe deficits in the MEL group. Melancholic features were a robust independent predictor of processing speed (AVF), whereas their association with executive function (SCWT) was only present in regression models and not significant after Bonferroni correction. These findings highlight the importance of cognitive assessment, especially for processing speed, in MEL patients.

ClinicalTrials.gov identifier: NCT02023567; registration date: 15 December 2013.

Binge-eating behaviors are key components of several types of eating disorders, yet their etiology remains unclear. Animal models have provided valuable insights by enabling experimentally controlled investigations of biological, behavioral, and environmental factors contributing to eating disorders. This narrative review examines the clinical relevance of animal models in advancing our understanding of binge-eating-related disorders. We propose five translational priorities focused on clinically-meaningful features of binge eating and their relevance for improving animal-model development: (1) loss of control and compulsivity, (2) negative affect and stress responsivity, (3) developmental timing and sex differences, (4) individual differences and variability, and (5) treatment responsiveness. Various animal models, including food restriction, stress-induced, and addiction-based paradigms, have been developed to study binge eating. Limitations include the inability of animal models to fully capture the psychological and sociocultural dimensions of binge eating, such as the sense of loss of control, stigma, distress, and body-image concerns. While existing models capture key biological and behavioral components of binge eating, closer alignment with clinically defining features, for example, through the inclusion of emotional stressors and varied outcome measures, could improve translational impact. By refining current models to match clinical reality, animal research may continue to enhance our understanding of eating disorders and inform the development of novel treatment approaches.

Small cell lung cancer (SCLC) patients frequently experience a remarkable response to first-line therapy. Follow up maintenance treatments aim to control residual tumor cells, but generally fail due to cross-resistance, inefficient targeting of tumor vulnerabilities, or dose-limiting toxicity, resulting in relapse and disease progression. Here we show that SCLC cells, similar to their cells of origin, pulmonary neuroendocrine cells, exhibit low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, regardless of their molecular subtype or resistance to first-line therapy. Importantly, unlike non-cancerous cells, SCLC cells cannot adapt to drug-induced ROS stress due to the suppression of ROS defense mechanisms by multiple layers of gene regulation. By exploiting this difference in oxidative stress management, we safely increase the therapeutic dose of TXNRD1 inhibitors in vivo by pharmacological activation of the NRF2 stress response pathway. This results in improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors for maintenance therapy in SCLC.

Purpose: This study aimed to comparatively analyze the lower-limb biomechanical differences between two populations with ankle dorsiflexion limitation during the stance phase of gait, thereby providing a scientific basis for clinical rehabilitation and athletic training. Methods: 12 males with congenital ankle dorsiflexion limitation and 12 males with acquired ankle dorsiflexion limitation, along with 12 healthy male controls were recruited into the study. Group differences in lower-limb kinematics, kinetics and surface electromyography (sEMG) during barefoot walking were subjected to statistical analysis using one-dimensional Statistical Parametric Mapping (SPM1D). Results: The Congenital Ankle Dorsiflexion-Limited Cohort (CDFL) had greater ankle dorsiflexion during the support phase (22-42%) than the Acquired Ankle Dorsiflexion-Limited Cohort (ADFL) (p = 0.003), with increased terminal plantar flexion torque and positive power, and higher average activation intensity of the gastrocnemius medialis (GM), while the power trajectory was close to that of the control group. The ADFL had higher plantar flexion torque during 0-83% of the gait cycle ( p = 0.001), increased knee flexion throughout the gait cycle ( p = 0.014), and elevated negative knee power and positive hip power in the middle and late stages, with increased average activation intensity of the rectus femoris (RF) and decreased activation intensity of the GM and tibialis anterior (TA). Conclusions: This study revealed phenotype-specific gait adaptations associated with different etiologies of ankle dorsiflexion limitation, ADFL predominantly exhibited a proximal-compensation pattern, whereas those with CDFL favored a distal strategy. These findings argue for etiology-tailored rehabilitation - strengthening ankle push-off and distal-proximal coordination in ADFL, and prioritizing terminal push-off and lateral stability in CDFL.

Fracture risk is increased after stroke, but there is a lack of specific, effective tools to screen and prevent minimal trauma fractures (MTF) post-stroke. While the FRAC-Stroke score, developed to predict fracture risk post-stroke, shows promising performance, it has not yet been widely adopted or validated in large cohorts outside of Canada.

We aimed to: 1) evaluate the reliability and validity of the FRAC-Stroke score in predicting MTF; and 2) determine the optimal score to classify patients at highest fracture risk following ischaemic stroke.

A retrospective cohort study was undertaken using data from the PRECISE study, which included person-level linked administrative data from the Australian Stroke Clinical Registry (AuSCR, 2014-2016). The FRAC-Stroke score at hospital discharge was determined for survivors of ischemic stroke, aged >50 years, using coded comorbidities derived in the prior 5-year period and modified Rankin Scale. Fine-Gray models were built to evaluate associations of the FRAC-Stroke score with MTF within 12 months post-discharge, accounting for death as the competing risk.

Among 4545 adults, the median FRAC-Stroke score was 8 (interquartile range 5-11) and 118 patients (2.6%) sustained a MTF within 12 months post-discharge. The optimal FRAC-Stroke score cut-point to stratify MTF risk was 11.5, with a c-statistic of 0.70. Participants with a FRAC-Stroke score >12 (vs <12) had a 5.5-fold increased risk of MTF (confidence interval 3.8-7.9, p<0.01). When stratified by quintiles of FRAC-Stroke score, those in quintile 5 (FRAC-Stroke score >14) had a 15.2-fold increased risk of MTF than those in quintile 1 (FRAC-Stroke score <3; confidence interval 6.6-35.2, p<0.01).

The FRAC-Stroke score reliably identifies increased fracture risk in the Australian ischemic stroke population, with a score of 12+ able to discriminate those at high risk of fracture.

The diagnosis of autism spectrum disorder is based on clinical judgment, as there are no clearly identified markers to determine the presence of this condition. Gaze patterns have been proposed as a potential biomarker for autism. This study aims to conduct an exploratory analysis of the eye-tracking data collected during a virtual reality-based intervention for social cognition in autistic children. Specifically, we evaluated the variations in social orientation toward social stimuli, the association of gaze patterns with autistic traits, theory of mind (ToM) and task performance, and the mediating effect of attentional mechanisms on the relationship between social cognition performance and autism symptomatology. Our findings identified an increase in social orientation time toward social stimuli, but eye-tracking measures did not significantly predict autism symptom severity or ToM ability. The mediation analysis also failed to find a significant mediating effect of gaze patterns on the relationship between task performance and autism severity. This study points to VR as a promising tool for improving social orienting in autistic children, although there is a need to further investigate the potential of eye-tracking measures as a behavioral marker for predicting social cognition performance.

ObjectiveSingle subcortical infarction (SSI) arises from heterogeneous mechanisms, most commonly parent artery disease (PAD) or intrinsic small vessel pathology. However, whether these mechanisms produce distinct in vivo hemodynamic signatures within perforating arteries remains unknown. We aimed to determine whether lenticulostriate artery (LSA) hemodynamics differ between SSI subtypes and whether such differences provide mechanistic insight into SSI pathophysiology.MethodsPatients with recent SSI confined to the LSA territory were prospectively enrolled and underwent 7T MRI. Based on intracranial vessel wall imaging, patients were classified as SSI+PAD (ipsilateral MCA plaque on T1-weighted vessel wall imaging defined by eccentric wall thickening)) or SSI-PAD (no ipsilateral MCA plaque). LSA flow velocity was quantified at the arterial ostium and distal segment using phase-contrast magnetic resonance angiography (PC-MRA), and along-vessel velocity decline was calculated. LSA morphology was assessed with time-of-flight MRA. Linear mixed-effects models adjusted for age and sex were used for group comparisons.ResultsForty-two patients (21 SSI+PAD and 21 SSI-PAD) were included. In SSI+PAD, ostial velocity in the symptomatic hemisphere was significantly lower than in the contralateral hemisphere (7.25 vs. 9.61 cm/s; p<0.001) and the symptomatic side of SSI-PAD (8.95 cm/s, p=0.001), indicating proximal inflow restriction. In contrast, SSI-PAD preserved ostial inflow (8.95 vs. 9.15 cm/s, p = 0.70) but exhibited a greater along-vessel velocity decline on both hemispheres compared with SSI+PAD, suggesting distal microvascular dysfunction. Morphologically, the symptomatic hemisphere showed fewer visible LSA branches and shorter LSA length than the contralateral hemisphere in both groups. In addition, LSA diameter tended to be smaller in SSI-PAD than in SSI+PAD.Conclusion7T PC-MRA revealed distinct hemodynamic patterns in SSI. SSI+PAD was characterized by proximal inflow limitation, whereas SSI-PAD reflected diffuse distal hypoperfusion characteristic of small vessel pathology. Quantitative perforator flow assessment may refine etiologic classification and guide second prevention in SSI.

Psychiatric disorders often arise from the interaction between genetic predisposition and chronic psychosocial stress, yet the molecular programs determining resilience versus susceptibility remain incompletely understood. Building on evidence that the transcriptional corepressor LSD1 links environmental stress to neuronal gene regulation, we investigated whether isoform-specific regulation of LSD1 splicing contributes to stress adaptation. Using a mouse model of chronic social defeat stress, we analyzed LSD1 microexon E8a splicing in the hippocampus of resilient and susceptible animals. RNA-seq was performed after the last stress session to capture genome-wide transcriptional responses during the window of LSD1 splicing regulation. Comparative analyses with published LSD1 knockdown, LSD1 ChIP-seq and chronic stress datasets were conducted. Hippocampal samples from suicide victims were analyzed to assess translational relevance. Analysis of LSD1 splicing dynamics revealed that resilient mice, but not susceptible animals, retained the ability to reiterate acute stress-induced exon E8a skipping after repeated stress exposure, preserving the capacity to upregulate the enzymatically active ubLSD1 isoform in the hippocampus. In susceptible mice this inducible splicing response was absent. Mechanistically, splicing regulation involved the long non-coding RNA MALAT1, which controls the neurospecific splicing factor nSR100, a regulator of LSD1 exon E8a inclusion. Reduced MALAT1 expression in susceptible mice coincided with marked overactivation of stress-responsive genes revealed by RNA-seq. Approximately 15% (86 of 595) of genes deregulated in susceptible versus resilient hippocampi overlapped with transcripts modulated by LSD1 knockdown in an independent neuronal system. Of these, 25 were direct LSD1 ChIP-seq targets. ESR1 emerged as a regionally divergent upstream regulator associated with susceptibility. The MALAT1-nSR100-LSD1 axis represents a regulatory pathway modulating stress adaptation. Downregulation of ubLSD1 and MALAT1 in the hippocampus of suicide victims recapitulates the molecular phenotype observed in stress-susceptible mice, linking disruption of this pathway to pathological behavioral outcomes.