IntroductionUnderstanding the mechanisms underlying direction selectivity in retinal ganglion cells (RGCs) is crucial in visual neuroscience. Retinal direction selectivity is critical for gaze stabilization through optokinetic and vestibulo-ocular reflexes, and its loss impairs the ability to stabilize gaze and track moving objects, potentially impacting behaviors that rely on accurate motion detection. The prevailing hypothesis proposes that the interplay between excitatory and inhibitory inputs is pivotal for the emergence of direction selectivity in RGCs.MethodsTo dissect the contributions of these inputs, we employed dynamic-clamp recordings utilizing computationally modeled, synthetic excitatory and inhibitory conductances of varying amplitudes and time onsets in mouse RGCs.ResultsThe use of combinations of excitatory and inhibitory conductances with altered amplitude or timing in configurations not found in natural physiological conditions, allowed us to evaluate the specific contribution and impact of these modified components on direction selectivity. We found that asymmetries in both excitatory and inhibitory inputs are critical for the emergence of sharp directional tuning.DiscussionOur findings contribute to advance our understanding of the cellular and synaptic mechanisms that underlie retinal direction selectivity.
Rebuilding spinal circuit function after spinal cord injury through a patient-specific interneuron precision model
Spinal interneurons constitute the physiological core of spinal circuitry, integrating excitatory and inhibitory inputs to generate the rhythmic patterns that drive locomotor, postural, and autonomic control. Their developmental logic, molecular diversity, and adaptive plasticity make them central determinants of functional recovery after spinal cord injury (SCI). Yet most regenerative strategies continue to emphasize cellular replacement rather than the restoration of the physiological integrity of spinal networks. In this article, we reframe spinal repair as the restoration of interneuron-mediated circuit organization rather than cellular replacement alone. We synthesize current insights into how embryonic patterning programs defined by Sonic Hedgehog (SHH), Wnt, and bone morphogenetic protein (BMP) gradients, refined by Notch and retinoic acid signaling, and consolidated by axon guidance cues, establish interneuron diversity, connectivity, and network symmetry that together encode the logic of motor coordination. SCI disrupts this developmental logic, fragmenting excitatory and inhibitory balance and desynchronizing rhythmic modules, while residual circuits retain latent capacity for resynchronization through plasticity and neuromodulation. Building upon this developmental and physiological continuum, we propose the Patient-Specific Interneuron Precision Model (PIPM), a feedback-informed conceptual framework that links patient-specific biological states, including progenitor competence, morphogen sensitivity, metabolic tone, inflammatory burden, and lesion-specific circuit preservation, to circuit-level function and recovery potential. Frameworks such as the PIPM may help integrate molecular, physiological, and clinical dimensions of recovery, providing a path toward more personalized strategies for treating SCI through restoration of interneuron-mediated network organization.
Prediction model for postoperative delirium risk in elderly hypertensive patients: machine learning-based development and validation
BackgroundPostoperative delirium (POD) is a severe complication in elderly hypertensive patients, associated with poor long-term outcomes. Existing models often rely on intraoperative data, limiting preoperative risk stratification. This study aimed to develop a non-invasive machine learning model to predict POD and investigate its preoperative markers’ impact on three-year mortality.MethodsPreoperative variables were selected using LASSO regression from a cohort of 1,782 patients. Ten machine learning models were trained and validated (7:3 ratio). Model performance was evaluated via AUC-ROC and decision curve analysis (DCA). The optimal model was interpreted using SHAP values. Long-term prognosis within the POD cohort was assessed using Kaplan-Meier curves and multivariable Cox proportional hazards regression.ResultsThe POD incidence was 10.9%. The Gradient Boosting Machine (GBM) demonstrated optimal performance (AUC = 0.868, 95% CI: 0.819–0.917). SHAP analysis identified MMSE score as the most influential predictor, followed by HADS score, age, CFS, frailty, and PSQI score. Multivariable Cox analysis revealed that lower MMSE, alongside elevated HADS, CFS, frailty, and PSQI scores—but not chronological age—were independent predictors of increased three-year mortality in POD patients (all P < 0.05).ConclusionWe developed a robust machine learning tool for individualized POD prediction. Cognitive impairment, psychological distress, frailty, and poor sleep quality serve as critical dual-prognostic markers for both acute POD occurrence and long-term survival. These findings underscore the necessity of routine multidimensional preoperative assessment to facilitate personalized interventions for vulnerable hypertensive populations.
Treatment outcomes of an integrated treatment model for patients with co-occurring opioid use and schizophrenia spectrum disorders
BackgroundIndividuals with schizophrenia spectrum disorders are at elevated risk for developing opioid use disorder and often experience higher substance use rates and morbidity. However, integrated treatment models for such patients remain rare.ObjectiveThis study addresses a gap in clinical knowledge by evaluating outcomes from a dual-diagnosis program tailored for patients with both disorders.MethodsThis retrospective case series analyzed electronic medical record data from when patients were enrolled in the program through March 1st, 2025 or program discharge.ResultsSeventeen patients attended at least one appointment. All patients had a diagnosis of opioid use disorder. Co-occurring psychotic disorders included schizoaffective disorder (13/17, 76%), schizophrenia (3/17, 18%), and unspecified psychotic disorder (1/17, 6%). On average, patients attended 58.8% of scheduled visits, and 47.1% remained actively enrolled as of 3/1/25. Medication adherence was high, with patients taking prescribed medications for opioid use disorder at 90.5% of visits and antipsychotics at 96.9% of visits. Compared to an equivalent pre-enrollment period, patients showed a significant reduction in emergency department visits (P=0.00051) and inpatient hospitalizations (P=0.00090).ConclusionFindings suggest that the integrated treatment model could offer benefits for patients with co-occurring opioid use disorder/schizophrenia spectrum disorders; patients had significantly reduced emergency department visit frequency and frequency/duration of hospitalizations. Patients demonstrated high adherence to medications for opioid use disorder and antipsychotics; appointment attendance remains an area for improvement. Further research with larger samples and longer follow-up is warranted.
Clinical practice guidelines and quality standards for early intervention in psychosis: an AGREE II appraisal and systematic review of service components
BackgroundEarly intervention in psychosis (EIP) is a key component of youth mental health care, yet recommended models of care for individuals at clinical high risk for psychosis (CHR-P) and first-episode psychosis (FEP) remain heterogeneous across jurisdictions. No previous study has combined a formal AGREE II appraisal with a structured synthesis of core service components for EIP.MethodsWe conducted a systematic review and AGREE II-based appraisal of international clinical practice guidelines (CPGs) and quality standards (QSs). MEDLINE (via PubMed), the Cochrane Library (CENTRAL), Web of Science, guideline repositories, and grey literature sources were searched to March 2025 in accordance with PRISMA 2020 guidance. Eligible documents were CPGs or QSs published in English or Italian from 2005 onward containing recommendations on the organization, assessment, and treatment of CHR-P and/or FEP. Methodological quality was appraised with AGREE II (inter-rater agreement assessed using ICCs); recommendations were extracted, and core components required endorsement by at least one third of relevant documents with at least one strong or mandatory recommendation. Twenty-six documents (24 CPGs and 2 QSs) were included. Methodological quality was moderate overall, with substantial variability across AGREE II domains: scores were generally strongest for scope and purpose, stakeholder involvement, and clarity of presentation, and more variable for Rigour of development, applicability, and editorial independence.ResultsWe identified 32 core recommendations. For CHR-P, the most consistent components were specialized services or dedicated pathways, comprehensive multidisciplinary assessment, cognitive-behavioural therapy, family interventions, and a cautious approach to antipsychotic use. For FEP, the most consistently endorsed components were specialized multidisciplinary teams, assertive and continuous follow-up, family work, psychoeducation, structured pharmacological monitoring, and supported education and employment.ConclusionThese findings provide a guideline-derived framework for youth EIP service delivery and model development, while highlighting the need for more methodologically robust and implementation-oriented guidance across settings.Systematic review registrationhttps://osf.io/cek7u, identifier cek7u.
Case Report: Multimodal clinical and neurophysiological effects of cranial electrotherapy stimulation in a patient with chronic stress and sleep disturbance
IntroductionCranial Electrotherapy Stimulation (CES) is a non-invasive brain stimulation (NIBS) technique used for anxiety and sleep disorders; however, case-level evidence linking clinical improvement with objective neurophysiological change remains limited. This case presents a multimodal examination of the therapeutic and neurophysiological effects of CES in a patient with sleep disturbances and chronic stress.MethodsA 51-year-old woman with chronic stress, anxiety, and persistent sleep disturbance following thyroid and parathyroid surgery, refractory to pharmacological treatment, underwent a 16-week CES intervention. Outcomes were assessed at baseline and follow-up using EQ-5D-5L, DASS-21, GAD-7, PSQI, and resting-state Electroencephalography (EEG).ResultsAnxiety, stress, and depressive symptoms improved to within normal ranges, alongside significant improvements in mental health-related quality of life. EEG demonstrated increased posterior alpha activity and improved frontal symmetry. Sleep quality showed modest improvement.ConclusionThis case suggests that CES may be a safe adjunctive intervention associated with symptomatic improvement and changes in neurophysiological patterns in stress-related conditions, supporting further controlled investigation.
Reduced serum cortisol, IGF-1, GLP-1, and T3 levels in medication-free children and adolescents with obsessive–compulsive disorder: a case–control study
IntroductionObsessive–compulsive disorder (OCD) frequently emerges during childhood and adolescence and has been associated with alterations in multiple neurobiological systems. Neuroendocrine pathways involved in stress regulation, neurodevelopment, metabolic signaling, and thyroid function interact closely to influence brain circuits implicated in OCD. However, studies simultaneously examining several neuroendocrine parameters in pediatric OCD remain limited.MethodsThis case–control study included 52 medication-free children and adolescents with OCD and 42 healthy controls aged 8–17 years. Psychiatric diagnoses were established using the Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL) according to DSM-5 criteria. Obsessive–compulsive symptom severity was assessed using the Children’s Yale–Brown Obsessive Compulsive Scale (CY-BOCS). Anxiety and depressive symptoms were evaluated using the Screen for Child Anxiety Related Emotional Disorders (SCARED) and the Children’s Depression Inventory (CDI), respectively. Serum levels of adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), Insulin-like growth factor-1 (IGF-1), Glucagon-like peptide-1 (GLP-1), relaxin-3 (RLN-3), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured using ELISA. Group differences were examined using covariance-based models controlling for age, sex, BMI percentile, anxiety (SCARED), and depressive symptoms (CDI).ResultsInitial analyses showed that children and adolescents with OCD had significantly lower serum levels of cortisol, IGF-1, GLP-1, and T3 compared with healthy controls. These differences remained significant after controlling for age, sex, BMI percentile, and the SCARED and CDI total score, with adjusted analyses showing lower levels of cortisol (p = 0.003), IGF-1 (p = 0.013), GLP-1 (p = 0.017), and T3 (p = 0.015) in the OCD group. Correlation analyses did not reveal significant associations between biochemical parameters and OCD symptom severity after correction for multiple comparisons.DiscussionThese findings suggest that pediatric OCD may be associated with alterations in several neuroendocrine pathways rather than isolated changes within a single hormonal system. Further longitudinal studies are needed to better clarify the biological basis and clinical significance of these findings.
Single-cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human solid tumors
Nature Biotechnology, Published online: 03 June 2026; doi:10.1038/s41587-026-03152-x
Interactions between the tumor microenvironment and antibody drugs are imaged with spatial proteomics.
Programmable control of bacterial operons with a single Cas13 RNA effector
Nature Biotechnology, Published online: 03 June 2026; doi:10.1038/s41587-026-03159-4
The SONAR system enables RNA-level control of bacterial operons using a single engineered Cas13 effector that can be modified to control transcript degradation, translation inhibition and translation activation through simple changes in crRNA design.
Reply to: Limited evidence of AI superiority in seasonal influenza vaccine strain selection
Nature Medicine, Published online: 03 June 2026; doi:10.1038/s41591-026-04460-0
Reply to: Limited evidence of AI superiority in seasonal influenza vaccine strain selection