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Antisense oligonucleotides (ASOs) represent a promising therapeutic modality for central nervous system (CNS) disorders, offering highly specific modulation of gene expression. However, their clinical utility is severely limited by their inability to cross the blood-brain barrier (BBB), necessitating effective shuttling strategies. While transferrin receptor (TfR1)-mediated shuttling has shown therapeutic promise, the fundamental mechanisms governing the delivery of antibody-ASO conjugates across the BBB remain poorly understood. This study directly addresses this critical knowledge gap by establishing a mechanistic understanding of how the ASO cargo impacts major cellular interactions during the BrainshuttleTM-mediated transport across the BBB. Using a panel of advanced in vitro assays developed specifically for this purpose, including quantitative transcytosis, detailed imaging-based intracellular trafficking, and binding assays with brain endothelial cells (BECs), the shuttling process was systematically investigated. We demonstrate that ASO conjugation profoundly alters the cellular fate of the BrainshuttleTM. Specifically, conjugation increased the binding to BECs of low-affinity TfR1 shuttles via avidity effects while paradoxically reducing the binding strength of high-affinity shuttles. Functional assays confirmed the biological activity of the delivered ASOs; however, transcytosis of high-to-moderate affinity binders across the BBB model was significantly delayed upon ASO conjugation. Building on these mechanistic insights, we engineered TfR1 BrainshuttlesTM with optimized affinity and explored the shuttling potential of an alternative BBB receptor, CD98hc. These efforts culminated in the development of a novel bispecific BrainshuttleTM targeting both CD98hc and TfR1. This dual-targeting strategy exploits distinct and potentially non-competing trafficking pathways to overcome ASO-induced delays and significantly enhance in vitro transcytosis efficiency. The in vitro findings in this study underscore the necessity of mechanism-driven design to overcome ASO-induced limitations in delivery across the BBB. The bispecific CD98/TfR1 approach presented here provides a promising new strategy for maximizing delivery efficiency and enabling more effective therapeutic outcomes for CNS diseases.

Mind&#x2011;body practices, such as meditation and yoga, involve paying attention to breathing sensations. During these practices, individuals report "interoceptive lapses," moments when attention drifts away from internal bodily sensations. While lapses in attention to the external world have been widely studied, little is known about the physiological and neural mechanisms of interoceptive lapses. Interoceptive lapses may share markers with exteroceptive lapses-such as reaction time variability and default-mode network (DMN) connectivity-but may also depend on distinct brain systems and breathing physiology. We examined behavioral, physiological, and neural signals preceding lapses in a sample of 93 adolescents enriched for GAD and depression symptoms. Participants performed a 20-min breath counting task in the fMRI scanner with simultaneous breath recordings. Lapses were defined as moments when counting errors occurred. The sample was split into training and validation sets to test machine learning models predicting attentional lapses. The strongest predictors were timing and variability of button responses (AUCs > 0.75). Breathing variability and breathing-behavior synchronization showed smaller but generalizable predictive value (AUCs < 0.65). Whole-brain connectivity models also predicted lapses (AUC &#x2248; 0.65), incorporating the DMN, dorsal and ventral attention, and somatomotor networks. Furthermore, models that included brain connectivity marginally outperformed behavior-only models. Comparisons to previous exteroceptive findings indicate some common markers (e.g., reaction time variability) and some unique markers (e.g., selective perceptual coupling with attentional networks). Although limited by the clinical sample and lack of a control task, these results highlight brain-body markers of interoceptive attention that may inform real-time monitoring during mind-body interventions.

Deep Brain Stimulation (DBS) is an established treatment for advanced Parkinson's disease (PD), yet registry-based data from developing countries remain limited. This study reports the establishment and feasibility of the Iranian Deep Brain Stimulation Registry for Parkinson's Disease (IDBSR-PD). We conducted a single-center feasibility study at the Research Center for Neuromodulation and Pain, including all PD patients undergoing DBS implantation since 2014. Primary feasibility outcomes included patient enrollment coverage, follow-up adherence, data completeness, multidisciplinary implementation, and the sustainability of technical infrastructure. Secondary outcomes included descriptive patient characteristics. Only descriptive statistics were performed; no hypothesis testing or longitudinal outcome analyses were conducted. A total of 208 patients were enrolled (65.4% male; mean age 58.4&#x2009;&#xb1;&#x2009;10.2 years). Enrollment increased progressively over time, peaking in 2024 (n&#x2009;=&#x2009;41). Patients were referred from multiple provinces across Iran. Data validation mechanisms and regular surveillance ensured acceptable data completeness. The IDBSR-PD demonstrates the feasibility and sustainability of a web-based DBS registry in a developing country. These findings confirm the viability of structured data collection and provide a foundation for future multicenter and longitudinal outcome research.

The clinical benefit of intracranial pressure (ICP) monitoring in severe traumatic brain injury (TBI) remains controversial. This study compared functional outcomes between ICP guided therapy and conventional management in routine trauma practice and explored whether treatment effects differed across clinically relevant patient subgroups. We conducted a retrospective cohort study of 1112 patients with severe TBI (Glasgow coma scale (GCS) score 3 - 8) admitted to a tertiary trauma center between January 1, 2004 and December 31, 2024. Patients were managed either with ICP monitoring and targeted therapy (n = 408) or conventional management guided by clinical assessment and neuroimaging (n = 704). Functional outcomes were assessed using the Glasgow outcome scale-extended at 7 days, 3 months, and 6 months. Multivariate logistic regression was used to identify independent predictors of favorable outcome at 6 months. Prespecified subgroup analyses were performed according to injury type, initial GCS score, and neurosurgical emergency status. Baseline characteristics differed between groups, with the ICP monitoring group demonstrating a higher frequency of diffuse brain injury (58.8% vs. 27.3%, p < 0.001), chest injury (25.5% vs. 9.1%, p = 0.009), hypoxia at admission (7.8% vs. 0%, p = 0.017), and anemia at admission (7.8% vs. 0%, p = 0.017). Despite receiving more intensive therapies, including sedation, vasopressors, osmotherapy, and induced hypothermia, functional outcomes did not differ significantly between treatment strategies at any time point. At 6 months, favorable outcomes were observed in 78.9% of patients in the ICP monitoring group and 78.7% in the conventional management group (p = 0.973). In multivariable logistic regression analysis, increasing age (adjusted odds ratio (OR): 0.93, 95% confidence interval (CI): 0.89 - 0.98, p = 0.010), initial GCS score 6 - 8 (adjusted OR: 10.71, 95% CI: 2.48 - 46.28, p = 0.001), absence of diffuse brain injury (adjusted OR: 11.57, 95% CI: 1.14 - 117.20, p = 0.038), absence of subdural hematoma (adjusted OR: 2.60, 95% CI: 2.74 - 11.29, p = 0.009), and absence of neurosurgical emergency conditions (adjusted OR: 23.65, 95% CI: 1.91 - 292.91, p = 0.014) were independently associated with favorable outcome. ICP monitoring was not independently associated with favorable outcome (adjusted OR: 2.42, 95% CI: 0.40 - 14.49, p = 0.334). No significant interactions were observed in prespecified subgroup analyses. In this real-world cohort of patients with severe TBI, ICP-guided therapy was not associated with improved functional outcomes compared with structured conventional management.

Shaken Baby Syndrome and Abusive Head Trauma are significant traumatic brain injuries observed in infants and represent a critical public health issue. Although there is a vast literature on this subject, conducting a descriptive bibliometric analysis is essential to map the topic's quantitative development over time and to reveal its current geographical and conceptual distribution objectively. This study systematically analyzes 3,571 articles published between 1977 and 2025 in the Web of Science Core Collection database, examining the distribution of publications by year and country, leading journals, citation rates, and keyword networks. Our findings indicate a linear increase in the volume of SBS/AHT research publications since the 2000s. The analysis highlights two significant strengths and shifts in the literature. First, the emergence of countries from diverse regions-such as Romania, the United Arab Emirates, Malaysia, and Russia-in the literature network, alongside traditional research hubs, objectively confirms the subject's expanding global scope. Second, the fact that the highest citation rates and publication density are not limited to clinical medicine journals (e.g., Pediatrics) but are simultaneously concentrated in pioneering journals with social and legal content (e.g., Child Abuse & Neglect) highlights the field's multidimensional and interdisciplinary nature. In conclusion, this study provides an objective resource for all stakeholders-including physicians, forensic scientists, and legal professionals-by visualizing the current geographic diversity of scientific output, key terms, and journal dynamics.

Cells release heterogeneous extracellular vesicles and particles (EVPs) into circulation, carrying RNA and proteins that reflect their origin. Recently, brain-derived EVs have gained significant attention as non-invasive biomarkers for Alzheimer's disease (AD). Here, we identified sub-50nm extracellular nanoparticles in human brain and blood that lack the hallmarks of small EVs, exosomes, exomeres, and supermeres but are enriched for brain-specific markers, hereafter termed small EPs or 'SECmeres'. We discovered that RNAs associated with SECmeres discriminated AD cases from controls with higher significance than small EVs, large EVs showed no differences. Discriminating RNAs were enriched in small EVs (Synaptotagmin, Alpha-synuclein, MAPT) or SECmeres (L1CAM, Syntaxin, Neurogranin), indicating distinct brain-derived signatures. Single-cell RNAseq deconvolution shows small EVs contain RNAs from diverse brain cells, whereas SECmeres enrich brain endothelial transcripts, lining cerebral blood vessels and forming the blood-brain barrier (BBB). These findings challenge the prevailing view that small EVs are the primary carriers of biomarkers. Collectively, our study shows that blood EVPs carry brain-specific information for liquid biopsy, pending validation in larger blinded clinical trials.

The prevalence of brain tissue hypoxia (BTH; PbtO2&#x2009;<&#x2009;20&#xa0;mm Hg) in patients with spontaneous ICH is not well established. In this study, we aimed to quantify the prevalence of BTH and to assess determinants of brain tissue normoxia (BTN; PbtO2&#x2009;&#x2265;&#x2009;20&#xa0;mm Hg) and BTH resolution. This retrospective cohort study included 58 patients with ICH admitted to a neurological intensive care unit (ICU) between 2010 and 2020 with multimodal invasive neuromonitoring. BTN was sought by avoiding low cerebral perfusion pressure (CPP) and low blood hemoglobin levels, and by maintaining normocapnia, normoxemia, normothermia, and metabolic homeostasis. Hourly PbtO2, CPP, and temperature data were matched with intermittent variables (blood gases, hemoglobin, glucose, sodium, and microdialysis) over 10&#xa0;days. Regression analyses were performed&#xa0;using generalized estimating equations to account for repeated measurements. Patients were 61 [interquartile range (IQR), 55-69] years old and presented with an ICH score of 2 (1-3). Of the patients, 52 (90%) underwent surgical evacuation via hemicraniectomy and/or craniotomy, while 6 (10%) received invasive neuromonitoring only. The median initial ICH volume was 40.2 (IQR 29.5-55.8) mL. Surgical evacuation achieved a median reduction of 86.6% (IQR 69.0-94.2), leaving a median residual volume of 5.5 (IQR 3.0-14.1) mL. The overall prevalence of BTH was 31%. In multivariable analysis, the following factors led to the highest percentage of BTN: CPP 80-89&#xa0;mm Hg [odds ratio (OR) 1.88, 95% confidence interval (CI) 1.32-2.68, p&#x2009;<&#x2009;0.001; reference:&#x2009;<&#x2009;60&#xa0;mm Hg], partial pressure of oxygen (PaO2) 90-99&#xa0;mm Hg (OR 1.64, 95% CI 1.15-2.14, p&#x2009;=&#x2009;0.001; reference:&#x2009;<&#x2009;80&#xa0;mm Hg), core body temperature 36.0-37.4&#xa0;&#xb0;C (OR 2.10, 95% CI 1.34-3.28, p&#x2009;=&#x2009;0.001; reference:&#x2009;<&#x2009;36.0&#xa0;&#xb0;C), PaO2/fraction of inspired oxygen (FIO2) 100-199 (OR 3.52, 95% CI 1.60-7.75, p&#x2009;=&#x2009;0.002; reference:&#x2009;<&#x2009;100) in a model corrected for probe position. Only CPP [74.6 (66.8-82.7) vs. 72.5 (64.9-80.2) mm Hg, p&#x2009;<&#x2009;0.001)] was significantly higher after BTH resolution as compared with the time when PbtO2 was lowest during 229 BTH episodes. BTH was observed during 31% of the monitored time in patients with a large hematoma volume despite the use of a PbtO2-targeted therapy. These findings generate the hypothesis that physiological determinants, such as CPP, are significantly associated with the achievement of BTN in regions near to the ICH.

Temozolomide, a chemotherapy drug used to treat glioblastoma, has high-dose and dose-related side effects, limiting its use. Resveratrol, a natural polyphenol, showed potential in the treatment of glioblastoma. Many studies showed the synergistic activity of resveratrol and temozolomide against glioblastoma, but no analytical method for simultaneous estimation in a biological matrix is available till date. This study aimed to develop and validate a simple, rapid, and sensitive bioanalytical method using HPLC technique for simultaneous estimation of temozolomide and resveratrol in rat plasma and brain for pharmacokinetic study. Isocratic reversed-phase high-performance liquid chromatography (RP-HPLC) method using C18 column was used. Theophylline and caffeine were used as internal standards for Temozolomide and Resveratrol, respectively. The mobile phase methanol: 0.1% glacial acetic acid (30:70) with flow rate 1.0&#x2009;mL/min and 310-nm wavelength was used. The LOD for temozolomide and resveratrol in the plasma was 0.96 and 1.29&#x2009;&#x3bc;g/mL, respectively, whereas LOQ was 2.91 and 3.89&#x2009;&#x3bc;g/mL, respectively. The LOD for temozolomide and resveratrol in brain homogenate was 1.01 and 1.24&#x2009;&#x3bc;g/mL, respectively, whereas LOQ was 3.07 and 3.76&#x2009;&#x3bc;g/mL, respectively. This analytical method can be used for simultaneous estimation of temozolomide and resveratrol in biological samples, with higher sensitivity, resulting in more meaningful and appropriate pharmacokinetic analysis.

Major depressive disorder (MDD) heterogeneity impedes the discovery of robust neurobiological markers. This study investigated the brain sex continuum (BSC) score, which is a system-level functional architecture marker reflecting psychological androgyny (Zhang et al., 2021), as a persistent neurobiological alteration and replicable diagnostic marker in MDD and its association with symptoms and treatment. Resting-state functional connectivity (rsFC) was analyzed in two independent longitudinal cohorts of unmedicated MDD patients (Xiangya Hospital, XYH: n&#x202f;=&#x202f;173 and Peking University, PKU: n&#x202f;=&#x202f;79) and healthy controls (n&#x202f;=&#x202f;238 and 89, respectively). We confirmed the applicability of the BSC score in current samples. Group differences, effects of 8-week antidepressant treatment, and associations with depressive symptoms (17-item Hamilton depression rating scale, HAMD-17) were evaluated. No single individual rsFC consistently differentiated MDD patients from controls across both cohorts. However, BSC scores were reproducibly elevated in unmedicated MDD patients versus controls (PKU: Odds Ratio,OR=7.69,95%CI,0.08to34.45, and XYH: OR=2.39,95%CI,0.99to5.81), indicating a shift toward the extreme male end of the continuum. This BSC shift was primarily driven by elevated alterations in between-network connectivity, particularly in female patients. Crucially, this shift persisted post-treatment in both cohorts and substantially improved diagnostic accuracy. Strikingly, BSC scores showed no significant association with baseline HAMD or symptom changes post-treatment. The BSC represents a persistent neurobiological marker in MDD that is dissociated from clinical symptom expression. This uncoupling reveals a core neuropathology distinct from symptom-based diagnostic frameworks, advancing biomarker development for heterogeneous depression.

The cochlear aqueduct, located within the temporal bone, forms a narrow connection between the cerebrospinal fluid (CSF) in the subarachnoid space and the perilymph of the scala tympani in the inner ear. The anatomical linkage provides a potential interface for pressure regulation, molecular exchange, and therapeutic access to the cochlea. Recent findings further indicate that the cochlear aqueduct is functionally coupled to the brain's glymphatic system, permitting CSF flow to the inner ear and raising the possibility of an inner ear glymphatic system. Morphological studies demonstrate substantial interspecies variability in cochlear aqueduct size and patency among species, and identified a diaphragm-like terminal membrane at its lateral end. In mice, immunocytochemical analyses indicate a lymphatic-like phenotype reminiscent of the subarachnoid lymphatic-like membrane (SLYM). The presence of macrophages with phagocytic capacity and the fact that the membrane is activated during bacterial meningitis further supports a role in local immune surveillance. The translational relevance of the cochlear aqueduct has gained attention with advances in inner-ear gene therapy. Tracers injected in cisterna magna in mice reach the inner ear rapidly. In rodents and non-human primates, intracisternal injection of viral vectors via achieves efficient bilateral cochlear transduction, including restoration of hearing in VGLUT3-deficient mice, a model of nonsyndromic deafness. These findings position the cochlear as a minimally invasive route for inner-ear therapy, potentially avoiding direct cochlear surgery. However, interspecies differences and age-related changes in cochlear aqueduct patency must be carefully evaluated before clinical translation.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) are severe psychiatric disorders with distinct and overlapping clinical and neurobiological features. Despite extensive evidence of brain structural abnormalities, the transdiagnostic neuropathological mechanisms remain poorly understood. A comprehensive literature search was performed for voxel-based morphometry (VBM) studies reporting altered gray matter volume (GMV) in MDD, BD or SZ. A transdiagnostic meta-analysis was conducted to identify common and disorder-specific GMV alterations using the Seed-based d Mapping toolbox. Disease epicenter and buffering mapping were further investigated using a normative functional connectome to understand the network-constrained GM atrophy patterns. A total of 221 studies (MDD: n&#x2009;=&#x2009;66; BD: n&#x2009;=&#x2009;59; SZ: n&#x2009;=&#x2009;96) encompassing 10,485 patients and 12,128 healthy controls were included. Transdiagnostic GMV reductions were identified in the medial prefrontal cortex and superior temporal gyrus. Less atrophy in the limbic/paralimbic regions and temporoparietal junction were observed for MDD, whereas SZ patients exhibited more pronounced GMV reductions in these areas. The ventrolateral prefrontal cortex emerged as a shared disease epicenter and the precuneus as a common buffer across these affective and psychotic disorders. The visual and dorsal attention networks exhibited the most pronounced buffering effects, while epicenter effects were primarily concentrated within the limbic, frontoparietal, subcortical and default mode networks. These findings suggested that affective and psychotic disorders are characterized by both shared and unique network-constrained GM atrophy patterns, which might advance precision diagnostics and inform targeted therapeutic strategies in the future.

Single-cell RNA sequencing has advanced our understanding of cellular heterogeneity. Ensuring the replicability of identified cell clusters across studies is essential for determining their biological robustness. We assess the replicability of cell clusters identified in two large mouse brain atlases, one generated using single-cell RNA sequencing and the other with single nuclei. Both profile over 4 million cells and group them into over 5,000 clusters. Using transcriptome-wide neighbor voting, we identify 2,009 reciprocally matched cluster pairs with consistent spatial localization and coordinated gene expression, which were also observed in datasets from multiple species. Reciprocal clusters are enriched in the cerebellum, where lower diversity aids replicability, while the hypothalamus's heterogeneity limits agreement. Distinguishing close clusters is much more challenging than differentiating a cluster from most others, especially when using marker genes. By incorporating replicability data, we provide a stronger foundation for investigating the atlas-defined clusters and their biological meaning.

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Speech imagination is one of the most important research directions in the field of brain-computer interfaces. However, there is insufficient research on silent brain-computer interfaces based on the Chinese stimulating materials. An experimental paradigm for Chinese speech imagery, which features a distinctive&#xa0;initial-and-final&#xa0;structure, is designed in this paper. According to the characteristics of vocalization and structure, the collected EEG data can be organized into a multi-level tree structure. Compared to conventional multi-label classification, our paper aims to study how to effectively utilize hierarchical structural information in the multi-granularity hierarchical classification tasks. We propose a hierarchical capsule network based on bidirectional knowledge transfer by using multi-band feature matrix, which is tailor-made for the phonological structure of Mandarin Chinese. The adoption of capsule network as the primary architecture is mainly due to the dynamic routing mechanism that can naturally model hierarchical relationships in the syllable hierarchy. In addition, we introduce the bidirectional knowledge transfer strategy to further improve the classical dynamic routing. Specifically, features from coarse-grained levels are added to fine-grained levels to fully utilize the dependency information between levels. In order to mitigate error propagation in the forward learning process, we also employ reverse knowledge transfer constrained via soft labels. The hierarchical classification results and ablation experiments both demonstrate the effectiveness of our proposed algorithm. The highest recognition rates for each layer reach 90.86%, 73.69%, and 69.45%, respectively. This article offers a novel perspective for decoding&#xa0;hierarchical Chinese silent BCI paradigms. Our study not only reveals the potential of linguistic domain knowledge in guiding neural network architectures for task-specific applications, but also provides a robust foundation for future individual phoneme classification.

Mounting evidence shows sex-based differences in sleep experiences and outcomes, including the prevalence of insomnia disorder. However, the impact of biological sex on brain oscillations during sleep remains poorly understood, especially in the context of insomnia disorder. This is a notable gap, given that neurophysiological aspects of sleep are associated with brain health and overall sleep quality. We systematically reviewed and meta-analysed data from studies reporting spindle and slow wave activity in adults with and without insomnia disorder. We conducted systematic searches in PubMed, Embase, Scopus, and PsycInfo. Risk of bias was evaluated using the Newcastle Ottawa and the PEDro scales. Forty-three studies met our inclusion criteria, with thirteen studies of normal sleepers (N&#x2009;=&#x2009;668) reporting sufficient data for random-effects meta-analyses. Compared with males, female normal sleepers had higher spindle density, sigma and delta power. Most studies recruited individuals with primary insomnia, and data pooling for insomnia and mixed groups was not possible due to insufficient statistical reporting. Moreover, group-by-sex interactions were limited, inconsistent, and varied across studies and sample characteristics. Further research is needed to explore sex-specific differences in sleep microarchitecture and their role in normal sleep and the manifestation of insomnia disorder.

Brain health disorders (BHDs) remain a concern for people with HIV (PWH) despite antiretroviral therapy access and viral suppression. The contribution of HIV to brain health is often obscured by comorbidities in high-income settings which are less prevalent in sub-Saharan Africa. Neurofilament light chain (NfL), a biomarker of axonal injury, may offer insight into underlying mechanisms. 338 virally-suppressed PWH and 250 people without HIV (PWoH) completed a Research Domain Criteria-informed battery assessing cognitive, sensorimotor, and social processing systems. Demographically-adjusted norms were derived from PWoH. Serostatus differences in impairment (&#x2265;&#x2009;1SD below the mean) were examined using multivariable logistic regression. Additional models examined associations between NfL (plasma, cerebrospinal fluid [CSF]) and task performance. PWH were similar to PWoH in age (43.9 vs. 43.5yrs), sex (female, 54 vs. 46%), and education (6.1 vs. 5.8yrs). PWH had higher odds of impairment in the cognitive control and attention (Color Trails, Symbol Digit) and sensorimotor (Grooved Pegboard) domains. Plasma NfL was associated with sensorimotor impairment in both groups. Similar trends held in CSF NfL but did not reach statistical significance, likely due to sample size (n&#x2009;=&#x2009;85). Cognitive and sensorimotor difficulties are common in PWH in Rakai, independent of typical Western confounders. The profile of impairment differs from reports in high-income settings where declarative memory deficits are often observed. NfL was associated with sensorimotor impairment, suggesting that NfL may capture ongoing axonal injury and motor system vulnerability in PWH and PWoH. These findings suggest NfL's potential as a biomarker of sensorimotor impairment in sub-Saharan Africa.

Co-design is increasingly used in chronic pain research; however, terminology remains inconsistent, guidance is lacking, and most research is concentrated in high-income countries. This international three-round e-Delphi study aimed to establish consensus on key terminology and core components, and to identify common barriers and strategies for co-design in chronic pain management. The e-Delphi survey was conducted from November 2024 to June 2025. Panel used a five-point Likert scale to rate agreement and importance, with consensus defined 75% thresh-hlod agreement. Open-ended responses on barriers and strategies were analysed using thematic content analysis. A total of 117 panel members participated in Round 1, 98 in Round 2, and 92 in Round 3, representing 30 countries. Though panel members prioritise "co-design" and "collaborative design" as the most appropriate standardised terms to describe the collaboration process in developing and evaluating chronic pain interventions, "co-design" has the highest percentage agreement. Twelve core components of co-designed interventions were identified, including engaging people with lived experience and key interest-holders, addressing biopsychosocial factors, ensuring accessibility and availability, applying evidence-based practices, emphasising person-centredness, conducting needs assessments, supporting goal-oriented care, empowering self-management, promoting interdisciplinary collaboration, ensuring sustainability, incorporating patient-reported outcome measures, and integrating technology. The identified five barriers to co-design were: resource, cultural and contextual; knowledge and educational; interpersonal and professional; and system and policy. Corresponding strategies included enhanced resource allocation, training and education, improved communication, strengthened interdisciplinary collaboration, and supportive policy and organisational structures. These findings provide a clear, consensus-based guide for developing and implementing co-designed chronic pain interventions. PERSPECTIVE: This e-Delphi study established standardised terminology, core components for co-designed chronic pain intervention development, and outlined key barriers and overcoming strategies for them. The findings could enhance research and clinical communication and support embedding co-design principles into clinical service development to improve shared decision-making and patient-centred care.

Glucagon-like peptide-1 receptor (GLP-1R) activation is widely assumed to regulate the metabolic disorder in Alzheimer's disease (AD). However, direct evidence for this hypothesis is lacking, and currently, there is no oral GLP-1R agonist with effective blood-brain barrier-penetrating ability. Here, we show that a candidate peptide, OHP2, an oral GLP-1R agonist with blood-brain barrier permeability, exhibits promising therapeutic potential for AD. OHP2 primarily activates GLP-1R on astrocytes, leading to increased aerobic glycolysis and driving lactate release. Astrocyte-derived lactate is taken up by neurons and elevates histone H3 lysine 9 lactylation (H3K9la), which in turn facilitates lipid transport from neurons back to astrocytes. This astrocyte-neuron metabolic coupling sustains continuous aerobic glycolysis and offers a potential treatment strategy for AD. The H3K9la derived from OHP2 links glucose and lipid metabolic cycle and facilitates metabolic coupling between astrocytes and neurons, which leads to remission of metabolic disturbances in AD. Thus, our study provides a new candidate molecule for drug research in treating AD and illustrates that intracerebral GLP-1R activation, which facilitates astrocyte-neuron metabolic coupling, may be a potential approach for the treatment of AD.

Epilepsy is a devastating neurological disorder affecting about 1-2% of the global population and is characterized by recurrent, unprovoked seizures that can severely impair quality of life. Despite the availability of antiseizure medications, nearly one-third of individuals with epilepsy continue to experience drug-resistant seizures, underscoring the need for novel therapeutic strategies. Growing evidence supports neuroinflammation as a key driver of epileptogenesis following brain insults. At the biochemical level, this neuroinflammatory response is largely propagated through the classic arachidonic acid metabolic cascade. Within this pathway, lipoxygenase (LOX) enzymes play a pivotal role in mediating oxidative stress, lipid peroxidation, and pro-inflammatory signaling through the generation of bioactive lipid metabolites. Dysregulation of LOX activity contributes to epileptogenic processes, such as blood-brain barrier disruption, glial activation, cytokine release, immune-cell infiltration, neuronal hyperexcitability, and neuronal death. Emerging evidence indicates that LOX pathways, particularly those mediated by 5-LOX and 12/15-LOX, play a major role in the pathophysiology of epileptic seizures and may also contribute to neuropsychiatric comorbidities that substantially reduce quality of life. In this review, we discuss the therapeutic potential of targeting 5-LOX and 12/15-LOX for seizure disorders, integrating current preclinical evidence and mechanistic insights to advance the development of novel, safer, and more effective therapies for epilepsy and its associated neurological comorbidities. Together, these perspectives highlight promising avenues for future research and therapeutic innovation.