Brain, Behavior, and Immunity

Background: Acute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. Methods: We conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. Findings: The RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.

ImportanceEmerging data show that B-cell depleting chemotherapies, which are increasingly used to treat autoimmune disorders and multiple sclerosis, can be associated with mucosal side effects such as inflammatory vaginitis. ObjectiveEvaluate the impact of rituximab treatment on vaginal mucosal immune markers, endocervical immune cell populations and vaginal microbiome. DesignCross-sectional observational study conducted between 2022 - 2024. SettingAcademic medical center, Boston Massachusetts. ParticipantsWe enrolled women aged >18 years who were either 1) receiving rituximab for autoimmune renal disease or were 2) healthy controls ExposureTreatment with rituximab, an anti CD20 monoclonal antibody. Main outcome and measureWe compared endocervical immune cell populations, vaginal fluid immune markers, vaginal fluid immunoglobulins and vaginal microbiome composition between individuals being treated with rituximab and healthy controls. ResultsWe enrolled 26 women treated with rituximab for autoimmune renal disease and 26 healthy controls. Median circulating and endocervical B-cell and plasma cell proportions were significantly lower in treated participants compared to controls. Median vaginal fluid IgA concentrations were significantly lower in participants treated with rituximab, while ILE, IgM, IgG1, IgG2, IgG3 and IgG4 were not different between groups. Total T cell frequencies were similar between groups, but the proportion of activated T cells (CD4+CD38+HLADR+) was significantly lower in people treated with rituximab. Concentrations of IL10, IL13, IL17, IL21, IL23, IL4, ITAC and TNFa were elevated in vaginal fluid from the rituximab group, while IL-8 was lower. A CST-IV-C, low-Lactobacillus pattern of vaginal microbiota was more common in the rituximab group. Conclusions and RelevanceSystemic B-cell depletion is associated with reduced vaginal fluid IgA, a more diverse microbiome composition, and increases in many vaginal fluid immune markers compared to healthy controls. The reduction in vaginal fluid IgA may provide opportunities for vaginal bacteria to induce inflammation. Key pointsO_ST_ABSQuestionC_ST_ABSHow does circulating B-cell depletion impact the vaginal microenvironment? FindingsIn this cross-sectional study of 52 women, B cell and plasma cell proportions were significantly lower in both blood and vaginal mucosa among rituximab-treated participants compared to healthy controls. Vaginal IgA concentrations, but not other immunoglobulins, were significantly lower in rituximab treated participants. In treated participants, vaginal cytokine concentrations were elevated, and microbiome composition shifted toward non-Lactobacillus-dominant communities. In six people with inflammatory vaginitis, both circulating and endocervical B cells were lowest in people with the most severe symptoms. MeaningSystemic B cell depletion is associated with alterations in vaginal mucosal immune markers and microbiome composition which increase local inflammation.

ObjectiveStudies of nutritional status and host responses during severe and critical illness have focused predominantly on obesity; in contrast, the relationship between undernutrition, host responses, and clinical outcomes in adults hospitalized with severe infection remains poorly defined. We sought to determine whether severe undernutrition is associated with distinct host responses and clinical outcomes in adults hospitalized with severe infection. DesignProspective cohort study. SettingTwo public referral hospitals in Uganda. PatientsNon-pregnant adults ([≥]18 yr) hospitalized with severe, undifferentiated infection. InterventionsNone. Measurements and Main ResultsWe analyzed clinical data and serum Olink proteomic data from 432 participants (median age, 45 yr [IQR, 31-57 yr]; 44% male). Overall, 213 participants (49%) met prespecified criteria for undernutrition, including 52 (12%) with severe undernutrition. Clinically, severe undernutrition was associated with HIV coinfection, microbiologically diagnosed tuberculosis, greater physiological instability, and higher mortality. After adjustment for age, sex, illness duration, study site, and HIV, malaria, and tuberculosis coinfection, severe undernutrition was associated with higher expression of proteins involved in pro-inflammatory immune signaling, endothelial and vascular remodeling, hypoxia and oxidative stress responses, and extracellular matrix remodeling, together with lower expression of proteins linked to growth signaling, anticoagulant regulation, and lipid homeostasis. ConclusionsSevere undernutrition is associated with a distinct high-risk clinical phenotype and biologic signature in adults hospitalized with severe infection. These findings suggest that undernutrition may potentiate key domains of sepsis pathobiology, with implications for strengthening nutritional support and informing host-directed treatment strategies in low- and middle-income countries where malnutrition is common. Key PointsO_ST_ABSQuestionC_ST_ABSHow does undernutrition influence immune, metabolic, and endothelial responses to severe infection in adults? FindingsIn this multicenter cohort study of 432 adults hospitalized with severe infection in Uganda, severe undernutrition was associated with greater physiologic instability, higher mortality, and a distinct proteomic host-response profile. Adults with severe undernutrition exhibited a proteomic signature characterized by pro-inflammatory immune signaling, endothelial and extracellular matrix remodeling, and hypoxia and oxidative stress responses, together with lower expression of proteins involved in growth signaling, anticoagulant regulation, and lipid homeostasis. MeaningSevere undernutrition is associated with a distinct high-risk clinical and biologic phenotype during severe infection, with implications for nutritional support, risk stratification, and host-directed therapeutic strategies, particularly in low- and middle-income countries.

ImportanceBlood-based biomarkers hold promise for psychiatric diagnosis and prognosis, yet clinical translation is constrained by poor reproducibility. Psychiatric biomarker studies are typically small, and demographic, behavioral, and temporal covariates often go undetected or cannot be adequately modeled. This may lead to residual confounding and unstable associations. ObservationsLeveraging UK Biobank data (N=~500,000), we systematically quantified how technical, demographic, behavioral, and temporal covariates influence 29 blood biomarkers commonly measured in research studies in psychiatry. Variance analyses showed substantial differences across biomarkers. Technical factors explained 1-6% and demographic factors explained 5-15% of the variance, with pronounced age-by-sex interactions for lipids and sex hormones. Behavioral covariates, particularly body mass index (BMI) and smoking, strongly influenced inflammatory markers. Temporal factors introduced systematic confounding. Chronotype was associated with blood collection time, multiple biomarkers exhibited marked diurnal rhythms (including testosterone, triglycerides, and immune markers), and inflammatory markers showed seasonal peaks in winter. In association analysis of biomarkers with major depression, bipolar disorder and schizophrenia, covariate adjustments attenuated or eliminated a substantial proportion of the biomarker-disorder associations, with BMI emerging as the dominant confounder. These findings demonstrate that such confounding structures exist and can be characterized in large cohorts, though specific biomarker-disorder relationships require validation in clinical samples. Conclusions and RelevancePoor reproducibility of biomarkers may not only stem from insufficient biological signal but also from inconsistent handling of confounders. We propose a systematic framework distinguishing technical factors (to be removed), demographic factors (addressed through adjustment or stratification), temporal factors (ideally controlled at design stages), and behavioral factors (requiring explicit causal reasoning). Associations robust to multiple adjustment strategies should be prioritized for clinical biomarker development. Standardized collection protocols, comprehensive covariate measurement, and transparent reporting across models are essential to improve reproducibility and identify biomarkers that reflect genuine illness-related pathophysiology.

Chronic inflammation is a common feature of aging and is observed across various age-related neurodegenerative diseases, including Alzheimers disease (AD). It has, however, been challenging to develop measurements of brain structure directly linked to peripheral measures of neuroinflammation. This cross-sectional study examined whether plasma levels of markers related to inflammation are associated with diffusion magnetic resonance imaging (dMRI) measures of white matter microstructure: mean diffusivity (MD) and Neurite Orientation Dispersion and Density Imaging (NODDI) free water fraction (FWF) and orientation dispersion index (ODI). Participants included 457 dementia-free individuals (mean age=63.82, SD=7.63). Blood plasma markers related to inflammation included two measures of systemic inflammation, (1) high-sensitivity C-reactive protein (CRP), and (2) a composite of pro-inflammatory cytokines (IL-1, IL-1{beta}, IL-2, IL-6, IL-8, TNF-, TNF-{beta}), as well as (3) glial fibrillary acidic protein (GFAP), a measure of astrocytic activation. Higher cytokine composite levels were associated with higher values of all three measures (FWF, ODI, MD) in cerebral white matter, and with higher ODI in the cerebellar peduncles. Higher CRP levels were associated with higher ODI in cerebral and cerebellar white matter. Associations with GFAP were not significant after adjusting for multiple comparisons. Results were consistent after accounting for plasma biomarkers of AD pathology (p-tau181/A{beta}42). Thus, higher levels of peripheral pro-inflammatory markers are associated with white matter microstructure (higher FWF, ODI, and MD), supporting the view that these dMRI-based metrics are sensitive to inflammatory processes. Additionally, the sensitivity of dMRI-based measures to inflammation may differ by inflammatory marker types.

ObjectiveTo describe the design, feasibility, and baseline characteristics of the Migraine Impact on Neurocognitive Dynamics (MIND) study, a 30-day smartphone-based cohort for high-frequency assessment of cognition and symptoms in adults with migraine. BackgroundCognitive symptoms are an important component of migraine burden, but they are difficult to measure using single-visit testing or retrospective questionnaires. Repeated smartphone-based assessment may better capture real-world variability in cognition and symptoms. MethodsAdults meeting International Classification of Headache Disorders, 3rd edition, criteria for migraine were enrolled remotely and completed 30 days of once-daily ecological momentary assessments and mobile cognitive tasks delivered through the Mobile Monitoring of Cognitive Change platform. Baseline measures assessed demographics, migraine characteristics, disability, mood, stress, and treatment patterns. Feasibility was evaluated using enrollment, completion, and retention metrics. ResultsA total of 177 participants enrolled (mean age 38.8 {+/-} 11.9 years; 79.7% female), including 80/177 (45.2%) with chronic migraine. Across the 30-day protocol, 3688 daily assessments were completed, representing 70.8% of all possible study days, and 70.6% of participants completed at least 20 days of monitoring. Completion remained above 60% across study days. At baseline, chronic migraine was associated with greater burden than low-frequency and high-frequency episodic migraine, including higher MIDAS scores (98.6 vs. 38.7 and 70.3), more days with concentration difficulty (16.0 vs. 7.9 and 11.5), and more days with functional interference (18.5 vs. 7.6 and 13.0). ConclusionsThe MIND study demonstrates the feasibility of high-frequency smartphone-based assessment of cognition and symptoms in migraine and provides a methodological foundation for future analyses of within-person cognitive and symptom dynamics across the migraine cycle.

Progranulin (PGRN) is a neurotrophic and anti-inflammatory factor produced mainly by neurons and microglia in the central nervous system. Progranulin haploinsufficiency causes frontotemporal dementia (FTD). In a previous study we showed that transgenic restoration of progranulin in neurons in progranulin knockout mice (NestinGrn KOBG knockout background) did not prevent the dementia-like phenotype. Here, we assessed if pharmacologic microglia depletion via PLX3397-diet (CSF1R-antagonist) had therapeutic value in these mice. Microglia depletion and spontaneous repopulation was confirmed in immunofluorescence and rtPCR studies. There was no difference in depletion or repopulation efficiency between NesGrn KOBG, PGRN KO and heterozygous (het) PGRN mice, but microglia repopulated faster than in control Grn-flfl mice, and the morphology of primary PGRN deficient microglia during repopulation was closer to homeostatic microglia, and it was accompanied by a remarkable restoration of dendritic spines and synaptic structures. Regardless of these positive effects, NesGrn KOBG and PGRN het mice experienced serious side effects during microglia depletion which peaked around the microglia nadir. Overactivity and excessive grooming escalated and caused serious skin lesions. Bulk transcriptomic and metabolomic studies in the brain taken 8 weeks after the end of PLX-diet clearly revealed differences between genotypes but mostly no lasting impact of PLX-diet, except for a further increase of proinflammatory genes, cathepsins and complement factors in PLX-treated groups. Cell type specific lipidomic studies revealed a time dependent switch not only in microglia but also astrocytes upon PLX3397 treatment. While nadir-microglia were triglyceride-laden, repopulated microglia returned to normal TG levels but were enriched in ether-bound phosphatidylcholines (PC-O) and lysophosphatidylglycerol species which are pro-inflammatory lipids; and astrocytes overtook the TG burden during repopulation. Our data suggest that microglia depletion may cause a deterioration in progranulin-deficiency.

Biological aging is accelerated in people with multiple sclerosis, but whether such acceleration occurs during the pre-symptomatic phase or varies by organ system is understudied. We analyzed two independent proteomics datasets profiled using distinct platforms: the Johns Hopkins cohort profiled using the SomaScan platform (348 multiple sclerosis/49 age-matched controls) and the Department of Defense cohort profiled using the Olink platform (134 multiple sclerosis/79 age-matched controls), including 117 pre-symptomatic samples from people with multiple sclerosis (median lead time: 4.0 years), to estimate systemic and organ-specific proteomic age gaps using established clocks in pre-symptomatic and symptomatic phases, and assess their associations with severity. In the Johns Hopkins cohort, people with multiple sclerosis demonstrated acceleration of systemic ({beta}=2.2, 95% CI 1.2-3.2, P<0.001, FDR<0.001), brain ({beta}=1.7, 95% CI 0.6-2.7, P=0.003, FDR=0.01), muscle ({beta}=2.5, 95% CI 1.3-3.7, P<0.001, FDR<0.001), and immune age ({beta}=1.8, 95% CI 0.6-2.9, P=0.003, FDR=0.01), with findings reproduced in the Department of Defense cohort for systemic ({beta}=0.7, 95% CI 0.0-1.4, P=0.04, FDR=0.34) and brain age (3.2 years, 95% CI 2.1-4.3, P<0.001, FDR<0.001). Proteomic age acceleration was evident prior to symptom onset [systemic: ({beta}=1.0, 95% CI 0.4-1.7, P=0.002, FDR=0.02); brain: ({beta}=2.4, 95% CI 1.2-3.7, P<0.001, FDR=0.002)], whereas no immune age acceleration was detected before or after onset. Higher systemic age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.14, 95% CI 0.05-0.24, P=0.005, FDR=0.03) and slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.006, FDR=0.04), while higher muscle age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.17, 95% CI 0.10-0.24, P<0.001, FDR<0.001), poorer manual dexterity ({beta}=0.28, 95% CI 0.04-0.52, P=0.03, FDR=0.30), slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.002, FDR=0.02), lower peripapillary retinal nerve fiber layer ({beta}= -0.26, 95% CI -0.41 to -0.10, P=0.001, FDR=0.02) and ganglion cell-inner plexiform layer thicknesses ({beta}= -0.35; 95% CI -0.65 to -0.05; P=0.02, FDR=0.30). Higher brain age gap was associated with several imaging measures, including lower whole-brain ({beta}= -0.002, 95% CI -0.003 to -0.001, P=0.002, FDR=0.02), and lower peripapillary retinal nerve fiber layer thickness ({beta}= -0.21, 95% CI -0.39 to -0.03, P=0.02, FDR=0.10). Proteomic age acceleration in multiple sclerosis is detectable years before symptom onset and distinct organ-specific aging signatures are associated with disease severity. Proteomic aging may provide a biologically informative marker of early disease processes and a clinically relevant readout of disease heterogeneity.

The central role of microglia in CNS function in health and disease has resulted in large interest in targeting microglial as treatments for neurodegenerative disease; understanding the factors that regulate microglial gene expression will be crucial to this goal. microRNAs (miRNAs) are among the most abundant post transcriptional regulators of gene expression. miRNAs suggests miRNA were likely key to significant evolutionary events as regulators of gene expression. The miRNAome of microglia is critical to their correct functioning but the miRNA that define microglia identity and regulate key functions have not been fully defined. In this study we performed a detailed analysis of the microglial miRNAome to identify miRNA enriched in microglia that are conserved across species (human, mouse, and xenopus). We further characterised the expression of these conserved miRNAs during demyelination and remyelination and identified conserved function of a microglial-enriched miRNA across species. These findings reveal evolutionary conservation of specific miRNAs, suggesting an important role in establishing and maintaining microglial identity. They also highlight miRNAs that may be critical for microglial function in the central nervous system in both health and disease. Overall, this work advances our understanding of the factors that regulate microglial gene expression.

The 7-nicotinic acetylcholine receptor (7nAChR) has driven extensive research over the past three decades for its pro-cognitive potential. It is the leading druggable target for the cognitive deficits associated with schizophrenia and has motivated major pharmaceutical and clinical efforts to ameliorate similar impairments in other neurological disorders, such as Alzheimers disease (AD). Yet, a systematic evaluation of the role played by 7nAChR in cognition, and its mechanistic underpinnings, is still lacking. Here we report that 7nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of 7nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an 7nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic 7nAChRs. Together, these findings identify astrocytes and D-serine/NMDAR signaling as a central mechanism through which 7nAChR, a major drug target, promotes cognitive behavior.

BackgroundPsilocybin is a classic psychedelic that acutely alters brain functional connectivity. These changes are linked to therapeutic doses and subjective effects, with some evidence that changes persist beyond acute drug administration. However, the effects of lower doses on sustained connectivity changes remain unclear. MethodsTen healthy volunteers received three psilocybin doses (between 5 and 20 mg) in a randomized and blinded order, with at least one week between doses. Resting-state functional magnetic resonance imaging was completed at baseline and one week after a single dose. Functional connectivity changes were analyzed in relation to dose and altered conscious states at both the level of individual brain region connections (edges) and resting-state networks. ResultsDose-dependent changes in 77 edges (76 increases, 1 decrease, of 1275 possible) were observed, but none survived multiple-comparison correction. At the network level, we observed one dose-dependent between-network increase (of 21 possible), and one dose-dependent within-network increase (of seven possible); the latter surviving correction. Alterations in conscious state were positively associated with widespread connectivity changes (dose-adjusted), with many network-level associations surviving correction. These directional patterns showed that lower doses and smaller conscious state alterations were linked to decreased connectivity, whereas higher doses and greater conscious state alterations were linked to increased connectivity. ConclusionsDose level and acute subjective effects were positively associated with multiple functional connectivity changes one week after a low-to-moderate psilocybin dose. Further research is warranted to characterize these sustained effects and their therapeutic relevance to inform studies adopting similar dosing regimens in clinical cohorts. Trial RegistrationAustralian New Zealand Clinical Trials Registry: ACTRN12621000560897 Date registered: 12 May 2021 URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381526&isReview=true

Background: The etiology and nosological status of seasonal affective disorder (SAD) as a specifier of depressive episodes versus a transdiagnostic disorder are the subject of debate. In this study, we investigated the underlying etiology of SAD and dimensional seasonality by examining their association with latitude and genetic risk for a range of traits, and investigated gene-environment interactions. Methods: This study included 12,460 adults aged 18-90 with a history of depression from the Australian Genetics of Depression Study. Regression models included predictors for latitude (distance from equator) and polygenic scores for eight traits; major depressive disorder, bipolar disorder, anxiety disorders, chronotype, sleep duration, body mass index, vitamin D levels, and educational attainment. Outcomes were SAD status and general seasonality score. Results: SAD was positively associated with latitude (OR[95%CI] = 1.05[1.03-1.06], padjusted<0.001), and there was nominal evidence of additive and multiplicative interactions between chronotype genetic risk and latitude (OR = 0.99[0.99-0.99], padjusted=0.381; OR=0.98[0.97-0.99], padjusted=0.489). General seasonality score was associated with latitude (IRR=1.01[1.01-1.01], padjusted 0.001) and genetic risk for major depressive disorder (IRR =1.02[1.01-1.03], padjusted<0.001), bipolar disorder (IRR=1.02[1.01-1.03], padjusted=0.001), anxiety disorders (IRR=1.03[1.01-1.04], padjusted<0.001), vitamin D levels (OR=0.89[0.80-0.95], padjusted=0.048), and educational attainment (IRR=0.97[0.96-0.99], padjusted<0.001). Conclusions: These findings enhance understanding of SAD etiology, highlighting contributions of psychiatric genetic risk and geographic measures on seasonal behavior, and support examining seasonality as a continuous dimension.

Traumatic brain injuries (TBIs) are more than mere lesions and generate a persistent secondary pathology. This, combined with functional reorganization of circuits post-injury, may explain the increased risk for psychiatric disorders in patients with TBI. In the current studies, we demonstrate that frontal TBI changed the Pavlovian behavioral response to reinforcer-predicting cues and reduced the motivational value of cues. TBI also chronically impaired decision-making on a gambling-like task with reinforcer-paired cues. To investigate how these changes occur, we evaluated the nucleus accumbens (NAc) core. At a subacute time point (14 days), we confirmed reduced input to the NAc with optogenetics and evaluated electrophysiological and transcriptional changes. TBI increased neuronal excitability and the single nucleus RNA sequencing profile indicated a substantial stress and inflammatory response, but also high indicators of plasticity, particularly in D1- and D2-positive medium spiny neurons. To evaluate how these subacute changes transitioned to chronic NAc dysfunction, we measured immunohistochemical surrogates of activity post-mortem and recorded calcium activity from the NAc after TBI during Pavlovian conditioning. TBI reduced histological markers of activity and reduced cue-evoked calcium activity. Overall, these data indicate that substantial reorganization of the NAc occurs following frontal brain injury. A primary effect of this is to reduce the salience of environmental cues linked to outcomes. The inability to properly process outcomes could contribute to broader psychiatric symptoms after TBI, including impairments in decision-making, behavioral flexibility, and impulsivity but also presents a potential treatment target.

BackgroundChronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. MethodsPatients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. ResultsSixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. ConclusionCRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.

Chronic pain and nicotine use frequently co-occur, and individuals with chronic pain often experience greater difficulty quitting. Therefore, we examined nicotine withdrawal behaviors and analgesic-like effects in pain-naive and chronic pain conditions. Adult male and female rats underwent chronic constriction injury or sham surgery. After pain establishment, rats received twice-daily subcutaneous nicotine (0.3 or 0.7 mg/kg) or saline for 14 days. 24 h after the final injection, withdrawal was assessed, including physical signs and anxiety-like behavior. Depressive-like responses were evaluated at 72 h. Pain sensitivity and nicotines analgesic-like effects were assessed throughout. Chronic pain increased physical signs of withdrawal in both sexes, with greater effects in females. It also induced anxiety-like behavior in controls of both sexes. In rats with comorbid chronic pain and withdrawal, anxiety-like behavior was further enhanced in males, whereas females showed variable responses across assays, with increases or decreases depending on the test. Chronic pain induced depressive-like behavior in males but not in females. During withdrawal, depressive-like responses in males with chronic pain were not greater than those in the chronic pain alone group, while chronic nicotine exposure reduced depressive-like behavior in females. Nicotine produced acute analgesic-like effects that diminished over time in both pain-naive and chronic pain conditions, indicating tolerance. In pain-naive rats, repeated nicotine exposure induced mechanical hypersensitivity. Chronic pain intensified nicotine withdrawal severity in a nicotine concentration- and sex-dependent manner. These findings highlight the importance of considering pain status and sex when developing effective cessation strategies, particularly for individuals with comorbid chronic pain. SummaryChronic pain exacerbates nicotine withdrawal severity. Chronic nicotine exposure induces pain hypersensitivity and tolerance to analgesic effects. These effects vary by nicotine concentration and sex.

In recent years, immunotherapy of patients with higher-risk non-muscle invasive bladder cancer (NMIBC) in North America has relied on the use of the TICE strain of BCG. However, limitations in the supply chain have warranted investigation of the therapeutic benefit of other strains of BCG, such as BCG-Russia. Trained immunity, a form of innate immune memory, is now widely believed to be an important component of the therapeutic benefit of BCG. Therefore, in the present study we compared the effects of BCG-TICE and BCG-Russia on the acquisition of trained immunity and related secondary immune responses. C57BL/6 mice received a single intravenous injection of BCG-Russia or BCG-TICE. Four weeks later, bone marrow was collected for flow cytometric analysis of hematopoietic stem and progenitor cell (HSPC) populations, generation of bone marrow-derived macrophages, functional assessment of trained immunity, and transcriptomic profiling. Compared with BCG-Russia, BCG-TICE elicited stronger levels of trained immunity, characterized by higher production of several proinflammatory cytokines upon secondary activation. BCG promoted the expansion of HSPCs independent of strain. BCG-TICE was linked to upregulation of key inflammation-related genes and enrichment of functionally relevant pathways. The results of this study reveal strain-dependent differences in the ability of BCG to induce innate immune memory and inflammatory pathways that could ultimately determine efficacy of immunotherapy of patients with NMIBC.

BackgroundScalable, low-burden behavioral interventions are needed to address rising subclinical mental health symptoms. However, few randomized controlled trials have evaluated ultra-brief, remotely delivered, meditation using multimodal outcome assessment under real-world conditions. MethodsWe conducted a fully remote randomized controlled trial (ClinicalTrials.gov: NCT06014281) evaluating a focused-attention meditation intervention delivered via brief instructor training and independent daily practice. A total of 299 meditation-naive adults were randomized to immediate intervention or waitlist control in a delayed-intervention design. Participants practiced [&ge;]10 minutes daily for 8 weeks within a 16-week study. Outcomes included validated self-report measures, web-based cognitive tasks, and wearable-derived physiological metrics. ResultsAcross randomized and within-participant replication phases, the intervention was associated with significant reductions in anxiety and mind wandering, with effects remaining stable during 8-week follow-up. Improvements were greatest among participants with higher baseline symptom burden. Sleep disturbance improved selectively among individuals with poorer baseline sleep. Secondary outcomes, including rumination, perceived stress, social connectedness, and quality of life, also improved. Cognitive performance showed modest improvements primarily among lower-performing participants. Resting heart rate exhibited nominal reductions. ConclusionsAn ultra-brief, fully remote meditation intervention requiring 10 minutes per day was associated with sustained improvements in psychological functioning and smaller, baseline-dependent effects on cognition in a non-clinical population. These findings support digital delivery of low-dose meditation as a scalable preventive mental health strategy.

Background: Narcolepsy is a debilitating sleep disorder caused by hypocretin deficiency. Aside from its role to induce wakefulness, hypocretin is linked to modulated appetite and metabolism, often resulting in weight gain. Study objectives: We aimed to unravel the comprehensive epidemiological connection between narcolepsy and major cardiometabolic outcomes. Methods: We analyzed cardiovascular and metabolic disease distribution in the FinnGen study. Using longitudinal electronic health records, we assessed associations between narcolepsy, cardiac/metabolic markers, and prescriptions for relevant drugs. Results: Our findings demonstrate significant associations between narcolepsy and metabolic traits (OR [95% CI] = 2.65 [1.81, 3.89]) as well as stroke (OR = 2.36 [1.38, 4.04]). Narcolepsy patients exhibit a less favourable metabolic profile, including higher glucose levels (OR = 1.1143 [1.0599, 1.1715]) and dyslipidaemia. This is supported by increased prescriptions of insulin (OR = 2.269 [1.46, 3.53]), simvastatin (OR = 2.292 [1.59, 3.31]), and metformin (OR = 2.327 [1.66, 3.25]), reflecting high metabolic disturbances. Furthermore, positive associations with antihypertensive and antiplatelet medications were observed, consistent with elevated cardiovascular risk. Conclusion: Taken together, our findings highlight the cardiometabolic burden in narcolepsy. This study enhances understanding of the metabolic and cardiovascular consequences of narcolepsy and offers timely guidance for effective disease control.

Pain captures attention and interferes with executive and motor processes but task performance may be preserved at the cost of more effort. In a preregistered fMRI study, 40 participants performed a visuomotor force-matching task at two force levels under individually calibrated painful or non-painful thermal stimulation, while reporting the intensity of perceived effort. Maintaining task performance under pain was associated with increased perceived effort and recruited brain regions involved in pain modulation and cognitive control. Region-of-interest analysis showed perceived effort was consistently linked to decreased anterior midcingulate cortex activity, whereas supplementary motor area contributions varied depending on its role in motor execution or pain processing. Across experimental condition, motor, pain-modulatory and cognitive-control regions were associated with effort perception. Independently of condition, effort perception was modulated by ventromedial prefrontal cortex and ventral striatum. These findings indicate that effort perception reflects brain activity within areas involved in motor, executive and valuation processes.

Background: China has implemented policies to strengthen its pharmacist workforce since the 2009 healthcare reform, yet a comprehensive evaluation of their long-term systemic effects is lacking. Objective: To systematically analyze the evolution of Chinas pharmacist workforce in healthcare institutions from 2007 to 2023 across four dimensions: quantity, quality, structure, and distribution, providing an empirical foundation for policy optimization. Methods: A retrospective analysis was conducted using longitudinal data from the China Health Statistics Yearbooks. Trends were delineated via descriptive statistics. Equity and spatial evolution were assessed using the Gini coefficient, Theil index decomposition, and spatial autocorrelation analyses (Global Morans I and hotspot analysis). Results: From 2007 to 2023, the total number of pharmacists increased from 357,700 to 569,500 (average annual growth: 2.2%). This growth lagged behind physicians (4.6%) and nurses (7.4%), causing the pharmacist-to-physician ratio to decline from 1:5.15 to 1:8.39. The workforce showed trends of feminization (female proportion rose from 59.7% to 70.8%) and aging. While quality improved, 51.1% still held an associate degree or below, and only 6.6% held senior titles. Equity analysis revealed the provincial Gini coefficient improved from 0.145 to 0.093. Theil index decomposition confirmed intra-provincial disparities as the primary inequality driver. Spatial analysis showed a non-significant global Morans I by 2023 (0.154, P*>0.05), down from 0.254 (P<0.01) in 2007. Hotspot analysis confirmed this transition, revealing a contraction of high-confidence clusters and a trend toward balanced distribution. Conclusions: China has made measurable progress in expanding pharmacist workforce size and improving inter-provincial equity since 2007. However, persistent structural challenges remain: relative workforce contraction compared to other health professions, an aging demographic, a shortage of senior talent, and significant intra-provincial inequity. Future policies must prioritize optimizing workforce structure and enhancing clinical service capabilities to catalyze a shift toward patient-centered pharmaceutical care.