Multiple Sclerosis and Related Disorders

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system marked by demyelination and neurodegeneration. Beyond physical symptoms, MS is often linked to clinically relevant sleep disturbances. The variability and unpredictability of symptoms and disease progression can also fuel fear of relapse (FoR), undermining well-being and potentially increasing morbidity through inflammatory processes. Understanding biopsychosocial risk factors, including childhood maltreatment (CM) and sleep, in relation to FoR remains an important gap in MS management and research. Methods: Data from N = 48 participants were collected via an online survey. We used the Pittsburgh Sleep Quality Index (PSQI), the Fear-of-Relapse Scale (FoR), and the Childhood Trauma Questionnaire (CTQ) to assess the variables of interest. In addition, time points of exposure to different CM subtypes were assessed. Linear regression analyses were conducted to examine associations within the proposed negative triad. Results: A significant negative association between overall sleep quality and FoR was observed. In the total cohort, the interaction between CM and sleep was not a significant predictor of FoR. However, exploratory analysis revealed a significant interaction between CM and sleep among male participants, whereas the same interaction was not significant among female participants. Conclusion: A history of CM and impaired sleep quality introduce new stressors in managing one's own illness that have received little attention to date. However, the present study found that these factors were at least partly influential on the FoR. The results underscore the translational need for additional support services to enhance prevention and personalized care.

Background: Brain age is a biomarker of brain tissue integrity associated with disability in multiple sclerosis. While new lesion formation is central to MS diagnosis and treatment monitoring, its direct relationship to brain aging has not been established. Methods: We analyzed 163 people with MS with clinical and MRI assessments at baseline and years 3, 6, and 8. Brain age was estimated using BrainAgeNeXt. Annualized brain age acceleration was modeled as a function of radiological activity using generalized estimating equations, adjusting for age, sex, disease duration, baseline T2 lesion volume, normalized brain volume (NBV), brain age difference (BAD), and disease-modifying therapy. Secondary analyses examined dose-response effects, post-activity recovery, paramagnetic rim lesion (PRL) associations, and disability associations. Results: 105 participants had at least one new T2 lesion over 8 years. Radiologically active intervals (138 of 333) were associated with +0.19 yr/yr greater brain age acceleration than stable intervals (95% CI: 0.03-0.37; p=0.022), scaling with lesion count (beta=+0.18; p=0.001) and volume. Older age, greater baseline BAD, and NBV were independently associated with reduced brain age acceleration. Brain age acceleration in individuals with new lesions normalized during subsequent stable intervals (0.41 vs -0.06 yr/yr; p=0.001). Both PRLs and non-PRL lesions were associated with greater brain age acceleration than stable intervals. Baseline BAD, but not annualized acceleration, predicted Expanded Disability Status Scale (EDSS) and Nine-Hole Peg Test (9HPT) worsening. Conclusions: New focal lesion formation is associated with a quantifiable, dose-response acceleration of brain aging in MS that normalizes once lesion activity is suppressed.

Objective: The Brief-cope questionnaire explore coping behavior. However, the underlying factor structure remains a subject of ongoing debate. Exploratory factor analyses (EFA) conducted across different populations have identified factor solutions ranging from two to fourteen factors. As of yet, the underlying factor structure of the Brief-cope has not been investigated in patients with seropositive rheumatoid arthritis (RA). Therefore, the aim of this study was to explore the underlying factor structure of the Brief-cope in a German population of seropositive RA. Methods: 216 outpatients with seropositive RA completed the Brief-cope. An EFA with principal axis factoring and Promax rotation was conducted. Results: EFA indicated a five-factor solution. The five-factor solution explained 51.95% of variance. The identified factors were: (1) problem-focused coping (Cronbach's = .851), (2) emotion-focused coping ( = .754), (3) maladaptive coping ( = .747), (4) religious coping ( = .851), and (5) substance-use coping ( = .869). Conclusion: A five-factor solution provided the most appropriate representation of the underlying factor structure of the Brief-cope in patients with seropositive RA. This factor structure may serve as a suitable basis for future analyses of Brief-cope data in comparable RA populations.

Background: Heatwrap is recommended for acute low back pain (ALBP), and previous research found heatwrap plus exercise more effective than each intervention alone. While recommended by clinical guidelines, their impact on mechanistic outcomes is unknown. This trial aimed to (i) assess immediate and short-term effects of heatwrap alone or combined with exercise, compared with a sham heatwrap, on pain sensitivity, lumbar muscle activity, current pain intensity, and trunk flexion range of motion, and (ii) explore whether changes in pain sensitivity and lumbar muscle activity are associated with changes in clinical symptoms from baseline to 1-week follow-up. Methods: A randomised controlled trial took place at a single research center. Of 315 individuals screened for eligibility, 99 adults with ALBP were recruited and assigned to one of three intervention groups: heatwrap plus exercise (n=34), heatwrap alone (n=33) or sham heatwrap (n=32). Interventions were applied for one hour at the first visit, and immediate effects were measured. Then, interventions were applied for 7 days, and short-term effects were measured at 1-week follow-up. Outcomes included pressure pain threshold, temporal summation of pain, flexion-relaxation ratio, trunk range of motion and current pain intensity. Results: Heatwrap and exercise did not produce greater effects over time than heatwrap alone or a sham heatwrap on all outcomes, and changes in sensorimotor outcomes at one week were not associated with changes in symptoms. Conclusions: Heatwrap and/or exercises did not influence specifically the potential sensorimotor mechanisms tested in individuals with ALBP. Trial registration: ClinicalTrials.gov; registration number: NCT03986047

Background: Aerobic exercise is recommended during stroke rehabilitation to improve cardiorespiratory fitness and support recovery; however, participation rates remain low. While institutional and system-level barriers have been widely examined, less is known about how individual patient factors influence engagement in aerobic exercise during rehabilitation. Objectives: We aimed to determine whether depressive symptoms, apathy, self-efficacy and outcome expectations for exercise, perceived barriers, or past exercise history were associated with aerobic exercise participation in stroke rehabilitation. Methods: In this prospective cohort sub-study, adults admitted to in- or out-patient stroke rehabilitation at three urban hospitals completed validated questionnaires assessing depressive symptoms, apathy, exercise self-efficacy, outcome expectations for exercise, perceived barriers to being active, and premorbid exercise history. Participants were separated into two groups for analysis: those who completed aerobic exercise during rehabilitation and those who did not. Equivalence testing and between-group comparisons were performed. Results: Sixty-two participants were enrolled; 16 participated in aerobic exercise and 46 did not. Groups were not equivalent on any individual-level factors. Compared to non-participants, those who performed aerobic exercise had significantly higher depressive symptom scores (p=0.0025) and lower self-efficacy for exercise (p=0.0087). Non-participants demonstrated significantly higher apathy (p=0.0007). No significant differences were found for outcome expectations, perceived barriers, or exercise history. Conclusion: Depressive symptoms and lower self-efficacy did not impede aerobic exercise participation during rehabilitation. Increased apathy, however, was associated with non-participation. Findings highlight the need for individually tailored aerobic exercise prescriptions that consider motivational and affective factors to optimize engagement during stroke rehabilitation.

Background and purpose: Patellofemoral pain syndrome (PFPS) is a multifaceted condition where proximal, local, and distal factors may contribute to symptoms and limitations. How these factors collectively contribute to PFPS remains poorly understood. Therefore, this study compared proximal, local, and distal mechanical characteristics between individuals with and without PFPS and investigated their association with pain intensity and functional disability. Methods: Eighty participants were included: 40 individuals with unilateral or bilateral PFPS, 40 healthy controls. Isometric muscle strength of hip, trunk, and ankle was assessed using a handheld dynamometer. Joint alignment (Q-angle, rearfoot angle, pelvic tilt) and muscle flexibility (iliotibial band, hamstrings, quadriceps, gastrocnemius, and soleus) were measured using standard clinical techniques. Pain severity was assessed using a visual analog scale (VAS), and functional disability was evaluated using the Kujala score. Results: Individuals with PFPS showed reduced iliotibial band flexibility, decreased hamstring and soleus length, lower hip abductor strength, and greater anterior and lateral pelvic tilt (all p < 0.02). Multivariate analysis identified reduced iliotibial band flexibility (OR = 7.48) and greater anterior pelvic tilt (OR = 11.75) as independent associates of PFPS. Anterior pelvic tilt predicted pain severity, while anterior trunk muscle strength and Q-angle predicted disability. Discussion: Reduced iliotibial band flexibility and increased anterior pelvic tilt were independently associated with PFPS, while anterior pelvic tilt predicted pain severity and anterior trunk muscle strength and Q-angle predicted functional disability. Clinical assessment and rehabilitation of PFPS should therefore extend beyond the knee to include iliotibial band flexibility, pelvic alignment, and trunk muscle strength.

Background Mirror therapy (MT)-specifically paradigms using mirror visual feedback (MVF)-is widely used in neurorehabilitation; however, mechanistic implementations vary substantially in movement content, rhythmicity and attentional demands. This protocol describes an acute mechanistic, within-participant fNIRS screening study designed to compare three prespecified upper-limb mirror-therapy task paradigms and to quantify associated subjective experience after each condition in healthy adults during a single visit. Methods and analysis This is a single-centre, within-participant, randomised crossover study conducted at Wuhan Wuchang Hospital (Wuhan, China). Healthy adults aged 18-35 years will complete three task conditions once each in a counterbalanced order using a 3*3 Latin-square scheme: UMT1 (task-oriented rhythmic functional movement), UMT2 (open-ended free movement with auditory control), and UMT3 (non-functional rhythmic movement). fNIRS will be acquired using the NirSmart-6000A system during a standardised block design. The primary outcome is ROI-level HbO activation quantified as GLM-derived {beta} estimates within the prespecified primary ROIs (bilateral SM1/M1 and bilateral PMC). Secondary outcomes include ROI-level windowed {Delta}HbO (5-20 s post-onset relative to the immediately preceding rest; descriptive only), ROI-level {Delta}HbR, and post-condition subjective ratings (illusion, immersion, confusion and fatigue; 1-7 Likert). Condition effects will be analysed using linear mixed-effects models with fixed effects for condition and period and prespecified multiplicity-adjusted pairwise contrasts. Ethics and dissemination Ethics approval was obtained from the Ethics Committee of Wuchang Hospital Affiliated to Wuhan University of Science and Technology (Approval No.: 2025-112-01; approved on 2025-08-21). The study is expected to be minimal risk. Findings will be disseminated through publication of this protocol manuscript and subsequent results manuscripts and conference presentations. Trial registration number Chinese Clinical Trial Registry (ChiCTR2600116634). This study is conducted as a prespecified mechanistic sub-study under the overarching registered project.

Background: The primary neuroanatomical site of Huntington-s disease (HD) pathology resides in the striatum and its atrophy identifies important disease progression from HD-ISS Stage 0 to Stage 1. Immune-associated proteins may capture variation in HD that is incompletely represented by markers of neuroaxonal injury. Objectives: To determine whether cerebrospinal-fluid myeloperoxidase contributes information about striatal volume loss beyond genetic disease burden and neurofilament light. Methods: Cross-sectional data from 88 persons with HD were analyzed. Cerebrospinal-fluid myeloperoxidase and neurofilament light were measured with a nucleic acid-linked immunosandwich assay. Normalized putamen volume was derived from structural magnetic resonance imaging. Linear regression adjusted for genetic disease burden and sex. Results: Higher neurofilament light was associated with smaller normalized putamen volume (standardized {beta} = -0.322, (P=.0066)). Higher myeloperoxidase was associated with larger normalized putamen volume after adjustment for genetic disease burden, sex, and neurofilament light (standardized {beta} = 0.183, (P=.0386)). Adding myeloperoxidase increased explained variance in striatal loss. Conclusions: Cerebrospinal fluid myeloperoxidase contributed modest incremental information about striatal volume in this cross-sectional sample. Independent longitudinal studies are needed to determine its biological source, temporal behavior, and potential biomarker value. Findings advance efforts to characterize multicomponent biological markers of HD.

Impaired gait performance and stability is a key symptom often defining disease outcome in people with Multiple Sclerosis. Step-by-step foot placement control in response to variations in the center-of-mass kinematic state is a crucial gait stability mechanism, especially in the mediolateral direction. Even though it is known that people with Multiple Sclerosis are at an increased risk of falling, step-by-step foot placement control remains to be characterized in this population. Here, we explored characteristic foot placement control in ten people with early stage Multiple Sclerosis, compared to 21 controls walking at a similar average gait speed, during 1-minute steady-state treadmill walking. Kinematic data were analyzed using a linear feedback model that correlated foot placement with the center-of-mass kinematic state during the preceding swing phase. People with Multiple Sclerosis demonstrated step-by-step foot placement control in both the mediolateral and anteroposterior directions. No differences were found in foot placement precision between groups. However, foot placement responses to variations in center-of-mass velocity proved stronger in people with Multiple Sclerosis. Moreover, the contribution of mediolateral center-of-mass velocity feedback to the control mechanism was higher in people with Multiple Sclerosis as compared to neurologically healthy controls. Our results suggest that foot placement control is still retained in early clinically evident stages of Multiple Sclerosis, but is realized through differently weighted sensory feedback control.

Objective: Cognitive impairment is a common comorbidity among people with epilepsy (PWE) and is associated with disability and reduced quality of life. We characterized the burden of cognitive impairment and identified factors associated with cognitive performance in a large, population-based cohort of PWE living in Northern Peru, a region highly endemic for Taenia solium where neurocysticercosis (NCC) is a common cause of acquired epilepsy. Methods: PWE enrolled in a population-based cohort in Northern Peru between 2007 and 2020 completed the Mini-Mental State Examination (MMSE) at enrollment. Cognitive impairment was defined as an MMSE score <24. Demographic and clinical data, including epilepsy characteristics and NCC status, were collected. Negative binomial regression was used to identify factors associated with the number of MMSE errors. Results: Among 764 participants, the mean MMSE score was 26.4 (SD 4.2), and 16.4% met criteria for cognitive impairment. Memory and attention were the most affected domains. In multivariable analysis, older age and lower educational attainment were independently associated with poorer cognitive performance. Conclusion: In this large, community-based cohort from Northern Peru, approximately 1 in 6 PWE had abnormal global cognition on the MMSE, with memory and attention most affected. These findings underscore the importance of incorporating cognitive evaluation and management into comprehensive epilepsy care, particularly in resource-limited settings where cognitive morbidity may be underrecognized. Given the potential for cognitive difficulties to compound disability and adversely affect quality of life, identifying and addressing cognitive morbidity may be especially important in populations already facing substantial barriers to epilepsy care.

Background: Aneurysmal subarachnoid haemorrhage (aSAH) is frequently complicated by delayed cerebral ischaemia (DCI), for which current therapies incompletely target the underlying multifactorial pathophysiology. Transauricular vagus nerve stimulation (taVNS) modulates inflammatory, vasoactive and autonomic pathways and may attenuate secondary brain injury after aSAH. Methods: We conducted a prospective, single-centre, single-blind, randomised, sham-controlled pilot trial in adults within 5 days of aneurysm securing for non-traumatic aSAH. Participants were allocated 1:1 to active taVNS (left tragus) or sham (left earlobe) using a portable device delivered for 45 minutes twice daily over 5 days. Primary outcomes were safety (taVNS-related serious adverse events), acceptability, and compliance; secondary outcomes included inflammatory biomarkers, DCI, in-hospital complications, and functional outcomes to 1 month. Results: Thirty patients were randomised (16 taVNS, 14 sham), with numerically more severe aSAH at baseline in the taVNS arm. No taVNS-related serious adverse events occurred; side effects were generally mild and transient, and over 80% of planned sessions were completed. TaVNS produced greater reductions in serum tumour necrosis factor- and trends towards reductions in interleukin-1{beta} and interleukin-10, with numerically fewer DCI events (6.6% vs 35.7%) and neurological impairments (16.7% vs 53.8%), although functional outcomes were not statistically different at 1 month. Conclusions: Early taVNS after aSAH is safe, acceptable, and feasible in the neurocritical care setting and shows biologically plausible signals warranting evaluation in larger multi-centre trials.

Children and adolescents with hearing loss frequently encounter reduced auditory access and delayed language development, factors that may influence the maturation of executive functions. This study examined developmental differences in planning, a core executive function, in 98 children and adolescents with hearing loss or normal hearing aged 7 to18 years using the Tower of London task. Compared to normal hearing peers, participants with hearing loss made more unnecessary moves and rule violations and initiated problem-solving more rapidly, suggesting reduced preplanning efficiency and increased impulsivity. These group differences were most pronounced in adolescents, who showed faster initiation and greater movement inefficiency than age-matched normal hearing participants. Within the hearing loss group, adolescents displayed higher accuracy and longer initiation times than children, reflecting developmental improvements despite persistent gaps relative to hearing peers. Language development age did not alter the main effects. Findings indicate that reduced early auditory and language access may contribute to differences in planning development, highlighting the need for targeted executive functions support in educational and clinical settings for youth with hearing loss.

Background: On-call clinicians frequently report the anecdotal impression of 'theme shifts' during which specific acute neurological diagnoses appear to cluster. Whether such clustering reflects a statistically true and reproducible phenomenon has not been systematically investigated; the present paper examines seasonality and temporal clustering within six different acute neurological conditions. Methods: In this retrospective, single-center cohort study, we identified all patients admitted to a tertiary neurological department between July 2016 and June 2026 with acute unilateral vestibulopathy, cerebral artery dissection, generalized epileptic seizures, primary intracerebral hemorrhage, peripheral facial nerve palsy, or transient global amnesia (TGA) (n = 2,140). Monthly and seasonal distributions were assessed using chi-squared goodness-of-fit and cosinor analysis. Short-term temporal clustering was tested by Monte Carlo permutation across time windows from 24 hours to 90 days, and endogenous cluster dynamics were characterized using Hawkes self-exciting point process modeling. Results: Admissions for generalized epileptic seizures showed a statistically significant deviation from a uniform monthly distribution with a winter distribution (p<0.001 and q = 0.002), and a significant temporal clustering across time windows from 72 hours to 90 days (all q < 0.05). Peripheral facial nerve palsy presented significant clustering at the 90-day window (q = 0.029) and TGA at 60-day time window (q = 0.041) without seasonality; the diagnostic groups of acute unilateral vestibulopathy, cerebral artery dissection and primary intracerebral hemorrhage showed neither seasonality nor clustering after correction for multiple comparison. No diagnostic group showed clustering within a 24-hour window, statistically significant self-excitation in Hawkes process modelling, or a significant linear trend in monthly case counts over the study period. Conclusion: The anecdotal impression of diagnostic 'theme shifts' among on-call neurologists appears to have a measurable basis, although clustering is confined to specific conditions and rather on a time scale of weeks to months. Generalized epileptic seizures were the only diagnostic group that uniquely combined seasonality with temporal clustering, suggesting a shared trigger, while facial palsy and TGA showed episodic, yet non-seasonal clustering.

Abstract: Objective: Post-traumatic epilepsy (PTE) is a common sequela of traumatic brain injury (TBI). Research indicates that individuals with PTE tend to experience greater cognitive difficulties compared to those with TBI alone. However, it is plausible that a distinct cognitive profile exists that distinguishes between TBI cases with and without PTE. We aimed to identify longitudinal changes in cognitive measures among TBI patients to better assess the changes associated with developing PTE. Setting: Outpatient. Participants: Prospective subjects who had suffered TBI within 6 months post-injury (TBI-6M, n=32), retrospective subjects with pre-existing PTE diagnoses (PTE, n=20), and healthy control subjects (HC, n=41). Design: We examined cognitive performance for TBI patients within 6 months post-injury, then again within 12 months (TBI-12M, n=26), and within 18-months (TBI-18M, n=25), and compared this with cognitive performance among HC and PTE. Main Measures: Cognitive tests administered yielded 15 test components for analysis. We utilized linear mixed effects modeling to examine cohort-level differences cognitive function. Results: 11/15 tests showed a significant performance deficit in the PTE subjects compared to HC. TBI-6M was not significantly different from the PTE subjects; with time, 9/15 tests showed some degree of recovery in TBI subjects. Tests for information processing speed/working memory and executive function showed strong recovery (TBI-6M vs. TBI-18M, SDMT written: p<0.0001, SDMT oral and COWAT: p<0.001). Tests for visual attention/working memory also showed a smaller but significant recovery (TBI-18M vs. PTE, p<0.05). By contrast, tests for verbal memory [HVLT-R Delayed Recall] showed chronic impairment in TBI (TBI-18M vs HC, p<0.0001). TBI subjects generally trend towards recovery in cognitive performance post-TBI. Conclusions: Information processing speed/working memory are strong indicators for TBI recovery, while auditory learning/memory shows chronic impairment. The stagnation of recovery in cognitive domains typically characterized by robust recovery may correlate with an elevated risk of developing PTE.

INTRODUCTION: Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer disease (AD), and healthy controls (HC). METHODS: Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain-Barr&eacute syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot-Marie-Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS: Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS: Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.

Background: Major depressive disorder (MDD) is a severe mental illness associated with severe clinical consequences and substantial societal burden. It's characterized by immune-inflammatory dysregulation and immune sensitization. Objective: To determine whether in vitro ketamine attenuates phytohemagglutinin (PHA)/lipopolysaccharide (LPS)-induced immune sensitization in patients with MDD and healthy controls (HCs). Methods: Whole blood from 18 patients with MDD and 18 HCs was stimulated with PHA/LPS and exposed to ketamine (0.3 M, 0.6 M, and 6 M) for 72 hours. Cytokines, chemokines, growth factors, and composite immune profiles, including M1/M2 macrophages, T helper (Th)1/2/17, the immune-inflammatory response system (IRS), and compensatory immunoregulatory system (CIRS), were synthesized and determined. Results: Under PHA and LPS stimulation in vitro, the MDD group exhibited markedly elevated immune profiles, including M1, M2, Th1, Th2, Th17, IRS, CIRS, chemokines, and growth factors, consistent with immune sensitization. Significant group-by-treatment interactions were observed for Th1-Th2, M2, growth factors, IL-12(p70), M1, and chemokines. Ketamine produced minimal changes in HCs but broader suppression in MDD, particularly at the highest concentration, without normalizing the sensitized immune phenotype. Among the immune markers with no notable group-by-treatment interactions, ketamine exerted diagnosis-independent effects, decreasing MIP-1{beta}, IL-1&{beta}, Th1, TNF-{beta} IRS, IFN-{gamma}, and IL-2 compared to the control condition. Conclusions: Ketamine exhibited two distinct immunoregulatory patterns: selective, disease-dependent attenuation of sensitized immune pathways and broader, diagnosis-independent suppression of the stimulated immune response, predominantly at higher concentrations. However, these effects were insufficient to normalize the immune-sensitized phenotype of MDD.

Background The time trend in long-term survival after a stroke is to some extent unknow due to (relatively) short follow up periods in available data. The objective of this study is to identify and quantify differences in long-term stroke survival in Sweden between men and women and patients with different attained educational levels, comparing two time-periods, 2000-2009 and 2010-2022. Methods This study employs total population Swedish register data pertaining to hospital-based care and mortality due to stroke for the period 2000-2022 in order to estimate survival (all-cause mortality) after ischaemic and haemorrhagic stroke, respectively, and pertaining to attained educational level. Kaplan-Meier survival functions are estimated stratifying for time-period, sex and educational level. Cox regressions are employed to quantify mortality hazard ratios between the strata. Age is taken into account in complementary analyses (supplement). Results Taking only time-period (2000-2009 vs 2010-2022) into account resulted in significantly higher survival in the second period for ischaemic stroke patients (HR: 0.84; 95% CI: 0.83-0.84), while no significant difference could be detected for haemorrhagic stroke. Stratifying for sex showed that men gained more than women in terms of reduced mortality hazard rate between the periods. Further stratifying by educational level and estimating survival separately for men and women showed that, for both men and women, patients with the lowest education were relatively worse off (compared to patients with higher education) in the second period. Further analyses, taking age into account, reversed the relative hazard ratio between men and women, but corroborated the result that low education is associated with poorer outcome than high education. Conclusions The results suggest that there are considerable differences in expected long-term survival after stroke between the sexes, but that this may be due to differences in age between the sexes at the time of stroke. Moreover, lower educational level is significantly associated with lower long-time survival.

Background: Shiftwork disrupts natural sleep-wake cycles, alters light exposure patterns, and contributes to circadian misalignment. Detrimental health consequences associated with shift work include elevated risk for metabolic disorders, cardiovascular disease, cancer and all-cause mortality. Healthcare workers have one of the highest rates of shift work exposure, yet there are relatively few non-pharmacological interventions (with good evidence) developed to improve sleep outcomes in this population. Objective: A pre-post pilot interventional study assessed the acceptability and perceived effectiveness of commercial noise-masking earbuds on improving subjective sleep characteristics among National Health Service (NHS) healthcare staff working fast rotating shifts. Methods: Noise-masking sleep earbuds (Kokoon NightBuds) were worn for a pilot six-week intervention by twenty-seven NHS nurses (aged 26-43 years, 88.9% female) working fast rotating shifts from the EClocker Study. Sensors inside the earbuds were paired with a smartphone app to monitor sleep. An audio library in the smartphone app delivered personalised relaxation exercises and sleep techniques drawn from cognitive behavioural therapy for insomnia (CBT-I). A pre-post two-week monitoring period with daily smartphone-based Experience Sampling Methods (ESM) captured perceived daily sleep patterns. Acceptability and perceived effectiveness of the earbuds in promoting better sleep outcomes was assessed. Results: Use of the noise-masking sleep earbuds over a six-week period was associated with positive sleep improvement trends and elicited promising acceptability. Almost two thirds of NHS fast rotating shift nurses (63%) subjectively reported reductions in general sleep disturbance symptoms (PSQI Global), one in four experienced perceived sleep quality improvements (SQ; 25.9%), one in five reported sleeping longer (TST; 22.2%), and a third perceived falling asleep faster (SOL; 33.3%), had better sleep efficiency (SE; 33.3%) and improved daytime dysfunction (33.3%) (PSQI subcomponent scores). Sleep diaries (CSD) collected daily using smartphone-based ESM also demonstrated small improvements post-sleep earbud use; nurses reported sleeping an average 18 minutes longer (TST) and fell asleep more easily, on average 11 minutes faster (SOL). Sleep earbuds were generally well tolerated; 56% of nurses reported the earbuds as (somewhat to very) helpful, 52% reported (somewhat to strongly) falling asleep more easily (SOL), 44% felt (somewhat to strongly) their sleep quality was improved (SQ) and 30% agreed (somewhat to strongly) they slept longer (TST) and had less disturbed sleep. Conclusions: To our knowledge, this is the first study in Europe to pilot noise-masking earbuds as a potential non-pharmacological aid to improve sleep-wake behaviours or mitigate fatigue for healthcare staff. Preliminary results showed promising acceptability and (small) perceived sleep improvement trends following a targeted six-week earbud intervention in NHS fast rotating shift nurses.

Introduction: B cell depletion with rituximab leads to complete or partial remission (CR/PR) in only ~60% of patients with primary membranous nephropathy (PMN). Adding belimumab to rituximab may result in greater depletion of memory B cells, limit the re-emergence of autoreactive B cells, and improve clinical responses. Methods: REBOOT Part A (NCT03949855) is a single arm, open-label, pharmacokinetic study where all participants had proteinuria [&ge;] 4g/day and detectable serum anti-phospholipase A2 receptor (anti-PLA2R) antibodies. Participants received belimumab 200 mg subcutaneously weekly for 52 weeks and rituximab 1000 mg intravenously at weeks 4 and 6. Assessments included belimumab exposure at week 4 and CR/PR at week 104. Results: Seventeen participants started belimumab. Belimumab exposure was not significantly reduced in those with high (> 9 g/day) proteinuria at week 4. Among all treated participants, 59% (10/17) achieved CR/PR at week 104, while in per protocol analyses, 91% (10/11) achieved CR/PR at week 104. All participants in per protocol analyses had normal serum albumin and undetectable serum anti-PLA2R by week 104. Circulating memory B cells increased before rituximab and were depleted by rituximab. B cell re-constitution occurred after week 52 with primarily naive and transitional B cells. Belimumab with rituximab was well-tolerated, with one participant discontinuing belimumab due to infection. Conclusion: In this study, a high proportion of participants receiving belimumab with rituximab achieved CR/PR. Thus, a multi-targeted approach to B cell depletion may improve immunologic and clinical outcomes in PMN and is being studied in a larger, randomized, placebo-controlled clinical trial.

Background Sleep, mood, and affective states are mutually connected. There is a paucity of studies, however, that have considered bidirectional relationships between daily sleep-affective dyads in naturalistic settings, particularly for shift workers. Objective To evaluate the dynamic and temporal interplay of daily smartphone-based self-reported sleep measurements, dimensions of affective experience and cognitive processing in UK shift working nurses. Methods The EClocker Study prospectively monitored 102 National Health Service (NHS) nurses (aged 25-61 years, 83.3% female) working standard (day shift) and non-standard (fast rotating shifts) schedules over a two-week period. Smartphone-based Experience Sampling Methodology (ESM) recorded daily sleep, mood, momentary affect and cognitive attentional functioning. Self-reported burnout, emotional dysregulation, emotion reactivity and affective dimensions (positive and negative) were also collected. Findings Overall, NHS nurses reported a high prevalence of depressive symptoms, stress, burnout and sleep-circadian rhythm disturbances. Generalised Additive Modelling (GAMs) revealed that NHS nurses higher perceived sleep quality predicted better next-day mood state, while better daytime mood was associated with reduced sleep onset latency, such that participants reported falling asleep faster. In contrast, daytime mood or affect (positive and negative) had no substantial, direct impact on nurses subjective sleep parameters (sleep quality, sleep duration, sleep efficiency). Exposure to fast rotating night shifts across the two-week study was associated with more frequent response errors on a Choice Reaction Time (CRT) cognitive task, while daytime somnolence did not adversely influence nurses momentary reaction time speeds or attentional function. Conclusions Clinically relevant sleep impairments, insomnia-related symptoms, elevated stress, and poor mood were pervasive in a sample of UK NHS nurses, regardless of shift type. Sleep quality impacted next-day mood and daytime mood impacted sleep latency, while rotating shifts led to an increase in cognitive errors. Recognising the impact of shiftwork and designing interventions to promote better sleep quality offer potential to enhance mood and performance in healthcare professionals. Clinical implications We need to implement and evaluate interventions that regularise sleep patterns and promote sleep quality to alleviate mood symptoms among frontline NHS shift workers.