Multiple Sclerosis and Related Disorders

BackgroundAccelerated long-term forgetting (ALF), defined as an increased rate of memory loss over extended intervals, has so far been detected in a pilot study of patients with mild multiple sclerosis (MS). This study aimed to (I) confirm the presence of ALF in a larger, heterogeneous MS sample, (II) explore associations with patient-reported outcomes, and (III) assess the diagnostic performance of ALF tests for subjective memory impairment. MethodsThis study compared 62 MS patients and 65 age-, sex-, and education-matched healthy controls using standardized memory tests (RAVLT, WMS-IV Logical Memory subtest). Recall was assessed immediately, after 30 minutes, and after 7 days. Seven-day/30-minute recall ratios (QRAVLT, QWMS) served as primary outcomes. Self-report measures included memory complaints, fatigue, depression, and sleep disturbances. Linear regression and Receiver operating characteristic (ROC) analyses assessed predictors and diagnostic accuracy. ResultsALF was observed in multiple sclerosis since QRAVLT was lower in patients than in controls (0.64 [95% CI 0.59-0.69] vs. 0.78 [0.73-0.82], p < 0.001), as was QWMS (0.79 [95% CI 0.74-0.84] vs. 0.95 [0.90-1.00], p < 0.001), despite comparable initial learning. Greater fatigue, higher memory complaints, longer disease duration, older age, and greater disability were associated with lower ALF scores. The combined ALF score moderately discriminated subjective memory impairment (AUC 0.74; sensitivity 0.73; specificity 0.73). ConclusionMS patients showed ALF despite normal initial learning, indicating a specific memory deficit undetected by standard tests. Long-delay recall using RAVLT and WMS-IV Logical Memory subtest may improve cognitive impairment detection in MS.

T-cell activation may be contributing to severe psychiatric disorders. Soluble CD27 (sCD27) - a marker for T-cell activation and disease activity in several autoimmune diseases - was evaluated as a tool for distinguishing T-cell activity in selected patients with severe psychiatric disorders, multiple sclerosis (MS), and controls. We hypothesise that elevated sCD27 levels will be associated with comorbid autoimmune disease (AID). sCD27 was measured in cerebrospinal fluid (CSF) and blood from a population enriched for suspected immunological comorbidity: the Immunopsychiatry Cohort (IP; n=115) and patients with MS (n=37), where levels in both groups were higher when compared with age matched controls undergoing surgery (n=154). Positive sCD27 (sCD27+), was defined as values >97.5% of controls. In IP, 23% were CSF sCD27+ and 15% blood sCD27+, compared to patients with MS where 88% were CSF sCD27+ and 22% were blood sCD27+. CSF-sCD27+ was confirmed as a sensitive marker for MS. In IP, CSF-sCD27+ was associated with comorbid AID (X2=4.847, p =0.028;) and AID disease activity (OR=5.14, p=0.029). Associations with AID were stronger when CSF and/or blood sCD27+ were combined (X2=8.559, p=0.003). CSF-sCD27+ in IP was also associated with pleocytosis, CSF-Total-tau, and CSF-NfL. In patients with severe psychiatric disorders, the sCD27+ cases were more likely to have comorbid AID and established markers for neuroinflammation in CSF. Combining analyses of CSF and blood improved sensitivity and specificity for AID suggesting compartmentalized T-cell activation. Psychiatric symptoms may precede somatic symptoms - or be the prominent symptom - of AID and sCD27 is a candidate marker for identification of this subgroup.

Disability worsening is the critical long-term outcome in multiple sclerosis, yet the Expanded Disability Status Scale incompletely captures neurological deterioration and has limited sensitivity in the short time windows of clinical trials. Composite endpoints incorporating functional measures have been proposed to address these limitations, but whether they reliably improve detection of treatment effects has not been established across trials. We conducted a post-hoc analysis of individual patient data from ten phase III randomised controlled trials (ASCEND, BRAVO, CONFIRM, DEFINE, EXPAND, INFORMS, OLYMPUS, OPERA I/II, and ORATORIO; n = 9,369), spanning relapsing-remitting and progressive multiple sclerosis. Confirmed disability worsening was defined using harmonised criteria with the msprog package and confirmed at 24 weeks. Treatment effects were estimated using Cox proportional hazards models and combined across trials in a one-stage individual patient data framework. Composite endpoints were constructed from the Expanded Disability Status Scale, the timed 25-foot walk test, and the nine-hole peg test using logical unions (OR-type), intersections (AND-type), and majority-vote structures. Sensitivity to treatment effect was quantified using Z-scores (the ratio of the pooled log-hazard ratio to its standard error) and compared to the Expanded Disability Status Scale reference using interaction tests. Event rates varied across components: the timed walk test generated the highest rates (up to 46.8%) while the nine-hole peg test generated the lowest (as low as 2.1%). OR-type composite endpoints showed weaker treatment effects than the Expanded Disability Status Scale alone, with the largest reductions in sensitivity observed for endpoints incorporating the timed walk test ({Delta}Z up to +2.26; interaction p = 0.004). These findings were confirmed across disease subtypes and were pronounced in relapsing-remitting trials, where no composite endpoint outperformed the Expanded Disability Status Scale. In progressive multiple sclerosis, the combination of the Expanded Disability Status Scale and the nine-hole peg test showed numerically stronger treatment effects ({Delta}Z = -1.65), though interaction tests did not reach statistical significance (p = 0.051). Composite endpoints do not systematically improve treatment effect detection in multiple sclerosis trials. Increased event capture driven by the timed walk test introduces noise that dilutes the treatment signal rather than amplifying it, highlighting that event rate and endpoint quality are not interchangeable. Upper limb function assessed by the nine-hole peg test provides complementary and specific information, particularly in progressive disease. The combination of global disability and upper limb measures represents a promising direction for future endpoint development in progressive multiple sclerosis trials, warranting validation.

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.

Background: Current medical large language model (LLM) evaluations largely rely on small collections of cases, whereas rigorous safety testing requires large-scale, diverse, and complex cases with verifiable ground truth. Multiple Sclerosis (MS) provides an ideal evaluation model, with validated diagnostic criteria and numerous paraclinical tests informing differential diagnosis, investigation, and management. Methods: We generated synthetic MS cases with ground-truth labels for diagnosis, localisation, and management. Four frontier LLMs (Gemini 3 Pro/Flash, GPT 5.2/5 mini) were instructed to analyse cases to provide anatomical localisation, differential diagnoses, investigations, and management plans. An automated evaluator compared these outputs to the ground-truth labels. Blinded subspecialty experts validated 70 cases for realism and automated evaluator accuracy. We then evaluated LLM decision-making across 1,000 cases and scaled to 10,000 to characterise rare, catastrophic failures. Results: Subspecialist expert review confirmed 100% synthetic case realism and 99.8% (95% CI 95.5 to 100) automated evaluation accuracy. Across 1,000 generated MS cases, all LLMs successfully included MS in the differential diagnoses for more than 91% cases. However, diagnostic competence did not associate with treatment safety. Gemini 3 models had low rates of clinically appropriate steroid recommendations (Flash: 7.2% 95% CI 5.6 to 8.8; Pro: 15.8% 95% CI 13.6 to 18.1) compared to GPT 5 mini (23.5% 95% CI 20.8 to 26.1), frequently overlooking contraindications like active infection. OpenAI models inappropriately recommended acute intravenous thrombolysis for MS cases (9.6% GPT 5.2; 6.4% GPT 5 mini) compared to below 1% for Gemini models. Expanded evaluation (to 10,000 cases) probed these errors in detail. Thrombolysis was recommended in 10.1% of cases lacking symptom timing information and paradoxically persisted (2.9%) even when symptoms were explicitly documented as more than 14 days old. Conclusion: Automated expert-level evaluation across 10,000 cases characterised artificial intelligence clinical blind spots hitherto invisible to small-scale testing. Massive-scale simulation and automated interrogation should become standard for uncovering serious failures and implementing safety guardrails before clinical deployment exposes patients to risk.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. Methods: Study AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional open-label program. The ENCALS model predicted survival of long-term survivors ([&ge;]5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). Results: Among 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population), and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate ({Delta}FS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function, and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease ({Delta}FS [&ge;]1.1 points/month) at baseline. Conclusions: Masitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinib effect on pro-inflammatory microglia may help identify responsive patients.

Despite important advances in understanding the etiopathology of multiple sclerosis, factors determining disease progression remain partially understood and often difficult to predict. Specific diagnostic and prognostic biomarkers are needed to optimize the risk-benefit ratio of treatment for each patient. The aim of our study was to identify a cerebrospinal fluid proteomic signature associated with diagnosis and short- to mid-term prognosis across the multiple sclerosis continuum. Our multicentric cohort study analyzed CSF samples from 120 patients using a proteomics data-independent acquisition strategy. Differentially expressed proteins were identified across diagnostic groups: 62 patients with multiple sclerosis, 15 patients with clinically isolated syndrome, and 43 healthy controls. We also compared the CSF of patients with no evidence of disease activity with those with disease activity at 2 and 5 years of follow-up. A diagnostic and prognostic classification model was built using iterative cross-validated logistic regression models on shared differentially expressed proteins across these two comparisons. A total of 1,257 proteins were quantified, and 162 differentially expressed proteins were identified across comparisons. We identified a set of ten proteins associated with the diagnosis and prognosis of multiple sclerosis, including previously identified potential biomarkers (CH3L2, IGHG1, IGKC, LAMP2, ADA2), proteins known to be involved in the pathophysiology of multiple sclerosis (A0A8J8YUT9, AT2A2, CO3A1) and two yet unreported proteins (DSC2 and MMRN2). Multivariate models based on these proteins achieved good accuracy for the diagnosis of MS compared with CIS (area under the receiver operating characteristics curve [AUROC] up to 80% using 3 proteins) and prognosis (NEDA vs. EDA; AUROC up to 96% at 2 and 5 years; using 5 proteins). These results, which will require further investigation to validate the new biomarkers, open new perspectives on multiple sclerosis pathophysiology and therapeutic targets.

Background: Sleep wake and circadian disturbances are increasingly recognised in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information. Methods: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim light conditions at six predefined time points around habitual sleep onset (HSO). Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined as the first time the fitted curve reached 3 pg/mL. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age and sex matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses. Results: Fifty plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 vs 20:58; p=0.028) despite similar HSO and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.02; p=0.017), and poorer survival/tracheostomy-free outcome. In re-sampled subgroup (n=28), DLMO and other melatonin-derived metrics did not change over 6 months. Conclusions: Circadian phase alterations are detectable in early ALS. Baseline DLMO may represent a non-invasive prognostic biomarker for progression, respiratory symptom emergence and survival, warranting validation in larger multicentre cohorts.

Objective: To develop the first inventory to measure psychosocial concerns about use of the non-preferred hand, toward the long-term goal of identifying the casual factors of left-right hand choices ("hand usage"). Design: Cross-sectional Setting: Online question battery Participants: 181 healthy adults Interventions; Not applicable Main Outcome Measures: Self-reported concerns about emotional and physical consequences of using the non-preferred hand. Results: Emotional and physical consequences reflected internally consistent categories (Cronbach's > 0.9) that were moderately correlated with each other ({rho} = 0.783 p = 0.002). Concerns were activity-dependent in each category ({rho} < 1x10-100). Reliability analysis and principal components analysis were used to reduce the battery to the 51-item Changed Hand Usage Concerns inventory, which encompasses everyday tasks and concerns about physical and emotional consequences of using the non-preferred hand in those tasks. Conclusions: Concerns about emotional vs. physical consequences of non-preferred hand use reflect coherent and internally consistent categories The Changed Hand Usage Concerns inventory allows assessment of psychosocial concerns about usage of the non-preferred hand for future attempts to manipulate hand usage via rehabilitation in patients with unilateral or asymmetric impairment.

Background: Lumbar spinal stenosis (LSS) can cause pain and severe walking limitation. Although surgery aims to improve walking, many patients do not achieve clinically meaningful gains. Rehabilitation can improve outcomes, yet existing programmes lack robust evidence and theoretical underpinning. This study aimed to (1) co-design a theory-informed rehabilitation programme to improve walking after LSS surgery, and (2) evaluate feasibility of conducting a future trial and acceptability of the intervention. Methods: A multi-methods study included intervention co-design followed by a single-arm feasibility study. Co-design used an adapted Experience-Based Co-Design approach with patients, carers, and healthcare professionals (n=39), integrating the Behaviour Change Wheel. This resulted in STructured Rehabilitation and InDividualised Exercise and Education (STRIDE), delivered over 12-week pre- and 12-weeks post-surgery, targeting knowledge, expectations, perceived control, physical capability, and fears. Adults aged [&ge;]50 years awaiting LSS surgery were recruited to a before-after feasibility study. Feasibility outcomes included recruitment and retention. Acceptability was assessed using the Theoretical Framework of Acceptability questionnaire (0-5 (high acceptability)) and focus groups. Clinical outcomes measured at baseline, post-prehabilitation, and post-rehabilitation included 6-minute walk distance (6MWD) and mean daily step count over 7 days. Results: Fifteen of 31 eligible participants were recruited (48%; mean age 70 years), with 80% retained to study end (2 decided against surgery, 1 unable to complete final assessment). Acceptability was high (median 5/5, IQR 0). Participants valued the personalised, supportive approach and reported improved motivation and preparation for surgery, though travel was burdensome. Small pre-operative and moderate-to-large post-operative improvements were observed in 6MWD (+49.9 m and +81.6 m) and daily step count (+868 and +1405 steps/day). Conclusions: This co-designed, physiotherapy-led, behaviour-change rehabilitation programme was acceptable to participants, with encouraging recruitment, retention, and signals of improved walking following LSS surgery. The findings support progression to a future trial.

Biological sex is a key determinant in the onset and progression of multiple diseases. In multiple sclerosis (MS), females exhibit higher disease prevalence, earlier onset, and more pronounced inflammatory activity, whereas males tend to experience a more severe neurodegenerative course, characterized by accelerated central nervous system damage and increased brain atrophy. The gut microbiome has emerged as a critical factor in MS, as its composition can either ameliorate or exacerbate disease progression. In this study, we aimed to identify reproducible sex-associated differences in gut microbial composition across independent cohorts of MS patients. Through a systematic search we identified six independent studies based on 16S rRNA gene sequencing, comprising a total of 337 samples. Despite substantial inter-study variability, sex-associated differences were more pronounced in MS patients than in healthy controls. We identified 11 microbial taxa showing significant sex-associated differences in MS, nine enriched in females and two in males. Notably, the female-enriched taxa Eggerthella and Eisenbergiella were associated with specific MS subtypes and higher disability. To facilitate the use of our findings by the scientific community, we developed a freely accessible web-based tool that provides full access to our results. Thus, in this work we identified consistent and reproducible sex differences in the gut microbiota of MS patients, highlighting the importance of incorporating sex as a critical variable in microbiome research, with potential implications for understanding disease heterogeneity in MS. IMPORTANCEMultiple sclerosis (MS) affects females and males differently, but the biological reasons behind these differences are not fully understood. One potential factor is the gut microbiome (i.e., the community of microorganisms living in our intestines) which can influence immune function and disease progression. In this study, we analyzed data from multiple independent cohorts and found consistent differences in gut microbial composition between female and male MS patients. Notably, certain bacteria were more abundant in females and were linked to more severe disease features. We also developed a freely accessible web tool where researchers can explore the complete findings in detail. Our results highlight the importance of considering sex as a key factor in microbiome research and may help guide more personalized approaches to understanding and treating MS.

Background and purpose: People after mild traumatic brain injury (mTBI) show persistent deficits in reactive balance. Cortical processes engaged during preparation and execution of balance reactions are reflected in distinct cortical activity signatures that can be measured with electroencephalography (EEG). The purpose of this study was to 1) compare preparatory cortical beta activity and evoked cortical N1 responses during balance recovery in people with mTBI and controls, and 2) explore relationships between preparatory and evoked cortical activity. Methods: Participants (age 21-35 years) with symptomatic mTBI (n=5, 27 +/- 13 days post-injury) and controls (n=5) completed the instrumented and modified push & release tests of reactive balance. Cortical activity was recorded using encephalography (EEG). Main outcome measures were 1) preparatory sensorimotor cortical beta-bust power and duration prior to balance perturbation onset (-1s-0s), and 2) cortical N1 response amplitude and latency during the post-perturbation balance recovery (50-250ms). Results: People with mTBI exhibited lower preparatory beta-burst power compared to controls (p=0.044, g=1.18). During balance recovery, cortical N1 responses occurred earlier in people with mTBI compared to controls (p=0.045, g=3.28). Relationships between preparatory and evoked cortical activity were altered after mTBI compared to controls; people after mTBI with greater beta-burst power and longer duration elicited shorter N1 latencies (r's>0.77, p's<0.010). Discussion and conclusion: The results serve as preliminary, hypothesis-generating observations to guide future research directions investigating neural signatures of reactive balance deficits in people after mTBI. The preparatory brain state before reactive balance recovery should be explored as a potential target for post-mTBI balance rehabilitation.

Background Phonemic awareness deficits are a core feature of Specific Learning Disorder-Reading (SLD-R). How task- and language-specific factors influence these deficits in alphasyllabary languages may help clarify the cognitive mechanisms underlying reading impairment in SLD-R. Methods Thirty children with a DSM-5 diagnosis of SLD-R (mean age 11.4 years) and 29 age-matched typically developing children were given phoneme blending (words and pseudowords) and segmentation tasks in Malayalam. The effects of age and consonant clusters on task performance were evaluated. Results Children with SLD-R performed significantly worse than controls across most phonemic awareness tasks, with the largest deficits observed in pseudoword blending and word blending, and smaller deficits in segmentation. No significant difference was observed for initial phoneme deletion. In typically developing children, age showed strong positive correlations with phonemic performance across most tasks, whereas the SLD-R group showed weak or absent correlations, except in word blending and initial phoneme deletion. Consonant clusters significantly affected performance in both groups, with SLD-R showing more severe deficits. Conclusions Phonemic awareness deficits observed in SLD-R in alphasyllabary languages like Malayalam are more prominent in tasks where lexical support is absent, like pseudoword blending. These deficits vary across task types and linguistic complexity. Phonemic awareness improves with age in typically developing children, while improvement is uneven in children with SLD-R. The findings suggest that phonemic awareness deficits are a core feature of SLD-R across languages, but their manifestation is shaped by orthographic and linguistic characteristics of the writing system.

Background: Spinal cord injury (SCI) is associated with widespread reorganisation of cortical sensorimotor circuits. Persistent complications such as spasticity and neuropathic pain suggest that homeostatic plasticity, which normally helps stabilise and constrain activity-dependent changes in sensorimotor circuits, may be disrupted after SCI. Homeostatic plasticity can be probed using repeated blocks of transcranial direct current stimulation (tDCS); in healthy individuals, two closely spaced excitatory blocks typically leads to an inhibitory response, reflected as a reduction in corticomotor excitability. Objective: To determine whether individuals with SCI show reduced homeostatic suppression of corticospinal excitability in response to repeated anodal tDCS, compared with healthy controls. Methods: Twenty adults with thoracic or below SCI and 20 healthy controls completed three counterbalanced sessions. Each session comprised two 10-minute blocks of 2 mA tDCS separated by 5 minutes, with the second block always being anodal tDCS over left primary motor cortex. The first block was either anodal, cathodal, or sham tDCS, yielding 3 condition types: anodal-anodal, cathodal-anodal, and sham-anodal. To assess corticomotor excitability, transcranial magnetic stimulation-evoked motor evoked potentials (MEPs) were elicited at baseline, after priming, and every 5 minutes for 60 minutes after the second block. The primary outcome was percent change in MEP amplitude from baseline. Results: In the anodal-anodal condition, the SCI group showed greater facilitation than controls over 0-30 minutes (estimate = 83.09, 95% CI 49.75 to 116.43, p < 0.001), suggestive of a weaker homeostatic response. The cathodal-anodal condition led to a significant overall facilitatory effect with no between-group difference, while the sham-anodal condition showed no change in MEP amplitude relative to baseline. Within the SCI group, exploratory subgroup analysis suggests that those with neuropathic pain and a traumatic injury showed greater facilitation in the anodal-anodal condition than those without these features, indicative of a weaker homeostatic response. Conclusions: SCI is associated with impairment in the homeostatic regulation of corticomotor excitability following repeated excitatory brain stimulation. Disrupted plasticity stabilisation may be relevant to persistent symptoms such as neuropathic pain.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are complex chronic conditions that often follow infectious triggers with overlapping clinical features but poorly defined pathophysiological relationships. This study aimed to identify disease-specific immune signatures through multiparameter immunophenotyping of monocytes, dendritic cells, and T-cell subsets. A total of 207 participants were included (ME/CFS: n = 103; long COVID: n = 63; healthy controls: n = 41). Peripheral blood mononuclear cells were analyzed using multiparameter flow cytometry. Statistical analyses included non-parametric testing, age-adjusted ANCOVA, correlation network analysis, and principal component analysis (PCA). Long COVID was characterized by increased M2-like monocyte polarization, elevated CD80 expression across monocyte subsets, expansion of dendritic cells, and reduced expression of activation markers, indicating persistent immune activation with features of immune exhaustion. In contrast, ME/CFS exhibited reduced costimulatory molecule expression, impaired CCR7-mediated immune cell trafficking, and less coordinated activation patterns, consistent with a state of immune suppression. Correlation network analysis revealed more extensive and integrated immune interactions in long COVID, while PCA identified distinct immunophenotypic components and enabled moderate discrimination between the two conditions. These findings demonstrate that ME/CFS and long COVID are characterized by distinct immune profiles, supporting the concept of divergent immunopathological mechanisms. The identified signatures may contribute to biomarker development and guide targeted therapeutic approaches.

Background: Most trials of Parkinson's disease (PD) measure progression over a short to medium time-period using continuous rating scales that may be hard to interpret and less meaningful for patients. There is a lack of evidence connecting changes in these scales to changes in outcomes important to patients. Objectives: We present causal modelling to translate the causal, short-term disease-modifying treatment effects on functional rating scales to the 10-year risk of serious clinical progression milestones. Methods: We selected four important clinical milestones of disease progression from the Oxford Parkinson's Disease Centre "Discovery" cohort: dementia, any falls, frequent falls, and mortality. We proposed a causal framework for our research objectives so we could model the potential impact of a 30% reduction in disease progression slopes ("treatment effect") using the summation of parts I and II of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (UPDRS12). This outcome was regressed on time to milestone using flexible parametric survival models. Marginal predictions of survival and survival difference at year 10 were then calculated for the Discovery cohort, and a counterfactual cohort applying the treatment effect to estimate the relative and absolute reductions for the four clinical milestones. Results: The model increase in risk for each unit change in the UPDRS12 were as follows: dementia hazard ratio (HR)=1.52 (95% Confidence Interval (CI) 1.36-1.70), any falls HR=1.37 (95% CI 1.29-1.46), frequent falls HR=1.68 (95% CI 1.49-1.89), mortality=1.29 (95% CI 1.17-1.42). These models led to marginal predictions of absolute reductions, when the progression was reduced by 30%, between 4.0% (mortality) and 7.5% (frequent falls) at 10 years follow up. Conclusions: We have demonstrated how a treatment effect in a trial specified in terms of a progression change of a rating scale can be contextualised into a long-term reduction in the probability of clinically relevant milestones. Whilst we have used PD as our exemplar, we believe this methodological approach is generalisable to other chronic progressive diseases where trials are often limited to a relatively short follow-up period and use some scalar measure of progression, but significant clinical milestones usually take longer to be observed. Keywords: Clinical trials; disease modifying therapies; causal estimation; prediction models

Background: People with HIV (PWH) have increased risk for cardiovascular diseases and other age-related comorbidities. These risks can be reduced through moderate to vigorous physical activity (MVPA), but MVPA can be difficult to sustain over time. Purpose: We tested tailored text messages added to motivational interviewing (MI) to sustain MVPA among PWH. Messages were created based on Two Minds Theory and matched to daily survey responses about exercise barriers. Methods: 118 PWH ages > 50 were initially randomized to high-intensity interval training or continuous moderate-intensity exercise. After 16 weeks, 92 participants were re-randomized to receive either tailored messages plus MI, or educational control messages, for 12 weeks. Both groups completed daily barrier surveys and wore an ActiGraph monitor for 1 week/month. Results: PWH still receiving messages at 28 weeks maintained their MVPA, ending at M = 48.8 minutes per day (SD = 45.8, n = 22/29), compared to a decrease among PWH in the educational-control group, ending at M = 40.7 (SD = 24.6, n = 25/32), p = .01 for the group-by-time interaction. Findings were similar using both actigraphy and self-reported MVPA, and were robust to attrition based on intent-to-treat analysis. PWH in the tailored-messaging group also reported higher exercise self-efficacy and better perceived health over time, relative to those in the educational-control group. Conclusions: An automated tailored-messaging intervention led to sustained MVPA. Tailored messages were superior to non-tailored educational messages, and may help PWH maintain their long-term health. Exploratory analyses suggested these effects were additive to motivational interviewing.

Introduction: Adults with spinal cord injury (SCI) often experience reduced or lost sensation and movement, impairing the ability of the brain to locate paralyzed body parts, which, in turn, compromises sensorimotor recovery. This disruption of the internal body map of the brain, or mental body representations (MBR), also contributes to neuropathic pain in about 69% of adults with SCI. Medications for neuropathic pain are often ineffective and can cause adverse reactions. Our previous pilot clinical trial showed that Cognitive Multisensory Rehabilitation (CMR), a physical therapy that restores MBR, produced significant, lasting reductions in neuropathic pain, improved sensorimotor function, and enhanced brain function. Building on these results, we examined whether 8 weeks of CMR or adaptive fitness (1) improved sensorimotor function and reduced pain; (2) greater brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Sixteen participants (52+/-8 years old, 13+/-10 years post-SCI) were randomized to 8 weeks of CMR or adaptive fitness (45 min, 3x/week). Ten participants had neuropathic pain of 3/10 or greater. Pain and sensorimotor function were assessed at baseline, post-intervention, and 3-month follow-up using the Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS). Functional MRI included resting-state and 4 tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR, participants improved on AIS with large effect sizes (touch: d=1.54; pinprick: d=1.83; lower limb motor function: d=1.32), while adaptive fitness had small/moderate effects (touch: d=0.49; pinprick: d=0.53; lower limb motor function: d=0.74). CMR also showed larger effect sizes for NRS (core: d=2.19; upper limb: d=0.69; lower limb: d=0.74) than fitness (core: d=0.73; upper limb: d=0.34; lower limb: d=0.00). Benefits persisted at follow-up. Highest neuropathic pain intensity reduced post-CMR and at 3-month follow-up (d=0.48; d=0.63). Pain increased slightly after fitness (n=6; d=-0.19; d=-0.41). CMR increased brain connectivity and activation during the leg imagery task. Increased activation during whole-body imagery was greater after CMR than fitness. Discussion: These preliminary results support the potential of CMR to improve function and reduce neuropathic pain in adults with SCI, warranting larger confirmatory trials. Clinicaltrial.gov: NCT05167032

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.

ObjectiveUnlike several other fields of healthcare, little is known about the size of therapist effects on patient outcomes following rehabilitation for musculoskeletal conditions. We aimed to estimate the proportion of variance in patient outcomes from a structured rehabilitation program explained by therapist effects. MethodsFor our observational cohort study we accessed data from the national multicentre Good Life with osteoArthritis in Denmark (GLA:D) osteoarthritis management program. Analyses included 23,021 consecutive eligible adults with hip or knee osteoarthritis (mean (SD) age 65.0 (9.8) years, 71% female) treated by 657 therapists between October 2014 and February 2019. The primary outcome was [&ge;]30% reduction in pain intensity on 0-100 VAS at 3 months. Therapist effects were estimated as the variance partition coefficient (intra-class correlation coefficient (ICC)) from two-level random intercept logistic regression models before and after adjusting for patient-level case-mix factors and therapist-level characteristics (number of patients treated, days since therapist certification). Analyses were repeated for a range of secondary outcomes using multiply imputed data and complete-case analysis. Results52% of patients reported a [&ge;]30% reduction in pain intensity on 0-100 VAS at 3 months. In the null model the ICC was 0.007 (95%CI: 0.005, 0.009), which changed little after adjusting for patient- and therapist-level covariates. Upper confidence limits for ICC estimates across all secondary outcomes in multiply imputed and complete case analyses were less than 0.03. ConclusionsIn a nationally implemented osteoarthritis management program delivered by trained healthcare professionals, therapist effects made a minimal contribution to variation in patient outcomes. KEY MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABS Therapist effects - defined as the effect of a given therapist on patient outcomes as compared to another therapist - have been observed in several fields of healthcare and have important consequences for selection, training, and service improvement. In musculoskeletal rehabilitation five previous studies suggest that 1-12% of variation in patient-reported outcomes may be attributable to therapist effects, but these estimates were based on relatively small datasets resulting in substantial uncertainty. What this study addsOur cohort study analysed registry data from 2014-2019 on 23,021 patients and 647 trained therapists from the nationally implemented GLA:D structured osteoarthritis management program in Denmark. We found that therapist effects accounted for less than 3% of total variation in patient-reported pain and quality of life outcomes 3 months after beginning the program How this study might affect research, practice, or policyOur findings suggest that contextual factors that relate to therapist effects - therapist characteristics or therapist-patient interaction and alliance - make a minimal contribution to variation in patient outcomes from this structured, group-based rehabilitation intervention. Any contextual effects must be attributable to alternative sources, e.g. patient expectations, intervention setting.