Muscle & Nerve

Introduction Spinal muscular atrophy (SMA) is a monogenic neuromuscular disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Onasemnogene abeparvovec is a U.S. FDA-approved single-dose gene therapy for SMA. Both its intravenous formulation (Zolgensma, approximately USD 2.13 million per patient) and intrathecal formulation (Itvisma, around USD 2.59 million per patient) are prohibitively expensive, substantially limiting accessibility in low- and middle-income countries (LMICs). We conducted a clinical study of vesemnogene lantuparvovec, an alternative to onasemnogene abeparvovec developed for use in LMIC settings. Methods Sixteen patients with SMA, including 8 with type 1 SMA and 8 with type 2 SMA, received a single intrathecal administration of vesemnogene lantuparvovec. Eleven patients were treated with a low dose (1.5 * 10^14 vg) and five with a high dose (3.0 * 10^14 vg). The primary endpoints were safety and efficacy, assessed by changes from baseline in developmental gross motor milestones according to the World Health Organization criteria. Overall survival was primarily evaluated in type 1 SMA patients. This trial was registered with ClinicalTrials.gov NCT06288230. Results As of the March 2026 cutoff date, 15 of 16 treated patients had completed at least 12 months of follow-up after treatment, while the remaining one type 1 SMA patient died of disease progression at month 6 post-treatment. At 12 months post-treatment, among the surviving 7 patient with type 1 SMA, the median age was 21.6 months (range, 16.1 to 32.3 months). Among the 16 treated patients, the median age at diagnosis was 4.4 months (range, 0.0 to 18.0 months), and the median age at dosing was 10.7 months (range, 2.8 to 22.5 months). All patients experienced at least one AE. Thirty-one AESIs were reported in 13 patients, including hepatotoxicity, thrombocypenia-related events and cardiac events. No patient required prolonged prednisolone prophylaxis. SAEs, including pneumonia, lower respiratory tract infection, upper respiratory tract infection, and haemorrhagic diarrhoea, occurred in 5 of 8 (63%) patients with type 1 SMA and 2 of 8 (25%) patients with type 2 SMA. Two patients with type 1 SMA required invasive ventilation, and one of whom subsequently died. At 12 months post-treatment, 11 of 16 treated patients (69%) gained at least one new WHO motor milestone versus baseline, including 3 type 1 and 8 type 2 SMA patients; one type 2 patient gained six WHO motor milestones and achieved independent walking. Conclusions In patients younger than 24 months of age with type 1 or type 2 SMA, a single intrathecal dose of vesemnogene lantuparvovec was safe and generally well tolerated and was associated with improvements in developmental gross motor milestones compared with outcomes observed among referred but untreated patients. Additional studies are required to further evaluate the long-term safety and efficacy of this gene therapy.

Ankle clonus is a sustained, involuntary, rhythmic muscle contraction frequently observed in humans with spinal cord injury (SCI). Although its pathophysiology remains incompletely understood, converging evidence suggests a role for brainstem systems in its generation. Following SCI, brainstem neuromodulatory inputs partially compensate for the loss of descending motor pathways by regulating motoneuron excitability during involuntary contractions, suggesting their involvement in the generation of clonus. To test this hypothesis, motoneuron excitability in response to Ia synaptic input was quantified using the soleus H reflex and maximal motor response (H/M ratio), and brainstem involvement was probed using the long lasting component of the cutaneous reflex (LLR) in the tibialis anterior and soleus muscles, as well as the StartReact response-an involuntary release of a movement triggered by a startling stimulus thought to engage the reticulospinal tract. We studied individuals with chronic SCI, both with and without ankle clonus, using standardized clinical tests across two days. Participants with clonus showed elevated H/M ratios, indicating increased motoneuron excitability, whereas those without clonus exhibited lower values than controls. Additionally, individuals with clonus exhibited longer LLR duration and greater LLR magnitude in both muscles, along with shorter reaction times to startle stimuli, consistent with enhanced monoaminergic and reticulospinal contributions. Notably, LLR duration was positively correlated with both StartReact response and H/M ratio. Together, these findings support a role for descending brainstem systems-particularly monoaminergic and reticulospinal pathways-in the maintenance of clonus in chronic SCI.

Background and Objectives Patients with peripheral neuropathies (PN) commonly exhibit balance impairment. In clinical practice, balance is typically assessed using the Rombergs test and ataxia scales, which rely on examiner interpretation, while objective biomarkers for quantifying balance remain lacking. Wearable sensors are valuable tools for objectively quantifying gait abnormalities in PN patients and may capture clinically meaningful changes over time. By integrating these parameters, artificial intelligence (AI) can assist in generating a digital score that enables easy, objective, and reproducible monitoring of patients postural balance. This study aims to generate and assess an AI-generated digital Rombergs test to quantify balance impairments in a cohort of PN patients. Methods PN patients were assessed in a longitudinal study using a wearable system composed of inertial sensors placed on the trunk and plantar pressure sensors integrated in insoles. Patients performed the Rombergs test under both eyes-open and eyes-closed conditions and were classified according to ataxia severity (mild, moderate, or severe) following the score obtained in item 1 of MICARS and SARA scales. Results We included 97 patients with PN (including autoimmune and hereditary polyneuropathies), and 117 healthy controls (HC). Significant differences in trunk sway and center of pressure (COP) were observed between groups, particularly with eyes closed. Using wearable sensor parameters, we developed an AI digital Rombergs test, which correlated with clinician-rated Rombergs test performance and distinguished patients with and without ataxia (AUC=0.632) and across different PN pathologies. Longitudinally, digital Rombergs test and iRODS showed concordant trajectories. Also, changes [≥]25% in the score were associated with clinical changes in ataxia severity measured by an increase in MICARS-SARA score (+1.42 points), whereas improvement was associated with a decrease (-0.20 points) in the scale. Discussion This study demonstrates that wearable sensors are useful to detect and quantify balance impairment. The AI-generated Rombergs test is an objective and reproducible tool for postural balance assessment, with robust discriminatory performance across clinical ataxia severity in PN. Scores longitudinal changes aligned with clinical severity, supporting its potential for monitoring disease progression and treatment response. Its strong association with balance measures reinforces its role as a quantitative biomarker of postural control in ataxia patients.

Abstract Objectives: Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50-derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. Material and Methods: In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n =433) and validation cohort (Bonn, n =185). Results: In both cohorts TnT demonstrated a robust correlation with rD50-defined phases across all aggressiveness subgroups (p<0.001). There was no consistent pattern regarding sNfL and the rD50 phases. sNfL concentrations demonstrated a significant and inverse correlation with D50 applied for all disease aggressiveness subgroups (p<0.001). Correlations of TnT levels with D50 disease aggressiveness groups were generally less strong and inconsistent between the two cohorts. In the discovery cohort only low aggressiveness subgroups correlated significantly (p<0.001), intermediate aggressiveness subgroups showed only a weak correlation (p<0.05) with TnT levels. High disease aggressiveness subgroups showed no significant correlation with TnT. Conclusion: In application of the D50 disease progression model, TnT was strongly associated with disease accumulation (rD50) across all disease phases, independent of disease aggressiveness (D50), whereas sNfL robustly reflected disease aggressiveness but not overall disease burden. These complementary biomarker profiles highlight the value of an integrated approach for refined disease stratification in ALS. Combining TnT and sNfL may enhance clinical decision-making, improve monitoring of disease progression and treatment response, and support optimized clinical trial design.

ObjectiveSystemic sclerosis (SSc) predominantly affects females but exhibits greater disease severity in males, suggesting sex differences underlying SSc pathogenesis. We sought to define sex-associated alterations in the peripheral immune landscape of patients with SSc. MethodsWe performed high-dimensional immune profiling of PBMCs from 37 healthy donors (68% female) and 37 patients with SSc (11 limited, 26 diffuse; 68% female) using 30-color spectral flow cytometry, quantifying 56 immune cell subsets per donor. We conducted sex-stratified comparisons and correlation analysis, and used principal component analysis followed by linear discriminant analysis to derive a sex-discriminant immune cellular module. ResultsDiffuse cutaneous SSc (dcSSc) was associated with a distinct immune landscape characterized by increased monocyte and decreased natural killer-like and B cell frequencies, suggesting a myeloid-skewed peripheral immunophenotype. Males exhibited greater enrichment of innate immune subsets, including monocyte and dendritic cell subsets, while females exhibited greater enrichment of adaptive immune subsets. Among T cells, dcSSc was associated with coordinated remodeling across CD4+ and CD8+ subsets, including expansion of stem cell memory T cells (Tscm), and increased regulatory T cells, Th17 skewing, and decreased effector-memory CD8+ subsets. Females exhibited greater proportions of naive- and Tscm, and males exhibited higher proportions of effector-memory subsets. Integrating these data, we identified a sex-discriminant immune module comprised of 20 cell types that distinguishes males and females with dcSSc. ConclusionsSSc is associated with sex-specific differences in the peripheral immune landscape. A sex-associated immune program, further amplified in disease, may contribute to the paradox of female-biased susceptibility and male-biased severity in SSc.

ImportanceRecovery after upper extremity peripheral nerve injury (PNI) surgery depends on changes in cortical neural patterns that support sensorimotor control. Task-based functional connectivity (FC) can characterize these changes, yet few studies have explored FC during ecologically fine motor valid tasks after PNI. ObjectiveTo investigate task-based FC with the left primary motor cortex (M1) during right hand drawing in individuals following right hand PNI surgery. ParticipantsForty-four right-handed adults, including 12 patients post PNI surgery (n = 8 with nerve repair, n = 4 with nerve transfer) and 32 healthy controls. MethodsAll participants underwent fMRI while performing a RH visuomotor precision drawing task. Seed-based connectivity analysis was performed to characterize the pattern of FC between left M1 and all voxels in the brain. We hypothesized that left M1 FC would differ between patients and controls, between Repair and Transfer groups, and covary with time since surgery. ResultsPatients (vs. controls) showed greater FC between left M1 and right visual and premotor cortices. Nerve transfer (vs. repair) showed greater FC between left M1 and right inferior parietal areas. Time since surgery was not linearly related to FC, though exploratory analyses suggested a negative association between log-time and FC between left M1 and right inferior parietal lobule. ConclusionAfter PNI surgery, visuomotor precision drawing involved distinct and behaviorally relevant neural patterns, which varied by task demand and potentially by surgical group despite clinical heterogeneity. Inferior parietal cortex may be especially engaged in early months after surgery (i.e. log-time). To improve recovery of upper limb function after PNI, clinical recommendations include incorporating early function-specific dexterous training, tailoring rehabilitation across surgical and recovery stages, and using multidimensional assessments of hand function.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is characterized by prepubertal abrupt onset of obsessive-compulsive disorder (OCD). The sine qua non is group A streptococcus (GAS) infection, which is hypothesized to elicit an IgG-class anti-GAS antibody response that cross-reacts with antigens in the basal ganglia. However, the association between GAS antibody (GAS-IgG) levels and PANDAS has been inconsistent, and qualitative differences in GAS-IgG profiles have not been carefully evaluated in well-phenotyped cohorts. Moreover, independent studies have yet to converge on anti-neural autoantibodies that are specific to PANDAS. Here, we used phage display immunoprecipitation sequencing (PhIP-Seq) to perform ultra-deep anti-pathogen antibody repertoire profiling of serum from definitive pediatric PANDAS patients (N = 34) collected as part of a prior double-blind, placebo-controlled clinical trial of intravenous immunoglobulin (IVIg). PANDAS cases were compared to pediatric controls without a history of neuropsychiatric illness (N = 31). To assess for objective evidence of neuroglial injury, serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) levels were compared to healthy pediatric controls. Within PANDAS, NfL and GFAP levels were compared between pre- and post-treatment sera. To evaluate for central autoantibodies, a subset of baseline cerebrospinal fluid (CSF) samples (N = 25) was profiled by full-length human protein microarray. Though GAS reactivity by PhIP-Seq was well correlated with clinical anti-DNaseB and anti-streptolysin O titers, there were no quantitative or qualitative differences in GAS-IgG profiles between PANDAS and controls. Furthermore, NfL and GFAP levels did not differ between cases and controls. Within PANDAS, changes in NfL or GFAP levels at six weeks did not differ between placebo and IVIg groups. However, CSF autoantibody profiling by protein microarray revealed infrequent but notable candidate autoantibodies. In one patient, we identified autoantibodies against Argonaute family proteins (AGO-IgG), a marker of autoimmune sensory neuropathy. Longitudinal measurement of AGO-IgG in sera revealed that titers were unchanged after placebo, but decreased after IVIg, coinciding with symptomatic improvement, including a decrease in that patients CY-BOCS score. Overall, these results do not support an etiologic role for GAS-IgG in PANDAS. However, some individuals diagnosed with PANDAS may harbor anti-neural autoantibodies.

IntroductionVagus nerve stimulation modulates laryngeal, cardiac, pulmonary, and gastrointestinal functions. Knowledge of where along the vagal trunk organ-specific branches emerge may support alternative surgical placements of stimulation devices to engage targeted functions while avoiding off-target effects. However, no quantified map of how vagal branches emerge and how they relate to surgically relevant anatomical landmarks exists in humans. MethodsFifty-eight vagus nerves (29 left, 29 right) from 29 embalmed donor bodies (15 females) were dissected from the jugular foramen through the thoracic cavity. Branches were traced to end organs and allocated to seven groups -- sympathetic, muscular, vascular, cardiac, pulmonary, esophageal, and multiple targets -- and several sub-groups. Distances between branch emergence and the jugular foramen (JF) were normalized to three anatomical landmarks: carotid bifurcation, laryngeal prominence, and superior border of clavicle. ResultsBranch emergence follows a proximal-to-distal order: sympathetic (5.28 cm from JF), muscular (9.59 cm), vascular (10.70 cm), cardiac (19.65 cm), pulmonary (25.36 cm), and esophageal (26.57 cm). Vagal branches emerge into two embryological domains separated near the clavicle: pharyngeal arch-targeting branches cluster proximally (9.34 cm) and primitive mediastinum-targeting branches cluster distally (23.74 cm), with sympathetic, muscular, and vascular sub-groups occupying distinct zones within the proximal domain. The largest branch-free intervals occur above the left clavicle (2.33 {+/-} 2.80 cm) and below the left carotid bifurcation (2.58 {+/-} 3.17 cm). Alternate placement regions separating targeted organs from off-targets: sympathetic vs. cervical visceral at 6/8 cm (L/R), cardiac vs. carotid sinus/bifurcation at 14/10 cm, and recurrent laryngeal vs. other cervical visceral at 18/13 cm from JF. Overall, no differences were found between male and female donors. ConclusionsThis study provides a quantified, landmark-registered map of cervical and thoracic vagal branch emergence, offering a standardized anatomical template that may inform strategies for more function-selective vagal neuromodulation.

Eya3 and Eya4 are two Eya genes expressed in adult myogenic stem cells, where they may act as SIX cofactors. We analyzed muscle regeneration in single and compound Eya3 and satellite cell-specific Eya4 mutant mice. A kinetic analysis of muscle regeneration after Notexin injury of the Tibialis Anterior revealed no major phenotype at 4, 14, and 30 days after injury in terms of PAX7+ cell number and myofiber cross-sectional area in Eya3 mutants, while all parameters were decreased in Eya4 mutants and further worsened in Eya3/Eya4 double mutants, in which we also observed a modification of the myofiber phenotype at 30 days after injury. Satellite cells were cultured ex vivo and Eya4 deletion was induced by Ad-Cre-mediated recombination. While single Eya3 mutant cells showed normal proliferation and differentiation, double mutant cells exhibited normal proliferation but failed to fuse. Analysis of their transcriptome revealed that the expression of Myomixer, Follistatin, and Noggin was severely downregulated specifically in double mutant cells, explaining their fusion deficiency. To gain a better understanding of the involvement of Eya genes during embryonic development and the genesis of PAX7+ myogenic stem cells, we analyzed Eya1 / ;Eya2 / , Eya3 / , Eya4 / , and Eya3 / ;Eya4 / E18.5 mutant fetuses at the limb and craniofacial levels. In Eya1 / ;Eya2 / fetuses, we confirmed the absence of distal limb muscles and observed reduced craniofacial muscles. In Eya3 / ;Eya4 / fetuses, craniofacial myogenesis appeared preserved and PAX7+ myogenic stem cells were present. BackgroundThe Eyes absent (Eya) genes encode transcriptional co-activators and phosphatases that function within the PAX-SIX-EYA-DACH (PSED) regulatory network. In skeletal muscle, EYA proteins cooperate with SIX homeoproteins to control myogenic gene expression during both embryonic development and adult regeneration. While Eya1 and Eya2 are predominantly expressed in embryonic myogenic progenitors and Eya3 and Eya4 are the dominant paralogs in adult satellite cells (SC), the specific and redundant contributions of individual family members to myogenesis remain poorly characterized. MethodsWe analyzed compound Eya mutant mice during adult Tibialis anterior muscle regeneration and during embryogenesis. We complemented this analysis by performing ex vivo myogenic stem cell cultures from compound Eya mutants and examining their fusion capacity. ResultsAnalysis of muscle regeneration following Notexin injury revealed that Eya2 and Eya3 single mutants display no major regenerative deficit. In contrast, satellite cell-specific deletion of Eya4 (Eya4sc/sc) caused a transient impairment of early regeneration, with reduced numbers of smaller regenerating MYH3+ (embryonic myosin heavy chain) myofibers and a transient decrease in SC number at 4 days post-injury (dpi). Compound Eya3-/-;Eya4sc/scdouble mutants showed a more severe and persistent phenotype, with decreased myofiber cross-sectional area, reduced myonuclear accretion, accumulation of PAX7+ cells associated with regenerated myofibers, and altered fiber-type composition at 14 and 30 dpi. Ex vivo analysis of double mutant SCs revealed a specific and complete blockade of myogenic fusion without defects in proliferation or MYOD expression. Transcriptomic analysis identified severe downregulation of Myomixer, Noggin, and Follistatin in differentiating Eya3-/-;Eya4-/- SCs. Open-access SIX1 and SIX4 ChIP-seq publicly available data confirmed direct binding at the Myomixer, Noggin, and Follistatin loci, supporting a direct SIX-EYA transcriptional mechanism. In parallel, embryonic analysis demonstrated that Eya1-/-;Eya2-/-E18.5 fetuses lack distal limb musculature and display severe craniofacial muscle hypoplasia, while in Eya3-/-;Eya4-/-fetuses limb and craniofacial musculature developed with no detectable defects. ConclusionsThese results reveal distinct temporal requirements for EYA proteins in skeletal muscle: EYA1 and EYA2 are essential SIX cofactors for embryonic myogenic fate acquisition in hypaxial and craniofacial progenitors, while EYA3 and EYA4 act redundantly in adult satellite cells to enable myogenic fusion by maintaining BMP antagonist expression and Myomixer activation downstream of the SIX-EYA transcriptional complex.

IntroductionSpinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD) are progressive genetic neuromuscular disorders imposing substantial caregiving demands on families. In Pakistan, where disease-modifying therapies remain largely inaccessible, care is predominantly supportive, frequently resulting in psychological distress and diminished caregiver confidence. An individuals belief in their capacity to execute required behaviours, self-efficacy, is a recognised determinant of caregiving quality, yet evidence on caregiver self-efficacy in SMA and DMD within low-resource settings remains sparse. This study aims to evaluate the effect of a multicomponent, digitally delivered intervention on self-efficacy among primary caregivers of children with SMA and DMD in Pakistan. Methods and AnalysisThis single-group, pre-post study will recruit 30 primary caregivers of children with SMA or DMD enrolled in the Treat-NMD Registry of Pakistan. An eight-week intervention will be delivered via online support groups, comprising educational video clips, expert-led live sessions, pictorial guides, and progressively tapering audio reminders. The primary outcome, self-efficacy, will be measured using a culturally adapted, content-validated Urdu version of the DMD Caregiver Self-Efficacy Scale (DMD-CSES), assessed at baseline (T0) and eight weeks post-intervention (T1). Pre-post scores will be compared using a paired t-test or Wilcoxon signed-rank test depending on data distribution, with analyses conducted in STATA Version 17. Ethics and DisseminationEthical approval has been granted by the Ethics Review Committee of Aga Khan University (2025-11875-37040). Verbal informed consent will be obtained from all participants, with confidentiality maintained throughout. Findings will be disseminated via peer-reviewed publication, conference presentations, and shared with the Treat-NMD registry network. Trial registration numberNCT07356063, Date of registration: 11/January/2026

Abstract Purpose: MyotonPRO (MTP) and time-harmonic elastography (THE) are increasingly used to assess muscle mechanical properties, yet they operate on fundamentally different physical principles. MTP measures composite MTP stiffness (N/m) through surface oscillations, while THE quantifies intrinsic shear modulus (THE stiffness, kPa) via propagating shear waves. This study aimed at systematically compare MTP and THE measurements in the vastus lateralis muscle across different contraction intensities and examine how the skin layer and subcutaneous fat (SLSF) thickness influence their relationship. Methods: Twenty-six healthy adults (15 males, 11 females; age 25 [SD 4] years) underwent MTP and THE measurements of the vastus lateralis at rest and during isometric contractions at 15% and 30% maximal voluntary contraction (MVC). Effects of contraction intensities on tissue properties were assessed using univariate analyses of variance with repeated measures. Associations between the different outcomes of THE and MTP technologies were explored using Pearson's correlations and partial correlation coefficients separately for each contraction intensity with adjustment of the SLSF thickness of participants. Results: Both technologies detected contraction intensity-dependent stiffening across all outcomes (p < 0.001). THE stiffness increased from 5.3 [1.2] kPa at rest to 15.6 [6.1] kPa at 30% MVC; THE wave attenuation increased from 0.83 [0.19] to 1.42 [0.36] s/m while MTP stiffness increased from 337.3 [49.3] N/m at rest to 529.4 [160.7] N/m at 30% MVC. Correlations between modalities were weak and condition-dependent. THE wave attenuation did not significantly correlate with any MTP outcome across conditions. Conclusion: MTP and THE detect contraction-induced stiffening through fundamentally different physical mechanisms and should not be regarded as interchangeable. Their correlation is modest at rest and breaks down (or reverses) during active contraction, with subcutaneous fat as a key modifying factor. Clinical trial number: Not applicable.

BackgroundSickle cell disease (SCD) is the most common recessive genetic disorder, caused by pathogenic variants of the HBB gene. SCD is associated with a range of clinical manifestations, including vaso-occlusive crises, infections, and severe anaemia, which contribute to increased morbidity and mortality. The frequency of pathogenic alleles is high in Sub-Saharan African countries, with heterozygous carriers reaching up to 25% of the population. Several methods can be employed for molecular diagnostics, with HBB gene sequencing being the most precise. However, access to DNA analyses and sequencing in Low- and Middle-Income Countries (LMICs), where SCD prevalence is high, is limited. Understanding genetic profiles is crucial at both individual and population levels, as it can guide public health strategies and facilitate accurate genetic counselling. AimThis feasibility study aimed to demonstrate that a portable medical genetic laboratory (in suitcases) can be used to genotype individuals for the HBB A, S, and C alleles and their combinations within a few hours outside of a laboratory setting. Methods and resultsWe established a portable medical genetics laboratory capable of DNA extraction and isothermal DNA amplification using a commercially available kit for the A, S, and C alleles of the HBB gene. During one single study day, this portable lab was set up in a room where the Swiss Association of Patients with SCD was holding its annual meeting. We analysed the samples of 27 participants who were aware of their A, S, or C status. We collected buccal swabs and dried blood samples for genotyping. Genotype results for all participants were obtained within five hours after sample collection. In four cases, we observed discrepancies between the buccal swab and blood genotypes; three were resolved upon repeat testing, and one reflected donor chimerism following hematopoietic stem-cell transplantation. ConclusionsThis study demonstrates the feasibility and efficiency of using a portable medical genetics laboratory for rapid genotyping of HBB SCD alleles in community settings.This approach can improve access to molecular diagnostics in resource-limited environments. Such tools have the potential to significantly enhance local capabilities for genetic screening, counselling, and public health planning in regions heavily affected by SCD.

Background: Spinal pain, including neck pain and low back pain (LBP), is a common musculoskeletal condition and major contributor to disability worldwide. Evidence comparing disability, fatigue and mental health across acute and chronic stages remains limited, particularly in conflict-affected and low-resource settings. This study assessed these outcomes among patients with acute and chronic neck pain and LBP in the Gaza Strip. Methods: A comparative cross-sectional study was conducted among 410 adults attending outpatient physical therapy at Nasser Medical Complex, Khan Younis, Gaza Strip. Participants included 204 with neck pain and 206 with LBP, classified as acute neck pain (n=101), chronic neck pain (n=103), acute LBP (n=102) and chronic LBP (n=104). Disability, fatigue, psychological distress and sleep disturbance were assessed using the Neck Disability Index (NDI)/Oswestry Disability Index (ODI), Fatigue Severity Scale (FSS), Patient Health Questionnaire-4 (PHQ-4) and PROMIS Sleep Disturbance Short Form 8a. Independent t-tests, adjusted linear regression, correlation analyses, clinical-threshold analyses and binary logistic regression were performed. Results: Chronic neck pain and chronic LBP were associated with significantly higher disability, fatigue and psychological distress than acute pain. Chronic neck pain patients had higher NDI, FSS and PHQ-4 scores than acute neck pain patients; chronic LBP patients had higher ODI, FSS and PHQ-4 scores than acute LBP patients (all p<0.001). Sleep disturbance did not differ significantly between groups. Female participants reported higher psychological distress in both pain groups, with higher fatigue in neck pain and higher disability in LBP. Adjusted analyses confirmed that chronic pain status remained associated with higher disability, fatigue and psychological distress. Fatigue was the most consistent factor independently associated with chronic pain status. Conclusions: Chronic spinal pain was associated with greater disability, fatigue and psychological distress than acute spinal pain, while sleep disturbance was common across groups. These findings support early multidimensional assessment, including screening for fatigue and psychological distress. Longitudinal studies are needed to clarify whether these factors contribute to transition from acute to chronic spinal pain.

A hallmark of damaged skeletal muscle fibers is displaced myonuclei that are no longer peripherally positioned. Displaced myonuclei are dogmatically thought to be derived exclusively from muscle stem cell (satellite cell) fusion. Using a surgical resection muscle injury model and in vivo recombination-independent resident myonuclear labeling, we detail the prevalence, time course, and origin of displaced myonuclei in response to a non-chemically-mediated muscle trauma. We found that: 1) non-satellite cell-derived (resident) displaced myonuclei emerge seven days after surgical injury in similar proportion to exogenous (satellite cell-derived) displaced myonuclei in intact muscle fibers, with a biased prevalence in myosin heavy chain IIB muscle fibers, 2) muscle fibers with multiple ([&ge;]2) displaced resident myonuclei was an unexpected but noteworthy feature of muscle fibers 7 days after injury, 3) embryonic myosin-expressing fibers at seven days post-surgery expectedly contain predominantly satellite-cell derived displaced myonuclei, but a subset have displaced resident myonuclei, and 4) satellite cell numbers in intact muscle do not increase until 7 days post-surgery. These data may help inform whether to target satellite cell-initiated processes, myonuclear-initiated processes, or both to facilitate muscle fiber injury repair. This information could lead to more effective therapeutic strategies for treating muscle trauma.

Measuring neuromotor control after stroke is crucial for identifying the mechanisms underlying asymmetrical walking and guiding rehabilitation. The lower extremity portion of the Fugl-Meyer (FM-LE) and the number of muscle synergies are commonly used measures, but have important limitations. The dynamic motor control index has emerged as a complementary metric, yet its relationship to established clinical measures (i.e., FM-LE), muscle synergy number, and gait biomechanics remains unclear. This study evaluated the ability of the dynamic motor control index to quantify post-stroke neuromotor impairment relative to FM-LE and muscle synergy number and examined its relationship with propulsion asymmetry. Electromyography data from 22 individuals post-stroke and 31 neurotypical controls were analyzed using non-negative matrix factorization. The dynamic motor control index and not the muscle synergy number differentiated paretic, non-paretic, and neurotypical limbs ({chi}2(2) = 27.57, p < .001). It also differed significantly between less and more impaired individuals classified by FM-LE (p = .05) and demonstrated good discriminative performance between these groups (AUC: 0.777, p = .017). The index also moderated the relationship between FM-LE and propulsion asymmetry ({Delta}R2 = 0.223, p = .007). These findings support the dynamic motor control index as a clinically relevant msarker of post-stroke neuromotor impairment and recovery.

Mitochondrial diseases (MDs) are genetically and phenotypically diverse and can be difficult to diagnose. Prevalence estimates derive largely from diagnosed cases and may underestimate population MD risk. Population-based studies are limited in scope and number but indicate MD variants are common. As genomic sequencing advances have made comprehensive population-based evaluation feasible, we sought to evaluate nuclear MD variation in a population cohort to understand variant prevalence and differences in MD risk estimates We identified disease-associated nuclear gene variants in 270 nuclear MD genes across 2,845 healthy older individuals in the Medical Genome Reference Bank. From Pathogenic or Likely Pathogenic Variants (PLPVs) we estimated autosomal recessive (AR) and autosomal dominant (AD) MD risk for individual genes and all nuclear variant-associated MDs. We identified 554 PLPV alleles representing 357 unique variants in 145 genes. Combined AR MD risk was estimated at 25.8 per 100,000 (95% CI 18.7 to 32.9), or 1 in 3,880 individuals. SPG7 (12.65 per 100,000; 95% CI 7.52-20.6) and POLG (4.23 per 100,000; 95% CI 2.10-8.01) contributed the greatest single gene AR MD risks and OPA1 variants posed the greatest AD MD risk. We observed a high rate of MD-associated nuclear gene variation in this healthy older cohort. The estimated lifetime AR MD risk was higher than commonly quoted prevalence estimates for all MDs, and the presence of common AD variants suggests variant penetrance may be lower than previously understood. These data help contextualise population MD risk and may inform clinical counselling and care.

The severity stratification of carpal tunnel syndrome (CTS) relies on ultrasound morphological markers and electromyography. However, it remains unclear how structural imaging can reliably infer functional impairment. Clarifying the structure-function relationship is critical for efficient diagnostic pathways. A retrospective cohort of 55 patients with symptoms related to CTS was analyzed at the Shanghai Sixth Peoples Hospital. All patients were subjected to ultrasound and EMG. 72.7% cases were diagnosed with CTS with a female predominance and equal left-right involvement. Random-forest classifiers were trained using surrogate splits, and performance was evaluated using predictions outside the bag. A full-feature model (34 candidate variables) was compared against a simplified model (8 core variables) capturing the core morphological and electrophysiological features. A residual-based framework was then used to characterize the structure-function mismatch within severity grades (1a-3c). The simplified model improved discriminative performance compared to the full-feature model (AUC 0.789 to 0.824). The simplified model achieved an overall accuracy of 77.3%. Analysis of predicted probability distributions and 10-bin calibration curves indicated stable and clinically interpretable risk estimation in most probability ranges. Permutation-based importance analysis confirmed that both ultrasound and electrophysiological features contributed substantively to prediction. Residual-based grading further revealed structure- function heterogeneity within each main severity grade. CTS severity can be stratified using a limited set of complementary morphological and electrophysiological features. Structure-function mismatch supports an imaging-led initial screening, with electrophysiology reserved for selected patients.

ObjectiveN-acetylcysteine (NAC) is a clinically available antioxidant with potential applications in trauma-induced hypermetabolic states, including burn injury and crush syndrome. However, its effects on heat-stressed skeletal muscle cells remain incompletely characterized. This study conducted a secondary analysis of a publicly available dataset to quantify NACs protective effects against heat-stress-induced cellular damage. MethodsWe re-analyzed a publicly available dataset (Lu J, 2024, Mendeley Data, doi:10.17632/wffrtcgbnx.1) containing 21 observations across three conditions: Control (n=3), Heat Stress only (HS, n=3), and HS with NAC at five doses (0.5-8.0 mM, n=3 per dose). The primary outcome was the protective ratio [(HS+NAC - HS) / (Control - HS)], where 1.0 indicates complete protection. Statistical analyses included one-way ANOVA, post-hoc t-tests with Bonferroni correction, Cohens d effect sizes, and bootstrap confidence intervals. ResultsHeat stress significantly reduced cell viability by 56.3% (Control: 100.0 {+/-} 12.2 vs HS: 43.7 {+/-} 5.1; t(4)=7.37, p=0.002, Cohens d=6.02). NAC demonstrated a biphasic dose-response with maximal protection at 2.0 mM (66.7 {+/-} 14.4), yielding a protective ratio of 0.409 (95% CI: 0.146-0.675), representing 40.9% protection against heat stress damage. The comparison between HS and HS+NAC (2.0 mM) showed a large effect size (Cohens d = 2.12) but did not reach statistical significance (p = 0.060) due to the small sample size. One-way ANOVA confirmed overall group differences (F(2,18)=32.39, p<0.001, 2=0.783). ConclusionsNAC provides partial protection against heat stress-induced skeletal muscle cell damage at 2.0 mM, with a large effect size suggesting clinical relevance despite limited statistical power. These preliminary findings support further investigation of NAC as an adjunct therapy in trauma-induced hypermetabolic states. All analysis code is provided for reproducibility.

Wearable digital health technologies may complement traditional gait assessments in amyotrophic lateral sclerosis (ALS) by sensitively capturing real-world mobility changes. In this study, we validated six digital gait metrics derived from ankle-worn sensors in a natural history cohort of 182 individuals with ALS. Investigated metrics correspond to various aspects of gait, including volume, speed, intensity, similarity, variability, and fragmentation. Longitudinal analyses showed significant declines in step count, peak cadence, stride intensity, and stride similarity, with increasing stride duration variability and walking fragmentation over 52 weeks. Many participants exhibited greater relative change in the gait metrics than the self-reported ALS Functional Rating Scale-Revised (ALSFRS-RSE). Stratified analyses revealed that digital metrics captured significant functional decline even in participants with stable walking scores on the ALSFRS-RSE. These findings support the potential utility of these metrics for disease monitoring in ALS clinical care and trials.

Background: Huntington ' s disease (HD) causes progressive postural control deficits, but how sensory reweighting mechanisms degrade across disease stages remains poorly understood. Objective: To determine whether objective markers of postural sway track disease severity and altered sensory reweighting across the HD spectrum. Methods: Ninety-seven adults (46 {+/-} 14 yrs) were categorized into four groups: 29 with HD, 27 pre-manifest (PM), 28 not at risk (AR-), and 13 age-matched healthy controls (HC). Participants performed three trials of quiet standing with eyes open and eyes closed on a force plate. Results: Manifest HD individuals exhibited greater AP, ML, and total COP sway displacement compared with the PM, AR-, and HC groups. HD and PM groups demonstrated greater instability with eyes closed. COP wavelet power was concentrated below 1 Hz across all groups. The eyes-open to eyes-closed change in 0-1 Hz power predicted total COP sway in HC (68%), AR- (45%), and PM (46%), but this relation was substantially weaker in HD. Conclusions: Progressive weakening of oscillatory-sway coupling distinguishes manifest HD from premanifest stages. PM individuals demonstrate early sensory reweighting deficits that manifest only when vision is removed, while HD individuals show decoupled oscillatory activity that fails to support stable postural regulation. This progressive decoupling may serve as a candidate marker of disease conversion prior to overt motor diagnosis.