William David Arnold

Age‐related weakness is strongly associated with disability and mortality in older adults. While muscle atrophy contributes to weakness, strength declines at a faster rate than muscle mass, implicating neural mechanisms such as changes at the spinal cord and neuromuscular junction. Yet, the role of the motor cortex in age‐related weakness remains largely unexplored. We previously identified layer V pyramidal neurons (LVPNs) of the primary motor cortex as hyperexcitable in aged mice, but whether this phenotype was coupled to neuromuscular dysfunction was unknown. Here, we show that aged mice exhibit impaired strength, coordination, and neuromuscular excitability. However, cortical motor output to muscle measured in vivo was enhanced, with patch‐clamp recordings from the same aged animals confirming LVPN hyperexcitability. This was accompanied by altered excitatory and inhibitory synaptic responses evoked by layer II/III stimulation, and by transcriptional changes in excitability‐related genes of aged LVPNs. Statistical analysis across 250 cortical–neuromuscular/behavioral pairwise relationships revealed that greater cortical excitability is broadly and consistently correlated with worse whole‐animal neuromuscular and behavioral outcomes. Most strikingly, LVPN firing frequency emerged as the single strongest correlate of neuromuscular dysfunction and statistically accounted for 75% of the age effect on neuromuscular function, while the reverse analysis showed that neuromuscular dysfunction accounted for 42.2% of the age effect on LVPN firing frequency. These findings identify the motor cortex as a potential contributor to age‐related weakness—a finding with broader significance given that hyperexcitability of LVPNs is a shared feature of motor dysfunction across neurodegenerative disease contexts.

Peripheral nerve injuries (PNIs) remain a major clinical challenge, often leaving patients with lifelong sensory, motor, and functional impairments despite surgical repair. While gene and cell therapies hold promise, their translation has been hampered by the lack of safe, efficient, and targeted delivery strategies. Here, we introduce vasculogenic tissue nanotransfection (TNT) as a nonviral, reprogramming-based therapeutic platform to enhance nerve regeneration to augment surgical reconstruction. This one-time, millisecond-scale intervention reprograms resident cells in situ toward a vasculogenic phenotype, fostering neovascularization and vascular remodeling to support axonal regeneration. Through integrated in vitro screening and in vivo validation, we identified an optimized formulation of vasculogenic genes ( Etv2 , Fli1 , and Foxc2 ; EFF ) that maximized reprogramming efficiency and regenerative potential. In a long-segment nerve defect model reconstructed with isografts, TNT-mediated delivery of EFF markedly improved functional recovery, including grip strength and muscle contractility, accompanied by increased vascular density and myelinated axon counts. Together, these findings establish TNT-mediated vasculogenic reprogramming as a transformative adjunct to surgical repair of PNIs, offering a clinically translatable strategy to accelerate nerve regeneration and restore function.

Background: Thermoceptive dysfunction is a frequent but understudied feature of peripheral neuropathies and aging. Patients often report abnormal heat perception, yet the underlying sensory mechanisms remain unclear. This study evaluated thermoceptive behavior and corresponding structural changes in mouse models of inherited dysmyelinating neuropathy and natural aging to identify shared and divergent mechanisms. Methods: Thermal preference was assessed using a user‐independent gradient apparatus spanning physiological to noxious temperatures, with automated quantification of time in zone, distance traveled, and velocity. Nocifensive responses were evaluated by hot plate latency. Intraepidermal nerve fiber density (IENFD) was measured in paw pads, and TRPV1‐positive dorsal root ganglion (DRG) neurons were analyzed by immunofluorescence and confocal imaging. Results: Thermal gradient testing revealed preserved temperature preference in CMT1A and HNPP mice but significantly altered behavior in aged animals, which spent less time in warmer zones. Hot plate testing showed prolonged times to nocifensive behavior in aged and CMT1A mice, whereas HNPP mice exhibited variable responses. IENFD was markedly reduced in aged mice but preserved in CMT1A and HNPP. DRG analysis revealed smaller soma diameters and reduced proportions of TRPV1‐positive Aδ neurons in aged mice, while CMT1A animals maintained normal morphology. Interpretation: Aging produces thermoceptive deficits through axonal degeneration and selective Aδ‐fiber vulnerability, whereas CMT1A mice display conduction‐related impairment due to dysmyelination. Both models reproduce key human sensory phenotypes and provide translational platforms for studying small‐fiber dysfunction and therapeutic interventions in peripheral neuropathies.

Clinical and translational research is important for health care and the growth of medical specialties. Physical medicine and rehabilitation offers many opportunities for research, but research growth in physical medicine and rehabilitation is lacking, and research resources and productivity vary across academic physical medicine and rehabilitation departments across North America. The Physiatric Research Consulting Program was developed by the Association of Academic Physiatrists to provide customized recommendations to enhance research capacity and productivity in physical medicine and rehabilitation departments. This report outlines the three components of the Physiatric Research Consulting Program, including a previsit needs assessment, an in-person visit, and a postvisit follow-up final report. The report also provides a qualitative assessment of the impact of the Physiatric Research Consulting Program, with general themes of feedback, site visit evaluations, and final report evaluations. The Physiatric Research Consulting Program was found to be valuable in identifying gaps and needs for physical medicine and rehabilitation departments, providing outside perspectives, and energizing faculty toward research growth in their departments.

Background: Global dementia cases, currently exceeding 55 million, are projected to triple by 2050. In the absence of disease-modifying therapies, identifying modifiable risk factors is critical. Preclinical studies show that herpes simplex virus type-1 (HSV-1) is neurotropic and can drive amyloid-beta accumulation and tau hyperphosphorylation. Epidemiologic findings remain inconsistent, partly because many studies lack standardized designs for real-world data. Objective: To quantify the association between clinically coded HSV-1 diagnosis and incident cognitive impairment or dementia among patients receiving care in a health-system electronic health record (EHR) network. Methods: We assembled a retrospective cohort within an Observational Medical Outcomes Partnership (OMOP)–mapped EHR data lake (2010‐2024), comparing patients with a first HSV-1 diagnosis (n=6274) to those without HSV-1 codes but with parallel baseline criteria (n=379,975). Eligibility required at least 365 days of prior observation and absence of baseline cognitive, HIV, selected neurotropic viral, or recent transplant codes. The outcome combined mild cognitive impairment and Alzheimer disease and related dementias (ADRD). A high-dimensional propensity score (PS) incorporating approximately 17,000 baseline covariates was estimated with regularized logistic regression; 4 strata weights were applied in a Cox model. Sensitivity analyses examined equipoise trimming, doubly adjusted models, fixed 1-, 5-, and 10-year censoring horizons, and a dementia-only outcome subset. Negative-control outcomes (n=271) were prespecified to assess empirical calibration. Results: The HSV-1 cohort contributed 23,186 person-years (PY) and 469 events; the non-HSV-1 cohort contributed 1,519,827 PY and 24,764 events. Crude incidence was 20.23 (95% CI 18.44‐22.14) per 1000 PY in the HSV-1 cohort and 16.29 (95% CI 16.09‐16.50) in the non-HSV-1 cohort, an absolute difference of 3.94 events per 1000 PY. PS-stratified analysis yielded a hazard ratio (HR) of 1.14 (95% CI 1.03‐1.25; P =.007). Estimates were comparable after equipoise trimming (HR 1.12, 95% CI 1.01‐1.25, P =.04), doubly adjusted modeling (HR 1.13, 95% CI 1.02‐1.24, P =.01), and fixed 5-year ( P =.008) and 10-year follow-up ( P =.004) (both HR 1.15). The 1-year censored model showed HR 1.00 (95% CI 0.84‐1.20; P =.96). The dementia-only endpoint mirrored the primary analysis (HR 1.14, 95% CI 1.03‐1.25; P =.008). No postindex events occurred for any negative-control outcome, so empirical calibration could not be performed and all estimates are uncalibrated. Conclusions: Within an OMOP-standardized EHR cohort, an HSV-1 diagnosis was associated with a small elevation in the hazard of subsequent cognitive impairment or dementia compared with individuals with no recorded HSV-1 diagnosis. Given the ubiquity of HSV-1, even a modest elevation in individual hazard could translate to a meaningful population-level increment if the association is causal. Confirmation in external data sets with laboratory viral typing, antiviral treatment records, and mortality linkage is warranted.

BACKGROUND Global dementia cases, currently exceeding 55 million, are projected to triple by 2050. In the absence of disease-modifying therapies, identifying modifiable risk factors is critical to mitigating this impending crisis. Preclinical studies have demonstrated that herpes simplex virus type-1 (HSV-1) exhibits neurotropism and can invade the central nervous system and drive pathological processes such as amyloid-beta accumulation and tau hyperphosphorylation, supporting the hypothesis that HSV-1 contributes to neurodegenerative processes. Epidemiologic findings are inconsistent, partly because many studies lack standardized designs for real-world data (RWD). OBJECTIVE To quantify the association between clinically coded HSV-1 infection and diagnosis of cognitive impairment or dementia among patients receiving care in a health-system electronic health record (EHR) network. METHODS We assembled a retrospective cohort within an OMOP-mapped EHR data lake (2010-2024), comparing patients with a first HSV-1 diagnosis (n = 6,274) to those without HSV-1 codes but with parallel baseline criteria (n = 379,975). Eligibility required ≥365 days of prior observation and absence of baseline cognitive, HIV, selected neurotropic viral, or recent transplant codes. The outcome combined mild cognitive impairment and Alzheimer disease-related dementias. A high-dimensional propensity score incorporating ~17 000 baseline covariates was estimated with regularized logistic regression; four strata weights were applied in a Cox model. Sensitivity analyses examined equipoise trimming, doubly adjusted models, fixed 1, 5, and 10-year censoring horizons, and a dementia-only outcome subset. Negative-control outcomes (n = 271) were analyzed for empirical calibration. RESULTS The HSV-1 cohort contributed 23,186 person-years (PY) and 469 events; the non-HSV-1 cohort contributed 1,519,828 PY and 24,764 events. The crude incidence rate was 20.23 (95% CI 18.44-22.14) per 1,000 person-years in the HSV-1 cohort compared to 16.29 (95% CI 16.09-16.50) in controls, yielding an absolute difference of 3.94 events per 1,000 person-years. Propensity-score-stratified analysis yielded a hazard ratio (HR) of 1.14 (95 % CI 1.03-1.25, P=.01). Estimates were comparable after equipoise trimming (HR 1.12, 95 % CI 1.01-1.25, P=.037), doubly adjusted modeling (HR 1.13, 95 % CI 1.02-1.24, P=.014), and fixed 5 year (P=.008) and 10-year follow-up (P=.004) (both HR 1.15). The 1-year censored model showed HR 1.00 (95 % CI 0.84-1.20, P=1). Results for the dementia-only endpoint mirrored the primary analysis (HR 1.14, 95 % CI 1.03-1.25, P=.008). Negative-control calibration was not performed due to zero events. CONCLUSIONS Within an OMOP-standardized EHR cohort, an HSV-1 diagnosis was associated with a small elevation in the hazard of subsequent cognitive impairment or dementia. Given the ubiquity of HSV-1 infection, even a modest increase in dementia risk may translate to substantial additional cases at the population level. Confirmation in external data sets that include laboratory viral typing, antiviral treatment records, and mortality linkage is warranted.

As a researcher and a physician working together to combat amyotrophic lateral sclerosis (ALS), we are acutely aware of both the urgent need for innovation and the persistent divide between laboratory discoveries and clinical care

Sarcopenia, the pathological age‐related decline in muscle mass and strength, compromises independence and quality of life in older adults. Currently, no effective treatments are available. To enhance translational research using aged mouse models, we developed and validated the weighted cart pull (WCP) as a novel assessment of sustained motor function. The WCP test involved attaching a weighted cart to the tail of a mouse as it climbed a ramp to a ‘resting house’. Mass was increased incrementally until failure, defined as either five consecutive hindquarter pokes without progress or sliding backwards. In experiment 1, reliability (inter‐ and intra‐rater) was evaluated in middle‐aged mice (9 months, n = 10, 50% female). In experiment 2, young ( n = 8, 50% female) and old ( n = 8, 50% female) mice were tested on WCP, all‐limb grip and rotarod. In experiment 3, middle‐aged mice (7–9 months, n = 20, 50% female) underwent behavioural tests, in vivo electrophysiology and muscle physiology to correlate WCP with assessments of neuromuscular function. WCP showed high intra‐rater repeatability [intraclass correlation coefficient = 0.611, P = 0.018, 95% confidence interval (CI) = (0.046, 0.885)]. WCP demonstrated phenotypic differences between young and old mice (Student's unpaired t ‐test, P < 0.0001). WCP was significantly correlated with all‐limb grip [Pearson's r = 0.5820, P = 0.0071, 95% CI = (0.1878, 0.8147)], percentage decrement upon repetitive nerve stimulation at 50 Hz [Pearson's r = 0.4613, P = 0.0468, 95% CI = (0.008973, 0.7569)], twitch torque [Pearson's r = 0.6241, P = 0.0033, 95% CI = (0.2509, 0.8358)], tetanic torque [Pearson's r = 0.5100, P = 0.0216, 95% CI = (0.08718, 0.7771)] and bilateral gastrocnemius and soleus muscle mass [Pearson's r = 0.5878, P = 0.0064, 95% CI = (0.1964, 0.8177)]. The WCP provides a cost‐effective, comprehensive measure of strength and sustained motor function, improving preclinical assessments.