Journal of Neurotrauma

Background. Tethered cord syndrome (TCS) is classically associated with a low-lying conus medullaris, yet many surgically treated children have a normally positioned conus (occult TCS). Large-scale normative data on conus position in children, and the diagnostic value of quantitative conus assessment, are limited. Purpose. To establish a large-cohort reference distribution for conus medullaris termination level in children, to quantify conus position in children surgically treated for presumed (occult) TCS, and to test whether automated conus segmentation and radiomics can distinguish TCS from normal. Materials and Methods. In this retrospective single-center study, conus termination level was extracted from structured radiology reports of consecutive pediatric lumbosacral MRI examinations and encoded numerically (L1 = 1, L2 = 2, etc.). Children surgically treated for tethered cord were identified by linkage to an operative registry (name and date of birth) and restricted to preoperative examinations. A deep-learning model (nnU-Net) was trained for conus segmentation on axial T2-weighted images. IBSI-compliant radiomic features were extracted; reproducibility was assessed by intra- and inter-observer intraclass correlation (ICC). A case-control radiomics analysis used batch-only ComBat harmonization and cross-validated L1-penalized logistic regression; discrimination was compared with conus level by paired bootstrap. Results. Among 9,808 examinations with a parseable conus level (98.5% of reports; parser validated against dual blinded annotation, 99.4% agreement, weighted kappa 0.946), the conus terminated in the L1 region in 85.7% and the L2 region in 14.3% of the reference cohort (postoperative examinations excluded, n = 9,655); a low-lying conus (>=L3) occurred in only 0.05% (5/9,655), and remained rare (0.14%, 14/9,808) including operated examinations (median L1; mean 1.13 +/- 0.33). A slightly more cephalad position was seen with increasing age (negligible correlation). Among 475 preoperative children surgically treated for tethered cord, 99.6% had a normally positioned conus (<=L2) and only 0.4% were low-lying. Automated conus segmentation achieved a held-out Dice of 0.85. Conus radiomics likewise did not distinguish TCS from controls (equivalence-tested null; full segmentation/radiomics pipeline reported in the companion methodological paper). Conclusion. In children, the conus medullaris terminates at L1-L2 in more than 99% of cases and is normally positioned in virtually all children surgically treated for TCS. Within the conus, neither position nor texture (radiomics) identifies tethered cord; whether the filum terminale carries a diagnostic signal was not tested here.

Introduction: Reduced or lost sensation and movement after a spinal cord injury (SCI) impairs the brain s ability to accurately localize paralyzed body parts, causing deficits in its internal body map, or mental body representations (MBR). These deficits hinder functional recovery and contribute to neuropathic pain. Medications for neuropathic pain are often ineffective and carry side effects. Our pilot trials found that in-person Cognitive Multisensory Rehabilitation (CMR), a physical therapy restoring MBR, led to prolonged pain reduction, improved sensorimotor function, and enhanced brain function, to greater extent than adaptive fitness. To explore more accessible interventions for those in rural areas or with transportation challenges, we examined whether 12 weeks of remotely delivered CMR or exercise would (1) improve function and reduce pain; (2) increase brain activity and connectivity related to sensorimotor function and MBR in adults with SCI. Methods: Of 19 adults with SCI who consented, 15 (51+/-15 years old, 8+/-10 years post-SCI) were randomized to 12 weeks of remotely delivered CMR or exercise (45min, 3x/week). Eight reported neuropathic pain equal or greater than 3/10. The Numeric Pain Rating Scale (NPRS), ASIA Impairment Scale (AIS), and Neuromuscular Recovery Scale (NRS) assessed pain and sensorimotor function at baseline, post-intervention, and 6-month follow-up. Functional MRI included resting-state and four tasks: imagining feeling the left leg, imagining moving the left leg, whole-body movement imagery, and a sensation task. Results: After CMR (n=8), participants improved on AIS (large effect sizes: touch: d=1.30; pinprick: d=1.21; lower limb motor function: d=1.83). Exercise (n=7) produced smaller improvements (touch: d=0.35; pinprick: d=0.36; lower limb motor function: d=0.80). CMR showed greater NRS effect sizes (core: d=1.48; upper limb: d=0.69; lower limb: d=1.25) than exercise (core: d=0.31; upper limb: d=0.74; lower limb: d=0.83). Benefits persisted at follow-up for both AIS and NRS, especially in the CMR group. Highest neuropathic pain intensity decreased in both groups post-intervention (CMR: d=-0.61; exercise: d=-0.73) and at 6-month follow-up (CMR: d=-0.55; exercise: d=-0.55). Unlike previous studies, group effects for CMR were not found due to high heterogeneity. Increased task-based activation, including in the lateral occipital cortex involved in visual body perception and spatial awareness, was seen for the exercise group (n=5). Discussion: These preliminary results support the potential of remotely delivered CMR and exercise to improve function and reduce neuropathic pain in adults with SCI, highlighting the need for larger trials. Clinicaltrial.gov: NCT05870189

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

PURPOSE: As the armamentarium of BPH therapies continues to expand, it remains imperative to maximize patient satisfaction and minimize decisional regret. We sought to determine the impact of time from BPH diagnosis to index treatment on symptom improvement and subsequent procedural events. MATERIALS AND METHODS: We queried the American Urological Association Quality Registry for men [&ge;] 40 years old with BPH, available IPSS data, and no receipt of prior BPH treatment. Index treatment included medication, surgery, or minimally invasive surgical therapy (MIST). Outcomes included IPSS over 3 years of follow-up, change in percentage of mild lower urinary tract symptoms (LUTS) by 3 months, and time to procedural event. Patients were stratified by time from index diagnosis to treatment by <12 months, 1-3 years, and >3 years. Outcomes were compared across time-to-treatment cohorts with appropriate statistical tests with p < 0.05 as significant. RESULTS: 43,919 patients met criteria with 19,642 pursuing treatments. Patients pursued treatment at comparably lower baseline IPSS compared to prior prospective series. Patients undergoing surgery and MIST had significantly higher baseline IPSS, while medical comorbidities were significantly more common among men initiating pharmacotherapy. Early surgery and MIST were associated with significant improvement in IPSS within 6-12 months and an increase in mild LUTS by 3 months. All forms of early treatment were associated with delayed time to procedural events, including catheterization and fulguration. CONCLUSIONS: Early procedural intervention for BPH is associated with early symptom improvement and delayed time to procedural events among real-world, contemporary practice.

Background Evidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement. Method We linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status. Results Among 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors. Conclusions CMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.

Introduction: Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a debilitating condition characterised by severe fatigue and post-exertional malaise (PEM). Reported neuropsychophysiological abnormalities suggest ME/CFS is multifactorial, but current knowledge remains fragmented. This study protocol outlines a multimodal investigation designed to (1) compare neuropsychophysiological mechanisms between ME/CFS patients and healthy participants, (2) test an integrative model of ME/CFS, (3) identify neuropsychophysiological subgroups within the patient population, and (4) identify predictors of symptom response during rehabilitation. Methods and analysis: This study will enroll 115 ME/CFS patients and 55 healthy participants. Groups will be comparable in age, sex, and education level, with a larger patient sample enabling subgroup and longitudinal analyses. A cross-sectional assessment at baseline will be carried out in both groups. Patients will then be evaluated longitudinally throughout a standardized cognitive-behavioral therapy rehabilitation program delivered as routine care. Baseline measures include systemic inflammation and general health biomarkers, measures of autonomic and central nervous system function, neuroinflammation (magnetic resonance spectroscopy, [18F]DPA714 PET in a subsample), serum short-chain fatty acid levels, gut microbiota composition and function, and neuroendocrine and self-reported responses to psychosocial stress. Fatigue severity (physical and cognitive) and PEM will be assessed through validated questionnaires, ecological momentary assessment, and laboratory tasks. These will be re-evaluated during therapy, and all non-neuroimaging measures will be repeated after the rehabilitation program. Statistical analyses will comprise multivariate analysis of variance, general linear models, classification algorithms, structural equation models, least absolute shrinkage selection operator principal component regression (LASSO-PCR), cluster analysis and latent class growth analysis (LCGA).

Objective: Outcome after surgical hematoma evacuation for intracerebral hemorrhage (ICH) depends on hematoma location. As corticospinal tract (CST) integrity affects motor recovery after stroke, we hypothesized that CST integrity drives heterogeneity in surgical outcomes and investigated this in a secondary analysis of MISTIE-III participants. Methods: Risk of CST injury was categorized into four levels, based on the interaction between the CST, the hematoma, and perihematomal edema (PHE) on automatically segmented stability CT: no risk, PHE infiltration, hematoma infiltration, and complete interruption of the CST. Associations with outcome were tested using multivariable linear regression for motor National Institutes of Health Stroke Scale (NIHSS) at day 180 and ordinal regression for modified Rankin Scale (mRS) at day 365, introducing an interaction term between CST risk and treatment group. Results: Day 180 motor NIHSS was significantly lower for 'no risk' ({beta}:-3.77, [95% confidence interval [CI]: -5.8 to -1.70], p=0.0003) and 'PHE infiltration' ({beta}:-2.3, [95%CI: -3.5 to -1.1]; p=0.0002) vs. 'complete interruption'. Surgery was associated with lower Day 180 motor NIHSS in participants with hematoma infiltration ({beta}:-2.07, [95%CI: -3.8 to -0.4], p=0.016). Compared to complete interruption, 'no risk' (adjusted odds ratio [aOR]:0.27, [95%CI: 0.10 to 0.74], p=0.01) and 'PHE infiltration' (aOR:0.41, [95%CI: 0.23 to 0.74]; p=0.003) were associated with lower odds of unfavorable day 365 mRS. Surgery was associated with lower mRS in participants with no risk (aOR:0.23, [95%CI: 0.05 to 0.97, p=0.045). Interpretation: Increasing CST risk is associated with worse motor recovery (day 180) and disability (day 365). CST risk modifies the effect of the MISTIE-III procedure on motor recovery and disability.

Brain-derived tau (BD-tau) is an emerging blood-based biomarker for neurodegeneration, yet there are currently limited well validated BD-tau assays available for research and clinical use. To enhance access to this vital biomarker for neurological disorders including traumatic brain injury (TBI), we developed a novel blood-based immunoassay for BD-tau on the ultra-sensitive Quanterix HD-X platform using Single Molecule Array technology. Analytical validation assessed dilution linearity, specificity, precision, detection limits, and spike recovery, each recording robust metrics in agreement with international expert recommendations. The assay demonstrated robust validation metrics, achieving between-run stability of 95% when analyzing aliquots from six independent plasma and serum samples across five analytical runs. It also showed strong dilution linearity when diluted four-fold and achieved over 90% recovery when spiked with cerebrospinal fluid. Next, we evaluated the clinical utility of the assay in cohorts of individuals with traumatic brain injury (TBI), where strong performances were recorded whether using the 2-step or 3-step assay formats ({rho}= 0.94; p < 0.0001). Furthermore, plasma BD-tau distinguished samples from TBI patients based on time from injury and severity (AUC=0.93). Plasma BD-tau differentiated between favorable and unfavorable functional outcomes in the acute-severe group. Our findings underscore the significant potential of the BD-tau assay as a biomarker for TBI in the severe phase.

Objectives: Incisional hernia (IH) affects 13-30% of people after abdominal surgery, resulting in substantial morbidity and costs. While clinical risk factors have been studied extensively, genomic risk for IH is incompletely understood. We aimed to evaluate the impact of polygenic risk scores (PRS) on IH risk prediction. Methods] We created and evaluated three PRS for abdominal hernia, ventral hernia and latent hernia susceptibility for prediction of IH in an institutional biobank. The primary outcome was defined as the diagnosis or repair of an IH based on ICD-9/10-CM/PCS and CPT codes. Clinical covariates included age, sex, body mass index (BMI), smoking status, index procedure type, and perioperative surgical site infection. A phenome-wide association study (PheWAS) was performed to assess clinical associations with increased PRS. We then tested the ability of the PRS to improve prediction for IH by modeling clinical covariates with and without PRS in patients who underwent abdominal surgery. Model performance was assessed using 10 iterations of 5-fold cross-validation to estimate Brier scores and area under the receiver operating characteristic curve (AUROC), which were compared using cross-model Bayesian analysis of variance. Results: In 55,809 subjects, assessed PRS was significantly associated with incisional, umbilical, and ventral hernia on PheWAS, with 1.19 greater odds of developing IH per 1-SD increase in PRS (95% CI: 1.13-1.25, P \< 0.001). Of 9,909 subjects who underwent qualifying abdominal surgery, 706 developed IH. In this cohort, the latent hernia susceptibility PRS was associated with a 16% increased hazard of developing IH per 1-SD increase (HR 1.16; 95% CI: 1.07-1.26; P \< 0.001). Compared to a predictive model using clinical covariates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC = 0.660, 95% CI: 0.653-0.666), addition of the PRS showed similar Brier score and AUROC estimates (Brier score = 0.047, 95% CI: 0.046-0.048; AUROC: 0.667, 95% CI: 0.661-0.673) at five years. Cross-model Bayesian analysis demonstrated \>99% probability of practical equivalence when trying to detect a difference of [&ge;] 0.02. Conclusion: All three PRS for hernia were independently associated with IH, suggesting that genomic factors contribute significantly to IH development. However, none of the three PRS meaningfully improved clinical IH risk prediction in patients who underwent abdominal surgery. This suggests that clinical comorbidities and surgical techniques may be equally as important as genomic architecture.

Background. The emergency department in the United States of America functions as a residual access point for healthcare and social services for populations including rural communities, the uninsured, mental health and addiction patients, and the unhoused. The workforce variable that determines unit function (experience density, the concentration of accumulated clinical judgment within a unit workforce) is not measured in hospital accounting systems. Objective. To document workforce composition changes in U.S. emergency nursing across the 2018 and 2022 cycles of the National Sample Survey of Registered Nurses (NSSRN), and to specify falsifiable predictions for the 2026 cycle. Methods. We analyzed NSSRN public-use files using a four-way ED definition extending Castner et al. (2024) and a hospital-bedside-restricted comparator. Variance estimation used jackknife replicate weights for 2018 and Successive Differences Replication for 2022. Burnout was operationalized using the Norful et al. (2023) leaving-reasons proxy across cycles, with sensitivity analysis using the 2022 direct burnout item. Results. A 15-year trajectory (2008-2022) documents progressive experience-density compression: the ED's 15+ year veteran cohort fell from 41.9% to 28.0% over the decade preceding the pandemic, a loss of nearly a third of the senior cohort and a 19.6% decline in mean experience density, before recovering modestly to 33.3% as veteran nurses remained through the pandemic acute phase, leaving the ED as the youngest hospital setting throughout. Hospital non-ED bedside nurses lost senior tenure between cycles (mean 15.65[-&gt;]14.06 years since first licensure; 15+ year share 43.5%[-&gt;]38.7%), while ED nurses retained their senior tail (mean 11.60[-&gt;]12.58). Burnout endorsement rose sharply in both populations (non-ED 27.3%[-&gt;]46.0%; ED 34.2%[-&gt;]61.2%), with the ED-vs-non-ED gap more than doubling. Controlling for tenure, ED status was not independently associated with burnout in 2018 (OR 1.15, 95% CI 0.83-1.59) but was strongly associated in 2022 (OR 1.92, 95% CI 1.44-2.55; p<.001). The direct burnout item showed a parallel pattern (OR 2.92, 95% CI 1.62-5.28). Conclusions. A pandemic-era setting-specific burnout effect emerged in emergency nursing that workforce-composition controls cannot explain. The 2022 cycle establishes a pre-exit baseline against which the 2026 NSSRN will serve as the falsifiable test of post-Omicron veteran exit. Nursing pipeline replacement lag exceeds the interval before 2026 data arrives; the consequences of inaction fall on populations dependent on ED-based residual access.

Postoperative resilience varies widely among older adults, yet the biological drivers of recovery remain unclear. We evaluated whether preoperative immune profiles, measured in plasma and through ex vivo whole blood stimulation, predict resilience to the acute stress of total knee arthroplasty. A total of 152 adults (greater or equal to 60 years) in the PRIME KNEE cohort underwent elective total knee arthroplasty and had available blood samples for measurement of 45 immune biomarkers, quantified in plasma and in whole blood stimulated ex vivo for 24 hours with lipopolysaccharide (LPS) or influenza antigen (FLU). Resilience was assessed using Expected Recovery Differential (ERD) and Resilience Trajectory (RT) across pain severity, pain interference, lower extremity physical activities of daily living (LE PADLs), and step counts. An exploratory stability selection framework using LASSO identified biomarker predictors of postoperative outcomes. Plasma and stimulated biomarkers showed broadly similar predictive performance. A shared set of biomarkers, including LBP, leptin, TNFR1, CD30, and LIF, was consistently selected across models. Immune predictors explained ~12-24% of the variance in resilience outcomes. Distinct immune signatures emerged for pain versus functional recovery: pain related predictors mapped to local inflammatory and neuroimmune pathways, whereas function related predictors reflected systemic inflammatory load and cytokine signaling. Preoperative immune biomarkers, whether measured in plasma or after ex vivo stimulation, capture meaningful variance in postoperative resilience. The divergence between pain related and function related immune signatures highlights biologically distinct pathways underlying different dimensions of recovery and supports further development of immune based perioperative risk assessment.

ABSTRACT Background: Corticosteroids reduce mortality in severe COVID-19 requiring oxygen or invasive mechanical ventilation, yet emerging data suggest that SARS-CoV-2-associated acute lung injury is biologically heterogeneous and that treatment response may vary across molecularly defined disease states. Lung-derived molecular endotypes of severe COVID-19-associated acute lung injury have been described, but direct molecular profiling is not routinely available at the bedside. We evaluated whether a clinical predictor of previously defined lung molecular endotype identifies heterogeneity in corticosteroid treatment effect among mechanically ventilated patients with COVID-19. Methods: We utilized a single-center cohort of 5,000 patients with COVID-19 treated at the University of North Carolina Hospital between January 1, 2020, and December 31, 2022, to emulate a target trial assessing the effect of corticosteroid receipt on mortality, length of stay, and incident organ support. Confounding was addressed through inverse probability of treatment weighting (IPTW). Outcomes for severely ill patients requiring mechanical ventilation were compared to the RECOVERY trial results, with subsequent moderation analysis and stratified analysis by clinically predicted lung molecular endotype and vaccination status. The primary outcome was 28-day mortality. Secondary Outcomes were time to discharge alive and progression to additional organ support. Results: This emulated target trial showed a directionally favorable but non-statistically significant association between corticosteroid treatment and reduced 28-day mortality in patients requiring mechanical ventilation for SARS-CoV-2 infection. A clinical predictor of lung molecular endotype moderated the effect of corticosteroids on 28-day mortality (p-value for interaction 0.038) and identified distinct predicted endotype-specific treatment effect. Corticosteroid treatment was associated with lower 28-day mortality in the predicted Hyper-Inflammatory endotype (OR 0.62, 95% CI 0.39, 0.99) but not in the predicted Metabolic Dysregulation endotype (OR 1.15, 95% CI 0.82, 1.61). We did not detect significant effect modification by vaccination status (p-value for interaction 0.65), although inference was limited by the small, vaccinated subgroup (28-mortality OR 0.78, 95% CI 0.37, 1.65 in vaccinated vs 0.94, 95% CI 0.70, 1.26 in unvaccinated). Conclusions: In this target trial emulation of mechanically ventilated patients with severe COVID-19, corticosteroid treatment showed a directionally favorable but non-statistically significant association with reduced 28-day mortality in the overall cohort. However, a clinical predictor of lung molecular endotype identified significant heterogeneity in treatment effect, with benefit concentrated in the predicted Hyper-Inflammatory endotype and no apparent benefit in the predicted Metabolic Dysregulation endotype. These findings support prospective validation of clinically deployable endotype-guided corticosteroid treatment strategies in acute lung injury and ARDS.

Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) frequently co-occur in Veterans, producing overlapping symptoms and shared autonomic dysregulation. Heart rate variability (HRV) offers a noninvasive measure of autonomic function. Univariate HRV analyses often fail to capture complex, multivariate patterns associated with comorbidity. This study applied machine learning to HRV features extracted from MEG-derived electrocardiogram (M-ECG) signals to differentiate Veterans with TBI alone (TBI-alone; n = 42) from those with comorbid PTSD (TBI+PTSD; n = 40). Time-domain, frequency-domain, geometric, and nonlinear HRV metrics were analyzed using nested cross-validated Random Forest and XGBoost classifiers, with Boruta-based feature selection and SHapley Additive exPlanations for model interpretability. Both classifiers achieved above-chance discrimination (Random Forest AUC = 0.663; XGBoost AUC = 0.635). Multivariate models identified distributed autonomic signatures in TBI+PTSD, including altered sympathovagal balance, increased low-frequency proportion, and greater heart rate complexity. In contrast, univariate HRV differences were subtle and did not survive correction for multiple comparisons. These findings demonstrate how using multivariate machine learning HRV analysis could help with detecting comorbidity-specific autonomic patterns, suggesting that HRV-derived signatures may serve as exploratory biomarkers for risk assessment and targeted interventions in Veterans with TBI and PTSD.

Introduction: Acute low back pain is a leading cause of disability worldwide. Clinical guidelines recommend non-pharmacological therapies as first-line treatment and advise caution with opioid prescribing. However pharmacological therapies, including opioids and gabapentinoids, remain commonly used. The comparative risks of subsequent opioid use disorder (OUD) and overdose diagnosis associated with initial treatment modality in large, real-world populations is not well characterized. We estimated the incidence of new-onset OUD and overdose diagnosis among opioid-naive, Medicaid-insured adults with newly diagnosed acute low back pain and estimated the association between initial treatment modalities and subsequent OUD and overdose diagnosis risk. Methods: We conducted a retrospective cohort study using Medicaid T-MSIS Analytic files from 25 states (2016-2019). We identified opioid-naive adults with a new diagnosis of acute low back pain who initiated pharmacologic or non-pharmacologic treatment within 1 month of diagnosis. The primary outcome was incident OUD and overdose diagnosis (based on diagnosis codes in claims) during follow-up. Associations between initial treatment modality and OUD and overdose diagnosis risk were estimated using a non-parametric, doubly robust estimator to adjust for measured confounding. Results: The cohort included 525,002 opioid-naive adults initiating treatment for low back pain. The cumulative incidence of OUD and overdose diagnosis was 1.5% and 2.4% at 7 and 13 months, respectively. Compared to non-use, use of gabapentinoids during the first month of treatment was associated with the highest relative risk (increasing risk) by 130.1%, 95% confidence interval (CI): 117.8%, 142.3%), the second-highest relative risk was estimated for higher-dose opioids, defined as > 50 daily Morphine Milligram Equivalents (MME) (118.1%, 95% CI: 99.2%, 137.0%). Lower-dose, short-duration opioids ([&le;] 50 MME, [&le;] 7 days) were also associated with elevated risk, though substantially smaller in magnitude (20.8%, 95% CI: 13.8%, 27.9%). In contrast, non-pharmacologic, non-interventional therapies were associated with reduced OUD and overdose diagnosis risk, with physical therapy demonstrating the largest relative reduction of 34.0% (95% CI: -40.9%, -27.1%). Discussion: In opioid-naive Medicaid patients with acute low back pain, initial non-pharmacologic treatment was associated with reduced OUD and overdose diagnosis risk. Gabapentinoids and opioids were each associated with increased risk; for opioids, the degree of risk increased with higher doses and durations. These results support guideline recommendations favoring non-pharmacologic treatment as first-line therapy and indicate the importance of cautious prescribing when pharmacologic treatment is considered.

Background: Obsessive-compulsive disorder (OCD) is characterized by disturbing thoughts (obsessions) that initiate anxiety-reducing thoughts or behaviors (compulsions). For patients with treatment-resistant OCD (tr-OCD), neuromodulation techniques, like capsulotomy (a lesion in the anterior limb of the internal capsule) and deep brain stimulation (DBS), have emerged as interventions that likely regulate connectivity between the prefrontal cortex (PFC) and subcortical targets. Three patients (Cap-DBS1-3) underwent a failed capsulotomy followed by successful DBS. Here, we aimed to understand the brain connections disrupted by failed capsulotomy vs modulated by successful DBS. Methods: We used diffusion-weighted magnetic resonance imaging (dMRI) tractography in a control cohort with tr-OCD (n=12) and in two of the Cap-DBS patients themselves to determine connectivity profiles of the capsulotomy, volume of tissue activated (VTA), and potentially necessary tracts (VTA minus capsulotomy tracts). We used whole-brain, PFC-focused, and subcortically-focused tractography algorithms to fully explore the space of possible connections. Results: Capsulotomy regions-of-interest (ROIs) connected with a variety of PFC and subcortical regions. VTA ROIs and potentially necessary tracts had limited and inconsistent PFC connectivity but substantial subcortical connectivity. While correlated to the average OCD connectome (r = 0.214, 95% CI [0.177, 0.251]; r = 0.756, 95% CI [0.739, 0.772]), the Cap-DBS connectomes had many edges that were stronger (z-score > 3). Conclusions: The connectivity profile of potentially necessary tracts for successful DBS treatment after failed capsulotomy revealed a surprising proportion of subcortical regions and inconsistent PFC involvement, highlighting an often-ignored set of connections that may be critical to effective DBS.

Background: Late complications after stroke (LCAS), including cognitive symptoms, impact quality of life and recovery. It is not known if neighborhood-level measures of socioeconomic status (SES) influence LCAS. This study assessed associations between SES measures, including neighborhood income inequality (Gini) and area deprivation index (ADI), and cognitive symptoms after acute ischemic stroke (AIS) in a hospital leveraging active surveillance of LCAS. Methods: This retrospective cohort study included 512 patients hospitalized with AIS at Tufts Medical Center with subsequent follow-up (between zero and three months or between three and twelve months) in the Stroke Clinic from 1/1/2018 - 12/31/2022. Using ZIP code data, patients were characterized as low Gini (low inequality) and high ADI (high deprivation) (Gini <= 0.4302, ADI >= 5) by state medians. These variables were combined, indicating patients who were living in both a low Gini and high ADI neighborhood to evaluate the effects of living in a homogeneously deprived area. There were 206 and 281 patients in the low Gini and high ADI groups respectively. 140 patients lived in a low Gini and high ADI neighborhood. The multivariable logistic analysis assessed the likelihood of cognitive symptoms, adjusting for age, race, ethnicity, sex, NIH Stroke Scale (NIHSS), thrombolysis, active LCAS surveillance, poverty, and ADI-Gini combination. Results: There were no associations between high ADI (OR: 1.03, 95% CI: 0.67 ? 1.57) or low Gini (OR: 1.74, 95% CI: 0.98 ? 3.07) alone and cognitive symptoms after AIS. However, the combined variable demonstrated increased likelihood of cognitive symptoms in the high ADI-low Gini group (OR: 1.82, 95% CI: 1.08 ? 3.06). Conclusions: This study suggests that individuals living in homogeneously deprived neighborhoods report higher likelihood of cognitive symptoms after AIS. Further studies with increased power are needed to investigate the underlying causes of these disparities and to develop interventions to reduce these complications.

Background and rationale: Knee osteoarthritis (KOA) is a leading cause of lower limb disability worldwide, characterized by functional limitations, stiffness and pain. The incidence of KOA is especially tied to age and obesity. It is a disabling disease that often makes patients less physically active, thus increasing the risk of other diseases and mortality1. The clinical diagnosis of KOA is based on the symptoms and functional limitations of the joint. The diagnosis is usually supported with a radiograph (X-ray) of the weight-bearing knee. Radiographic features, such as Kellgren-Lawrence grade, are used as eligibility criteria for clinical studies while other features, such as joint space width (JSW), are used as endpoints for structural KOA progression2,3. While the use of these radiographic features is standard in academia, the use of JSW as a structural biomarker has received criticism. Critics point out that JSW is an indirect and projection dependent measure of cartilage deterioration which is sensitive to technical factors such as the angulation of the X-ray beam and the positioning of the knee. Small differences in these factors can alter the measured joint space and may not reflect true disease progression4,5. Despite limitations, minimum joint space width (mJSW) remains as one of the most widely used structural biomarkers in KOA trials and is currently one of the only structural imaging accepted in regulatory guidance as evidence of disease modification in OA drug development3. For JSW to be reliable and consistent in determining the advancement of KOA, the use of fixed-flexion devices is crucial to reduce the risk of unwanted narrowing or widening of the radiographic joint space width6,7. The LOSEIT trial, which the present study is based on, acknowledges the angulation problem and uses a standard clinical fixed-flexion device in weight-bearing PA views to get reliable JSW results8. Historically, a radiologist would draw on and grade radiographs of the knee-joint to extract the features. However, manual reading and annotation is time consuming with notable interobserver variance9. With increasing computational power and the use of deep neural networks, off-the-shelf artificial intelligence (AI) tools have become available for automatic extraction of radiograph features. Automation would free up time from radiologists and provide more consistent measurements due to the reproducible nature of the models10. These tools have received regulatory approval for commercial use, however, regulatory approval does not guarantee uniform or bias free performance when used on real-world data11. Furthermore, in a large multi-hospital chest X-ray study, Zech et al., showed that convolutional neural networks achieved worse results on data from other hospitals than on the original hospitals in which it was tested12. This highlights the risk of overestimating the accuracy of AI tools when only internally validated. It is therefore apparent that external validation is required when testing these AI models. Objectives: The aim of this analysis is to evaluate the agreement of a commercially available AI tool for measuring JSW with the best practice radiologist annotation in the tibiofemoral joint of the knee in radiographs stabilized with a fixed-flexion device and acquired as part of a clinical trial. Methods: This study is a secondary analysis of the data from the LOSEIT trial, a randomized, double-blind, placebo-controlled, single-center trial, where patients were randomized to either liraglutide or identically appearing placebo after an initial weight-loss period to investigate the effects on KOA. Radiographs of the tibiofemoral joint were acquired at enrollment (week -8) and at end-of-trial (week 52) for a total acquisition-to-acquisition time of 60 weeks13. The primary analysis will assess agreement between AI-derived and reference-derived change in JSW from enrolment to follow-up. Change will be calculated as follow-up minus enrolment separately for the AI tool and the reference measurement. The main measure of interest will be the change in medial minimal JSW (mmJSW), with change in lateral minimal JSW (lmJSW), medial fixed JSW (mfJSW) and lateral fixed JSW (lfJSW) as secondary measures. This study will follow an equivalence framework using the two one-sided tests (TOST) approach with a Bland-Altman analysis as the main outcome. The equivalence margin will be set at {delta} = 0.5 mm. Agreement consistent with equivalence will be considered established if the upper limit of the 95% confidence interval (95% CI) for the upper limit of agreement (LoA) and the lower limit of the 95% CI for the lower LoA are within the established margins. The reference JSW will be the average measurement of two independent resident radiologists. If there is a mismatch in the measurements of more than 0.40 mm between the two radiologists, the radiologists will re-annotate the case independently. If the difference remains greater than 0.40 mm, a musculoskeletal radiology consultant will review the radiograph and establish the reference JSW. The index test will be the measurements output by the AI tool. Populations: Patients aged 18 to 74 with symptomatic knee osteoarthritis, radiographically confirmed KL grade 1-3, with a BMI [&ge;]27, motivated for weight loss and in accordance with the LOSEIT trial inclusion criteria Further statistical details Sample size: Not applicable as this is a secondary analysis. Framework: This is an agreement study assessing the equivalence of a commercially available AI tool for radiographic evaluation of knee osteoarthritis with best practice radiologist measurements. Confidence intervals and P values: All 95% confidence intervals and P-values will be two-sided. Statistical software: SAS Studio and/or R version 4.2.2 (or newer).

Chronic pelvic pain (CPP) affects up to 26% of women worldwide. While its pathophysiology is poorly understood, disturbances in body perception have been identified in various similar chronic musculoskeletal disorders. The Fremantle Perineal Awareness Questionnaire (FrePAQ) is a novel tool designed to specifically assess disturbed body perception in the pelvic region, but its structural validity and reliability require formal evaluation. Methods: Patient partners with lived experience contributed to study design. Participants with (n=417 and without (n=277) chronic pelvic pain completed the FrePAQ at baseline, as well as one week later. We assessed the validity and reliability of the FrePAQ following COSMIN guidelines for Classical Test Theory. Results: The validated FrePAQ comprises a two factor model, with a six item Distress & Disconnection (D&D) subscale and a two item Size & Shape (S&S) subscale. Confirmatory analysis showed excellent fit (CFI = .988; RMSEA = .048) and measurement invariance between diagnostic groups. Internal consistency was high (cronbach alpha = .838 CPP, .819 controls). Test retest reliability was high for D&D (ICC = .863) and acceptable for S&S (ICC = .695). FrePAQ scores showed a weak to moderate correlation with pain scores (r = .234 to .255), psychological distress (r = .226 to .443), and functional impact (r = .172 to .295), particularly for the D&D subscale. Conclusion: The FrePAQ is a reliable and valid instrument to measure perineal perceptual disturbances in CPP. Future research will evaluate the tools potential to support phenotyping and guide individualised interventions. Improved understanding of body perception disturbance in CPP can enhance diagnosis and treatment precision.

Background: Mass gathering events (MGEs) are associated with several public health challenges and may cause a strain on healthcare services. Literature findings on the impact of MGEs on emergency departments (EDs) are heterogeneous. Objectives: To examine shifts in ED attendance characteristics during a major sporting tournament, namely the UEFA European Football Championship 2024 held in Germany. Methods: We conducted a retrospective observational study using ED data from the Emergency Department Data Registry. We compared baseline ED attendance characteristics between the tournament and the reference period, defined as two weeks before and two weeks after the tournament, and between Germany game days and non-Germany game days. Hourly attendance patterns were analysed for all Germany games using a reference range. Results: We included data from 41 EDs, totalling 253,493 attendances during the study period. A 1.57% increase in attendance was observed during the tournament compared to the reference period, with baseline characteristics remaining similar. The median daily attendance within all EDs was slightly lower on Germany game days (4066) compared to non-Germany game days (4128). Modest changes were observed in the hourly attendance on Germany game days, most notable during the last Germany game where a decrease in attendance below the reference range extended over three hours. Conclusions: The observed shifts in ED attendance were minimal, suggesting that no major changes of public health relevance occurred in ED attendance during the tournament. We highlight the utility of using ED data for monitoring and for enhancing the understanding of the public health risks and challenges associated with MGEs.

Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.