Simon Y. Tang

Background: For pediatric patients with presumed adolescent idiopathic scoliosis, surgeons rely on abnormal neurological exam, left-sided thoracic curve, or thoracic hyperkyphosis to initiate preoperative magnetic resonance imaging; however, the sensitivity of these screening criteria for detecting neural axis anomalies of Chiari malformation type I (CM1) and syrinx is not well understood. We aim to determine the frequency of abnormal neurological exam, left-sided thoracic curve, and hyperkyphosis of thoracic curves in patients with operative scoliosis and CM1 and/or syrinx. Methods: A retrospective analysis was conducted with patients who underwent surgical management for pediatric scoliosis and were diagnosed with either CM1 (n=4), syrinx (n=23), or both conditions (n=20). Neurological exams before surgery were reviewed and screened for abnormal deep tendon reflexes, abnormal abdominal reflexes, motor disturbance, sensory disturbance, muscle mass asymmetry, spasticity/contracture, abnormal gait, abnormal balance, and ankle clonus. Thoracic curvature direction, T2-T5 kyphosis, and T5-T12 kyphosis were also obtained. Results: Across all patients with CM1 and/or syrinx that underwent surgery for scoliosis, 9 of 47 (19%) had an abnormal preoperative neurological exam, 11 of 43 (26%) had a left-sided thoracic curve, 5 of 41 (12%) had a T2-T5 hyperkyphosis, and 9 of 41 (22%) had a T5-T12 hyperkyphosis. The T1-T12 kyphosis across the whole cohort averaged 38 degrees. In patients with known CM1 and/or syrinx, the sensitivity of neurological exam abnormality, left-sided curve, or hyperkyphosis was 27 of 41 (66%). Patients with both CM1 and syrinx were not more likely to have an abnormality on imaging or physical exam compared to patients with isolated CM1 or syrinx conditions. Conclusions: These results indicate that neurological exam abnormalities, left-sided thoracic curve, and thoracic hyperkyphosis have a relatively low sensitivity when used as a screening metric for detecting CM1 and/or syrinx in patients with scoliosis. Thirty-four percent of patients with CM1/syrinx and operative scoliosis had a normal neurological exam, right-sided curve, and a normal amount of kyphosis. Surgeons should consider the sensitivity of these screening metrics when determining which patients should obtain a preoperative MRI before scoliosis surgery. Levels of Evidence: Diagnostic studies—investigating a diagnostic test level III with a retrospective analysis.

Background: Compared with adults, children with intervertebral disc herniation often face delayed diagnoses due to atypical presentations and symptom overlap with other musculoskeletal disorders. While non-operative treatments such as physical therapy and NSAIDs are typically first-line, they may be insufficient in severe cases, where discectomy can be effective but carries a risk of recurrence. PROMIS (Patient-Reported Outcomes Measurement Information System) offers standardized measures of patient-reported pain and function. This study aims to evaluate PROMIS Pain Interference (Pain) and Mobility scores in pediatric disc herniation patients compared with the population average and assess treatment outcomes between non-operative and surgical cohorts. Methods: A retrospective cohort analysis included patients t tests and linear mixed-effects models (α=0.05). Results: Eighty patients (median age 16) met the inclusion criteria; 42 received non-operative care, and 38 underwent surgery. At presentation, mean PROMIS Pain was 59±7, and Mobility was 35±6, both significantly different from the norm ( P P P <0.001), though final scores were similar. Pain improvements in both groups at final follow-up showed no significant difference between treatment modalities. Conclusion: Pediatric patients with disc herniations experience significant pain and limited mobility. Patients who elect for discectomy present with worse pain and decreased mobility at baseline. However, those who undergo surgery can expect quicker relief of symptoms, and despite initially worse function, ultimately achieve outcome scores comparable to patients successfully managed non-operatively. Our study further validates that PROMIS scores effectively quantify symptom burden in pediatric disc herniation and reflect treatment response, supporting their use in this population. Level of Evidence: Level III—retrospective comparative study.

Inflammation-driven increases in nociception are prominent in pain pathologies associated with intervertebral disc (IVD) degeneration yet are difficult to model in vitro. Since neurons are exposed to multi-modal stimuli in vivo, it is critical for these exposures to be conserved in an in vitro test system. We developed a polydimethylsiloxane (PDMS)-based microfluidic platform to interrogate peripheral sensory neurons (SNs) in the presence of conditioned media from nucleus pulposus cells from the degenerated IVD, to model a potential impact of IVD cells’ secretome on pain sensing. Our platform enables controlled perfusion of cell-derived biochemical cues alongside a defined homogeneous electric field (EF) and supports real-time optical analysis. Computational modeling, fluid perfusion experiments, and conductivity measurements confirmed stable fluid transport and tunable homogeneous EF generation within the device. As proof of concept for neuronal stimulation, neuroblastoma (N2a) cells loaded with a fluorescent Ca ²⁺ indicator exhibited a 56% increase in Ca ²⁺ transient activity when exposed to media from degenerated IVDs, concomitant with increased IVD-derived IL-1β production. Importantly, EF-stimulated Ca ²⁺ transients increased in SNs derived from human induced pluripotent stem cells when exposed to conditioned media from primary human IVD cells, demonstrating the translation of this model system to human cells. Together, these results establish a versatile platform that enables controlled and simultaneous exposure to biochemical and electrical stimuli to quantify inflammation-driven peripheral neuronal hyperexcitability in tissue–neuron crosstalk.

Background: Impact microindentation (IMI) is a minimally invasive technique for assessing bone material properties that can be performed clinically. In this study, we aimed to determine how measurements obtained by IMI (bone material strength index [BMSi]) relate to bone strength, fracture resistance, and susceptibility to fracture. Questions/purposes: (1) Is BMSi associated with bone strength of the femur, radius, and vertebrae, and does incorporating BMSi alongside bone mineral density (BMD) improve the estimation of strength? (2) Does BMSi evaluate fracture toughness and mechanical properties of the bone tissue? (3) Can BMSi discriminate fracture susceptibility of the hip and wrist? Methods: This single-site laboratory study included the tibiae, femurs, radii, and L4 vertebrae from fresh-frozen cadavers (n = 67; mean ± SD age 71 ± 13 years). To answer the first question, IMI was performed on the tibia midshaft, dual-energy x-ray absorptiometry (DXA) was used to assess hip and spine BMD, and bone strength (ultimate fracture force) was mechanically determined for each site. To address the second question, stress intensity factor (K _C ) was quantified from notched cortical bone beam specimens from tibiae using the fracture toughness test. Bone mechanical behavior (ultimate stress, elastic modulus, work-to-fracture), microstructure (cortical porosity, tissue mineral density), and organic matrix quality (percentage of collagen denaturation, concentration of advanced glycation end products) were quantified from beam specimens from the femoral midshaft. To address the last question, hip and wrist fracture susceptibility was defined using the fall-load to fracture-load ratio, where values ≥ 1 indicate susceptibility. Receiver operating characteristic (ROC) curve analyses evaluated the ability of IMI and DXA to discriminate fracture susceptibility. Primary outcomes included evaluating the association between BMSi and BMD with bone strength and ROC analysis for discriminating fracture susceptibility. Results: Higher BMSi values were positively associated with higher bone strength, showing moderate association at the femur (r = 0.62 [95% confidence interval (CI) 0.49 to 0.72]; p < 0.001) and radius (r = 0.52 [95% CI 0.34 to 0.72]; p < 0.001) and weaker association at the L4 vertebrae (r = 0.31 [95% CI 0.03 to 0.53]; p = 0.02). At the femur, BMSi was more strongly associated with strength than total hip BMD (TH-BMD) (r = 0.45 [95% CI 0.3 to 0.62]; p < 0.001), and the inclusion of BMSi in multivariate analyses improved the explained variance in femur strength from 28% to 52% (ΔR ² = 0.24; p < 0.001). At the radius, both BMSi and TH-BMD (r = 0.50 [95% CI 0.31 to 0.71]; p < 0.01) showed moderate association with radius strength, with the combined model improving the explained variance in radius strength from 28% to 39% (ΔR ² = 0.11; p < 0.001). At the vertebrae, strength was weakly associated with BMSi (r = 0.31 [95% CI 0.03 to 0.53]; p = 0.02) but not with BMD. For the hip and wrist of each donor, BMSi discriminated hip fracture susceptibility with moderate accuracy (area under the curve [AUC] 0.75 [95% CI 0.63 to 0.88]; p < 0.001), whereas TH-BMD could not discriminate hip fracture susceptibility. Both BMSi (AUC 0.77 [95% CI 0.63 to 0.90]; p = 0.003) and TH-BMD (AUC 0.78 [95% CI 0.64 to 0.90]; p = 0.002) classified wrist fracture susceptibility with modest discriminatory performance. Conclusion: Our study demonstrates that BMSi provides information related to bone strength and discriminates fracture susceptibility of the hip and wrist. Clinical Relevance: IMI can be performed at the point of care using an FDA-cleared device and used to evaluate fragility in patients in whom fracture risk or bone strength is uncertain based on BMD alone. Prospective clinical studies are needed to determine whether IMI improves fracture risk prediction and informs patient treatment.

The bone matrix is precisely maintained and optimized to resist fractures. However, aging and disease deteriorate the bone matrix and increase fragility. Individuals with type 2 diabetes (T2D) have an elevated risk of bone fracture despite apparently normal bone mass. The chronic hyperglycemia in T2D promotes the formation of advanced glycation end-products (AGEs) in the bone tissue and modify the matrix mechanics. AGEs also bind to its receptor, RAGE, to activate inflammation and alter homeostasis. Using a leptin-receptor deficient mouse model of diabetes, we used a combination of high-resolution methods across multiple scales to evaluate the microarchitectural-, material- and cellular- level changes affected by the modulation of RAGE. To demonstrate the relevance of RAGE, we genetically ablated RAGE (RAGE-null) before the onset of diabetes; and to demonstrate the potency of RAGE as a disease modifying therapy, a RAGE antagonist (FPS-ZM1) was administered after prolonged diabetes. Diabetes impaired bone microstructure, the homeostatic actions of bone cells, the bone matrix nanomechanics, and whole- bone strength. The constitutive ablation of RAGE in diabetic animals prevented AGEs accumulation and the decline of trabecular connectivity; protected against the loss of osteocyte lacunae density and morphology; and maintained the matrix nanomechanics and bone strength. The inhibition of RAGE after the onset of diabetes reversed AGE accumulation and loss of bone volume; rescued osteocyte lacunae density and osteoclast activity; and restored matrix nanomechanics and bone strength. These results suggest that RAGE is a viable therapeutic target for diabetes-mediated impairments of bone quality. Graphical

Background: Chronic low back pain, commonly associated with intervertebral disc (IVD) degeneration, is highly prevalent in patients with Alzheimer's disease (AD), and the severity of the pain is correlated with the severity of the dementia. While incidences of both afflictions increase dramatically in the elderly population, it is unknown whether AD exacerbates the health of the IVD. Aims: The aim of this study is to examine how AD‐related mutations affect the structure and mechanics of the IVD. Materials and Methods: Utilizing one‐year‐old male and female 5xFAD mice that constitutively express human APP and PSEN1 transgenes with five AD‐linked mutations, we measured the lumbar IVD's extracellular matrix composition, the three‐dimensional structure, histopathological degeneration, and mechanical behaviour. Results: The amount of collagen, glycosaminoglycans, and advanced glycation end‐products in the IVD did not differ in the 5xFAD animals. Likewise, the 5xFAD IVDs were not histopathologically degenerated. However, the IVD volume, measured by contrast‐enhanced microCT, was larger in the 5xFAD animals ( p = 0.046; 1–β = 0.53; Cohen's d = 1.19). Morphologically, the 5xFAD IVD heights were homogeneous and flatter than the WT IVDs ( p = 0.043; 1–β = 0.60; Cohen's d = 1.41). Finally, dynamic micro compression revealed that 5xFAD IVDs have higher loss tangent ( p = 0.0062; 1–β = 0.85; Cohen's d = 1.60) and greater energy dissipation ( p = 0.0379; 1–β = 0.55; Cohen's d = 1.21). Discussion: Shifts in viscoelastic behaviour and disc morphology are associated with early tissue degradation and affect the IVD's ability to efficiently recover from mechanical loading, predisposing the IVD to eventual degeneration. Conclusion: This work suggests that IVD's structure, morphology, and mechanics are affected by AD. Future work will focus on defining the molecular mechanisms of these changes in the IVD and their consequences in individuals with AD.