Longitudinal in vivo cationic contrast-enhanced computed tomography classifies equine articular cartilage injury and repair.

Cationic contrast-enhanced computed tomography (CECT) capitalizes on increased contrast agent affinity to the charged proteoglycans in articular cartilage matrix to provide quantitative assessment of proteoglycan content with enhanced images. While high resolution microCT has demonstrated success, we investigate cationic CECT use in longitudinal in vivo imaging at clinical resolution. We hypothesize that repeated administration of CA4+ will have no adverse side effects or complications, and that sequential in vivo imaging assessments will distinguish articular cartilage repair tissue from early degenerative and healthy cartilage in critically sized chondral defects. In an established equine translational preclinical model, lameness and synovial effusion scores are similar to controls after repeated injections of CA4+ (eight injections over 16 weeks) compared to controls. Synovial fluid total protein, leukocyte concentration, and sGAG and PGE2 concentrations and articular cartilage and synovial membrane scores are also equivalent to controls. Longitudinal in vivo cationic CECT attenuation in repair tissue is significantly lower than peripheral to (adjacent) and distantly from defects (remote sites) by 4 weeks (p < 0.001), and this difference persists until 16 weeks. At the 6- and 8-week time points, the adjacent locations exhibit significantly lower cationic CECT attenuation compared with the remote sites, reflecting peri-defect degeneration (p < 0.01). Cationic CECT attenuation at clinical resolution significantly correlates with cationic CECT (microCT) (r = 0.69, p < 0.0001), sGAG (r = 0.48, p < 0.0001), and ICRS II histology score (r = 0.63, p < 0.0001). In vivo cationic CECT imaging at clinical resolution distinguishes fibrous repair tissue from degenerative and healthy hyaline cartilage and correlates with molecular tissue properties of articular cartilage.

Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

Quantitative 1H Magnetic Resonance Imaging on Normal and Pathologic Rat Bones by Solid-State 1H ZTE Sequence with Water and Fat Suppression.

BACKGROUND: Osteoporosis (OP) and osteomalacia (OM) are metabolic bone diseases characterized by mineral and matrix density changes. Quantitative bone matrix density differentiates OM from OP. MRI is a noninvasive and nonionizing imaging technique that can measure bone matrix density quantitatively in ex vivo and in vivo. PURPOSE: To demonstrate water + fat suppressed 1H MRI to compute bone matrix density in ex vivo rat femurs in the preclinical model. STUDY TYPE: Prospective. ANIMAL MODEL: Fifteen skeletally mature female Sprague-Dawley rats, five per group (normal, ovariectomized (OVX), partially nephrectomized/vitamin D (Vit-D) deficient), 250-275 g, ∼15 weeks old. FIELD STRENGTH/SEQUENCE: 7T, zero echo time sequence with water + fat (VAPOR) suppression capability, µCT imaging, and gravimetric measurements. ASSESSMENT: Cortical and trabecular bone segments from normal and disease models were scanned in the same coil along with a dual calibration phantom for quantitative assessment of bone matrix density. STATISTICAL TESTS: ANOVA and linear regression were used for data analysis, with P-values <0.05 statistically significant. RESULTS: The MRI-derived three-density PEG pellet densities have a strong linear relationship with physical density measures (r2 = 0.99). The Vit-D group had the lowest bone matrix density for cortical bone (0.47 ± 0.16 g cm-3), whereas the OVX had the lowest bone matrix density for trabecular bone (0.26 ± 0.04 g cm-3). Gravimetry results confirmed these MRI-based observations for Vit-D cortical (0.51 ± 0.07 g cm-3) and OVX trabecular (0.26 ± 0.03 g cm-3) bone groups. DATA CONCLUSION: Rat femur images were obtained using a modified pulse sequence and a custom-designed double-tuned (1H/31P) transmit-receive solenoid-coil on a 7T preclinical MRI scanner. Phantom experiments confirmed a strong linear relation between MRI-derived and physical density measures and quantitative bone matrix densities in rat femurs from normal, OVX, and Vit-D deficient/partially nephrectomized animals were computed. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

A missed opportunity: A scoping review of the effect of sex and age on osteoarthritis using large animal models.

OBJECTIVE: The objective was to critically analyze the published literature accounting for sex differences and skeletal age (open vs. closed physis) in preclinical animal models of OA, including the disaggregation of data by sex and skeletal maturity when data is generated from combined sex and/or multi-aged cohorts without proper confounding. METHOD: A scoping literature review of PubMed, Web of Science, EMBASE, and SCOPUS was performed for studies evaluating the effect of sex and age in experimental studies and clinical trials utilizing preclinical large animal models of OA. RESULTS: A total of 9727 papers were identified in large animal (dog, pig, sheep, goat, horse) models for preclinical OA research, of which 238 ex vivo and/or in vivo studies disclosed model type, animal species, sex, and skeletal age sufficient to analyze their effect on outcomes. Dogs, followed by pigs, sheep, and horses, were the most commonly used models. A paucity of preclinical studies evaluated the effect of sex and age in large animal models of naturally occurring or experimentally induced OA: 26 total studies reported some kind of analysis of the effects of sex or age, with 4 studies discussing the effects of sex only, 11 studies discussing the effects of age only, and 11 studies analyzing both the effects of age and sex. CONCLUSION: Fundamental to translational research, OARSI is uniquely positioned to develop recommendations for conducting preclinical studies using large animal models of OA that consider biological mechanisms linked to sex chromosomes, skeletal age, castration, and gonadal hormones affecting OA pathophysiology and treatment response.

Musculoskeletal health: an ecological study assessing disease burden and research funding.

Background: Exacerbated by an aging population, musculoskeletal diseases are a chronic and growing problem in the United States that impose significant health and economic burdens. The objective of this study was to analyze the correlation between the burden of diseases and the federal funds assigned to health-related research through the National Institutes of Health (NIH). Methods: An ecological study design was used to examine the relationship between NIH research funding and disease burden for 60 disease categories. We used the Global Burden of Disease (GBD) Study 2019 to measure disease burden and the NIH Research, Condition, and Disease Categories (RCDC) data to identify 60 disease categories aligned with available GBD data. NIH funding data was obtained from the RCDC system and the NIH Office of Budget. Using linear regression models, we observed that musculoskeletal diseases were among the most underfunded (i.e., negative residuals from the model) with respect to disease burden. Findings: Musculoskeletal diseases were underfunded, with neck pain being the most underfunded at only 0.83% of expected funding. Low back pain, osteoarthritis, and rheumatoid arthritis were also underfunded at 13.88%, 35.08%, and 66.26%, respectively. Musculoskeletal diseases were the leading cause of years lived with disability and the third leading cause in terms of prevalence and disability-adjusted life years. Despite the increasing burden of these diseases, the allocation of NIH funding to the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has remained low compared to other institutes. Interpretation: Despite the increasing health burden and economic cost of $980 billion annually, the allocation of NIH funding to the NIAMS has remained low compared to other institutes. These findings suggest that the NIH may need to reassess its allocation of research funding to align with the current health challenges of our country. Furthermore, these clinically relevant observations highlight the need to increase research funding for musculoskeletal diseases and improve their prevention, diagnosis, and treatment. Funding: No funding.

Cationic tantalum oxide nanoparticle contrast agent for micro computed tomography reveals articular cartilage proteoglycan distribution and collagen architecture alterations.

OBJECTIVE: Cationic tantalum oxide nanoparticles (Ta2O5-cNPs), as a newly introduced contrast agent for computed tomography of cartilage, offer quantitative evaluation of proteoglycan (PG) content and biomechanical properties. However, knowledge on the depth-wise impact of cartilage constituents on nanoparticle diffusion, particularly the influence of the collagen network, is lacking. In this study, we aim to establish the depth-dependent relationship between Ta2O5-cNP diffusion and cartilage constituents (PG content, collagen content and network architecture). METHODS: Osteochondral samples (n = 30) were harvested from healthy equine stifle joints (N = 15) and the diffusion of 2.55 nm diameter cationic Ta2O5-cNPs into the cartilage was followed with micro computed tomography (µCT) imaging for up to 96 hours. The diffusion-related parameters, Ta2O5-cNP maximum partition (Pmax) and diffusion time constant, were compared against biomechanical and depth-wise structural properties. Biomechanics were assessed using stress-relaxation and sinusoidal loading protocols, whereas PG content, collagen content and collagen network architecture were determined using digital densitometry, Fourier-transform infrared spectroscopy and polarized light microscopy, respectively. RESULTS: The Pmax correlates with the depth-wise distribution of PGs (bulk Spearman's ρ = 0.87, p < 0.001). More open collagen network architecture at the superficial zone enhances intake of Ta2O5-cNPs, but collagen content overall decreases the intake. The Pmax values correlate with the equilibrium modulus (ρ = 0.80, p < 0.001) of articular cartilage. CONCLUSION: This study establishes the feasibility of Ta2O5-cNPs for the precise and comprehensive identification of biomechanical and structural changes in articular cartilage via contrast-enhanced µCT.

Quantitative 31P magnetic resonance imaging on pathologic rat bones by ZTE at 7T.

BACKGROUND: Osteoporosis is characterized by low bone mineral density (BMD), which predisposes individuals to frequent fragility fractures. Quantitative BMD measurements can potentially help distinguish bone pathologies and allow clinicians to provide disease-relieving therapies. Our group has developed non-invasive and non-ionizing magnetic resonance imaging (MRI) techniques to measure bone mineral density quantitatively. Dual-energy X-ray Absorptiometry (DXA) is a clinically approved non-invasive modality to diagnose osteoporosis but has associated disadvantages and limitations. PURPOSE: Evaluate the clinical feasibility of phosphorus (31P) MRI as a non-invasive and non-ionizing medical diagnostic tool to compute bone mineral density to help differentiate between different metabolic bone diseases. MATERIALS AND METHODS: Fifteen ex-vivo rat bones in three groups [control, ovariectomized (osteoporosis), and vitamin-D deficient (osteomalacia - hypo-mineralized) were scanned to compute BMD. A double-tuned (1H/31P) transmit-receive single RF coil was custom-designed and in-house-built with a better filling factor and strong radiofrequency (B1) field to acquire solid-state 31P MR images from rat femurs with an optimum signal-to-noise ratio (SNR). Micro-computed tomography (µCT) and gold-standard gravimetric analyses were performed to compare and validate MRI-derived bone mineral densities. RESULTS: Three-dimensional 31P MR images of rat bones were obtained with a zero-echo-time (ZTE) sequence with 468 µm spatial resolution and 12-17 SNR on a Bruker 7 T Biospec having multinuclear capability. BMD was measured quantitatively on cortical and trabecular bones with a known standard reference. A strong positive correlation (R = 0.99) and a slope close to 1 in phantom measurements indicate that the densities measured by 31P ZTE MRI are close to the physical densities in computing quantitative BMD. The 31P NMR properties (resonance linewidth of 4 kHz and T1 of 67 s) of ex-vivo rat bones were measured, and 31P ZTE imaging parameters were optimized. The BMD results obtained from MRI are in good agreement with µCT and gravimetry results. CONCLUSION: Quantitative measurements of BMD on ex-vivo rat femurs were successfully conducted on a 7 T preclinical scanner. This study suggests that quantitative measurements of BMD are feasible on humans in clinical MRI with suitable hardware, RF coils, and pulse sequences with optimized parameters within an acceptable scan time since human femurs are approximately ten times larger than rat femurs. As MRI provides quantitative in-vivo data, various systemic musculoskeletal conditions can be diagnosed potentially in humans.

A polymer network architecture provides superior cushioning and lubrication of soft tissue compared to a linear architecture.

We report the relationships between linear vs. network polymer architecture and biomechanical outcomes including lubrication and cushioning when the polymers are applied to the surface of articulating knee cartilage. Aqueous formulations of the bioinspired polymer poly(2-methacryloyloxylethyl phosphorylcholine) (pMPC) exhibit tuneable rheological properties, with network pMPC exhibiting increased elasticity and viscosity compared to linear pMPC. Application of a polymer network, compared to a linear one, to articulating tissue surfaces reduces friction, lessens tissue strain, minimizes wear, and protects tissue - thereby improving overall tissue performance. Administration of the network pMPC to the middle carpal joint of skeletally mature horses elicits a safe response similar to saline as monitored over a 70 day period.

Assessment of Bone Healing: Opportunities to Improve the Standard of Care.

➤ Bone healing is commonly evaluated by clinical examination and serial radiographic evaluation. Physicians should be mindful that personal and cultural differences in pain perception may affect the clinical examination. Radiographic assessment, even with the Radiographic Union Score, is qualitative, with limited interobserver agreement.➤ Physicians may use serial clinical and radiographical examinations to assess bone healing in most patients, but in ambiguous and complicated cases, they may require other methods to provide assistance in decision-making.➤ In complicated instances, clinically available biomarkers, ultrasound, and magnetic resonance imaging may determine initial callus development. Quantitative computed tomography and finite element analysis can estimate bone strength in later callus consolidation phases.➤ As a future direction, quantitative rigidity assessments for bone healing may help patients to return to function earlier by increasing a clinician's confidence in successful progressive healing.

Parental caregivers' perception of their transition from hospital to home in children with cerebral palsy who have undergone orthopedic surgery.

PURPOSE: Evaluate parental perception of the quality of discharge teaching, readiness for discharge, and the impact of these on post discharge coping difficulty and resource utilization in children with cerebral palsy (CP) following surgery. DESIGN AND METHODS: Prospective cohort study conducted from September 2017-March 2021 at a pediatric academic medical center. Demographics were collected pre-operatively. Parents completed the Readiness for Hospital Discharge Scale (RHDS) and Quality of Discharge Teaching Scale (QDTS) within four hours of discharge. Four weeks post-discharge, parents completed the Post-discharge Coping Difficulty Scale (PDCDS). Utilization of healthcare resources were extracted from the electronic health record for 90 days post-operatively. Associations among demographics, RHDS, QDTS, PDCDS and resource utilization were assessed using general linear models; PDCDS's open-ended questions were analyzed using directed content analysis. RESULTS: 114 parental caregivers participated. Post discharge coping was significantly associated with additional resource utilization: length of stay (p = 0.046), readmissions (p = 0.001), emergency department visits (p = 0.001), clinic calls (p = 0.001) and unplanned clinic visits (p = 0.006). PDCDS was negatively correlated with the QDTS Quality of Teaching Delivered subscale (r = -0.32; p = 0.004) and three of five RHDS subscales: 1) Child's Personal Status (r = -0.24; p = 0.02); 2) Knowledge (r = -0.30; p = 0.005); and 3) Coping Ability (r = -0.39; p < 0.001). Four themes explicated parental coping difficulties. CONCLUSION: Parents experiencing coping difficulties were more likely to have difficulty managing their child's care needs at home and required additional health care resources. PRACTICE IMPLICATIONS: Recognizing that parents' readiness for discharge may not reflect their coping abilities post-discharge requiring nurses to coordinate pre- and post-discharge education and support services.

Re-evaluating consensus and uncertainty among treatment options for early onset scoliosis: a 10-year update.

PURPOSE: Consensus and uncertainty in early onset scoliosis (EOS) treatment were evaluated in 2010. It is currently unknown how treatment preferences have evolved over the past decade. The purpose of this study was to re-evaluate consensus and uncertainty among treatment options for EOS patients to understand how they compare to 10 years ago. METHODS: 11 pediatric spinal surgeons (similar participants as in 2010) were invited to complete a survey of 315 idiopathic and neuromuscular EOS cases (same cases as in 2010). Treatment options included the following: conservative management, distraction-based methods, growth guidance/modulation, and arthrodesis. Consensus was defined as ≥ 70% agreement, and uncertainty was < 70%. Associations between case characteristics and consensus for treatments were assessed via chi-squared and multiple regression analyses. Case characteristics associated with uncertainty were described. RESULTS: Eleven surgeons [31.7 ± 7.8 years of experience] in the original 2010 cohort completed the survey. Consensus for conservative management was found in idiopathic patients aged ≤ 3, whereas in 2010, some of these cases were selected for surgery. There is currently consensus for casting idiopathic patients aged 1 or 2 with moderate curves, whereas in 2010, there was uncertainty between casting and bracing. Among neuromuscular cases with consensus for surgery, arthrodesis was chosen for patients aged 9 with larger curves. CONCLUSION: Presently, preferences for conservative management have increased in comparison to 2010, and casting appears to be preferred over bracing in select infantile cases. Future research efforts with higher levels-of-evidence should be devoted to elucidate the areas of uncertainty to improve care in the EOS population. LEVEL OF EVIDENCE: Level V.

Barriers to Discharge After Hip Reconstruction Surgery in Non-ambulatory Children With Neurological Complex Chronic Conditions.

BACKGROUND: Hip reconstruction surgery in patients with neurological complex chronic conditions (CCC) is associated with prolonged hospitalization and extensive resource utilization. This population is vulnerable to cognitive, developmental, and medical comorbidities which can increase length of stay (LOS). The aims of this study were to characterize barriers to discharge for a cohort of children with neurological CCC undergoing hip reconstruction surgery and to identify patient risk factors for prolonged hospitalization and delayed discharge. METHODS: Retrospective chart review of nonambulatory patients with neurological CCC undergoing hip reconstruction surgery between 2007-2016 was conducted. Hospitalization ≥1 day past medical clearance was characterized as delayed discharge. Barriers were defined as unresolved issues at the time of medical clearance and categorized as pertaining to the caregiver and patient education, durable medical equipment, postdischarge transportation/placement, and patient care needs. RESULTS: The cohort of 116 patients was 53% male, 16% non-English speaking, and 49% Gross Motor Function Classification System (GMFCS) V with the mean age at surgery of 9.1±3.64 years. Median time from admission to medical clearance was 5 days with median LOS of 6 days. Approximately three-quarters of patients experienced delayed discharge (73%) with barriers identified for 74% of delays. Most prevalent barriers involved education (30%) and durable medical equipment (29%). Postdischarge transportation and placement accounted for 26% of barriers and 3.5 times longer delays ( P <0.001). Factors associated with delayed discharge included increased medical comorbidities ( P <0.05) and GMFCS V ( P <0.001). Longer LOS and medical clearance times were found for female ( P =0.005), older age ( P <0.001), bilateral surgery ( P =0.009), GMFCS V ( P =0.003), and non-English-speaking patients ( P <0.001). CONCLUSIONS: Patients with neurological CCC frequently encounter postoperative barriers contributing to increased LOS and delayed discharge. Patients that may be at higher risk for prolonged hospitalization and greater resource utilization include those who are female sex, adolescent, GMFCS V, non-English speaking, have additional comorbidities, and are undergoing bilateral surgery. Standardized preoperative assessment of educational needs, perioperative equipment requirements, and posthospital transportation may decrease the LOS, reduce caregiver and patient burden/distress, cost, and ultimately reduce variation in care delivery. LEVEL OF EVIDENCE: Level III, Retrospective Case Series.

Management of arthrofibrosis in neuromuscular disorders: a review.

Arthrofibrosis, or rigid contracture of major articular joints, is a significant morbidity of many neurodegenerative disorders. The pathogenesis depends on the mechanism and severity of the precipitating neuromuscular disorder. Most neuromuscular disorders, whether spastic or hypotonic, culminate in decreased joint range of motion. Limited range of motion precipitates a cascade of pathophysiological changes in the muscle-tendon unit, the joint capsule, and the articular cartilage. Resulting joint contractures limit functional mobility, posing both physical and psychosocial burdens to patients, economic burdens on the healthcare system, and lost productivity to society. This article reviews the pathophysiology of arthrofibrosis in the setting of neuromuscular disorders. We describe current non-surgical and surgical interventions for treating arthrofibrosis of commonly affected joints. In addition, we preview several promising modalities under development to ameliorate arthrofibrosis non-surgically and discuss limitations in the field of arthrofibrosis secondary to neuromuscular disorders.

Nusinersen for Patients With Spinal Muscular Atrophy: 1415 Doses via an Interdisciplinary Institutional Approach.

BACKGROUND: Spinal deformity and prior spinal fusion pose technical challenges to lumbar puncture (LP) for nusinersen administration for patients with spinal muscular atrophy (SMA). In this retrospective study over two study phases, we evaluated (1) factors associated with difficult LP or unscheduled requirement for image guidance and (2) effectiveness of a triage pathway for selective use of image guidance and nonstandard techniques, particularly for patients with spinal instrumentation/fusion to the sacrum. METHODS: With institutional review board approval, electronic health records, imaging, and administrative databases were analyzed for patients receiving nusinersen from January 2012 through September 2021. Descriptive statistics and univariate analyses were used. RESULTS: From January 2012 to March 2018 (phase 1), among 82 patients with SMA, 461 of 464 (99.4%) LP attempts were successful. Univariate analyses associated difficulty with prior spinal instrumentation, higher body mass index, and severity of the spinal deformity. Based on this experience, starting in April 2018 (phase 2), 125 patients were triaged selectively for ultrasound, fluoroscopy, or Dyna computed tomography. Patients with spinal instrumentation/fusion to the sacrum were treated primarily via intrathecal ports (137 doses) or transforaminal LP (55 doses). From April 2018 through September 2021, 704 of 709 (99.3%) LPs were successful. In total from January 2012 to September 2021, 1415 doses were administered. Over 50% of LPs were performed by neurology nurse practitioners without image guidance. Safety outcomes were excellent. CONCLUSIONS: A stratified approach resulted in successful intrathecal nusinersen delivery and efficient resource allocation for patients with SMA, with or without complex spinal anatomy.

A FoxA2+ long-term stem cell population is necessary for growth plate cartilage regeneration after injury.

Longitudinal bone growth, achieved through endochondral ossification, is accomplished by a cartilaginous structure, the physis or growth plate, comprised of morphologically distinct zones related to chondrocyte function: resting, proliferating and hypertrophic zones. The resting zone is a stem cell-rich region that gives rise to the growth plate, and exhibits regenerative capabilities in response to injury. We discovered a FoxA2+group of long-term skeletal stem cells, situated at the top of resting zone, adjacent the secondary ossification center, distinct from the previously characterized PTHrP+ stem cells. Compared to PTHrP+ cells, FoxA2+ cells exhibit higher clonogenicity and longevity. FoxA2+ cells exhibit dual osteo-chondro-progenitor activity during early postnatal development (P0-P28) and chondrogenic potential beyond P28. When the growth plate is injured, FoxA2+ cells expand in response to trauma, and produce physeal cartilage for growth plate tissue regeneration.

Spinal Fusion in Pediatric Patients With Low Bone Density: Defining the Value of DXA.

BACKGROUND: Children with medical complexity are at increased risk of low bone mineral density (BMD) and complications after spinal fusion compared with idiopathic scoliosis patients. Our aim was to compare treatments and outcomes of children with medical complexity undergoing spinal fusion in those who had dual-energy x-ray absorptiometry (DXA) scans versus those who did not in an effort to standardize the workup of these patients before undergoing spinal surgery. METHODS: We conducted a retrospective review of patients with low BMD who underwent spinal fusion at a tertiary care pediatric hospital between 2004 and 2016. We consulted with a pediatric endocrinologist to create standard definitions for low BMD to classify each subject. Regardless of DXA status, all patients were given a clinical diagnosis of osteoporosis [at least 2 long bone or 1 vertebral pathologic fracture(s)], osteopenia (stated on radiograph or by the physician), or clinically low bone density belonging to neither category. The last classification was used for patients whose clinicians had documented low bone density not meeting the criteria for osteoporosis or osteopenia. Fifty-nine patients met the criteria, and 314 were excluded for insufficient follow-up and/or not meeting a diagnosis definition. BMD Z -scores compare bone density ascertained by DXA to an age-matched and sex-matched average. Patients who had a DXA scan were also given a DXA diagnosis of low bone density (≤-2 SD), slightly low bone density (-1.0 to -1.9 SD), or neither (>-1.0 SD) based on the lowest BMD Z -score recorded. RESULTS: Fifty-nine patients were analyzed. Fifty-four percent had at least 1 DXA scan preoperatively. Eighty-one percent of DXA patients received some form of treatment compared with 52% of non-DXA patients ( P =0.03). CONCLUSIONS: Patients referred for DXA scans were more likely to be treated for low BMD, although there is no standardized system in place to determine which patients should get scans. Our research highlights the need to implement clinical protocols to optimize bone health preoperatively. LEVEL OF EVIDENCE: Level II-retrospective prognostic study.

Mortality in Early-Onset Scoliosis During the Growth-friendly Surgery Era.

INTRODUCTION: Early-onset scoliosis (EOS) is a spinal deformity that occurs in patients 9 years of age or younger. Severe deformity may result in thoracic insufficiency, respiratory failure, and premature death. The purpose of this study is to describe the modern-day natural history of mortality in patients with EOS. METHODS: The multicenter Pediatric Spine Study Group database was queried for all patients with EOS who are deceased, without exclusion. Demographics, underlying diagnoses, EOS etiology, operative and nonoperative treatments or observation, complications, and date of death were retrieved. Descriptive statistics and survival analysis with Kaplan-Meier curves were performed. RESULTS: There were 130/8009 patients identified as deceased for a registry mortality rate of 16 per 1000 patients. The mean age at death was 10.6 years (range: 1.0 to 30.2 y) and the most common EOS etiology was neuromuscular (73/130, 56.2%; P<0.001). Deceased patients were more likely be treated operatively than nonoperatively or observed (P<0.001). The mean age of death for patients treated operatively (12.3 y) was older than those treated nonoperatively (7.0 y) or observed (6.3 y) (P<0.001) despite a larger deformity and similar index visit body mass index and ventilation requirements. Kaplan-Meier analysis confirmed an increased survival time in patients with a history of any spine operation compared with patients without a history of spine operation (P<0.0001). Operatively treated patients experienced a median of 3.0 complications from diagnosis to death. Overall, cardiopulmonary related complications were the most common (129/271, 47.6%; P<0.001), followed by implant-related (57/271, 21.0%) and wound-related (26/271, 9.6%). The primary cause of death was identified for 78/130 (60.0%) patients, of which 57/78 (73.1%) were cardiopulmonary related. CONCLUSIONS: This study represents the largest collection of EOS mortality to date, providing surgeons with a modern-day examination of the effects of surgical intervention to better council patients and families. Both fatal and nonfatal complications in children with EOS are most likely to involve the cardiopulmonary system. LEVEL OF EVIDENCE: Level IV-therapeutic.

Epidural Analgesia Versus Lumbar Plexus Blockade After Hip Reconstruction Surgery in Children With Cerebral Palsy and Intrathecal Baclofen Pumps: A Comparison of Safety and Efficacy.

BACKGROUND: Epidural analgesia is commonly used for pain control after reconstructive hip surgery, but its use is controversial in the presence of an intrathecal baclofen pump (ITB). The purpose of this retrospective study was to investigate the rate of serious anesthetic and postoperative complications as well as the efficacy of epidural analgesia compared with lumbar plexus blocks (LPBs) for pain management after neuromuscular hip reconstruction in children with cerebral palsy (CP) and ITB. METHODS: Pediatric patients with CP and ITB undergoing hip reconstructive surgery from 2010 to 2019 were retrospectively identified. Patients receiving epidural analgesia were compared with those receiving LPB. Morphine milligram equivalents per kilogram were used as a surrogate measure for pain-related outcomes, as pain scores were reported with wide ranges (eg, 0 to 5/10), making it unfeasible to compare them across the cohort. Postoperative complications were graded using the modified Clavien-Dindo classification. RESULTS: Forty-four patients (26/44, 59% male) underwent surgery at an average age of 10.3 years (SD=3.4 y, range: 4 to 17 y). The majority utilized LPB (28/44, 64%) while the remaining utilized epidural (16/44, 36%). There were no differences in rates of serious complications, including no cases of ITB malfunction, damage, or infection. During the immediate postoperative course, patients who received LPB had higher morphine milligram equivalents per kilogram requirements than patients who received epidural analgesia. CONCLUSIONS: In patients with CP undergoing hip reconstruction surgery with an ITB in situ, epidural anesthesia was associated with improved analgesia compared with LPB analgesia, with a similar risk for adverse outcomes. Epidural catheters placed using image-guided insertion techniques can avoid damage to the ITB catheter while providing effective postoperative pain control without increasing rates of complications in this complex patient population. LEVEL OF EVIDENCE: Level III.

Mendelian etiologies identified with whole exome sequencing in cerebral palsy.

OBJECTIVES: Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP. METHODS: We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline. RESULTS: We included 50 probands in this analysis (20 females, 30 males). Twenty-four had cryptogenic CP, 20 had non-cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic-ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty-six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST-related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non-cryptogenic CP (n = 3/20) had a Mendelian disorder on WES. INTERPRETATION: WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.