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Background: The decision whether to treat benign skeletal lesions surgically can be difficult to make. The purpose of this study was to validate our previously published method of predicting fracture risk with use of quantitative computed tomography-based structural analysis.Methods: We prospectively studied a group of children who presented to a major children's hospital with a benign appendicular skeletal lesion between 2002 and 2007. As in our previous study, the resistance of the affected bone to compressive, bending, and torsional loads was calculated with rigidity analysis performed with the use of serial transaxial quantitative computed tomography data obtained along the length of the bone containing the lesion and from homologous cross sections through the contralateral, normal bone. At each cross section, the ratio of the structural rigidity of the affected bone to that of the normal, contralateral bone was determined.Results: Forty-one patients who had not received surgical treatment for the skeletal lesion met the criteria for our study. Thirty-four (83%) of these individuals completed our activity questionnaire at least two years after the quantitative computed tomography-based rigidity analysis. None of the patients for whom no increased fracture risk had been predicted by the rigidity analysis sustained a fracture, even though they had not received surgical treatment.Conclusions: Many considerations other than the predicted fracture risk are factored into the decision of whether to treat a benign skeletal lesion. However, this study indicated that quantitative computed tomography-based rigidity analysis is more specific (97% specificity) than criteria based on plain radiographs (12% specificity) for predicting the risk of a pathologic fracture since fracture risk indices based on lesion size alone fail to account for the compensatory remodeling of the host bone that occurs in response to the presence of the lesion in a growing child.Level Of Evidence: Prognostic Level I. See Instructions to Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

STUDY DESIGN.: Using a rabbit model of postnatal pulmonary hypoplasia, we investigated how expansion thoracoplasty affected growth of the spine and lungs. OBJECTIVE.: By constricting the hemithorax in a growing rabbit to create postnatal pulmonary hypoplasia, we quantified how expansion thoracoplasty affects lung volume, respiratory function, alveolar morphology, and spine growth. SUMMARY OF BACKGROUND DATA.: In children with thoracic insufficiency syndrome, expansion thoracoplasty of the constricted hemithorax improves respiratory function and controls scoliosis. We hypothesize that expansion thoracoplasty of the constricted hemithorax improves pulmonary hypoplasia by allowing the lung to expand, improving respiratory function and stimulating lung growth. METHODS.: Postnatal pulmonary hypoplasia and scoliosis were induced in 5-week old rabbits by constricting left ribs 3 to 8. Expansion thoracoplasty through the fused ribs was performed at 10 weeks. These were compared with Disease rabbits allowed to grow with a constricted left hemithorax and Normal rabbits. Spine and thoracic deformity, right and left lung volumes were measured on reconstructed 3-dimensional computed tomography images and functional residual capacity measured by plethysmography. At maturity, lungs were excised and quantitative histology performed to measure alveolar air fraction and surface density. RESULTS.: Expansion thoracoplasty of the constricted left hemithorax improved scoliosis but increased left lung volumes only moderately compared with Disease rabbits. For Disease and Thoracoplasty Treated rabbits, a compensatory increase in the volume of the right lung maintained total lung volumes equivalent to Normal. Alveolar air space fraction was greater in Disease rabbits, suggestive of emphysema improved by expansion thoracoplasty. Capillaries adjacent to the alveoli were prominent in Thoracoplasty Treated rabbits. CONCLUSION.: Expansion thoracoplasty reduces scoliosis and increases the volume of the constricted hemithorax, but the relative increase in the ipsilateral lung volume is small since compensatory hypertrophy of the contralateral lung also occurred. Expansion thoracoplasty may improve respiratory function by increasing alveolar capillaries and preventing emphysematous changes. [ABSTRACT FROM AUTHOR]

Background: Closed reduction and percutaneous pin fixation is the treatment of choice for completely displaced (type-III) extension supracondylar fractures of the humerus in children, although controversy persists regarding the optimal pin-fixation technique. The purpose of this study was to compare the efficacy of lateral entry pin fixation with that of medial and lateral entry pin fixation for the operative treatment of completely displaced extension supracondylar fractures of the humerus in children.Methods: This prospective, randomized clinical trial had sufficient power to detect a 10% difference in the rate of loss of reduction between the two groups. The techniques of lateral entry and medial and lateral entry pin fixation were standardized in terms of the pin location, the pin size, the incision and position of the elbow used for medial pin placement, and the postoperative course. The primary study end points were a major loss of reduction and iatrogenic ulnar nerve injury. Secondary study end points included radiographic measurements, clinical alignment, Flynn grade, elbow range of motion, function, and complications.Results: The lateral entry group (twenty-eight patients) and the medial and lateral entry group (twenty-four patients) were similar in terms of mean age, sex distribution, and preoperative displacement, comminution, and associated neurovascular status. No patient in either group had a major loss of reduction. There was no significant difference between the rates of mild loss of reduction, which occurred in six of the twenty-eight patients treated with lateral entry and one of the twenty-four treated with medial and lateral entry (p = 0.107). There were no cases of iatrogenic ulnar nerve injury in either group. There were also no significant differences (p > 0.05) between groups with respect to the Baumann angle, change in the Baumann angle, humerocapitellar angle, change in the humerocapitellar angle, Flynn grade, carrying angle, elbow flexion, elbow extension, total elbow range of motion, return to function, or complications.Conclusions: With use of the specific techniques employed in this study, both lateral entry pin fixation and medial and lateral entry pin fixation are effective in the treatment of completely displaced (type-III) extension supracondylar fractures of the humerus in children.Level Of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: There are no proven radiographic guidelines for predicting fracture risk in children and young adults with a benign skeletal lesion. An in vivo diagnostic study was conducted to determine whether a reduction in the load-carrying capacity of a bone measured with quantitative computed tomography was more accurate than current radiographic guidelines for predicting pathologic fracture in patients with a benign skeletal lesion.Methods: Eighteen patients who presented with a fracture through a benign skeletal lesion were compared with eighteen patients who had a benign skeletal lesion that had been thought to be at increased risk for fracture on the basis of currently used radiographic criteria but had not fractured over a two-year period. Structural analysis was performed to calculate the resistance of the affected bones to compressive, bending, and torsional loads with use of serial transaxial quantitative computed tomography data obtained along the length of the bone containing the lesion and from homologous cross sections through the contralateral, normal bone. At each cross section, the ratio of the structural rigidity of the affected bone divided by that of the normal, contralateral bone was determined. The cross section with the greatest reduction in compressive, bending, and torsional rigidity was identified as that most likely to fracture.Results: The mean age (and standard deviation) of the thirty-six patients was 12.5 +/- 3.6 years. Twenty lesions were located in the femur; eleven, in the tibia; three, in the humerus; one, in the ulna; and one, in the pelvis. A combination of the minimum bending and torsional rigidities calculated from the tomographic data provided optimal performance in differentiating between the fracture and non-fracture groups (100% sensitivity and 94% specificity). In contrast, plain radiographic criteria demonstrated 28% to 83% sensitivity and 6% to 78% specificity.Conclusions: The combination of bending and torsional rigidity measured noninvasively with quantitative computed tomography was more accurate (97%) for predicting pathologic fracture through benign bone lesions in children than were standard radiographic criteria (42% to 61% accuracy). We believe that this method can provide accurate objective criteria for planning treatment of benign bone lesions and monitoring treatment response. [ABSTRACT FROM AUTHOR]

Nitrates and calcium channel blockers (CCBs) have been shown to decrease lower esophageal sphincter pressure and theoretically may precipitate or aggravate gastroesophageal reflux. Thus, the authors hypothesized that patients who receive these agents would have greater use of acid-suppressive drug use, defined as histamine2 antagonists or proton pump inhibitors. A retrospective cohort design was used to assess the use of acid-suppressive drug use in hypertensive patients with respect to both nitrates and antihypertensive therapy. Of 15,662 treated hypertensive patients, 20% received acid-suppressive therapy. An increased use of acid-suppressive therapy was associated with nitrate (odds ratio [OR] = 1.71), CCB (OR = 1.46), and alpha 1 antagonist (OR = 1.32) treatment, which appeared to be additive when patients received two or more of the agents. Within the class of CCBs, there was no significant difference among the individual agents. As the clinical and economic burden may be substantial, further study is warranted. [ABSTRACT FROM AUTHOR]

Importance: Malnourished adolescents and young adults with anorexia nervosa (AN) are at high risk for skeletal deficits., Objective: To examine whether low-magnitude mechanical signals (LMMS) could preserve bone mineral density (BMD) throughout 6 months in adolescents and young adults with AN., Design, Setting, and Participants: This double-blind, sham-controlled randomized clinical trial, conducted in a hospital-based specialty clinic, assessed female adolescents and young women without medical comorbidity or medication use that would compromise bone health. A total of 837 female adolescents were screened from January 1, 2012, to December 31, 2019, of whom 317 met the study criteria. Data analysis was performed from 2020 to 2024., Intervention: Platform delivering low-magnitude mechanical signals (LMMS) (0.3 g at 32-37 Hz) or sham (ie, placebo) signals for 10 minutes daily for 6 months., Main Outcomes and Measures: The primary outcome was trabecular volumetric BMD (vBMD) as measured by peripheral quantitative computed tomography of the tibia at baseline and 6 months. Secondary outcomes included cortical vBMD, cross-sectional area (CSA), areal BMD and body composition measured by dual-energy x-ray absorptiometry, and serum bone turnover markers., Results: Forty female adolescents and young women (median [IQR] age, 16.3 [15.1-17.6] years; median [IQR] percentage median BMI for age, 87.2% [81.0%-91.6%]) completed the trial. Total bone vBMD changes were nonsignificant in both groups (95% CI for difference in median change between groups, -57.11 to 2.49): in the LMMS group, vBMD decreased from a median (IQR) of 313.4 (292.9-344.6) to 309.4 (290.4-334.0) mg/cm3, and in the placebo group, it increased from a median (IQR) of 308.5 (276.7-348.0) to 319.2 (309.9-338.4) mg/cm3. Total CSA at the 4% tibia site increased from a median (IQR) of 795.8 (695.0-844.8) mm2 to 827.5 (803.0-839.4) mm2 in the LMMS group, whereas in the placebo group, it decreased from 847.3 (770.5-915.3) mm2 to 843.3 (828.9-857.7) mm2 (95% CI for difference in median change between groups, 2.94-162.53). Median (IQR) trabecular CSA at the 4% tibia site increased from 616.3 (534.8-672.3) mm2 to 649.2 (638.0-661.4) mm2 in the LMMS group but decreased in the placebo group from 686.4 (589.0-740.0) mm2 to 647.9 (637.3-661.9) mm2 (95% CI for difference in median change between groups, 2.80-139.68 mm2). Changes in cortical vBMD, cortical section modulus, and muscle CSA were not significant between groups. The 6-month changes in trabecular and total bone CSA at the tibia 4% site (weight-bearing trabecular bone) were significantly different between groups (these measures increased in the LMMS group but decreased in the placebo group; total bone CSA: 95% CI, 2.94-162.53; P = .01; trabecular CSA: 95% CI, 2.80-139.68; P = .02). Greater increases in body mass index were seen in the placebo group (median [IQR] gain, 0.5 [-0.3 to +2.1]) than in the LMMS group (median [IQR] gain, +0.4 [-0.3 to +2.1]), perhaps due to differences in fat mass accrual. No adverse events occurred related to the LMMS intervention., Conclusions and Relevance: In this randomized clinical trial of female adolescents and young women with AN, a 6-month LMMS intervention did not yield improvement in tibial trabecular vBMD. However, LMMS led to increases in total and trabecular CSA at the tibia. These results suggest an early positive response of increased bone turnover and trabecular bone quantity due to the LMMS intervention. Future studies should use a longer duration of intervention, consider strategies to optimize adherence, and potentially focus on a more profoundly malnourished patient population., Trial Registration: ClinicalTrials.gov Identifier: NCT01100567.

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 PGE 2 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., (© 2024 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

The ability of articular cartilage to withstand significant mechanical stresses during activities, such as walking or running, relies on its distinctive structure. Integrating detailed tissue properties into subject-specific biomechanical models is challenging due to the complexity of analyzing these characteristics. This limitation compromises the accuracy of models in replicating cartilage function and impacts predictive capabilities. To address this, methods revealing cartilage function at the constituent-specific level are essential. In this study, we demonstrated that computational modeling derived individual constituent-specific biomechanical properties could be predicted by a novel nanoparticle contrast-enhanced computer tomography (CECT) method. We imaged articular cartilage samples collected from the equine stifle joint (n = 60) using contrast-enhanced micro-computed tomography (µCECT) to determine contrast agents' intake within the samples, and compared those to cartilage functional properties, derived from a fibril-reinforced poroelastic finite element model. Two distinct imaging techniques were investigated: conventional energy-integrating µCECT employing a cationic tantalum oxide nanoparticle (Ta 2 O 5 -cNP) contrast agent and novel photon-counting µCECT utilizing a dual-contrast agent, comprising Ta 2 O 5 -cNP and neutral iodixanol. The results demonstrate the capacity to evaluate fibrillar and non-fibrillar functionality of cartilage, along with permeability-affected fluid flow in cartilage. This finding indicates the feasibility of incorporating these specific functional properties into biomechanical computational models, holding potential for personalized approaches to cartilage diagnostics and treatment., (© 2024. The Author(s).)

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 1 H 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 (r 2  = 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 ( 1 H/ 31 P) 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., (© 2024 International Society for Magnetic Resonance in Medicine.)

Joint kinematic instability, arising from congenital or acquired musculoskeletal pathoanatomy or from imbalances in anabolism and catabolism induced by pathophysiological factors, leads to deterioration of the composition, structure and function of cartilage and, ultimately, progression to osteoarthritis (OA). Alongside articular cartilage degeneration, synovial fluid lubricity decreases in OA owing to a reduction in the concentration and molecular weight of hyaluronic acid and surface-active mucinous glycoproteins that form a lubricating film over the articulating joint surfaces. Minimizing friction between articulating joint surfaces by lubrication is fundamental for decreasing hyaline cartilage wear and for maintaining the function of synovial joints. Augmentation with highly viscous supplements (that is, viscosupplementation) offers one approach to re-establishing the rheological and tribological properties of synovial fluid in OA. However, this approach has varied clinical outcomes owing to limited intra-articular residence time and ineffective mechanisms of chondroprotection. This Review discusses normal hyaline cartilage function and lubrication and examines the advantages and disadvantages of various strategies for restoring normal joint lubrication. These strategies include contemporary viscosupplements that contain antioxidants, anti-inflammatory drugs or platelet-rich plasma and new synthetic synovial fluid additives and cartilage matrix enhancers. Advanced biomimetic tribosupplements offer promise for mitigating cartilage wear, restoring joint function and, ultimately, improving patient care., (© 2024. Springer Nature Limited.)

Background: Breast cancer (BrCa) is a predominant malignancy, with metastasis occurring in one in eight patients, nearly half of which target the bone, leading to serious complications such as pain, fractures, and compromised mobility. Structural rigidity, crucial for bone strength, becomes compromised with osteolytic lesions, highlighting the vulnerability and increased fracture risk in affected areas. Historically, two-dimensional radiographs have been employed to predict these fracture risks; however, their limitations in capturing the three-dimensional structural and material changes in bone have raised concerns. Recent advances in CT-based Structural Rigidity Analysis (CTRA), offer a promising, more accurate non-invasive 3D approach. This study aims to assess the efficacy of CTRA in monitoring osteolytic lesions' progression and response to therapy, suggesting its potential superiority over existing methodologies in guiding treatment strategies., Methods: Twenty-seven female nude rats underwent femoral intra-medullary inoculation with MDA-MB-231 human breast cancer cells or saline control. They were divided into Control, Cancer Control, Ibandronate, and Paclitaxel groups. Osteolytic progression was monitored weekly using biplanar radiography, quantitative computed tomography (QCT), and dual-energy X-ray absorptiometry (DEXA). CTRA was employed to predict fracture risk, normalized using the contralateral femur. Statistical analyses, including Kruskal-Wallis and ANOVA, assessed differences in outcomes among groups and over time., Results: Biplanar radiographs showed treatment benefits over time; however, only certain time-specific differences between the Control and other treatment groups were discernible. Notably, observer subjectivity in X-ray scoring became evident, with significant inter-operator variations. DEXA measurements for metaphyseal Bone Mineral Content (BMC) did not exhibit notable differences between groups. Although diaphyseal BMC highlighted some variance, it did not reveal significant differences between treatments at specific time points, suggesting a limited ability for DEXA to differentiate between treatment effects. In contrast, the CTRA consistently demonstrated variations across different treatments, effectively capturing bone rigidity changes over time, and the axial- (EA), bending- (EI), and torsional rigidity (GJ) outcomes from the CTRA method successfully distinguished differences among treatments at specific time points., Conclusion: Traditional approaches, such as biplanar radiographs and DEXA, have exhibited inherent limitations, notably observer bias and time-specific inefficacies. Our study accentuates the capability of CTRA in capturing real-time, progressive changes in bone structure, with the potential to predict fractures more accurately and provide a more objective analysis. Ultimately, this innovative approach may bridge the existing gap in clinical guidelines, ushering in enhanced Clinical Decision Support Tool (CDST) for both surgical and non-surgical treatments., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors have no conflicts to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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 ( 31 P) 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 ( 1 H/ 31 P) transmit-receive single RF coil was custom-designed and in-house-built with a better filling factor and strong radiofrequency (B 1 ) field to acquire solid-state 31 P 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 31 P 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 31 P ZTE MRI are close to the physical densities in computing quantitative BMD. The 31 P NMR properties (resonance linewidth of 4 kHz and T 1 of 67 s) of ex-vivo rat bones were measured, and 31 P 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., Competing Interests: Declaration of competing interest The authors have no declarations to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Cationic tantalum oxide nanoparticles (Ta 2 O 5 -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 Ta 2 O 5 -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 Ta 2 O 5 -cNPs into the cartilage was followed with micro computed tomography (µCT) imaging for up to 96 hours. The diffusion-related parameters, Ta 2 O 5 -cNP maximum partition (P max ) 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 P max 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 Ta 2 O 5 -cNPs, but collagen content overall decreases the intake. The P max values correlate with the equilibrium modulus (ρ = 0.80, p < 0.001) of articular cartilage., Conclusion: This study establishes the feasibility of Ta 2 O 5 -cNPs for the precise and comprehensive identification of biomechanical and structural changes in articular cartilage via contrast-enhanced µCT., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: IMA has received grants from the American Heart Association and the National Institutes of Health. JDK serves on the Scientific Advisory Board for OnPoint Surgical. MM possesses the founder’s stock and options, has received consulting fees for Miach Orthopedics, and serves an uncompensated role of secretary with the Medical Publishing Board of Trustees of AOSSM., (© 2023 The Author(s).)

Introduction: Little is known about the impact of tidal volumes delivered by emergency medical services (EMS) to adult patients with out-of-hospital cardiac arrest (OHCA). A large urban EMS system changed from standard adult ventilation bags to small adult bags. We hypothesized that the incidence of return of spontaneous circulation (ROSC) at the end of EMS care would increase after this change., Methods: We performed a retrospective analysis evaluating adults treated with advanced airway placement for nontraumatic OHCA between January 1, 2015 and December 31, 2021. We compared rates of ROSC, ventilation rate, and mean end tidal carbon dioxide (ETCO 2 ) by minute before and after the smaller ventilation bag implementation using linear and logistic regression., Results: Of the 1,994 patients included, 1,331 (67%) were treated with a small adult bag. ROSC at the end of EMS care was lower in the small bag cohort than the large bag cohort, 33% vs 40% (p = 0.003). After adjustment, small bag use was associated with lower odds of ROSC at the end of EMS care [OR 0.74, 95% CI 0.61 - 0.91]. Ventilation rates did not differ between cohorts. ETCO 2 values were lower in the large bag cohort (33.2 ± 17.2 mmHg vs. 36.9 ± 19.2 mmHg, p < 0.01)., Conclusion: Use of a small adult bag during OHCA was associated with lower odds of ROSC at the end of EMS care. The effects on acid base status, hemodynamics, and delivered minute ventilation remain unclear and warrant additional study., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This research did not receive any external funding. Robert Walker is a biomedical engineer employed by Stryker Emergency Care. Nicholas Johnson receives research funding from National Institutes of Health, Centers for Disease Control and Prevention, and University of Washington Royalty Research Fund for unrelated work and serves on a Scientific Advisory Board for Neuroptics, Inc. Thomas Rea has received support from Philips. Michael Sayre has received consulting fees from Stryker Emergency Care. The remaining authors have no conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

➤ 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., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H584 )., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

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., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Most fish consumption advisories in the United States (U.S.) are issued for mercury and polychlorinated biphenyls (PCBs), and recently per- and polyfluoroalkyl substances (PFAS) have become a contaminant group that warrants fish consumption advice. An unequal probability survey design was developed to allow a comprehensive characterization of mercury, PCB, and PFAS contamination in fish from U.S. rivers on a national scale. During 2013-14 and 2018-19, fish fillet samples were collected from 353 and 290 river sites, respectively, selected randomly from the target population of rivers (≥5th order in size) in the conterminous U.S. These comprised nationally representative samples, with results extrapolated to chemical-specific sampled populations of 48,826-79,448 river kilometers (km) in 2013-14 and 66,142 river km in 2018-19. National distribution estimates were developed for total mercury, all 209 PCB congeners, and up to 33 PFAS (including perfluorooctane sulfonate or PFOS) in river fish. All fillet tissue samples contained detectable levels of mercury and PCBs. One or more PFAS were detected in 99.7 % and 95.2 % of the fillet samples from fish collected in 2013-14 and 2018-19, respectively. Fish tissue screening levels applied to national contaminant probability distributions allowed an estimation of the percentage of the sampled population of river lengths that contained fish with fillet concentrations above a level protective of human health. Fish tissue screening level exceedances for an average level of fish consumption ranged from 23.5 % to 26.0 % for mercury, 17.3 % to 51.6 % for PCBs, and 0.7 % to 9.1 % for PFOS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Scoliosis Research Society.)

Introduction: Guidelines recommend monitoring end-tidal carbon dioxide (E T CO 2 ) during out-of-hospital cardiac arrest (OHCA), though its prognostic value is poorly understood. This study investigated the relationship between E T CO 2 and return of spontaneous circulation (ROSC) after defibrillation in intubated non-traumatic OHCA patients., Methods: This retrospective, observational cohort analysis included adult OHCA patients who received a defibrillation shock during treatment by an urban EMS agency from 2015 to 2021. Peak E T CO 2 values were determined for the 90-second periods before and after the first defibrillation in an intubated patient (shock of interest [SOI]). Values were analyzed for association between the change in E T CO 2 from pre- to post-shock and the presence of ROSC on the subsequent pulse check., Results: Of 518 eligible patients, mean age was 61, 72% were male, 50% had a bystander-witnessed arrest, and 62% had at least one episode of ROSC. The most common arrest etiology was medical (92%). Among all patients, peak E T CO 2 during resuscitation prior to SOI was 36.8 mmHg (18.6). E T CO 2 increased in patients who achieved ROSC immediately after SOI (from 38.3 to 47.6 mmHg; +9.3 CI: 6.5, 12.1); patients with sustained ROSC experienced the greatest increase in E T CO 2 after SOI (from 37.8 to 48.2 mmHg; +10.4 CI: 7.2, 13.6), while E T CO 2 in patients who did not achieve ROSC after SOI rose (from 36.4 to 37.8 mmHg; +1.4 CI: -0.1, 2.8)., Conclusions: E T CO 2 rises after defibrillation in most patients during cardiac arrest. Patients with sustained ROSC experience larger rises, though the majority experience rises of less than 10 mmHg., (Copyright © 2022. Published by Elsevier B.V.)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: J.G.B. is on the editorial board of JAMA Pediatrics . N.S.M. is a paid consultant for and received research support from Ascendis Pharma, research support from Ultragenyx, and financial support from UpToDate. D.J.H. is a paid consultant for Medtronic. L.I.K. received financial support from K2M. J.B.E. is a paid consultant for Biomet and Johnson & Johnson, receives IP royalties from DePuy, and is on the editorial board of the Journal of Children’s Orthopedics . M.T.H. is a board/committee member of the American College of Rheumatology Arthritis Foundation and the Pediatric Orthopaedic Society of North America, has stock/stock options in EOSI, and is on the editorial board of the New England Journal of Medicine . B.D.S. is a board/committee member of AAOS, Orthopaedic Research Society, Pediatric Orthopaedic Society of North America, and Scoliosis Research Society and an unpaid consultant for OrthoPediatrics. M.P.G. is a paid presenter for Biomet, DePuy, Medtronic, and Nuvasive, received research support as a member of HSG and PSSG, and is a paid consultant for Orthobullets and received financial support and stock/stock options from them. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2022. The Author(s).)

The development of treatments for osteoarthritis (OA) is burdened by the lack of standardized biomarkers of cartilage health that can be applied in clinical trials. We present a novel arthroscopic Raman probe that can "optically biopsy" cartilage and quantify key extracellular matrix (ECM) biomarkers for determining cartilage composition, structure, and material properties in health and disease. Technological and analytical innovations to optimize Raman analysis include (1) multivariate decomposition of cartilage Raman spectra into ECM-constituent-specific biomarkers (glycosaminoglycan [GAG], collagen [COL], water [H 2 O] scores), and (2) multiplexed polarized Raman spectroscopy to quantify superficial zone (SZ) COL anisotropy via a partial least squares-discriminant analysis-derived Raman collagen alignment factor (RCAF). Raman measurements were performed on a series of ex vivo cartilage models: (1) chemically GAG-depleted bovine cartilage explants (n = 40), (2) mechanically abraded bovine cartilage explants (n = 30), (3) aging human cartilage explants (n = 14), and (4) anatomical-site-varied ovine osteochondral explants (n = 6). Derived Raman GAG score biomarkers predicted 95%, 66%, and 96% of the variation in GAG content of GAG-depleted bovine explants, human explants, and ovine explants, respectively (p < 0.001). RCAF values were significantly different for explants with abrasion-induced SZ COL loss (p < 0.001). The multivariate linear regression of Raman-derived ECM biomarkers (GAG and H 2 O scores) predicted 94% of the variation in elastic modulus of ovine explants (p < 0.001). Finally, we demonstrated the first in vivo Raman arthroscopy assessment of an ovine femoral condyle through intraarticular entry into the synovial capsule. This study advances Raman arthroscopy toward a transformative low-cost, minimally invasive diagnostic platform for objective monitoring of treatment outcomes from emerging OA therapies., (© 2021 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

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., (© 2022. The Author(s).)

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., Competing Interests: K.B. declares having received a stipend from Medtronic, unrelated to this work. S.S.D.S. declares having received consulting fees from Alcyone Life Sciences and PTC Therapeutics, both unrelated to this work. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To evaluate the effect of hip reconstruction or spinal fusion on health-related quality of life (HRQoL) in non-ambulatory children with spastic cerebral palsy (CP) and caregiver burden., Method: This was a prospective, longitudinal study of changes in HRQoL and caregiver burden over the 5 years after surgical correction of hip instability or scoliosis in children with bilateral spastic CP classified in Gross Motor Function Classification levels IV or V. Serial parent proxy measures of HRQoL and caregiver burden were obtained before and 6 weeks, and 3, 6, 9, 12, 24, and 60 months after surgery using the Caregiver Priorities and Child Health Index of Life with Disabilities and the Assessment of Caregiver Experience with Neuromuscular Disease. Scores 5 years or more after surgery were compared to pre-surgery scores using paired Student's t-tests. Serial outcome trajectories were estimated by linear mixed modeling., Results: Of 69 participants (40 males, 29 females; mean age 11y 6mo, SD 4y 1mo, range 3y 10mo-20y 7mo), 43 had hip reconstruction and 26 had spinal fusion. Clinically significant improvements in HRQoL were detected (average increase 7.6 points) 5 years or more postoperatively, with hip reconstruction providing greater benefit. Domains improved by surgery included positioning, transferring/mobility, comfort/emotions, and health. Caregiver burden did not change as these children remain maximally dependent., Interpretation: Surgical treatment of hip and spine deformity improves HRQoL, especially for painful hip instability, but does not change caregiver burden., (© 2021 Mac Keith Press.)

Nanoparticle-based contrast agents, when used in concert with imaging modalities such as computed tomography (CT), enhance the visualization of tissues and boundary interfaces. However, the ability to determine the physiological state of the tissue via the quantitative assessment of biochemical or biomechanical properties remains elusive. We report the synthesis and characterization of tantalum oxide (Ta 2 O 5 ) nanoparticle (NP) contrast agents for rapid, nondestructive, and quantitative contrast-enhanced computed tomography (CECT) to assess both the glycosaminoglycan (GAG) content and the biomechanical integrity of human metacarpal phalangeal joint (MCPJ) articular cartilage. Ta 2 O 5 NPs 3-6 nm in diameter and coated with either nonionic poly(ethylene) glycol (PEG) or cationic trimethylammonium ligands readily diffuse into both healthy and osteoarthritic MCPJ cartilage. The CECT attenuation for the cationic and neutral NPs correlates with the glycosaminoglycan (GAG) content ( R 2 = 0.8975, p < 0.05 and 0.7054, respectively) and the equilibrium modulus ( R 2 = 0.8285, p < 0.05 and 0.9312, p < 0.05, respectively). The results highlight the importance of the surface charge and size in the design of NP agents for targeting and imaging articular cartilage. Further, nanoparticle CECT offers the visualization of both soft tissue and underlying bone unlike plain radiography, which is the standard for imaging bone in musculoskeletal diseases, and the ability to provide a real-time quantitative assessment of both hard and soft tissues to provide a comprehensive image of the disease stage, as demonstrated herein.

CA4+ is a novel cationic iodinated contrast agent utilized for contrast-enhanced microCT (CECT). In this study, we compared CA4+ CECT for cartilage quantification of unfixed and neutral buffered formalin (NBF)-fixed rabbit distal femur cartilage after 8-, 24- and 30-hours of contrast agent diffusion. The stability of CA4+ binding to cartilage after PBS soak and decalcification was also investigated by CECT. We further assessed the feasibility of cartilage histology and immunohistochemistry after CA4+ CECT. Contrast-enhanced CA4+ labeled unfixed and NBF-fixed cartilage tissues facilitate articular cartilage quantification and accurate morphological assessment. The NBF fixed tissues demonstrate higher cartilage intensity and imaging characteristics distinct from subchondral bone than unfixed tissues while maintaining stable binding even after decalcification with 10% EDTA. The unfixed tissues labeled with CA4+, after CECT imaging and decalcification, are amenable to H&E, Alcian blue, and Safranin O staining, as well as Col2 immunohistochemistry. In contrast, only H&E and Alcian blue staining can be accomplished with CA4+ labeled NBF fixed cartilage, and CA4+ labeling interferes with downstream immunohistochemistry and Safranin O staining, likely due to its positive charge. In conclusion, CA4+ CECT of NBF fixed tissues provides high quality microCT cartilage images and allows for convenient quantification along with feasible downstream H&E and Alcian blue staining after decalcification. CA4+ CECT of unfixed tissues enables researchers to obtain both quantitative microCT as well as cartilage histology and immunohistochemistry data from one set of animals in a cost-, time-, and labor-efficient manner., Competing Interests: JH received Royalties from Cooke Myocytes annually. Dr. Philippon, Education payments from Linvatec (2015); speaking fees and consulting fees from Smith & Nephew (through 2018), Synthes GmbH (2019); royalties from DJO (2015/16), Linvatec (through 2018), and Smith & Nephew (2015/16); and hospitality payments from Siemens Medical Solutions (2016)., (AJTR Copyright © 2021.)

Fish contaminant studies with human health protection objectives typically focus on muscle tissue, recognizing that fillets are the commonly consumed tissue fraction. Muscle biopsy punch sampling for mercury analysis has recently been used as an alternative to harvesting fish for fillets; however, there is limited information comparing fillet plug results to whole fillet results. This study was conducted to address that data gap and to test the applicability of plugs for monitoring associated with United States Environmental Protection Agency's fish tissue-based mercury and selenium water quality criteria. The mercury phase included 300 fillet homogenates and 300 field-extracted plug samples from 60 fish, and the selenium phase included 120 fillet homogenates and 120 plugs from 30 fish. Both phases showed that there were no statistically significant differences between fillet plug and homogenized fillet results at the community level; however, a selenium plug monitoring alternative must employ a sufficiently sensitive analytical method and consider total solids. Plug and fillet sampling alternatives have inherent advantages and disadvantages. Fillet sampling provides sufficient mass to consider multiple contaminants but requires fish to be harvested. Plug sampling only provides adequate mass for a single analyte but may allow fish survival, although additional research is needed on survival following plug removal., (© 2021. The Author(s).)

Cationic contrast-enhanced computed tomography (CECT) is a quantitative imaging technique that characterizes articular cartilage, though its efficacy in differentiating repair tissue from other disease states is undetermined. We hypothesized that cationic CECT attenuation will distinguish between reparative, degenerative, and healthy equine articular cartilage and will reflect biochemical, mechanical, and histologic properties. Chondral defects were created in vivo on equine femoropatellar joint surfaces. Within defects, calcified cartilage was retained (Repair 1) or removed (Repair 2). At sacrifice, plugs were collected from within defects, and at locations bordering (adjacent site) and remote to defects along with site-matched controls. Articular cartilage was analyzed via CECT using CA4+ to assess glycosaminoglycan (GAG) content, compressive modulus (E eq ), and International Cartilage Repair Society (ICRS) II histologic score. Comparisons of variables were made between sites using mixed model analysis and between variables with correlations. Cationic CECT attenuation was significantly lower in Repair 1 (1478 ± 333 Hounsfield units [HUs]), Repair 2 (1229 ± 191 HUs), and adjacent (2139 ± 336 HUs) sites when compared with site-matched controls (2587 ± 298, 2505 ± 184, and 2563 ± 538 HUs, respectively; all p < .0001). Cationic CECT attenuation was significantly higher at remote sites (2928 ± 420 HUs) compared with Repair 1, Repair 2, and adjacent sites (all p < .0001). Cationic CECT attenuation correlated with ICRS II score (r = .79), GAG (r = .76), and E eq (r = .71; all p < .0001). Cationic CECT distinguishes between reparative, degenerative, and healthy articular cartilage and highly correlates with biochemical, mechanical, and histological tissue properties., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Background: Recent focus on surgical site infections (SSIs) after posterior spine fusion (PSF) has lowered infection rates by standardizing perioperative antibiotic prophylaxis. However, efforts have neglected to detail antibiotic treatment of SSIs. Our aim was to document variability in antibiotic regimens prescribed for acute and latent SSIs following PSF in children with idiopathic, neuromuscular, and syndromic scoliosis., Methods: This study included patients who developed a SSI after PSF for scoliosis at a pediatric tertiary care hospital between 2004 and 2019. Patients had to be 21 years or younger at surgery. Exclusion criteria included growing rods, staged surgery, and revision or removal before SSI diagnosis. Infection was classified as acute (within 90 d) or latent. Clinical resolution of SSI was measured by return to normal lab values. Each antibiotic was categorized as empiric or tailored., Results: Eighty subjects were identified. The average age at fusion was 14.7 years and 40% of the cohort was male. Most diagnoses were neuromuscular (53%) or idiopathic (41%).Sixty-three percent of patients had an acute infection and 88% had a deep infection. The majority (54%) of subjects began on tailored antibiotic therapy versus empiric (46%). Patients with a neuromuscular diagnosis had 4.0 times the odds of receiving initial empiric treatment compared with patients with an idiopathic diagnosis, controlling for infection type and time (P=0.01). Ninety-two percent of patients with acute SSI retained implants at the time of infection and 76% retained them as of August 2020. In the latent cohort, 27% retained implants at infection and 17% retained them as of August 2020., Conclusions: Patients with acute infections were on antibiotics longer than patients with latent infections. Those with retained implants were on antibiotics longer than those who underwent removal. By providing averages of antibiotic duration and lab normalization, we hope to standardize regimens moving forward and develop SSI-reducing pathways encompassing low-risk patients., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Many patients with presumed idiopathic scoliosis are found to have Chiari I malformation (CM-I) on MRI. The objective of this study is to report on scoliosis progression in CM-I with no syringomyelia., Methods: A retrospective review of patients with scoliosis and CM-I was conducted from 1997 to 2015. Patients with syringomyelia and/or non-idiopathic scoliosis were excluded. Clinical and radiographic characteristics were recorded at presentation and latest follow-up. CM-I was defined as the cerebellar tonsil extending 5 mm or more below the foramen magnum on MRI., Results: Thirty-two patients (72% female) with a mean age of 11 years (range 1-16) at scoliosis diagnosis were included. The average initial curve was 30.3° ± SD 16.3. The mean initial Chiari size was 9.6 mm SD ± 4.0. Fifteen (46.9%) experienced Chiari-related symptoms, and three (9%) patients underwent Posterior Fossa Decompression (PFD) to treat these symptoms. 10 (31%) patients went on to fusion, progressing on average 13.6° (95% CI 1.6-25.6°). No association was detected between decompression and either curve progression or fusion (p = 0.46, 0.60). For those who did not undergo fusion, curve magnitude progressed on average 1.0° (95% CI - 4.0 to 5.9°). There was no association between age, Chiari size, presence of symptoms, initial curve shape, or bracing treatment and fusion., Conclusion: Patients with CM-I and scoliosis may not require surgical treatment, including PFD and fusion. Scoliosis curvature stabilized in the non-surgical population at an average progression of 1.0°. These results suggest that CM-I with no syringomyelia has minimal effect on scoliosis progression., (© 2021. Scoliosis Research Society.)

Growth modulation is an emerging method for treatment of angular skeletal deformities such as adolescent idiopathic scoliosis (AIS). The Hueter-Volkmann law, by which growth is stimulated in tension and inhibited in compression, is widely understood, and applied in current growth-modulating interventions such as anterior vertebral body tethering (AVBT) for AIS. However, without quantification of the growth rate effects of tension or compression, the possibility of under- or over- correction exists. A definitive mechanical growth modulation relationship relating to treatment of such skeletal deformities is yet to exist, and the mechanisms by which growth rate is regulated and altered are not fully defined. Review of current literature demonstrates that longitudinal (i.e., lengthwise) growth rate in multiple animal models depend on load magnitude, anatomical location, and species. Additionally, alterations in growth plate morphology and viability vary by loading parameters such as magnitude, frequency, and whether the load was applied persistently or intermittently. The aggregate findings of the reviewed studies will assist in work towards increasingly precise and clinically successful growth modulation methods. Part 1 of this review focuses on the effects of mechanical loading, species, age, and anatomical location on the macro-scale alterations in longitudinal bone growth, as well as factors that affect growth plate material properties. Part 2 considers the effects on micro-scale alterations in growth plate morphology such as zone heights and proportions, chondrocyte viability, and related gene and protein expression., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Macro-scale changes in longitudinal bone growth resulting from mechanical loading were shown in Part 1 of this review to depend on load magnitude, anatomical location, and species. While no significant effect on longitudinal growth was observed by varying frequency and amplitude of cyclic loading, such variations, in addition to loading duration and species, were shown to affect the morphology, viability, and gene and protein expression within the growth plate. Intermittent compression regimens were shown to preserve or increase growth plate height while stimulating increased chondrocyte presence in the hypertrophic zone relative to persistent and static loading regimens. Gene and protein expressions related to matrix synthesis and degradation, as well as regulation of chondrocyte apoptosis were shown to exhibit magnitude-, frequency-, and duration-dependent responses to loading regimen. Chondrocyte viability was shown to be largely preserved within physiological bounds of magnitude, frequency, amplitude, and duration. Persistent static loading was shown to be associated with overall growth plate height in tension only, reducing it in compression, while affecting growth plate zone heights differently across species and encouraging mineralization relative to intermittent cyclic loading. Lateral loading of the growth plate, as well as microfluidic approaches are relatively understudied, and age, anatomical location, and species effects within these approaches are undefined. Understanding the micro-scale effects of varied loading regimes can assist in the development of growth modulation methods and device designs optimized for growth plate viability preservation or mineralization stimulation based on patient age and anatomical location., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objective: To investigate the diffusion trajectory of a cationic contrast medium (CA4+) into equine articular cartilage, and to assess normal and degenerative equine articular cartilage using cationic contrast-enhanced computed tomography (CECT)., Design: In the first experiment (Exp1), equine osteochondral specimens were serially imaged with cationic CECT to establish the diffusion time constant and time to reach equilibrium in healthy articular cartilage. In a separate experiment (Exp2), articular cartilage defects were created on the femoral trochlea (defect joint) in a juvenile horse, while the opposite joint was a sham-operated control. After 7 weeks, osteochondral biopsies were collected throughout the articular surfaces of both joints. Biopsies were analyzed for cationic CECT attenuation, glycosaminoglycan (GAG) content, mechanical stiffness (E eq ), and histology. Imaging, biochemical and mechanical data were compared between defect and control joints., Results: Exp1: The mean diffusion time constant was longer for medial condyle cartilage (3.05 ± 0.1 hours) than lateral condyle cartilage (1.54 ± 0.3 hours, P = 0.04). Exp2: Cationic CECT attenuation was lower in the defect joint than the control joint ( P = 0.005) and also varied by anatomic location ( P = 0.045). Mean cationic CECT attenuation from the lateral trochlear ridge was lower in the defect joint than in the control joint (2223 ± 329 HU and 2667 ± 540 HU, respectively; P = 0.02). Cationic CECT attenuation was strongly correlated with both GAG (ρ = 0.79, P < 0.0001) and E eq (ρ = 0.61, P < 0.0001)., Conclusions: The equilibration time of CA4+ into equine articular cartilage is affected by tissue volume. Quantitative cationic CECT imaging reflects the biochemical, biomechanical and histological state of normal and degenerative equine articular cartilage.

Osteoarthritis (OA) is a disease of the entire joint, often triggered by cartilage injury, mediated by a cascade of inflammatory pathways involving a complex interplay among metabolic, genetic, and enzymatic factors that alter the biochemical composition, microstructure, and biomechanical performance. Clinically, OA is characterized by degradation of the articular cartilage, thickening of the subchondral bone, inflammation of the synovium, and degeneration of ligaments that in aggregate reduce joint function and diminish quality of life. OA is the most prevalent joint disease, affecting 140 million people worldwide; these numbers are only expected to increase, concomitant with societal and financial burden of care. We present a two-part review encompassing the applications of nanotechnology to the diagnosis and treatment of OA. Herein, part 1 focuses on OA treatment options and advancements in nanotechnology for the diagnosis of OA and imaging of articular cartilage, while part 2 (10.1002/jor.24842) summarizes recent advances in drug delivery, tissue scaffolds, and gene therapy for the treatment of OA. Specifically, part 1 begins with a concise review of the clinical landscape of OA, along with current diagnosis and treatments. We next review nanoparticle contrast agents for minimally invasive detection, diagnosis, and monitoring of OA via magnetic resonace imaging, computed tomography, and photoacoustic imaging techniques as well as for probes for cell tracking. We conclude by identifying opportunities for nanomedicine advances, and future prospects for imaging and diagnostics., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Osteoarthritis (OA) is a multifactorial disease of the entire joint which afflicts 140 million individuals worldwide regardless of economic or social status. Current clinical treatments for OA primarily center on reducing pain and increasing mobility, and there are limited therapeutic interventions to restore degraded cartilage or slow disease pathogenesis. This second installment of a two-part review on nanotechnology and OA focuses on novel treatment strategies. Specifically, Part 2 first discusses current surgical and nonsurgical treatments for OA and then summarizes recent advancements in nanotechnology-based treatments, while Part 1 (10.1002/jor.24817) described advances in imaging and diagnostics. We review nano delivery systems for small molecule drugs, nucleic acids, and proteins followed by nano-based scaffolds for neocartilage formation and osteochondral regeneration, and lastly nanoparticle lubricants. We conclude by identifying opportunities for nanomedicine advances, and prospects for OA treatments., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objective: miR-122 stimulates proliferation of growth plate chondrocytes whereas miR-451 stimulates terminal differentiation and matrix turnover. Here, we examined the potential of these microRNA as regulators of articular chondrocytes using an in vitro model of osteoarthritis., Methods: miR-122 and miR-451 presence in rat articular cartilage was assessed using the anterior cruciate ligament transection model of OA. In vitro testing used first passage rat articular chondrocytes (rArCs) that were transfected with lipofectamine (Lipo) and miR-122 or miR-451 for 24-h, then treated with 10 ng/mL IL-1β in order to mimic an osteoarthritic environment. Conditioned media were collected and MMP13, PGE2 and OA-related cytokines were measured. Matrix vesicles were collected from cell layer lysates using ultra-centrifugation. Cells were treated with miR-122 or miR-451 inhibitors to verify miR-specific effects., Results: Both miR-122 and miR-451 were increased in the OA articular cartilage compared to healthy tissue; rArCs expressed both microRNAs in MVs. miR-122 prevented IL-1β-dependent increases in MMP-13 and PGE2, whereas miR-451 significantly increased the IL-1β effect. Multiplex data indicated that miR-122 reduced the stimulatory effect of IL-1β on IL-1α, IL-2, Il-4, IL-6, GM-CSF, MIP-1A, RANTES and VEGF. In contrast, IL-2, IL-4, IL-6, GM-CSF, and MIP-1A were increased by miR-451 while VEGF was decreased. Inhibiting miR-122 exacerbated the response to IL-1β indicating endogenous levels of miR-122 were present. There were no differences in MMP-13 or PGE2 with miR-451 Locked Nucleic Acid (LNA) inhibitor treatment., Conclusions: Both miRs were elevated in OA in a rat bilateral anterior cruciate ligament transection (ACLT) model. miR-122 prevented, while miR-451 exacerbated the effects of IL-1β on rArCs., (Copyright © 2020 Osteoarthritis Research Society International. All rights reserved.)