Improvement in axial rotation with bracing reduces the risk of curve progression in patients with adolescent idiopathic scoliosis.

PURPOSE: New evidence highlights the significance of 3D in-brace correction for Adolescent Idiopathic Scoliosis (AIS) patients. This study explores how axial parameters relate to treatment failure in braced AIS patients. METHODS: AIS patients (Sanders 1-5) undergoing Rigo-Chêneau bracing at a single institution were included. Axial vertebral rotation (AVR) was determined by utilizing pre-brace and in-brace 3D reconstructions from EOS® radiographs. The primary outcome was treatment failure: surgery or coronal curve progression > 5°. Minimum follow-up was two years. RESULTS: 75 patients (81% female) were included. Mean age at bracing initiation was 12.8 ± 1.3 years and patients had a pre-brace major curve of 31.0° ± 6.5°. 25 patients (76% female) experienced curve progression > 5°, and 18/25 required surgical intervention. The treatment failure group had larger in-brace AVR than the success group (5.8° ± 4.1° vs. 9.9° ± 7.6°, p = 0.003), but also larger initial coronal curve measures. In-brace AVR did not appear to be associated with treatment failure after adjusting for the pre-brace major curve (Hazard Ratio (HR):0.99, 95% Confidence Interval (CI):0.94-1.05, p = 0.833). Adjusting for pre-brace major curve, patients with AVR improvement with bracing had an 85% risk reduction in treatment failure versus those without (HR:0.15, 95% CI:0.02-1.13, p = 0.066). At the final follow-up, 42/50 (84%) patients without progression had Sanders ≥ 7. CONCLUSIONS: While in-brace rotation was not an independent predictor of curve progression (due to its correlation with curve magnitude), improved AVR with bracing was a significant predictor of curve progression. This study is the first step toward investigating the interplay between 3D parameters, skeletal maturity, compliance, and brace efficacy, allowing a future prospective multicenter study. LEVEL OF EVIDENCE: Retrospective study; Level III.

Utilizing a comprehensive machine learning approach to identify patients at high risk for extended length of stay following spinal deformity surgery in pediatric patients with early onset scoliosis.

PURPOSE: Early onset scoliosis (EOS) patient diversity makes outcome prediction challenging. Machine learning offers an innovative approach to analyze patient data and predict results, including LOS in pediatric spinal deformity surgery. METHODS: Children under 10 with EOS were chosen from the American College of Surgeon's NSQIP database. Extended LOS, defined as over 5 days, was predicted using feature selection and machine learning in Python. The best model, determined by the area under the curve (AUC), was optimized and used to create a risk calculator for prolonged LOS. RESULTS: The study included 1587 patients, mostly young (average age: 6.94 ± 2.58 years), with 33.1% experiencing prolonged LOS (n = 526). Most patients were female (59.2%, n = 940), with an average BMI of 17.0 ± 8.7. Factors influencing LOS were operative time, age, BMI, ASA class, levels operated on, etiology, nutritional support, pulmonary and neurologic comorbidities. The gradient boosting model performed best with a test accuracy of 0.723, AUC of 0.630, and a Brier score of 0.189, leading to a patient-specific risk calculator for prolonged LOS. CONCLUSIONS: Machine learning algorithms accurately predict extended LOS across a national patient cohort and characterize key preoperative drivers of increased LOS after PSIF in pediatric patients with EOS.

Fusion mass to pelvis internal distraction technique using multiple-hook fixation for scoliosis correction: illustrative case.

BACKGROUND: Internal distraction rods have been described as an alternative to halo gravity traction for the treatment of severe scoliosis. Distraction rods can be challenging to use in patients with existing fusion masses. The authors report an internal distraction, construct-to-construct rod technique using multiple-hook fixation in a patient with a sharply angulated cervicothoracic scoliosis fusion mass. OBSERVATIONS: A 12-year-old female with previously diagnosed congenital scoliosis who had undergone cervical fusion in situ at age 2 presented to the clinic with shortness of breath exacerbated by increased levels of activity. Standing anteroposterior and lateral scoliosis radiographs revealed a left >150° cervicothoracic curve, right 140° thoracolumbar curve, and left 28° lumbosacral fractional curve with pelvic obliquity. The authors indicated this patient for a 3-stage all-posterior approach for spinal fusion and deformity correction. In the final fusion surgery, the authors set up a construct-to-construct internal distraction configuration connecting the left hemipelvis to the cervicothoracic fusion mass to aid in deformity correction. LESSONS: A construct-to-construct internal distraction rod technique connecting a fusion mass to the pelvis can assist with curve correction in severe scoliosis.

Evaluating compliance with the best practice guidelines for wrong-level surgery prevention in high-risk pediatric spine surgery.

PURPOSE: In 2018, Best Practice Guidelines (BPGs) were published for preventing wrong-level surgery in pediatric spinal deformity, but successful implementation has not been established. The purpose of this study was to evaluate BPG compliance 5 years after publication. We hypothesized higher compliance among BPG authors and among surgeons with more experience, higher caseload, and awareness of the BPGs. METHODS: We queried North American and European surgeons, authors and nonauthors, and members of pediatric spinal study groups on adherence to BPGs using an anonymous survey consisting of 18 Likert scale questions. Respondents provided years in practice, yearly caseload, and guideline awareness. Mean compliance scores (MCS) were developed by correlating Likert responses with MCS scores ("None of the time" = no compliance = MCS 0, "Sometimes" = weak to moderate = MCS 1, "Most of the time" = high = MCS 2, and "All the time" = perfect = MCS 3). RESULTS: Of the 134 respondents, 81.5% reported high or perfect compliance. Average MCS for all guidelines was 2.4 ± 0.4. North American and European surgeons showed no compliance differences (2.4 vs. 2.3, p = 0.07). Authors and nonauthors showed significantly different compliance scores (2.8 vs 2.4, p < 0.001), as did surgeons with and without knowledge of the BPGs (2.5 vs 2.2, p < 0.001). BPG awareness and compliance showed a moderate positive correlation (r = 0.48, p < 0.001), with non-significant associations between compliance and both years in practice (r = 0.41, p = 0.64) and yearly caseload (r = 0.02, p = 0.87). CONCLUSION: Surgeons reported high or perfect compliance 81.5% of the time with BPGs for preventing wrong-level surgery. Authorship and BPG awareness showed increased compliance. Location, study group membership, years in practice, and yearly caseload did not affect compliance. LEVEL OF EVIDENCE: Level V-expert opinion.

Evaluating compliance with the 2013 best practice guidelines for preventing surgical site infection in high-risk pediatric spine surgery.

PURPOSE: Best Practice Guidelines (BPGs) were published one decade ago to decrease surgical site infection (SSI) in pediatric spinal deformity. Successful implementation has not been established. This study evaluated surgeon compliance with items on the BPG. We hypothesized that BPG authors and surgeons with more experience, higher caseload, and awareness of the BPG would have higher compliance. METHODS: We queried North American and European surgeons, authors and non-authors, and members of various spine study groups on adherence to BPGs using an anonymous survey. Mean compliance scores (MCSs) were developed by correlating Likert responses with MCSs ("None of the time" = no compliance = MCS 0, "Sometimes" = weak to moderate = MCS 1, "Most of the time" = high = MCS 2, "All the time" = perfect = MCS 3). RESULTS: Of the 142 respondents, 73.7% reported high or perfect compliance. Average compliance scores for all guidelines was 2.2 ± 0.4. There were significantly different compliance scores between North American and European surgeons (2.3 vs 1.8, p < 0.001), authors and non-authors (2.5 vs. 2.2, p = 0.023), and surgeons with and without knowledge of the BPGs (2.3 vs. 1.8, p < 0.001). There was a weak correlation between BPG awareness and compliance (r = 0.34, p < 0.001) and no correlation between years in practice (r = 0.0, p = 0.37) or yearly caseload (r = 0.2, p = 0.78) with compliance. CONCLUSIONS: Compliance among our cohort of surgeons surveyed was high. North American surgeons, authors of the BPGs and those aware of the guidelines had increased compliance. Participation in a spine study group, years in practice, and yearly caseload were not associated with compliance. LEVEL OF EVIDENCE: Level V-expert opinion.

Reliability of Preoperative Supine Versus Bending Radiographs in Estimating the Structural Nature of Curves in EOS.

BACKGROUND: The study sought to evaluate the utility of a single supine radiograph in determining curve flexibility in early-onset scoliosis (EOS) patients. METHODS: EOS patients with upright (standing/seated), supine, and side-bending radiographs who underwent spinal deformity surgery were identified. Coronal parameters included: proximal thoracic (PT) curve, main thoracic (MT) curve, and thoracolumbar/lumbar (TL/L) curve. Each radiograph was measured twice by 2 different raters. Correlation coefficients were utilized to investigate associations between the different radiographs. Interrater Correlation Coefficient (ICC) assessed intrarater and interrater reliability. RESULTS: Thirty-seven EOS patients were identified (age at diagnosis: 7.0±2.9 y, preoperative age: 13.0±2.9 y; 73% female; etiologies: 54% idiopathic, 30% syndromic, and 16% neuromuscular). Supine PT and MT curve measurements were highly associated with corresponding side-bending measurements (PT: r=0.75, P<0.001; MT: r=0.80, P<0.001), and TL/L curves were very highly associated (TL/L: r=0.92, P<0.001). The mean absolute differences between supine and side-bending measurements were PT: 11.3±7.8 degrees, MT: 14.8±8.3 degrees, and TL/L: 16.2±7.6 degrees, where the side-bending was on average smaller than the supine measurement. The intrarater reliabilities were excellent, with an ICC ranging from 0.93 to 0.96 for side-bending films and 0.94 to 0.97 for supine films. The interrater reliability was excellent with ICC value of 0.88 for side-bending films and 0.93 for supine films. CONCLUSIONS: A single, preoperative supine radiograph was highly predictive of side-bending radiographs in patients with EOS. Supine curves measured an average of 15 degrees larger than bending curves in the MT and TL/L region. A single supine film may eliminate the need for effort-related, dual side-bending radiographs. LEVEL OF EVIDENCE: Level II-retrospective study.

Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury.

Continual efferocytic clearance of apoptotic cells (ACs) by macrophages prevents necrosis and promotes injury resolution. How continual efferocytosis is promoted is not clear. Here, we show that the process is optimized by linking the metabolism of engulfed cargo from initial efferocytic events to subsequent rounds. We found that continual efferocytosis is enhanced by the metabolism of AC-derived arginine and ornithine to putrescine by macrophage arginase 1 (Arg1) and ornithine decarboxylase (ODC). Putrescine augments HuR-mediated stabilization of the mRNA encoding the GTP-exchange factor Dbl, which activates actin-regulating Rac1 to facilitate subsequent rounds of AC internalization. Inhibition of any step along this pathway after first-AC uptake suppresses second-AC internalization, whereas putrescine addition rescues this defect. Mice lacking myeloid Arg1 or ODC have defects in efferocytosis in vivo and in atherosclerosis regression, while treatment with putrescine promotes atherosclerosis resolution. Thus, macrophage metabolism of AC-derived metabolites allows for optimal continual efferocytosis and resolution of injury.

Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution.

Regulatory T (Treg) cell responses and apoptotic cell clearance (efferocytosis) represent critical arms of the inflammation resolution response. We sought to determine whether these processes might be linked through Treg-cell-mediated enhancement of efferocytosis. In zymosan-induced peritonitis and lipopolysaccharide-induced lung injury, Treg cells increased early in resolution, and Treg cell depletion decreased efferocytosis. In advanced atherosclerosis, where defective efferocytosis drives disease progression, Treg cell expansion improved efferocytosis. Mechanistic studies revealed the following sequence: (1) Treg cells secreted interleukin-13 (IL-13), which stimulated IL-10 production in macrophages; (2) autocrine-paracrine signaling by IL-10 induced Vav1 in macrophages; and (3) Vav1 activated Rac1 to promote apoptotic cell engulfment. In summary, Treg cells promote macrophage efferocytosis during inflammation resolution via a transcellular signaling pathway that enhances apoptotic cell internalization. These findings suggest an expanded role of Treg cells in inflammation resolution and provide a mechanistic basis for Treg-cell-enhancement strategies for non-resolving inflammatory diseases.

Hypercholesterolemia induces T cell expansion in humanized immune mice.

Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell-mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting.

CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis.

Atherosclerosis is the underlying etiology of cardiovascular disease, the leading cause of death worldwide. Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. A distinct type of plaque containing large necrotic cores with thin fibrous caps often precipitates these acute events. Here, we show that Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages plays a major role in the development of necrotic, thin-capped plaques. Macrophages in necrotic and symptomatic atherosclerotic plaques in humans as well as advanced atherosclerotic lesions in mice demonstrated activation of CaMKII. Western diet-fed LDL receptor-deficient (Ldlr-/-) mice with myeloid-specific deletion of CaMKII had smaller necrotic cores with concomitantly thicker collagen caps. These lesions demonstrated evidence of enhanced efferocytosis, which was associated with increased expression of the macrophage efferocytosis receptor MerTK. Mechanistic studies revealed that CaMKIIγ-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKIIγ had increased expression of the transcription factor ATF6. We determined that ATF6 induces liver X receptor-α (LXRα), an Mertk-inducing transcription factor, and that increased MerTK expression and efferocytosis in CaMKIIγ-deficient macrophages is dependent on LXRα. These findings identify a macrophage CaMKIIγ/ATF6/LXRα/MerTK pathway as a key factor in the development of necrotic atherosclerotic plaques.