Study Design: Retrospective review of patients ages 10-18 who underwent posterior fusion for adolescent idiopathic scoliosis (AIS) at a single institution from 2014 to 2019. Objective: The aim was to evaluate a standardized Care Path to determine its effects on perioperative outcomes in patients undergoing spinal fusion for AIS. Summary of Background Data: AIS is the most common pediatric spinal deformity and thousands of posterior fusions are performed annually. Surgery presents several postoperative challenges, such as pain control, delayed mobilization, and opioid-related morbidity. Optimizing perioperative care of AIS is a high priority to reduce morbidity and improving health care efficiency. Materials and Methods: A total of 336 patients ages 10-18 were included in this study; 117 in the pre-Care Path cohort (2014-2015) and 219 in the post-Care Path cohort (2016-2019). Data compared included intraoperative details, length of stay, timing of mobilization, inpatient complications, emergency room (ER) visits, readmissions after discharge, postoperative complications, and reoperations. Results: The post-Care Path cohort had improved mobilization on postoperative day 0 (pre 16.7%, post 53.3%, P<0.00001), reduced length of stay (pre 4.14 days, post 3.36 days, P=0.00006), fewer total inpatient complications (pre 17.1%, post 8.1%, P=0.0469), and fewer instances of postoperative ileus (pre 8.5%, post 1.9%, P=0.0102). Within 60 days of surgery, the post-Care Path cohort had fewer ER visits (pre 12.8%, post 7.2%, P=0.0413), decreased postoperative infections (pre 5.1%, post 0.48%, P=0.00547), decreased readmissions (pre 6.0%, post 0.48%, P=0.0021), and decreased reoperations (pre 5.1%, post 0.96%, P=0.0195). There was a decrease in inpatient oral morphine equivalents in the Care Path cohort (pre 118.7, post 84.7, P=0.0003). Conclusions: Our Care Path for AIS patients demonstrated significant improvements in postoperative mobilization and decreases in length of stay, complications, infections, ER visits, readmissions, and reoperations.

Study objective: To evaluate the pharmacokinetics and safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery. Design: Multicenter, open-label, phase 3, randomized trial (PLAY; NCT03682302). Setting: Operating room. Patients: Two separate age groups were evaluated (age group 1: patients 12 to <17 years undergoing spine surgery; age group 2: patients 6 to <12 years undergoing spine or cardiac surgery). Intervention: Randomized allocation of liposomal bupivacaine 4 mg/kg or bupivacaine hydrochloride (HCl) 2 mg/ kg via local infiltration at the end of spine surgery (age group 1); liposomal bupivacaine 4 mg/kg via local infiltration at the end of spine or cardiac surgery (age group 2). Measurements: The primary and secondary objectives were to evaluate the pharmacokinetics (eg, maximum plasma bupivacaine concentrations [Cmax], time to Cmax) and safety of liposomal bupivacaine, respectively. Main results: Baseline characteristics were comparable across groups. Mean Cmax after liposomal bupivacaine administration was lower versus bupivacaine HCl in age group 1 (357 vs 564 ng/mL); mean Cmax in age group 2 was 320 and 447 ng/mL for spine and cardiac surgery, respectively. Median time to Cmax of liposomal bupivacaine occurred later with cardiac surgery versus spine surgery (22.7 vs 7.4 h). In age group 1, the incidence of adverse events (AEs) was comparable between liposomal bupivacaine (61% [19/31]) and bupivacaine HCl (73% [22/30]). In age group 2, 100% (5/5) and 31% (9/29) of patients undergoing spine and cardiac surgery experienced AEs, respectively. AEs were generally mild or moderate, with no discontinuations due to AEs or deaths. Conclusions: Plasma bupivacaine levels following local infiltration with liposomal bupivacaine remained below the toxic threshold in adults (similar to 2000-4000 ng/mL) across age groups and procedures. AEs were mild to moderate, supporting the safety of liposomal bupivacaine in pediatric patients undergoing spine or cardiac surgery.

Background: Approximately 60% of hospitalized children undergoing surgery experience at least 1 day of moderate-to-severe pain after surgery. Pain following spine surgery may affect opioid exposure, length of stay (LOS), and costs in hospitalized pediatric patients. This is a retrospective cohort analysis of pediatric patients undergoing inpatient primary spine surgery. Objectives: To examine the association of opioid-related and economic outcomes with postsurgical liposomal bupivacaine (LB) or non-LB analgesia in pediatric patients who received spine surgery. Methods: Premier Healthcare Database records (January 2015-September 2019) for patients aged 1-17 years undergoing inpatient primary spine surgery were retrospectively analyzed. Outcomes included in-hospital postsurgical opioid consumption (morphine milligram equivalents [MMEs]), opioid-related adverse events (ORAEs), LOS (days), and total hospital costs. A generalized linear model adjusting for baseline characteristics was used. Results: Among 10 189 pediatric patients, the LB cohort (n=373) consumed significantly fewer postsurgical opioids than the non-LB cohort (n=9816; adjusted MME ratio, 0.53 [95% confidence interval (CI), 0.45-0.61]; P<0.0001). LOS was significantly shorter in the LB versus non-LB cohort (adjusted rate ratio, 0.86 [95% CI, 0.80-0.94]; P=0.0003). Hospital costs were significantly lower in the LB versus non-LB cohort overall (adjusted rate ratio, 0.92 [95% CI, 0.86-0.99]; P=0.0227) mostly because of decreased LOS and central supply costs. ORAEs were not significantly different between groups (adjusted rate ratio, 0.84 [95% CI, 0.65-1.08]; P=0.1791). Discussion: LB analgesia was associated with shorter LOS and lower hospital costs compared with non-LB analgesia in pediatric patients undergoing spine surgery. The LB cohort had lower adjusted room and board and central supply costs than the non-LB cohort. These data suggest that treatment with LB might reduce hospital LOS and subsequently health-care costs, and additional cost savings outside the hospital room may factor into overall health-care cost savings. LB may reduce pain and the need for supplemental postsurgical opioids, thus reducing pain and opioid-associated expenses while improving patient satisfaction with postsurgical care. Conclusions: Pediatric patients undergoing spine surgery who received LB had significantly reduced in-hospital postsurgical opioid consumption, LOS, and hospital costs compared with those who did not.

Study Design: Retrospective comparative cohort study. Objective: To evaluate: (1) pain relief efficacy; (2) opioid consumption; (3) length of stay (LOS); (4) discharge disposition (DD); and (5) safety and adverse effects of liposomal bupivacaine (LB) in pediatric patients who underwent spinal deformity correction. Summary of Background Data: LB is a long-acting, locally injectable anesthetic. Previous orthopedic studies investigating its use have been limited to adult patients. The use of LB as part of postoperative pain management in pediatric patients undergoing spine deformity correction surgery is yet to be evaluated. Materials and Methods: A total of 195 patients that received LB as part of their postoperative pain management regimen were compared with 128 patients who received standard pain management without LB. Pain intensity, opioid consumption, LOS, and DD were recorded. Potential LB-related complications were reported as frequencies and statistically compared for superiority. Noninferiority tests were performed using the Farrington-Manning score test. Multivariate tests based on generalized estimating equations were performed to determine the common and average treatment effects. Odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results: The LB cohort demonstrated lower pain scores [postoperative day 1 (POD 1)-median=2, interquartile range (IQR)=(0-5) vs. 5 (2.5-7); POD 2-3 (0-5) vs. 4 (3-6); P<0.001], lower overall opioid consumption (78.2 vs. 129 morphine milligram equivalents; P=0.0001) and consistently from POD 0 to 3 (mean differences; 7.47, 9.04, 17.2, and 17.3 morphine milligram equivalents, respectively; P<0.01), shorter LOS (median=3 d, IQR=3-4 vs. 4 d, IQR=4-6; P<0.001), and similar to-home DD (98% vs. 97%). Complications were similar among the cohorts in superiority and 10% noninferiority analyses. Patients in the LB cohort had lower odds for complications (odds ratio=0.77; 95% CI, 0.64-0.93; P=0.009 and 0.67; 95% CI, 0.50-0.90; P=0.008). Conclusions: This study demonstrated the safety and efficacy of LB when added to the current multimodal postoperative pain management regimens after pediatric spinal surgery.

A relationship between the development of osteonecrosis of the femoral head and systemic corticosteroids has been well established in the literature, particularly in adults. However, the link between osteonecrosis and inhaled corticosteroids is less researched and understood. We report an usual case report of a 10-year-old male who developed ipsilateral femoral head osteonecrosis after long-term inhalational corticosteroid and intermittent short courses of oral steroid usage with a unique presentation and delayed diagnosis.

BACKGROUND:Spinal fusion surgery for the treatment of adolescent idiopathic scoliosis (AIS) is increasing. Health systems and surgeons are decreasing hospital length of stay (LOS) to decrease costs. The purpose of this study was to review the contribution of an accelerated discharge protocol on the total cost of a single episode of care related to the surgical treatment of AIS at a single institution.METHODS:A retrospective cost analysis was performed over an 18-month period, from January 2014 through June 2015, before and after the institution of an accelerated discharge program. Patients treated surgically with ICD-9 code 737.30 (Idiopathic Scoliosis) were reviewed. Itemized costs and LOS were analyzed collectively and by surgeon before and after the accelerated discharge protocol.RESULTS:Eighty AIS patients were treated surgically. The accelerated discharge program significantly reduced average LOS from 4.2 days in 2014 to 3.3 days during the first 6 months of 2015 (P≤0.05). There were no increases in complications. There was a 9% decrease in the total average costs per episode of care. A weighted average, a relative average change in costs, and an average cost savings per case were calculated for 12 different categories. Average Surgical Services and Nursing costs decreased during the study period while all other costs increased. The accelerated discharge program did not directly contribute significantly to this decrease in costs. Greatest cost reduction was associated with average bone graft and pedicle screw cost, with an overall 8.5% reduction in pedicle screw use and a 58% reduction in bone graft costs.CONCLUSIONS:Intraoperative variables under the direct control of the surgeon contribute much more to cost reduction than an accelerated discharge program for surgically treated AIS patients.

Disrupting the Wnt Planar Cell Polarity (PCP) signaling pathway in vivo results in loss of columnar growth plate architecture, but it is unknown whether activation of this pathway in vitro is sufficient to promote column formation. We hypothesized that activation of the Wnt PCP pathway in growth plate chondrocyte cell pellets would promote columnar organization in these cells that are normally oriented randomly in culture. Rat growth plate chondrocytes were transfected with plasmids encoding the Fzd7 cell-surface Wnt receptor, a Fzd7 deletion mutant lacking the Wnt-binding domain, or Wnt receptor-associated proteins Ror2 or Vangl2, and then cultured as three-dimensional cell pellets in the presence of recombinant Wnt5a or Wnt5b for 21 days. Cellular morphology was evaluated using histomorphometric measurements. Activation of Wnt PCP signaling components promoted the initiation of columnar morphogenesis in the chondrocyte pellet culture model, as measured by histomorphometric analysis of the column index (ANOVA p = 0.01). Activation of noncanonical Wnt signaling through overexpression of both the cell-surface Wnt receptor Fzd7 and receptor-associated protein Ror2 with addition of recombinant Wnt5a promotes the initiation of columnar architecture of growth plate chondrocytes in vitro, representing an important step toward growth plate regeneration.

Indian hedgehog (Ihh) is a key component of the regulatory apparatus governing chondrocyte proliferation and differentiation in the growth plate. Recent studies have demonstrated that the primary cilium is the site of Ihh signaling within the cell, and that primary cilia are essential for bone and cartilage formation. Primary cilia are also postulated to act as mechanosensory organelles that transduce mechanical forces acting on the cell into biological signals. In this study, we used a hydrostatic compression system to examine Ihh signal transduction under the influence of mechanical load. Our results demonstrate that hydrostatic compression increased both Ihh gene expression and Ihh-responsive Gli-luciferase activity. These increases were aborted by disrupting the primary cilia structure with chloral hydrate. These results suggest that growth plate chondrocytes respond to hydrostatic loading by increasing Ihh signaling, and that the primary cilium is required for this mechano-biological signal transduction to occur.

The transcription factor Sox9 is necessary for early chondrogenesis, but its subsequent roles in the cartilage growth plate, a highly specialized structure that drives skeletal growth and endochondral ossification, remain unclear. Using a doxycycline-inducible Cre transgene and Sox9 conditional null alleles in the mouse, we show that Sox9 is required to maintain chondrocyte columnar proliferation and generate cell hypertrophy, two key features of functional growth plates. Sox9 keeps Runx2 expression and β-catenin signaling in check and thereby inhibits not only progression from proliferation to prehypertrophy, but also subsequent acquisition of an osteoblastic phenotype. Sox9 protein outlives Sox9 RNA in upper hypertrophic chondrocytes, where it contributes with Mef2c to directly activate the major marker of these cells, Col10a1. These findings thus reveal that Sox9 remains a central determinant of the lineage fate and multistep differentiation program of growth plate chondrocytes and thereby illuminate our understanding of key molecular mechanisms underlying skeletogenesis.

Leptin is an obesity-associated cytokine-like hormone encoded by the ob gene. Recent studies reveal that leptin promotes proliferation and differentiation of chondrocytes, suggesting a peripheral role of leptin in regulating growth plate function. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcriptional regulator of adipogenesis. Locally, PPARγ negatively regulates chondrogenic differentiation and terminal differentiation in the growth plate. The aim of this study was to test the hypothesis that leptin may suppress the inhibitory effects of PPARγ on growth plate chondrocytes. Chondrocytes were collected from distal femoral growth plates of newborn rats and were cultured in monolayer or cell pellets in the presence or absence of leptin and the PPARγ agonist ciglitazone. The results show that leptin attenuates the suppressive effects of PPARγ on chondrogenic differentiation and T3-mediated chondrocyte hypertrophy. Leptin treatment also leads to a mild downregulation of PPAR mRNA expression and a significant MAPK/ERK-dependent PPARγ phosphorylation at serine 112/82. Blocking MAPK/ERK function with PD98059 confirmed that leptin antagonizes PPARγ function in growth plate chondrocytes through the MAPK/ERK signaling pathway. Furthermore, leptin signaling in growth plate cells is also negatively modulated by activation of PPARγ, implying that these two signaling pathways are mutually regulated in growth plate chondrocytes.

Leptin and thyroid hormone are two hormones that regulate energy balance through central signaling mechanisms. Recent studies in leptin-deficient ob/ob mice indicate that leptin also has peripheral effects in modulating the function of the growth plate, perhaps in terms of proliferation and differentiation enhancement. Thyroid hormone has been well-described as a potent stimulator of growth plate chondrocyte maturation. The objective of this study was therefore to investigate the interaction between leptin and thyroid hormone signaling in growth plate chondrocyte proliferation and terminal differentiation. Our in vitro data demonstrate that leptin synergistically functions with thyroid hormone through activation of both IGF-1/IGF1R signaling and Wnt/β-catenin signaling, two pathways that have been previously described as downstream effectors of thyroid hormone action. Leptin increases thyroid hormone receptor-α (TRα) expression and thyroid hormone receptor transcriptional activity. Thyroid hormone also activates leptin signaling in growth plate cells undergoing proliferation and hypertrophy. We conclude that leptin synergically interacts with thyroid hormone in promoting growth plate chondrocyte proliferation and terminal differentiation.

Thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulation of the Wnt/beta-catenin signaling pathway. Insulin-like growth factor 1 (IGF-1) has been described as a stabilizer of beta-catenin, and thyroid hormone is a known stimulator of IGF-1 receptor expression. The purpose of this study was to test the hypothesis that IGF-1 signaling is involved in the interaction between the thyroid hormone and the Wnt/beta-catenin signaling pathways in regulating growth plate chondrocyte proliferation and differentiation. The results show that IGF-1 and the IGF- receptor (IGF1R) stimulate Wnt-4 expression and beta-catenin activation in growth plate chondrocytes. The positive effects of IGF-1/IGF1R on chondrocyte proliferation and terminal differentiation are partially inhibited by the Wnt antagonists sFRP3 and Dkk1. T-3 activates IGF-1/IGF1R signaling and IGF-1-dependent PI3K/Akt/GSK-3 beta signaling in growth plate chondrocytes undergoing proliferation and differentiation to prehypertrophy. T-3-mediated Wnt-4 expression, beta-catenin activation, cell proliferation, and terminal differentiation of growth plate chondrocytes are partially prevented by the IGF1R inhibitor picropodophyllin as well as by the PI3K/Akt signaling inhibitors LY294002 and Akti1/2. These data indicate that the interactions between thyroid hormone and beta-catenin signaling in regulating growth plate chondrocyte proliferation and terminal differentiation are modulated by IGF-1/IGF1R signaling through both the Wnt and PI3K/Akt signaling pathways. While chondrocyte proliferation may be triggered by the IGF-1/IGF1R-mediated PI3K/Akt/GSK3 beta pathway, cell hypertrophy is likely due to activation of Wnt/beta-catenin signaling, which is at least in part initiated by IGF-1 signaling or the IGF-1-activated PI3K/Akt signaling pathway. (C) 2010 American Society for Bone and Mineral Research.

Carboxypeptidase Z (CPZ) removes carboxyl-terminal basic amino acid residues, particularly arginine residues, from proteins. CPZ contains a cysteine-rich domain (CRD) similar to the CRD found in the frizzled family of Writ receptors. We have previously shown that thyroid hormone regulates terminal differentiation of growth plate chondrocytes through activation of Wnt-4 expression and Wnt/beta-catenin signaling. The Wnt-4 protein contains a C-terminal arginine residue and binds to CPZ through the CRD. The objective of this study was to determine whether CPZ modulates Wnt/beta-catenin signaling and terminal differentiation of growth plate chondrocytes. Our results show that CPZ and Wnt-4 mRNA are co-expressed throughout growth plate cartilage. In primary pellet cultures of rat growth plate chondrocytes, thyroid hormone increases both Wnt-4 and CPZ expression, as well as CPZ enzymatic activity. Knockdown of either Wnt-4 or CPZ mRNA levels using an RNA interference technique or blocking CPZ enzymatic activity with the carboxypeptidase inhibitor GEMSA reduces the thyroid hormone effect on both alkaline phosphatase activity and Col10a1 mRNA expression. Adenoviral overexpression of CPZ activates Wnt/beta-catenin signaling and promotes the terminal differentiation of growth plate cells. Overexpression of CPZ in growth plate chondrocytes also removes the C-terminal arginine residue from it synthetic peptide consisting of the carboxyl-terminal 16 amino acids of the Wnt-4 protein. Removal of the C-terminal arginine residue of Wnt-4 by site-directed mutagenesis enhances the positive effect of Wnt-4 on terminal differentiation. These data indicate that thyroid hormone may regulate terminal differentiation of growth plate chondrocytes in part by modulating Writ signaling pathways through the induction of CPZ and subsequent CPZ-enhanced activation of Wnt-4.

BACKGROUND:Clinical outcomes of children with bacterial septic arthritis, common in the pediatric age group, are often satisfactory with early recognition, prompt surgical drainage, and appropriate antibiotic therapy. However, the optimal duration and route of antibiotic administration for treatment of septic arthritis continues to be debated, as traditional treatment favored longer intravenous (IV) therapies yet oral regimens are increasingly available that are more cost effective, safe and produce satisfactory disease resolution. METHODS:Records of 186 patients from two children's hospitals, one that was thought to convert from IV to oral antibiotic therapy considerably earlier than the other, treated between 1985 and 1995 for bacterial septic arthritis were reviewed. Patients with concurrent osteomyelitis were excluded. RESULTS:Patients at Hospital #1 were converted to oral antibiotics after 7.4+/-7.4 days of IV antibiotic therapy and at Hospital #2 after 18.6+/-13.6 (P<0.001) days of IV therapy. Both groups received an average of four weeks of total antibiotic treatment. There was similar time to defervescence (2.4+/-3.2 d vs. 2.4+/-3.8 d, P>0.05) and to normalization of erythrocyte sedimentation rate (35.7+/-19.7 d vs. 33.8+/-44.9 d, P>0.05) in the patients converted to oral therapy early compared to those converted late. One case of mild avascular necrosis with no clinical disability developed in a patient from Hospital #2. CONCLUSIONS:We conclude that the clinical outcome in patients with septic arthritis converted to oral antibiotic therapy early in their treatment based on defined criteria was similar to those converted late.

Thyroid hormone activates Wnt-4 expression and Wnt/beta-catenin signaling in rat growth plate chondrocytes. Wnt antagonists Frzb/sFRP3 and Dkk1 inhibit T3-induced Wnt/beta-catenin activation and inhibit the maturation-promoting effects of T3 in growth plate cells. This study indicates that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulating Wnt/beta-catenin signaling.Introduction: Thyroid hormone is a potent regulator of skeletal maturation in the growth plate, yet the molecular mechanisms underlying this profound effect remain unknown. Writ signaling has recently been recognized as an important signal transduction pathway in regulating chondrogenesis and terminal differentiation of growth plate chondrocytes. The objective of this study was to explore the interaction between the thyroid hormone and Writ signaling pathways in the growth plate.Materials and Methods: Rat epiphyseal chondrocytes were maintained in 3D pellet culture and treated with triiodothyronine (T3). Activation of Wnt/beta-catenin signaling pathway in response to T3 was detected by measurement of the expression of Wnt-4 mRNA, the cellular accumulation of P-catenin, the transcriptional activity of TCF/LEF, and the expression of the Wnt/beta-catenin responsive gene Runx2/cbfa1. Terminal differentiation of the chondrocytes was assessed by measurement of alkaline phosphatase enzymatic activity and Col10a1 gene expression.Results : Thyroid hormone treatment of growth plate chondrocytes upregulated both Wnt-4 mRNA and protein expression, increased cellular accumulation of stabilized P-catenin, increased TCF/LEF transcriptional activity. and stimulated the expression of the Runx2/cbfa1 gene. Overexpression of either Wnt-4 or a stabilized form of P-catenin promoted growth plate chondrocyte terminal differentiation. Blocking Writ ligand/receptor interactions with the secreted Writ antagonists Frzb/sFRP3 or Dkk1 inhibited these T3-induced increases in beta-catenin accumulation and Runx2 gene expression and inhibited the maturation-promoting effects of T3 in Growth plate cells.Conclusions: These data suggest that thyroid hormone regulates terminal differentiation of growth plate chondrocytes in part through modulating canonical Wnt/beta-catenin signaling.