Characterizing antibiotic prophylaxis practices in pediatric deformity spinal surgery and impact on 30-day postoperative infection: an NSQIP pediatric database study.

PURPOSE: The aim of this study was to characterize antibiotic prophylaxis practices in pediatric patients who have received posterior arthrodesis for spinal deformity and understand how these practices impact 30-day postoperative infection rates. METHODS: This was a retrospective cohort study using the National Surgical Quality Improvement Program Pediatric database for year 2021. Patients 18 years of age or younger who received posterior arthrodesis for scoliosis or kyphosis correction were included. The outcome of interest was 30-day postoperative infection. Fisher's exact test and multivariable regression analysis were used to analyze the impact of intravenous antibiotic prophylaxis, intraoperative intravenous antibiotic redosing after 4 h, postoperative antibiotic prophylaxis, intraoperative topical antibiotics on 30-day postoperative infection, and various antibiotic prophylaxis regimens. RESULTS: A total of 6974 patients were included in this study. The 30-day infection rate was 2.9%. Presurgical intravenous antibiotic (11.5% vs. 2.7%, p = 0.005), postoperative antibiotic (5.7% vs. 2.4%, p < 0.01), and intraoperative topical antibiotic (4.0% vs. 2.7%, p = 0.019) were associated with significantly reduced infection rates. There was no significant difference in infection rates between patients that received cefazolin versus vancomycin versus clindamycin. The addition of Gram-negative coverage did not result in significant differences in infection rates. Multivariable regression analysis found postoperative intravenous antibiotics and intraoperative topical antibiotics to reduce infection rates. CONCLUSIONS: We found the use of presurgical intravenous antibiotics, postoperative intravenous antibiotics, and intraoperative topical antibiotics to significantly reduce infection rates. Results from this study can be applied to future research on implementation of standardized infection prevention protocols. LEVEL OF EVIDENCE: Level II.

Pre-Emptive Opioid-Sparing Medication Protocol Decreases Pain and Length of Hospital Stay in Children Undergoing Posterior Spinal Instrumented Fusion for Scoliosis.

Background: Poorly controlled post-operative pain following Posterior Spinal Instrumented Fusion (PSIF) for scoliosis may be associated with delayed ambulation and longer hospital stays. Multimodal analgesia use has been shown to provide superior analgesia with improved recovery and reduction of post-operative morbidity in other orthopedic subspecialties, but has not been described with pediatric patients undergoing spinal surgery. Objective: We describe a novel, pre-emptive, opioid-sparing pediatric pain medication protocol that is started two days prior to surgery, in accordance with first-order pharmacokinetics, and continued post-operatively until discharge with the goal of decreasing post-operative pain, improving early mobilization, and ultimately decreasing the patient's length of hospital stay. Methods: We retrospectively reviewed 116 PSIF cases from March 2014 to November 2017. Fifty-two patients received standard analgesia before August 2016, and 64 patients after August 2016 received the pre-emptive protocol consisting of a standardized combination of acetaminophen, celecoxib, and gabapentin two days prior to surgery and continued during their inpatient stay. Scheduled oxycodone and intravenous hydromorphone via patient controlled analgesia (PCA) were given to both groups equally during the post-operative hospital stay. We analyzed length of stay, total opioid consumption, and maximum pain scores per day from surgical to discharge date. Results: 116 patients were included: 64 patients in the pre-emptive group and 52 patients in the standard group. Length of hospital stay significantly differed, with means of 3.9 days in the pre-emptive group and 4.5 days in the standard analgesia group (p<0.05). Patients in the pre-emptive group recorded significantly lower maximal pain levels than those in the standard analgesia group on post-operative days #1 (4.9 vs. 5.8, p=0.0196), #3 (4.4 vs. 6.1, p=0.0006), and #4 (4.2 vs. 5.4, p=0.0393). Total post-operative morphine equivalents taken did not significantly differ between the two groups. Conclusion: This is a preliminary report demonstrating a significant decrease in maximal pain score and length of stay following PSIF on a cohort of patients receiving a novel pre-emptive opioid-sparing pain medication protocol based on first order pharmacokinetics. Future studies should investigate degree of mobilization and opioid consumption and maximal pain level after discharge from the hospital. Level of Evidence: III.

The Effect of Adolescent Idiopathic Scoliosis on Natural Delivery and Epidural Use in Pregnant Females: A Matched Cohort Study.

STUDY DESIGN: Retrospective matched cohort study. OBJECTIVE: The aim of this study was to determine whether females with idiopathic scoliosis (IS), both with and without spine fusion, experience different rates of cesarean section (CS) and epidural anesthesia (EA) than females without scoliosis. SUMMARY OF BACKGROUND DATA: IS is a common spine condition with a higher prevalence in females. It is unclear whether females with scoliosis, treated nonoperatively or operatively, have different rates of cesarean delivery or EA. MATERIALS AND METHODS: Patients with IS who delivered in our integrated health care system during a 6-year period were identified (N = 1810). They were matched with a group without scoliosis who delivered during the same period (N = 1810). Rates and relative risk (RR) of CS and EA between cohorts and subgroups were calculated. RESULTS: The scoliosis cohort had significantly higher rates and RR of EA ( P = 0.002 and P = 0.004, respectively). Scoliosis patients treated nonoperatively had an 8% greater RR of EA ( P = 0.004) and had a significantly lower rate of CS (23.2% vs . 26%, P = 0.048) compared with the control group. Among only scoliosis patients, those treated with spine fusion had a 38% decreased RR of EA ( P < 0.001). Distal fusion level did not seem to influence the RR of EA or CS. CONCLUSIONS: Females with scoliosis were significantly more likely to receive EA at delivery compared with females without scoliosis. Rates and RR of cesarean delivery were not significantly lower among women with scoliosis, but females treated nonoperatively for scoliosis had a significantly lower CS rate than those without scoliosis. Females treated with spine fusion for scoliosis were far less likely to receive EA than both females without scoliosis and females with scoliosis treated nonoperatively.

Effect of gabapentin on length of stay, opioid use, and pain scores in posterior spinal fusion for adolescent idiopathic scoliosis: a retrospective review across a multi-hospital system.

BACKGROUND: Gabapentin has been adopted in Enhanced Recovery After Surgery protocols as a means to reduce opioid consumption while maintaining adequate post-operative analgesia. The purpose of our study was to review and compare changes in length of stay, opioid use, and patient reported pain scores after the addition of gabapentin into five, distinct pain protocols for posterior spinal fusion in adolescent idiopathic scoliosis. METHODS: A retrospective review was completed using a database of electronic medical data from a single pediatric orthopedic healthcare system that was queried for patients with adolescent idiopathic scoliosis who underwent first-time posterior spinal fusion. Perioperative data including demographics, hospital length of stay, surgical details, opioid use, patient reported pain scores, and non-opioid analgesic use were collected. RESULTS: From December 2012 to February 2019, 682 hospitalizations for posterior spinal fusion in adolescent idiopathic scoliosis were identified with complete inpatient data; 49% were administered gabapentin. For the gabapentin cohort, the system saw no statistically significant effect on length of stay or pain averaged over POD#0-3. Opioid use was statistically lower averaged over POD#0-3. Individual sites saw variation on length of stay and opioid use compared to the system. CONCLUSION: In conclusion, system-wide data showed gabapentin containing protocols reduced opioid use while maintaining clinically equivalent analgesia. However, variations of individual site results make it difficult to conclude the degree to which gabapentin were responsible for this effect.

Risk of early complication following anterior vertebral body tethering for idiopathic scoliosis.

PURPOSE: The purpose of this study was to determine peri-operative morbidity associated with anterior vertebral body tethering (aVBT) for idiopathic scoliosis. METHOD: Of 175 patients treated with aVBT, 120 patients had 2 year follow up and were included in this study. Prospectively collected clinical and radiographic data was analyzed retrospectively. RESULTS: Pre-operatively, the mean patient age was 12.6 year (8.2-15.7 year), Risser 0-3, with main thoracic scoliosis 51.2° (40-70°). Immediately post-operative, scoliosis improved to 26.9° (6-53°; p < 0.05), at 1-year post-operative was 23.0° (- 11 to 50°; p < 0.01 vs immediate post-op) and at 2-year post-operative was 27.5° (- 5 to 52; p = 0.64 vs immediate post-op). Pre-operative T5-T12 kyphosis was 16.0° (- 23 to 52°), post-operative was 16.9° (- 7 to 44°), at 1-year was 17.5° (- 14 to 61°) and at 2-year was 17.0° (- 10 to 50°; p = 0.72 vs pre-op). All patients underwent thoracoscopic approach, EBL 200 ml (20-900 ml), surgical time 215.3 min (111-472 min), anesthesia time 303.5 min (207-480 min), ICU stay of 0.2 day (0-2 days), and post-operative hospital stay 4.5 days (2-9 days). During the in-hospital peri-operative period, there were no unplanned return to the operating room (UPROR) and there was a 0.8% rate of complication: one pneumothorax requiring reinsertion of chest tube. By 90 days post-operative, there was no UPROR and a 5% rate of complication. Five additional patients developed complications after discharge: one CSF leak treated with blood patch injection in the clinic and resolved, two pleural effusions requiring chest tubes, one superficial wound infection and one pneumonia treated with outpatient antibiotics. By 1-year post-op, there was a 1.7% rate of UPROR and 8.3% rate of complication. Four additional patients developed complications beyond 90 days: two upper limb paresthesia required outpatient medical management, one CSF leak which initially treated blood patch injection in the clinic initially which then required UPROR, and one compensatory lumbar curve add on that was treated with extension of the tether. By 2-years post-op, there was a 6.7% rate of UPROR and 15.8% rate of complication. 9 additional complications developed after 1 year. One curve progression, one keloid scar, one right leg weakness, 4 cable failures and 2 curve overcorrections. CONCLUSION: This large, multicenter series of aVBT demonstrated a 15.8% complication rate and a 6.7% UPROR rate at 2 year post-operatively. This early study during the learning curve of aVBT found higher rates of CSF leaks and overall complications than would be expected for PSFI at 1 year post-operatively and a higher rate of overall complications and of UPROR than would be expected for PSFI at 2 year post-operatively. As is common with new procedures, the complication rate may fall with further experience.

Microdose protocol stereoradiography has similar reliability to standard low-dose protocol during concurrent Sanders skeletal maturity staging.

PURPOSE: Decreasing radiation exposure is important for scoliosis patients who require serial imaging. Microdose protocol stereoradiography is now increasingly utilized. Previous studies have reported similar reliability of concurrent Sanders skeletal maturity staging based on standard low-dose stereoradiography and standard hand radiographs. The purpose of our study was to investigate the reliability and radiation exposure of concurrent Sanders staging using microdose protocol compared to a standard protocol for adolescent idiopathic scoliosis. We hypothesized that surgeon-performed Sanders staging would have similar reliability when comparing microdose and standard-dose imaging protocols. METHODS: A randomized survey of 30 hand images using standard protocol spinal stereoradiography and an equal number from microdose protocol were distributed to six experienced pediatric orthopaedic spine surgeons. Images were graded by each surgeon according to the Sanders skeletal maturity grading system. Items were again randomized and graded after a 2-week interval. Fleiss' weighted kappa for inter and intraobserver reliability was calculated and an unpaired t test was used to test for significance. RESULTS: Interobserver reliability for all modalities was in the strong to almost perfect agreement (average weighted κ > 0.8) range. For the microdose protocol, κ was 0.82 and 0.84 for each separate round of grading. Standard low-dose protocol κ was 0.83 and 0.79. Intraobserver κ was 0.86 for microdose and 0.82 for standard. Average radiation for microdose was significantly less radiation (82.6%) than standard stereoradiography (0.3 ± 0.1 mGy vs. 1.9 ± 0.4 mGy, p < 0.001). CONCLUSIONS: Sanders staging reliability of a well-positioned hand during scoliosis stereoradiography was similarly excellent for both microdose and standard low-dose protocol. Microdose protocol used less radiation while still preserving the reliability of Sanders staging.

Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1).

Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).

A Five-year Review of the Designated Leadership Positions of Pediatric Orthopaedic Society of North America: Where Do Women Stand?

Despite the growing number of women entering medical school, female representation among orthopedic surgery is the lowest compared with all areas of medicine. In 2014, 47.7% of students entering medical school were women, but only 13.7% of orthopedic residents were women. Pediatric orthopedics have been successful in enrolling women compared with other orthopedic subspecialties. This is an investigation of female representation among the Pediatric Orthopaedic Society of North America membership roster, providing insight into the effect on the increased gender diversity in the membership of an organization and its correlation with leadership positions at different levels within the organization.

Structure-based design and discovery of potent and selective lysine-specific demethylase 1 (LSD1) inhibitors.

The histone demethylase LSD1 is a key enzyme in the epigenetic regulation of gene transcription. Here we present our efforts to discover small molecule reversible inhibitors of LSD1 as an attractive approach to treat hematologic malignancies and certain solid tumors. Using structure-based drug design, we designed and synthesized a novel series of heteroaromatic imidazole inhibitors that demonstrate potent inhibition of the demethylase activity and low nanomolar cell-based activity. This novel LSD1 inhibitor series was further optimized by attenuating the hERG inhibition and improving oral bioavailability.

Maximal Force Generated by Magnetically Controlled Growing Rods Decreases With Rod Lengthening.

OBJECTIVES: To evaluate the maximal force generated by magnetically controlled growing rods (MCGRs) at three different lengthened positions. SUMMARY OF BACKGROUND DATA: The introduction of MCGRs has been met with great enthusiasm by surgeons managing early-onset scoliosis. These devices offer the potential to decrease the cost and morbidity associated with repeated surgeries, compared to traditional growing rods. One potential negative consequences of growing rod treatments is the law of diminishing returns, where the spine length gained decrease with each subsequent lengthening. The cause of this phenomenon is unknown and probably multifactorial, yet it may be affected by the strength of the lengthening mechanism in the MCGRs. METHODS: Twelve MCGRs (90-mm actuator length) were obtained and tested to evaluate the maximal force generated at different lengths. The maximal lengthening force measured in pounds-of-force generated by each rod was recorded at expansion lengths of 0, 25, and 40 mm. Longitudinal analysis was performed using mixed effects linear regression to account for repeated measures and variability between individual implants. RESULTS: At 0 mm of actuator lengthening, the mean maximum force was 46.8 lb (standard deviation [SD] 2.06, range 43-50). At 25 mm of expansion, the mean maximum force was 44.9 lb (SD 2.48, range 39.4-49.5). At 40 mm of lengthening, the mean maximum force was 43.2 lb (SD 5.56, range 27.3-49.1). In the mixed effects linear model, there was a statistically significant decrease in the maximal force generated with progressive MCGR lengthening, at an average decrease of 0.089 lb of force (95% CI, 0.030-0.148; p = .003) per millimeter of lengthening. CONCLUSION: There is a small but statistically significant decrease in the maximal force generated by MCGR as the rods are lengthened. The decrease in force generated may result in diminished spine length gained with each subsequent MCGR lengthening. LEVEL OF EVIDENCE: Level IV.

Paper #26: Maximal Force Generated by Magnetically Controlled Growing Rods Decreases with Rod Lengthening.

The use of magnetically controlled growing rods (MCGR) has the potential to decrease the morbidity associated with repeated surgeries, yet, strength of the lengthening mechanism as it lengthens may have an impact on the length gained with each lengthening.We evaluated the maximal force generated by MCGR at 3 different lengthened positions and found an average decrease of 0.089 pounds per mm of additional length. This decrease may result in diminished spine length gained with each subsequent MCGR lengthening.

Results of the Scoliosis Research Society Morbidity and Mortality Database 2009-2012: A Report From the Morbidity and Mortality Committee.

INTRODUCTION: Members of the Scoliosis Research Society are required to annually submit complication data regarding deaths, visual acuity loss, neurological deficit and infection (2012-1st year for this measure) for all deformity operations performed. The purpose of this study is to report the 2012 results and the differences in these complications from the years 2009-2012. METHODS: The SRS M&M database is a self-reported complications registry of deformity operations performed by the members. The data from 2009-2012, inclusive, was tabulated and analyzed. Differences in frequency distribution between years were analyzed with Fisher's exact test. Significance was set at α = 0.05. RESULTS: The total number of cases reported increased from 34,332 in 2009 to 47,755 in 2012. Overall mortality ranged from 0.07% in 2011 to 0.12% in 2009. The neuromuscular scoliosis group had the highest mortality rate (0.44%) in 2010. The combined groups' neurological deficit rate increased from 0.44% in 2009 to 0.79% in 2012. Neurological deficits were significantly lower in 2009 compared to 2012 for idiopathic scoliosis >18 years, other scoliosis, degenerative and isthmic spondylolisthesis and other groups. The groups with the highest neurological deficit rates were dysplastic spondylolisthesis and congenital kyphosis. There were no differences in vision loss rates between years. The overall 2012 infection rate was 1.14% with neuromuscular scoliosis having the highest group rate at 2.97%. CONCLUSION: Neuromuscular scoliosis has the highest complication rates of mortality and infection. The neurological deficit rates of all groups combined have slightly increased from 2009 to 2012 with the highest rates consistently being in the dysplastic spondylolisthesis and congenital kyphosis groups. This could be due to a number of factors, including more rigorous reporting.

Effects of folylpolyglutamate synthase modulation on global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells.

Folylpolyglutamate synthase (FPGS) plays a critical role in intracellular folate homeostasis. FPGS-induced polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence FPGS modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression and aberrant DNA methylation is mechanistically linked cancer development. We investigated whether FPGS modulation would affect global and gene-specific promoter DNA methylation with consequent functional effects on gene expression profiles in HCT116 colon and MDA-MB-435 breast cancer cells. Although FPGS modulation altered global DNA methylation and DNA methyltransferases (DNMT) activity, the effects of FPGS modulation on global DNA methylation and DNMT activity could not be solely explained by intracellular folate concentrations and content of long-chain folylpolyglutamates, and it may be cell-specific. FPGS modulation influenced differential gene expression and promoter cytosine-guanine dinucleotide sequences (CpG) DNA methylation involved in cellular development, cell cycle, cell death and molecular transport. Some of the altered gene expression was associated with promoter CpG DNA methylation changes. In both the FPGS-overexpressed HCT116 and MDA-MB-435 cell lines, we identified several differentially expressed genes involved in folate biosynthesis and one-carbon metabolism, which might in part have contributed to the observed increased efficacy of 5-fluorouracil in response to FPGS overexpression. Our data suggest that FPGS modulation affects global and promoter CpG DNA methylation and expression of several genes involved in important biological pathways. The potential role of FPGS modulation in DNA methylation and its associated downstream functional effects warrants further studies.

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells.

γ-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain folylpolyglutamates are associated with functionally significant DNA methylation alterations in several important biological pathways.

Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.