Justin Scheer

A Common Allosteric Site and Mechanism in Caspases

We present a common allosteric mechanism for control of inflammatory and apoptotic caspases. Highly specific thiol-containing inhibitors of the human inflammatory caspase-1 were identified by using disulfide trapping, a method for site-directed small-molecule discovery. These compounds became trapped by forming a disulfide bond with a cysteine residue in the cavity at the dimer interface ≈15 Å away from the active site. Mutational and structural analysis uncovered a linear circuit of functional residues that runs from one active site through the allosteric cavity and into the second active site. Kinetic analysis revealed robust positive cooperativity not seen in other endopeptidases. Recently, disulfide trapping identified a similar small-molecule site and allosteric transition in the apoptotic caspase-7 that shares only a 23% sequence identity with caspase-1. Together, these studies show a general small-molecule-binding site for functionally reversing the zymogen activation of caspases and suggest a common regulatory site for the allosteric control of inflammation and apoptosis.

Defining Spino-pelvic Alignment Thresholds: Should Operative Goals in Adult Spinal Deformity Surgery Account for Age?

Study Design. Retrospective review of prospective, multicenter database. Objective. The aim of the study was to determine age-specific spino-pelvic parameters, to extrapolate age-specific Oswestry Disability Index (ODI) values from published Short Form (SF)-36 Physical Component Score (PCS) data, and to propose age-specific realignment thresholds for adult spinal deformity (ASD). Summary of Background Data. The Scoliosis Research Society-Schwab classification offers a framework for defining alignment in patients with ASD. Although age-specific changes in spinal alignment and patient-reported outcomes have been established in the literature, their relationship in the setting of ASD operative realignment has not been reported. Methods. ASD patients who received operative or nonoperative treatment were consecutively enrolled. Patients were stratified by age, consistent with published US-normative values (Norms) of the SF-36 PCS (<35, 35–44, 45–54, 55–64, 65–74, >75  y old). At baseline, relationships between between radiographic spino-pelvic parameters (lumbar-pelvic mismatch [PI-LL], pelvic tilt [PT], sagittal vertical axis [SVA], and T1 pelvic angle [TPA]), age, and PCS were established using linear regression analysis; normative PCS values were then used to establish age-specific targets. Correlation analysis with ODI and PCS was used to determine age-specific ideal alignment. Results. Baseline analysis included 773 patients (53.7 y old, 54% operative, 83% female). There was a strong correlation between ODI and PCS (r = 0.814, P < 0.001), allowing for the extrapolation of US-normative ODI by age group. Linear regression analysis (all with r > 0.510, P < 0.001) combined with US-normative PCS values demonstrated that ideal spino-pelvic values increased with age, ranging from PT = 10.9 degrees, PI−LL = −10.5 degrees, and SVA = 4.1 mm for patients under 35 years to PT = 28.5 degrees, PI−LL = 16.7 degrees, and SVA = 78.1 mm for patients over 75 years. Clinically, older patients had greater compensation, more degenerative loss of lordosis, and were more pitched forward. Conclusion. This study demonstrated that sagittal spino-pelvic alignment varies with age. Thus, operative realignment targets should account for age, with younger patients requiring more rigorous alignment objectives. Level of Evidence: 3

Patient Satisfaction after Adult Spinal Deformity Surgery Does Not Strongly Correlate with Health-Related Quality of Life Scores, Radiographic Parameters or Occurrence of Complications

Study Design. This is a multicenter retrospective review of prospectively collected cases. Objective. Our objective was to evaluate the relationship between patient satisfaction, health-related quality of life (HRQoL) scores, complications, and radiographic measures at 2 years postoperative follow-up. Summary of Background Data. For patients receiving operative management for adult spine deformity (ASD), the relationship between HRQoL measures, radiographic parameters, postoperative complications, and self-reported satisfaction remains unclear. Methods. Data from 248 patients across 11 centers within the United States who underwent thoracolumbar fusion for ASD and had a minimum of 2 years follow-up was collected. Pre- and postoperative scores were obtained from the Scoliosis Research Society 22-item (SRS-22r), the Oswestry Disability Index (ODI), the 36-Item Short Form Health Survey (SF-36), and the Visual Analogue Scale. Sagittal vertical axis, coronal C7 plumbline, lumbar lordosis, pelvic tilt, T1 pelvic angle, and the difference between pelvic incidence and lumbar lordosis were assessed using postoperative radiographic films. Satisfaction (SAT) was assessed using the SRS-22r; patients were categorized as highly satisfied (HS) or less satisfied (LS). The correlation between SAT and HRQoL scores, radiographic parameters, and complications was determined. Results. When compared with LS (n = 60) patients, HS (n = 188) patients demonstrated greater improvement in final ODI, SF-36 component scores, SRS-Total, and Visual Analogue Scale back scores (P < 0.05). The correlations between SAT and the final follow-up and 2 year change from baseline values were moderate for Mental Component Summary, Physical Component Summary, and ODI or weak for HRQoL scores (P < 0.0001). The HS and LS groups were equal in pre- or final postoperative radiographic parameters. Occurrence of complications had no effect on satisfaction. Conclusion. Among operatively treated ASD patients, satisfaction was moderately correlated with some HRQoL measures, and not with radiographic changes or postoperative complications. Other factors, such as patient expectations and relationship with the surgeon, may be stronger drivers of patient satisfaction. Level of Evidence: 3

Virtual Modeling of Postoperative Alignment Following Adult Spinal Deformity (ASD) Surgery Helps Predict associations between Compensatory Spinopelvic Alignment Changes, Overcorrection and Proximal Junctional Kyphosis (PJK)

Study Design. Retrospective review of a prospective multicenter database. Objective. To develop a method to analyze sagittal alignment, free of the influence of proximal junctional kyphosis (PJK), and then compare PJK to non-PJK patients using this method. Summary of Background Data. PJK after adult spinal deformity (ASD) surgery remains problematic as it alters sagittal alignment. The present study proposes a novel virtual modeling technique that attempts to eliminate the confounding effects of PJK on postoperative spinal alignment. Methods. A virtual spinal modeling technique was developed on a retrospective ASD cohort of patients with multilevel spinal fusions to the pelvis with at least 2-year postoperative follow-up. The virtual postoperative alignment (VIRTUAL) was created from the postoperative alignment of the instrumented segments and the preoperative alignment of the unfused segments. VIRTUAL was validated by comparisons to actual 2-year postoperative alignment (REAL) in non-PJK patients. Patients were then divided into two groups: PJK and non-PJK based on the presence/absence of PJK at 2 years postoperatively. PJK and non-PJK patients were compared using VIRTUAL and REAL. Results. A total of 458 patients (78F, mean 57.9 yr) were analyzed. The validation of VIRTUAL versus REAL demonstrated correlation coefficients greater than 0.7 for all measures except sagittal vertical axis (SVA; r = 0.604). At 2 years, REAL alignment in PJK patients demonstrated a smaller pelvic incidence minus lumbar lordosis and a larger thoracic kyphosis than non-PJK patients, but similar SVA, T1 pelvic angle, and pelvic tilt. An analysis of VIRTUAL demonstrated that patients with PJK had a smaller pelvic incidence minus lumbar lordosis, pelvic tilt, SVA, and T1 pelvic angle than non-PJK patients (P < 0.05). Conclusion. This technique demonstrated strong correlations with actual postoperative alignment. Comparisons between REAL and VIRTUAL alignments revealed that postoperative PJK may develop partially as a compensatory mechanism to the overcorrection of sagittal deformities. Future research will evaluate the appropriate thresholds for deformity correction according to age and ASD severity. Level of Evidence: 3

Prospective Multicenter Assessment of Intraoperative and Perioperative Complication Rates Associated with Adult Spinal Deformity (ASD) Surgery in 558 Patients

Introduction Few previous studies have focused on early (intraoperative and perioperative) complication rates for ASD surgery, with reported overall rates ranging from ~10% to 75%. However, most available studies are relatively small single- center series and likely underestimate complication rates due to retrospective design and lack of rigorous collection of complications. Accurately defining the early complication rates is particularly important for patient counseling with regard to the risks and benefits of surgical treatment. Material and Methods As part of a prospective ASD database, standardized collection forms, on-site coordinators and auditing helped ensure complete capture of complications. Intraop and periop (<6 wks) complications were collected for all patients with these available data, regardless of subsequent length of available follow-up. Results 558 patients underwent surgical treatment for ASD and had a mean age of 57 years, mean Charlson Comorbidity Index of 1.5 and previous surgery in 48%. The majority (98%) of patients had treatment including a posterior instrumented approach and included a 3-column osteotomy in 22% of patients. A total of 171 intraoperative complications (69 major, 102 minor) affected 127 (22.8%) patients, and a total of 272 perioperative complications (133 major, 139 minor) affected 185 (33.2%) patients. Collectively, 443 early complications (202 major, 241 minor) were reported, with 264 (47.3%) patients experiencing one or more complication. The overall mean numbers of intraoperative, perioperative and total complications per patient were 0.31, 0.49 and 0.79, respectively. Conclusion ASD surgery is associated with high rates of early complications, with 47.3% of patients having at least one complication. These rates are substantially higher than previously reported. These finding may prove useful in treatment planning and patient counseling.