Ataxia-Telangiectasia Mutated Loss-of-Function Displays Variant and Tissue-Specific Differences across Tumor Types.

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed. EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical data sets of patients treated with platinum-based chemotherapy or ATR inhibition. RESULTS: ART0380 had potent, selective antitumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10,609 ATM variants in 8,587 patient tumors. Cancer lineage-specific differences were seen in the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition. CONCLUSIONS: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.

Temporal analysis of complication rates of cervical spine surgery for degenerative spine disease between younger and older cohorts using the CSORN registry: Is age just a number?

STUDY DESIGN: An ambispective review of consecutive cervical spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network (CSORN) between January 2015 and September 2019. PURPOSE: To compare complication rates of degenerative cervical spine surgery over time between older (> 65) and younger age groups (< 65). More elderly people are having spinal surgery. Few studies have examined the temporal nature of complications of cervical spine surgery by patient age groups. METHODS: Adverse events were collected prospectively using adverse event forms. Binary logistic regression analysis was utilized to assess associations between risk modifiers and adverse events at the intra-, peri-operative and 3 months post-surgery. RESULTS: Of the 761 patients studied (age < 65, n = 581 (76.3%) and 65 + n = 180 (23.7%), the intra-op adverse events were not significantly different; < 65 = 19 (3.3%) vs 65 + = 11 (6.1%), p < 0.087. Peri-operatively, the < 65 group had significantly lower percentage of adverse events (65yrs (11.2%) vs. 65 + = (26.1%), p < 0.001). There were no differences in rates of adverse events at 3 months post-surgery (< 65 = 39 (6.7%) vs. 65 + = 12 (6.7%), p < 0.983). Less blood loss (OR = 0.99, p < 0.010) and shorter length of hospital stay (OR = 0.97, p < 0.025) were associated with not having intra-op adverse events. Peri-operatively, > 1 operated level (OR = 1.77, p < 0.041), shorter length of hospital stay (OR = 0.86, p < 0.001) and being younger than 65 years (OR = 2.11, p < 0.006) were associated with not having adverse events. CONCLUSION: Following degenerative cervical spine surgery, the older and younger age groups had significantly different complication rates at peri-operative time points, and the intra-operative and 3-month post-operative complication rates were similar in the groups.

Determining minimal clinically important difference estimates following surgery for degenerative conditions of the lumbar spine: analysis of the Canadian Spine Outcomes and Research Network (CSORN) registry.

BACKGROUND CONTEXT: There is significant variability in minimal clinically important difference (MCID) criteria for lumbar spine surgery that suggests population and primary pathology specific thresholds may be required to help determine surgical success when using patient reported outcome measures (PROMs). PURPOSE: The purpose of this study was to estimate MCID thresholds for 3 commonly used PROMs after surgical intervention for each of 4 common lumbar spine pathologies. STUDY DESIGN/SETTING: Observational longitudinal study of patients from the Canadian Spine Outcomes and Research Network (CSORN) national registry. PATIENT SAMPLE: Patients undergoing surgery from 2015 to 2018 for lumbar spinal stenosis (LSS; n = 856), degenerative spondylolisthesis (DS; n = 591), disc herniation (DH; n = 520) or degenerative disc disease (DDD n = 185) were included. OUTCOME MEASURES: PROMs were collected presurgery and 1-year postsurgery: the Oswestry Disability Index (ODI), and back and leg Numeric Pain Rating Scales (NPRS). At 1-year, patients reported whether they were 'Much better'/'Better'/'Same'/'Worse'/'Much worse' compared to before their surgery. Responses to this item were used as the anchor in analyses to determine surgical MCIDs for benefit ('Much better'/'Better') and substantial benefit ('Much better'). METHODS: MCIDs for absolute and percentage change for each of the 3 PROMs were estimated using a receiving operating curve (ROC) approach, with maximization of Youden's index as primary criterion. Area under the curve (AUC) estimates, sensitivity, specificity and correct classification rates were determined. All analyses were conducted separately by pathology group. RESULTS: MCIDs for ODI change ranged from -10.0 (DDD) to -16.9 (DH) for benefit, and -13.8 (LSS) to -22.0 (DS,DH) for substantial benefit. MCID for back and leg NPRS change were -2 to -3 for each group for benefit and -4.0 for substantial benefit for all groups on back NPRS. MCID estimates for percentage change varied by PROM and pathology group, ranging from -11.1% (ODI for DDD) to -50.0% (leg NPRS for DH) for benefit and from -40.0% (ODI for DDD) to -66.6% (leg NPRS for DH) for substantial benefit. Correct classification rates for all MCID thresholds ranged from 71% to 89% and were relatively lower for absolute vs percent change for those with high or low presurgical scores. CONCLUSIONS: Our findings suggest that the use of generic MCID thresholds across pathologies in lumbar spine surgery is not recommended. For patients with relatively low or high presurgery PROM scores, MCIDs based on percentage change, rather than absolute change, appear generally preferable. These findings have applicability in clinical and research settings, and are important for future surgical prognostic work.

Cost consequence analysis of waiting for lumbar disc herniation surgery.

The economic repercussions of waiting for lumbar disc surgery have not been well studied. The primary goal of this study was to perform a cost-consequence analysis of patients receiving early vs late surgery for symptomatic disc herniation from a societal perspective. Secondarily, we compared patient factors and patient-reported outcomes. This is a retrospective analysis of prospectively collected data from the CSORN registry. A cost-consequence analysis was performed where direct and indirect costs were compared, and different outcomes were listed separately. Comparisons were made on an observational cohort of patients receiving surgery less than 60 days after consent (short wait) or 60 days or more after consent (long wait). This study included 493 patients with surgery between January 2015 and October 2021 with 272 patients (55.2%) in the short wait group and 221 patients (44.8%) classified as long wait. There was no difference in proportions of patients who returned to work at 3 and 12-months. Time from surgery to return to work was similar between both groups (34.0 vs 34.9 days, p = 0.804). Time from consent to return to work was longer in the longer wait group corresponding to an additional $11,753.10 mean indirect cost per patient. The short wait group showed increased healthcare usage at 3 months with more emergency department visits (52.6% vs 25.0%, p < 0.032), more physiotherapy (84.6% vs 72.0%, p < 0.001) and more MRI (65.2% vs 41.4%, p < 0.043). This corresponded to an additional direct cost of $518.21 per patient. Secondarily, the short wait group had higher baseline NRS leg, ODI, and lower EQ5D and PCS. The long wait group had more patients with symptoms over 2 years duration (57.6% vs 34.1%, p < 0.001). A higher proportion of patients reached MCID in terms of NRS leg pain at 3-month follow up in the short wait group (84.0% vs 75.9%, p < 0.040). This cost-consequence analysis of an observational cohort showed decreased costs associated with early surgery of $11,234.89 per patient when compared to late surgery for lumbar disc herniation. The early surgery group had more severe symptoms with higher healthcare utilization. This is counterbalanced by the additional productivity loss in the long wait group, which likely have a more chronic disease. From a societal economic perspective, early surgery seems beneficial and should be promoted.

Deterioration After Surgery for Degenerative Cervical Myelopathy: An Observational Study From the Canadian Spine Outcomes and Research Network.

STUDY DESIGN: A Prospective cohort study. OBJECTIVE: To investigate the incidence, etiology, and outcomes of patients who experience neurological deterioration after surgery for Degenerative Cervical Myelopathy (DCM). SUMMARY OF BACKGROUND DATA: Postoperative neurological deterioration is one of the most undesirable complications that can occur after surgery for DCM. METHODS: We analyzed data from the Canadian Spine Outcomes and Research Network DCM prospective cohort study. We defined postoperative neurological deterioration as any decrease in modified Japanese Orthopaedic Association (mJOA) score by at least one point from baseline to three months after surgery. Adverse events were collected using the Spinal Adverse Events Severity protocol. Secondary outcomes included patient-reported pain, disability, and health-related quality of life. RESULTS: Among a study cohort of 428 patients, 50 (12%) deteriorated by at least one mJOA point after surgery for DCM (21 by one point, 15 by two points, and 14 by three points or more). Significant risk factors included older age, female sex, and milder disease. Among those who deteriorated, 13 experienced contributing intraoperative or postoperative adverse events, six had alternative non-DCM diagnoses, and 31 did not have an identifiable reason for deterioration. Patients who deteriorated had significantly lower mJOA scores at one year after surgery [13.5 (SD 2.7) vs. 15.2 (SD 2.2), P <0.01 and those with larger deteriorations were less likely to recover their mJOA to at least their preoperative baseline, but most secondary measures of pain, disability, and health-related quality of life were unaffected. CONCLUSIONS: The incidence of deterioration of mJOA scores after surgery for DCM was approximately one in 10, but some deteriorations were unrelated to actual spinal cord impairment and most secondary outcomes were unaffected. These findings can inform patient and surgeon expectations during shared decision-making, and they demonstrate that the interpretation of mJOA scores without clinical context can sometimes be misleading.

Minimally Invasive vs. Open Surgery for Lumbar Spinal Stenosis in Patients with Diabetes - A Canadian Spine Outcomes and Research Network Study.

STUDY DESIGN: Retrospective cohort. OBJECTIVES: To compare outcomes of minimally invasive surgery (MIS) vs open surgery (OPEN) for lumbar spinal stenosis (LSS) in patients with diabetes. METHODS: Patients with diabetes who underwent spinal decompression alone or with fusion for LSS within the Canadian Spine Outcomes and Research Network (CSORN) database were included. MIS vs OPEN outcomes were compared for 2 cohorts: (1) patients with diabetes who underwent decompression alone (N = 116; MIS n = 58 and OPEN n = 58), (2) patients with diabetes who underwent decompression with fusion (N = 108; MIS n = 54 and OPEN n = 54). Modified Oswestry Disability Index (mODI) and back and leg pain were compared at baseline, 6-18 weeks, and 1-year post-operation. The number of patients meeting minimum clinically important difference (MCID) or minimum pain/disability at 1-year was compared. RESULTS: MIS approaches had less blood loss (decompression alone difference 100 mL, P = .002; with fusion difference 244 mL, P < .001) and shorter length of stay (LOS) (decompression alone difference 1.2 days, P = .008; with fusion difference 1.2 days, P = .026). MIS compared to OPEN decompression with fusion had less patients experiencing adverse events (AEs) (difference 13 patients, P = .007). The MIS decompression with fusion group had lower 1-year mODI (difference 14.5, 95% CI [7.5, 21.0], P < .001) and back pain (difference 1.6, 95% CI [.6, 2.7], P = .002) compared to OPEN. More patients in the MIS decompression with fusion group exceeded MCID at 1-year for mODI (MIS 75.9% vs OPEN 53.7%, P = .028) and back pain (MIS 85.2% vs OPEN 70.4%, P = .017). CONCLUSIONS: MIS approaches were associated with more favorable outcomes for patients with diabetes undergoing decompression with fusion for LSS.

Practice Variation between Salaried and Fee-for-Service Surgeons for Lumbar Surgery.

OBJECTIVE: To examine differences in surgical practices between salaried and fee-for-service (FFS) surgeons for two common degenerative spine conditions. Surgeons may offer different treatments for similar conditions on the basis of their compensation mechanism. METHODS: The study assessed the practices of 63 spine surgeons across eight Canadian provinces (39 FFS surgeons and 24 salaried) who performed surgery for two lumbar conditions: stable spinal stenosis and degenerative spondylolisthesis. The study included a multicenter, ambispective review of consecutive spine surgery patients enrolled in the Canadian Spine Outcomes and Research Network registry between October 2012 and July 2018. The primary outcome was the difference in type of procedures performed between the two groups. Secondary study variables included surgical characteristics, baseline patient factors, and patient-reported outcome. RESULTS: For stable spinal stenosis (n = 2234), salaried surgeons performed statistically fewer uninstrumented fusion (p < 0.05) than FFS surgeons. For degenerative spondylolisthesis (n = 1292), salaried surgeons performed significantly more instrumentation plus interbody fusions (p < 0.05). There were no statistical differences in patient-reported outcomes between the two groups. CONCLUSIONS: Surgeon compensation was associated with different approaches to stable lumbar spinal stenosis and degenerative lumbar spondylolisthesis. Salaried surgeons chose a more conservative approach to spinal stenosis and a more aggressive approach to degenerative spondylolisthesis, which highlights that remuneration is likely a minor determinant in the differences in practice of spinal surgery in Canada. Further research is needed to further elucidate which variables, other than patient demographics and financial incentives, influence surgical decision-making.

Patient-Reported Outcomes Following Surgery for Lumbar Disc Herniation: Comparison of a Universal and Multitier Health Care System.

STUDY DESIGN: Ambispective cohort study. OBJECTIVE: Canada has a government-funded universal health care system. The United States utilizes a multitier public and private system. The objective is to investigate differences in clinical outcomes between those surgically treated for lumbar disc herniation in a universal health care and multitier health system. METHODS: Surgical lumbar disc herniation patients enrolled in the Canadian Spine Outcome Research Network (CSORN) were compared with the surgical cohort enrolled in the Spine Patients Outcome Research Trial (SPORT) study. Baseline demographics and spine-related patient-reported outcomes (PROs) were compared at 3 months and 1 year post-operatively. RESULTS: The CSORN cohort consisted of 443 patients; the SPORT cohort had 763 patients. Patients in the CSORN cohort were older (46.4 ± 13.5 vs 41.0 ± 10.8, P < .001) and were more likely to be employed (69.5% vs 60.3%, P = .003). The CSORN cohort demonstrated significantly greater rates of satisfaction after surgery at 3 months (87.2% vs 64.8%, P < .0001) and 1 year (85.6% vs 69.6%, P < .0001). Improvements in back and leg pain followed similar trajectories in the two cohorts, but there was less improvement on ODI in the CSORN cohort (P < .01). On multivariable logistic regression, the CSORN cohort was a significant independent predictor of patient satisfaction at 1-year follow-up (P < .001). CONCLUSIONS: Despite less improvement on ODI, patients enrolled in CSORN, as part of a universal health care system, reported higher rates of satisfaction at 3 months and 1 year post-operatively compared to patients enrolled within a multitier health system.

Prediction of 2-year clinical outcome trajectories in patients undergoing anterior cervical discectomy and fusion for spondylotic radiculopathy.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is often described as the gold standard surgical technique for cervical spondylotic radiculopathy. Although outcomes are considered favorable, there is little prognostic evidence to guide patient selection for ACDF. This study aimed to 1) describe the 24-month postoperative trajectories of arm pain, neck pain, and pain-related disability; and 2) identify perioperative prognostic factors that predict trajectories representing poor clinical outcomes. METHODS: In this retrospective cohort study, patients with cervical spondylotic radiculopathy who underwent ACDF at 1 of 12 orthopedic or neurological surgery centers were recruited. Potential outcome predictors included demographic, health, clinical, and surgery-related prognostic factors. Surgical outcomes were classified by trajectories of arm pain intensity, neck pain intensity (numeric pain rating scales), and pain-related disability (Neck Disability Index) from before surgery to 24 months postsurgery. Trajectories of postoperative pain and disability were estimated with latent class growth analysis, and prognostic factors associated with poor outcome trajectory were identified with robust Poisson models. RESULTS: The authors included data from 352 patients (mean age 50.9 [SD 9.5] years; 43.8% female). The models estimated that 15.5%-23.5% of patients followed a trajectory consistent with a poor clinical outcome. Lower physical and mental health-related quality of life, moderate to severe risk of depression, and longer surgical wait time and procedure time predicted poor postoperative trajectories for all outcomes. Receiving compensation and smoking additionally predicted a poor neck pain outcome. Regular exercise, physiotherapy, and spinal injections before surgery were associated with a lower risk of poor disability outcome. Patients who used daily opioids, those with worse general health, or those who reported predominant neck pain or a history of depression were at greater risk of poor disability outcome. CONCLUSIONS: Patients who undergo ACDF for cervical spondylotic radiculopathy experience heterogeneous postoperative trajectories of pain and disability, with 15.5%-23.5% of patients experiencing poor outcomes. Demographic, health, clinical, and surgery-related prognostic factors can predict ACDF outcomes. This information may further assist surgeons with patient selection and with setting realistic expectations. Future studies are needed to replicate and validate these findings prior to confident clinical implementation.

Postoperative recovery patterns following discectomy surgery in patients with lumbar radiculopathy.

This retrospective study of prospectively collected data aimed to identify unique pain and disability trajectories in patients following lumbar discectomy surgery. Patients of this study population presented chiefly with lumbar radiculopathy and underwent discectomy surgery from thirteen sites enrolled in the CSORN registry. Outcome variables of interest included numeric rating scales for leg/back pain and modified Oswestry disability index scores at baseline, 3, 12, and 24 months post-operatively. Latent class growth analysis was used to identify distinct courses in each outcome. Data from 524 patients revealed three unique trajectories for leg pain (excellent = 18.4%, good = 55.4%, poor = 26.3%), disability (excellent = 59.7%, fair = 35.6%, poor = 4.7%) and back pain (excellent = 13.0%, good = 56.4%, poor = 30.6%). Construct validity was supported by statistically significant differences in the proportions of patients attaining the criteria for minimal important change (MIC; 30%) or clinical success in disability (50% or Oswestry score ≤ 22) (p < 0.001). The variable proportions of patients belonging to poor outcome trajectories shows a disconnect between improved disability and persistence of pain. It will be beneficial to incorporate this information into the realm of patient expectation setting in concert with future findings of potential factors predictive of subgroup membership.

Effects of Workload on Return to Work After Elective Lumbar Spine Surgery.

STUDY DESIGN: Retrospective analysis was performed of a multi-center Canadian Spine Outcomes and Research Network (CSORN) surgical database. OBJECTIVE: To determine the rate and time to return to work (RTW) based on workload intensity after elective degenerative lumbar spine surgery. METHODS: Patients working pre-operatively, aged greater than 18, who underwent a primary one- or two-level elective lumbar spine surgery for degenerative conditions between January 2015 and October 2020 were evaluated. The percentage of patients who returned to work at 1 year and the time to RTW post-operatively were analyzed based on workload intensity. RESULTS: Of the 1290 patients included in the analysis, the overall rate of RTW was 82% at 1 year. Based on workload there was no significant difference in time to RTW after a fusion procedure, with median time to RTW being 10 weeks. For non-fusion procedure, the sedentary group had a statistically significantly quicker time to RTW than the light-moderate (P < .005) and heavy-very heavy (<.027) groups. CONCLUSIONS: The rate of RTW ranged between 84% for patients with sedentary work to 77% for patient with a heavy-very heavy workload. Median time to resumption of work was about 10 weeks following a fusion regardless of work intensity. There was more variability following non-fusion surgeries such as laminectomy and discectomy reflecting the patient's job demands.

Does extending a posterior cervical fusion construct into the upper thoracic spine impact patient-reported outcomes as long as 2 years after surgery in patients with degenerative cervical myelopathy?

OBJECTIVE: In multilevel posterior cervical instrumented fusion, extension of fusion across the cervicothoracic junction (CTJ) at T1 or T2 has been associated with decreased rates of reoperation and pseudarthrosis but with longer surgical time and increased blood loss. The impact on patient-reported outcomes (PROs) remains unclear. The primary objective was to determine whether extension of fusion through the CTJ influenced PROs at 3, 12, and 24 months after surgery. The secondary objective was to compare the number of patients who reached the minimal clinically important differences (MCIDs) for the PROs, modified Japanese Orthopaedic Association (mJOA) score, operative time, intraoperative blood loss, length of stay, discharge disposition, adverse events (AEs), reoperation within 24 months of surgery, and patient satisfaction. METHODS: This was a retrospective observational cohort study of prospectively collected multicenter data of patients with degenerative cervical myelopathy. Patients who underwent posterior instrumented fusion of 4 levels or greater (between C2 and T2) between January 2015 and October 2020 and received 24 months of follow-up were included. PROs (scores on the Neck Disability Index [NDI], EQ-5D, physical component summary and mental component summary of SF-12, and numeric rating scale for arm and neck pain) and mJOA scores were compared using ANCOVA and adjusted for baseline differences. Patient demographic characteristics, comorbidities, and surgical details were abstracted. The proportions of patients who reached the MCIDs for these outcomes were compared with the chi-square test. Operative duration, intraoperative blood loss, AEs, reoperation, discharge disposition, length of stay, and satisfaction was compared by using the chi-square test for categorical variables and the independent-samples t-test for continuous variables. RESULTS: A total of 198 patients were included in this study (101 patients with fusion not crossing the CTJ and 97 with fusion crossing the CTJ). Patients with a construct extending through the CTJ were more likely to be female and have worse baseline NDI scores (p > 0.05). When adjusted for baseline differences, there were no statistically significant differences between the two groups in terms of the PROs and mJOA scores at 3, 12, and 24 months. Surgical duration was longer (p < 0.001) and intraoperative blood loss was greater in the group with fusion extending to the upper thoracic spine (p = 0.013). There were no significant differences between groups in terms of AEs (p > 0.05). Fusion with a construct crossing the CTJ was associated with reoperation (p = 0.04). Satisfaction with surgery was not significantly different between groups. The proportions of patients who reached the MCIDs for the PROs were not statistically different at any time point. CONCLUSIONS: There were no statistically significant differences in PROs between patients with a posterior construct extending to the upper thoracic spine and those without such extension for as long as 24 months after surgery. The AE profiles were not significantly different, but longer surgical time and increased blood loss were associated with constructs extending across the CTJ.

Fulfillment of Patient Expectations After Spine Surgery is Critical to Patient Satisfaction: A Cohort Study of Spine Surgery Patients.

BACKGROUND: Patient satisfaction is an important indicator used to monitor quality of care and outcomes after spine surgery. OBJECTIVE: To examine the complex relationship between preoperative expectations, fulfillment of expectations, postsurgical outcomes, and satisfaction after spine surgery. METHODS: In this national study of patients undergoing elective surgery for degenerative spinal conditions from the Canadian Spine Outcomes and Research Network Registry, we used logistic regression to examine the relationships between patient satisfaction with surgery (1-5 scale), preoperative expectation score (0 = none to 100 = highest), fulfillment of expectations, and disability and pain improvement. RESULTS: Fifty-eight percent of patients were extremely satisfied, and 3% were extremely dissatisfied. Expectations were variable and generally high (mean 79.5 of 100) while 17.3% reported that none of their expectations were met, 49.8% reported that their most important expectation was met, and 32.9% reported that their most important expectation was not met but others were. The results from the fully adjusted ordinal logistic model for satisfaction indicate that satisfaction was higher among patients with higher preoperative expectations (odds ratio [OR] [95% CI]: 1.11, [1.04-1.19]), reporting important improvements in disability (OR [95% CI]: 2.52 [1.96-3.25]) and pain (OR [95% CI]: 1.64 [1.25-2.15]) and reporting that expectations were fulfilled (OR = 80.15, for all expectations were met). The results were similar for lumbar and cervical patients. CONCLUSION: Given the dominant impact of expectation fulfillment on satisfaction level, there is an opportunity for improving overall patient satisfaction by specifically assessing and mitigating the potential discrepancies between patients' preoperative expectations and likely surgical outcomes. The findings are likely relevant across elective surgical populations.

Surgical outcomes of patients who fail to reach minimal clinically important differences: comparison of minimally invasive versus open transforaminal lumbar interbody fusion.

OBJECTIVE: Treatment of degenerative lumbar diseases has been shown to be clinically effective with open transforaminal lumbar interbody fusion (O-TLIF) or minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF). Despite this, a substantial proportion of patients do not meet minimal clinically important differences (MCIDs) in patient-reported outcomes (PROs). The objectives of this study were to compare the proportions of patients who did not meet MCIDs after O-TLIF and MIS-TLIF and to determine potential clinical factors associated with failure to achieve MCID. METHODS: The authors performed a retrospective analysis of consecutive patients who underwent O-TLIF or MIS-TLIF for lumbar degenerative disorders and had been prospectively enrolled in the Canadian Spine Outcomes and Research Network. The authors analyzed the Oswestry Disability Index (ODI) scores, physical and mental component summary scores of SF-12, numeric rating scale (NRS) scores for leg and back pain, and EQ-5D scores of the patients in each group who did not meet the MCID of ODI at 2 years postoperatively. RESULTS: In this study, 38.8% (137 of 353) of patients in the O-TLIF cohort and 41.8% (51 of 122) of patients in the MIS-TLIF cohort did not meet the MCID of ODI at 2 years postoperatively (p = 0.59). Demographic variables and baseline PROs were similar between groups. There were improvements across the PROs of both groups through 2 years, and there were no differences in any PROs between the O-TLIF and MIS-TLIF cohorts. Multivariable logistic regression analysis demonstrated that higher baseline leg pain score (p = 0.017) and a diagnosis of spondylolisthesis (p = 0.0053) or degenerative disc disease (p = 0.022) were associated with achieving the MCID at 2 years after O-TLIF, whereas higher baseline leg pain score was associated with reaching the MCID after MIS-TLIF (p = 0.038). CONCLUSIONS: Similar proportions of patients failed to reach the MCID of ODI at 2 years after O-TLIF or MIS-TLIF. Higher baseline leg pain score was predictive of achieving the MCID in both cohorts, whereas a diagnosis of spondylolisthesis or degenerative disc disease was predictive of reaching the MCID after O-TLIF. These data provide novel insights for patient counseling and suggest that either MIS-TLIF or O-TLIF does not overcome specific patient factors to mitigate clinical success or failure in terms of the intermediate-term PROs associated with 1- to 2-level lumbar fusion surgical procedures for degenerative pathologies.

Factors Associated With Return to Work After Surgery for Degenerative Cervical Spondylotic Myelopathy: Cohort Analysis From the Canadian Spine Outcomes and Research Network.

STUDY DESIGN: Retrosepctive analysis of prospectively collected data from the multicentre Canadian Surgical Spine Registry (CSORN). OBJECTIVE: Degenerative cervical myelopathy (DCM) is the most common cause of spinal cord dysfunction in North America. Few studies have evaluated return to work (RTW) rates after DCM surgery. Our goals were to determine rates and factors associated with postoperative RTW in surgically managed patients with DCM. METHODS: Data was derived from the prospective, multicenter Canadian Spine Outcomes and Research Network (CSORN). From this cohort, we included all nonretired patients with at least 1-year follow-up. The RTW rate was defined as the proportion of patients with active employment at 1 year from the time of surgery. Unadjusted and adjusted analyses were used to identify patient characteristics, disease, and treatment variables associated with RTW. RESULTS: Of 213 surgically treated DCM patients, 126 met eligibility, with 49% working and 51% not working in the immediate period before surgery; 102 had 12-month follow-up data. In both the unadjusted and the adjusted analyses working preoperatively and an anterior approach were associated with a higher postoperative RTW (P < .05), there were no significant differences between the postoperative employment groups with respect to age, gender, preoperative mJOA (modified Japanese Orthopaedic Association) score, and duration of symptoms (P > .05). Active preoperative employment (odds ratio = 15.4, 95% confidence interval = 4.5, 52.4) and anterior surgical procedures (odds ratio = 4.7, 95% confidence interval = 1.2, 19.6) were associated with greater odds of RTW at 1 year. CONCLUSIONS: The majority of nonretired patients undergoing surgery for DCM had returned to work 12 months after surgery; active preoperative employment and anterior surgical approach were associated with RTW in this analysis.

Time to return to work after elective lumbar spine surgery.

OBJECTIVE: Time to return to work (RTW) after elective lumbar spine surgery is variable and dependent on many factors including patient, work-related, and surgical factors. The primary objective of this study was to describe the time and rate of RTW after elective lumbar spine surgery. Secondary objectives were to determine predictors of early RTW (< 90 days) and no RTW in this population. METHODS: A retrospective analysis of prospectively collected data from the multicenter Canadian Spine Outcomes and Research Network (CSORN) surgical registry was performed to identify patients who were employed and underwent elective 1- or 2-level discectomy, laminectomy, and/or fusion procedures between January 2015 and December 2019. The percentage of patients who returned to work and the time to RTW postoperatively were calculated. Predictors of early RTW and not returning to work were determined using a multivariable Cox regression model and a multivariable logistic regression model, respectively. RESULTS: Of the 1805 employed patients included in this analysis, 71% returned to work at a median of 61 days. The median RTW after a discectomy, laminectomy, or fusion procedure was 51, 46, and 90 days, respectively. Predictors of early RTW included male gender, higher education level (high school or above), higher preoperative Physical Component Summary score, working preoperatively, a nonfusion procedure, and surgery in a western Canadian province (p < 0.05). Patients who were working preoperatively were twice as likely to RTW within 90 days (HR 1.984, 95% CI 1.680-2.344, p < 0.001) than those who were employed but not working. Predictors of not returning to work included symptoms lasting more than 2 years, an increased number of comorbidities, an education level below high school, and an active workers' compensation claim (p < 0.05). There were fourfold odds of not returning to work for patients who had not been working preoperatively (OR 4.076, 95% CI 3.087-5.383, p < 0.001). CONCLUSIONS: In the Canadian population, 71% of a preoperatively employed segment returned to work after 1- or 2-level lumbar spine surgery. Most patients who undergo a nonfusion procedure RTW after 6 to 8 weeks, whereas patients undergoing a fusion procedure RTW at 12 weeks. Working preoperatively significantly increased the likelihood of early RTW.

Effectiveness of Surgical Decompression in Patients With Degenerative Cervical Myelopathy: Results of the Canadian Prospective Multicenter Study.

BACKGROUND: Conflicting evidence exists regarding the effectiveness of surgery for degenerative cervical myelopathy (DCM), particularly in mild DCM. OBJECTIVE: To prospectively evaluate the impact of surgery on patient-reported outcomes in patients with mild (modified Japanese Orthopaedic Association [mJOA] ≥ 15), moderate (mJOA 12-14), and severe (mJOA < 12) DCM. METHODS: Prospective, multicenter cohort study of patients with DCM who underwent surgery between 2015 and 2019 and completed 1-yr follow-up. Outcome measures (mJOA, Neck Disability Index [NDI], EuroQol-5D [EQ-5D], Short Form [SF-12] Physical Component Score [PCS]/Mental Component Score [MCS], numeric rating scale [NRS] neck, and arm pain) were assessed at 3 and 12 mo postoperatively and compared to baseline, stratified by DCM severity. Changes in outcome measures that were statistically significant (P < .05) and met their respective minimum clinically important differences (MCIDs) were deemed clinically meaningful. Responder analysis was performed to compare the proportion of patients between DCM severity groups who met the MCID for each outcome measure. RESULTS: The cohort comprised 391 patients: 110 mild, 163 moderate, and 118 severe. At 12 mo after surgery, severe DCM patients experienced significant improvements in all outcome measures; moderate DCM patients improved in mJOA, NDI, EQ-5D, and PCS; mild DCM patients improved in EQ-5D and PCS. There was no significant difference between severity groups in the proportion of patients reaching MCID at 12 mo after surgery for any outcome measure, except NDI. CONCLUSION: At 12 mo after surgery, patients with mild, moderate, and severe DCM all demonstrated improved outcomes. Severe DCM patients experienced the greatest breadth of improvement, but the proportion of patients in each severity group achieving clinically meaningful changes did not differ significantly across most outcome measures.

National adverse event profile after lumbar spine surgery for lumbar degenerative disorders and comparison of complication rates between hospitals: a CSORN registry study.

OBJECTIVE: Previous works investigating rates of adverse events (AEs) in spine surgery have been retrospective, with data collection from administrative databases, and often from single centers. To date, there have been no prospective reports capturing AEs in spine surgery on a national level, with comparison among centers. METHODS: The Spine Adverse Events Severity system was used to define the incidence and severity of AEs after spine surgery by using data from the Canadian Spine Outcomes and Research Network (CSORN) prospective registry. Patient data were collected prospectively and during hospital admission for those undergoing elective spine surgery for degenerative conditions. The Spine Adverse Events Severity system defined minor and major AEs as grades 1-2 and 3-6, respectively. RESULTS: There were 3533 patients enrolled in this cohort. There were 85 (2.4%) individual patients with at least one major AE and 680 (19.2%) individual patients with at least one minor AE. There were 25 individual patients with 28 major intraoperative AEs and 260 patients with 275 minor intraoperative AEs. Postoperatively there were 61 patients with a total of 80 major AEs. Of the 487 patients with minor AEs postoperatively there were 698 total AEs. The average enrollment was 321 patients (range 47-1237 patients) per site. The rate of major AEs was consistent among sites (mean 2.9% ± 2.4%, range 0%-9.1%). However, the rate of minor AEs varied widely among sites-from 7.9% to 42.5%, with a mean of 18.8% ± 9.7%. The rate of minor AEs varied depending on how they were reported, with surgeon reporting associated with the lowest rates (p < 0.01). CONCLUSIONS: The rate of major AEs after lumbar spine surgery is consistent among different sites but the rate of minor AEs appears to vary substantially. The method by which AEs are reported impacts the rate of minor AEs. These data have implications for the detection and reporting of AEs and the design of strategies aimed at mitigating complications.

The impact of pathoanatomical diagnosis on elective spine surgery patient expectations: a Canadian Spine Outcomes and Research Network study.

OBJECTIVE: Patients undergoing spine surgery generally have high expectations for improvement postoperatively. Little is known about how these expectations are affected by the diagnosis. The purpose of this study was to examine whether preoperative expectations differ based on diagnostic pathoanatomical patterns in elective spine surgery patients. METHODS: Patients with common degenerative cervical/lumbar pathology (lumbar/cervical stenosis, lumbar spondylolisthesis, and cervical/lumbar disc herniation) who had given their consent for surgery were analyzed using the Canadian Spine Outcomes and Research Network (CSORN). Patients reported the changes they expected to experience postoperatively in relation to 7 separate items using a modified version of the North American Spine Society spine questionnaire. Patients were also asked about the most important item that would make them consider the surgery a success. Sociodemographic, lifestyle, and clinical variables were also collected. RESULTS: There were 3868 eligible patients identified within the network for analysis. Patients with lumbar disc herniation had higher expectations for relief of leg pain compared with stenosis and lumbar degenerative spondylolisthesis cohorts within the univariate analysis. Cervical stenosis (myelopathy) patients were more likely to rank general physical capacity as their most important expectation from spine surgery. The multinomial regression analysis showed that cervical myelopathy patients have lower expectations for relief of arm or neck pain from surgery (OR 0.54, 0.34-0.88; p < 0.05). Patient factors, including age, symptoms (pain, disability, depression), work status, and lifestyle factors, were significantly associated with expectation, whereas the diagnoses were not. CONCLUSIONS: Patients with degenerative spinal conditions consenting for spine surgery have high expectations for improvement in all realms of their daily lives. With the exception of patients with cervical myelopathy, patient symptoms rather than diagnoses had a more substantial impact on the dimensions in which patients expected to improve or their most important expected change. Determination of patient expectation should be individualized and not biased by pathoanatomical diagnosis.

Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.