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.

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.

Versican-Derived Matrikines Regulate Batf3-Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer.

Colorectal cancer originates within immunologically complex microenvironments. To date, the benefits of immunotherapy have been modest, except in neoantigen-laden mismatch repair-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. In this article, we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8+ T cell infiltration in colorectal cancer, regardless of mismatch repair status. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8+ T cell infiltration. Tumor-intrinsic WNT pathway activation was associated with CD8+ T cell exclusion and VCAN accumulation. In addition to regulating VCAN levels at the tumor site, VCAN proteolysis results in the generation of bioactive fragments with novel functions (VCAN-derived matrikines). Versikine, a VCAN-derived matrikine, enhanced the generation of CD103+CD11chiMHCIIhi conventional dendritic cells (cDCs) from Flt3L-mobilized primary bone marrow-derived progenitors, suggesting that VCAN proteolysis may promote differentiation of tumor-seeding DC precursors toward IRF8- and BATF3-expressing cDCs. Intratumoral BATF3-dependent DCs are critical determinants for T cell antitumor immunity, effector T cell trafficking to the tumor site, and response to immunotherapies. Our findings provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker and VCAN-derived matrikines as novel immunotherapy agents.

Impact of Spinal Manipulation on Lower Extremity Motor Control in Lumbar Spinal Stenosis Patients: A Small-Scale Assessor-Blind Randomized Clinical Trial.

OBJECTIVE: The purpose of this study was to quantify the impact of a single lumbar spinal manipulation (SM) intervention on the leg movement performance of degenerative lumbar spinal stenosis (LSS) patients in a small-scale registered randomized clinical trial. METHODS: Participants with LSS (n = 14) were tested at baseline for pain, lumbar range of motion, and behavioral or kinematic motor performance (using an established Fitts' Law foot-pointing task), then underwent covariate adaptive randomization to receive SM or no intervention. Postintervention all dependent measures were repeated. Experimenters were blinded to patient group allocation. University ethics board approval was attained. RESULTS: For the primary outcome movement time, there was no significant difference between groups. As predicted by Fitts' Law, all participants had longer movement times as task difficulty increased. Secondary kinematic outcomes yielded no significant between-group differences. Consistent with Fitts' Law, kinematic measures changed significantly with task difficulty. Pairwise comparisons revealed the kinematic variables were more adversely affected by greater movement amplitudes than target size changes. No exploratory differences in pain or lumbar range of motion were observed. CONCLUSION: Changes in motor performance were not observed in this chronic pain population after a single SM intervention compared with a control group. Given the sample size, the study may have been underpowered to detect meaningful differences. Fitts' Law was observed for the lower extremity-pointing task for an LSS population and may provide an objective measure of motor performance.

Spontaneous recombinase activity of Cre-ERT2 in vivo.

Inducible Cre-ERT recombinase technology is widely used for gene targeting studies. The second generation of inducible Cre-ERT recombinase, hemizygous B6.129S-Tg(UBC-cre/ERT2)1Ejb/J (hereafter abbreviated as Cre-ERT2), a fusion of a mutated estrogen receptor and Cre recombinase, was engineered to be more efficient and specific than the original Cre-ERT. The putative mechanism of selective Cre-mediated recombination is Cre sequestration in the cytoplasm in the basal state with translocation to the nucleus only in the presence of tamoxifen. We utilized both a reporter mouse (B6.129 (Cg)-Gt(ROSA)26Sor tm4(ACTB-tdTomato,-EGFP)Luo /J) and endothelin converting enzyme-1 floxed transgenic mouse line to evaluate Cre-ERT2 activity. We observed spontaneous Cre activity in both settings. Unintended Cre activity is a confounding factor that has a potentially large impact on data interpretation. Thus, it is important to consider background Cre activity in experimental design.

Studies on the drug resistance profile of Enterococcus faecium distributed from poultry retailers to hospitals.

The multidrug resistant Enterococcus faecium (MEF) strains originating from farm animals are proliferating at a substantial pace to impact downstream food chains and could reach hospitals. This study was conducted to elucidate the drug susceptibility profile of MEF strains collected from poultry products in Ann Arbor, MI area and clinical settings from Michigan State Lab and Moffitt Cancer Center (MCC) in Florida. Presumptive positive Enterococcus isolates at species level were identified by Matrix Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) analysis. The antibiotic susceptibility profile for both poultry and clinical strains was determined by the Thermo Scientific's Sensititre conform to the National Committee for Clinical Laboratory Standards (NCCLS) and validated via quantitative real-time PCR (qPCR) methods. Out of 50 poultry samples (Turkey: n = 30; Chicken: n = 20), 36 samples were positive for Enterococcus species from which 20.83% were identified as E. faecium. All the E. faecium isolates were multidrug resistant and displayed resistance to the last alternative drug, quinupristin/dalfopristin (QD) used to treat vancomycin resistant E. faecium (VRE) in hospitals. Results indicate the presence of MEF strains in food animals and clinical settings that are also resistant to QD.

Big endothelin changes the cellular miRNA environment in TMOb osteoblasts and increases mineralization.

INTRODUCTION: Endothelin (ET1) promotes the growth of osteoblastic breast and prostate cancer metastases. Conversion of big ET1 to mature ET1, catalyzed primarily by endothelin converting enzyme 1 (ECE1), is necessary for ET1's biological activity. We previously identified the Ece1, locus as a positional candidate gene for a pleiotropic quantitative trait locus affecting femoral size, shape, mineralization, and biomechanical performance. METHODS: We exposed TMOb osteoblasts continuously to 25 ng/ml big ET1. Cells were grown for 6 days in growth medium and then switched to mineralization medium for an additional 15 days with or without big ET1, by which time the TMOb cells form mineralized nodules. We quantified mineralization by alizarin red staining and analyzed levels of miRNAs known to affect osteogenesis. Micro RNA 126-3p was identified by search as a potential regulator of sclerostin (SOST) translation. RESULTS: TMOb cells exposed to big ET1 showed greater mineralization than control cells. Big ET1 repressed miRNAs targeting transcripts of osteogenic proteins. Big ET1 increased expression of miRNAs that target transcripts of proteins that inhibit osteogenesis. Big ET1 increased expression of 126-3p 121-fold versus control. To begin to assess the effect of big ET1 on SOST production we analyzed both SOST transcription and protein production with and without the presence of big ET1 demonstrating that transcription and translation were uncoupled. CONCLUSION: Our data show that big ET1 signaling promotes mineralization. Moreover, the results suggest that big ET1's osteogenic effects are potentially mediated through changes in miRNA expression, a previously unrecognized big ET1 osteogenic mechanism.

Solving time-dependent CYP3A4 inhibition for a series of indole-phenylacetic acid dual antagonists of the PGD(2) receptors CRTH2 and DP.

Based on their structural similarity to previously described compound AMG 009, indole-phenyl acetic acids were proposed to be potent dual inhibitors of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2) and prostanoid D receptor (DP or DP1). This series was equipotent to AMG 009 in binding assays against both receptors but exhibited decreased serum shift. We discovered early in the optimization of these indole-phenylacetic acid compounds that they demonstrated CYP3A4 time-dependent inhibition (TDI). Hypothesizing that the source of TDI was the indole core we modified the 1,2,3-substitution to eventually afford a highly potent modulator of CRTH2 and DP which did not exhibit TDI.

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.

Fluoroscopic-guided approaches to radiofrequency vein ablation.

PURPOSE: Ultrasound-guided antegrade access during endovenous lower-extremity vein ablation may be problematic. This study describes fluoroscopic-guided retrograde access to the target veins in cases in which antegrade access proved unfeasible. MATERIALS AND METHODS: The retrograde technique was used to treat a total of 38 legs in 33 patients in whom antegrade access failed. This approach was selected because of small caliber or spasm of the proximal (ie, lower) great saphenous vein (GSV; n = 22), proximal (ie, lower) GSV spasm during access (n = 2), previous incomplete vein ablation (n = 7), skin disease over the proximal GSV (n = 6), and tortuous proximal GSV anatomy (n = 1). Thirty-two legs were treated with an ipsilateral retrograde approach and six were treated with a contralateral retrograde approach. Radiofrequency ablation with or without sclerotherapy was then performed. RESULTS: The technical success rate for retrograde access and subsequent ablation was 100%. No procedural complications occurred. At 1 month, five patients with active ulcers exhibited ulcer healing (100%). CONCLUSIONS: The fluoroscopic retrograde approach can be used to treat GSV reflux when traditional antegrade access is not feasible.

Blood pressure, artery size, and artery compliance parallel bone size and strength in mice with differing ece1 expression.

The recombinant congenic mouse strains HcB-8 and HcB-23 differ in femoral shape, size, and strength, with HcB-8 femora being more gracile, more cylindrical, weaker, and having higher Young's modulus. In previous work, we mapped a robust, pleiotropic quantitative trait locus for these bone traits. Ece1, encoding endothelin converting enzyme 1, is a positional candidate gene for this locus, and was less expressed in HcB-8 bone. We hypothesized that the same genetic factors would impose analogous developmental trajectories on arteries to those in bones. Cardiovascular hemodynamics and biomechanics of carotids were measured in adult HcB-8 and HcB-23 mice. Biological differences in heart and arteries were examined at mRNA and protein levels. As in bone, Ece1 expression was higher in HcB-23 heart and arteries (p < 0.05), and its expression was correlated with that of the endothelin B type receptor target Nos3, encoding endothelial nitric oxide synthase. HcB-8 mice had higher ambulatory blood pressure (p < 0.005) than HcB-23 mice. Ex vivo, at identical pressures, HcB-8 carotid arteries had smaller diameters and lower compliance (p < 0.05), but the same elastic modulus compared to HcB-23 carotid arteries. HcB-8 hearts were heavier than HcB-23 hearts (p < 0.01). HcB-8 has both small, stiff bones and small, stiff arteries, lower expression of Ece1 and Nos3, associated in each case with less favorable function. These findings suggest that endothelin signaling could serve as a nexus for the convergence of skeletal and vascular modeling, providing a potential mechanism for the epidemiologic association between skeletal fragility and atherosclerosis.

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.

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.

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.

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.

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.

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.

Sequential metabolism of AMG 487, a novel CXCR3 antagonist, results in formation of quinone reactive metabolites that covalently modify CYP3A4 Cys239 and cause time-dependent inhibition of the enzyme.

CYP3A4-mediated biotransformation of (R)-N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-N-(pyridin-3-ylmethyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (AMG 487) was previously shown to generate an inhibitory metabolite linked to dose- and time-dependent pharmacokinetics in humans. Although in vitro activity loss assays failed to demonstrate CYP3A4 time-dependent inhibition (TDI) with AMG 487, its M2 phenol metabolite readily produced TDI when remaining activity was assessed using either midazolam or testosterone (K(I) = 0.73-0.74 µM, k(inact) = 0.088-0.099 min(-1)). TDI investigations using an IC(50) shift method successfully produced inhibition attributable to AMG 487, but only when preincubations were extended from 30 to 90 min. The shift magnitude was ∼3× for midazolam activity, but no shift was observed for testosterone activity. Subsequent partition ratio determinations conducted for M2 using recombinant CYP3A4 showed that inactivation was a relatively inefficient process (r = 36). CYP3A4-mediated biotransformation of [(3)H]M2 in the presence of GSH led to identification of two new metabolites, M4 and M5, which shifted focus away from M2 being directly responsible for TDI. M4 (hydroxylated M2) was further metabolized to form reactive intermediates that, upon reaction with GSH, produced isomeric adducts, collectively designated M5. Incubations conducted in the presence of [(18)O]H(2)O confirmed incorporation of oxygen from O(2) for the majority of M4 and M5 formed (>75%). Further evidence of a primary role for M4 in CYP3A4 TDI was generated by protein labeling and proteolysis experiments, in which M4 was found to be covalently bound to Cys239 of CYP3A4. These investigations confirmed a primarily role for M4 in CYP3A4 inactivation, suggesting that a more complex metabolic pathway was responsible for generation of inhibitory metabolites affecting AMG 487 human pharmacokinetics.

A review of the ecology, genomics, and stress response of Listeria innocua and Listeria monocytogenes.

Listeria monocytogenes is a Gram-positive foodborne pathogen responsible for a severe disease occurring in immuno-compromised populations. Foodborne illness caused by L. monocytogenes is a serious public health concern because of the high associated mortality. Study of the closely related, but nonpathogenic Listeria innocua has accounted for a better understanding of the behavior of L. monocytogenes in environments beyond the laboratory. Traditionally, the ecological co-habitation, genomic synteny, and physiological similarity of the two species have supported use of L. innocua for predicting the behavior of L. monocytogenes in farm and food processing environments. However, a careful review of the current literature indicates that in a given situation it may not be prudent to use L. innocua as a surrogate for L. monocytogenes without prior confirmation of their similar phenotypes, as an increasing number of studies have arisen demonstrating differences in L. monocytogenes and L. innocua stress response, and furthermore, there are differences among the L. monocytogenes subgroups. Future research should take into consideration that multiple surrogates might be required to accurately model even a single condition depending on the L. monocytogenes subgroup of interest.

Optimization of phenylacetic acid derivatives for balanced CRTH2 and DP dual antagonists.

Our first generation CRTH2 and DP dual antagonists, represented by AMG 009, are more potent toward the CRTH2 receptor than to the DP receptor. Here we report our efforts in the discovery of CRTH2 and DP dual antagonists with more balanced potencies to both receptors, such as compound 15.