Development of the cervical myelopathy severity index: a new patient reported outcome measure to quantify impairments and functional limitations.

BACKGROUND CONTEXT: Existing degenerative cervical myelopathy (DCM) severity scales have significant shortcomings, creating a strong impetus for the development of a practical measurement tool with sound psychometric properties. PURPOSE: This work reports the item generation and reduction of the Cervical Myelopathy Severity Index (CMSI), a new DCM patient-reported outcome measure of symptoms and functional limitations. DESIGN: Prospective observational study. PATIENT SAMPLE: Adult DCM patients belonging to one of three distinct treatment groups: (1) observation cohort, (2) preoperative surgical cohort, (3) 6 to 12 months postoperative cohort. OUTCOME MEASURES: Patient-reported outcome measure of symptoms and functional limitations. METHODS: Item generation was performed using semi-structured patient focus groups emphasizing symptoms experienced and functional limitations. Readability was assessed through think-aloud patient interviews. Item reduction involved surveys of DCM patients with a spectrum of disease severity and board-certified spine surgeons experienced in the treatment of DCM. A priori criteria for item removal included: patient median importance/severity <2 (of 4), 30% or more no severity (response of zero), item severity correlations ≤ 0.80 (Spearman), item severity reliability (weighted kappa <0.60) based on a 2-week interval and clinician median importance <2 with retention of items with very high clinical importance. RESULTS: There were 42 items generated from a combination of specialist input and patient focus groups. Items captured sensorimotor symptoms and limitations related to upper and lower extremities as well as sphincter dysfunction. Ninety-eight patients (43, 30, 25 observation, pre- and postsurgery respectively) and 51 surgeons completed the assessment. Twenty-three items remained after application of median importance and severity thresholds and weighted kappa cutoffs. After elimination of highly correlated (>0.80) items and combining two similar items, the final CMSI questionnaire list included 14 items. CONCLUSIONS: The CMSI is a new DCM patient-reported clinical measurement tool developed using patient and clinician input to inform item generation and reduction. Future work will evaluate the reliability, validity, and responsiveness of the CMSI in relation to existing myelopathy measurement indices.

A Practical Classification System for Acute Cervical Spinal Cord Injury Based on a Three-Phased Modified Delphi Process From the AOSpine Spinal Cord Injury Knowledge Forum.

STUDY DESIGN: A modified Delphi study. OBJECTIVE: To assess current practice patterns in the management of cervical spinal cord injury (SCI) and develop a simplified, practical classification system which offers ease of use in the acute setting, incorporates modern diagnostic tools and provides utility in determining treatment strategies for cervical SCI. METHODS: A three-phase modified Delphi procedure was performed between April 2020 and December 2021. During the first phase, members of the AOSpine SCI Knowledge forum proposed variables of importance for classifying and treating cervical SCI. The second phase involved an international survey of spine surgeons gauging practices surrounding the role and timing of surgery for cervical SCI and opinions regarding factors which most influence these practices. For the third phase, information obtained from phases 1 and 2 were used to draft a new classification system. RESULTS: 396 surgeons responded to the survey. Neurological status, spinal stability and cord compression were the most important variables influencing decisions surrounding the role and timing of surgery. The majority (>50%) of respondents preferred to perform surgery within 24 hours post-SCI in clinical scenarios in which there was instability, severe cord compression or severe neurology. Situations in which <50% of respondents were inclined to operate early included: SCI with mild neurological impairments, with cord compression but without instability (with or without medical comorbidities), and SCI without cord compression or instability. CONCLUSIONS: Spinal stability, cord compression and neurological status are the most important variables influencing surgeons' practices surrounding the surgical management of cervical SCI. Based on these results, a simplified classification system for acute cervical SCI has been proposed.

Right Lobe Versus Left Lobe Living Donor Liver Transplantation: A Systematic Review and Meta-analysis of Donor and Recipient Outcomes.

BACKGROUND: Living donor liver transplantation (LDLT) is an established treatment for advanced liver disease. Whether right lobe (RL) or left lobe (LL) LDLT provides the best outcomes for donors and recipients remains contentious. METHODS: MedLine, Embase, PubMed, and Cochrane Central were searched to identify studies comparing RL- and LL-LDLT and reporting donor and/or recipient outcomes. Effect sizes were pooled using random-effect meta-analysis. Meta-regressions were used to explore heterogeneity. RESULTS: Sixty-seven studies were included. RL donors were more likely to experience major complications (relative risk [RR] = 1.63; 95% confidence interval [CI] = 1.30-2.05; I2 = 19%) than LL donors; however, no difference was observed in the risk of any biliary complication (RR = 1.41; 95% CI = 0.91-2.20; I2 = 59%), bile leaks (RR = 1.56; 95% CI = 0.97-2.51; I2 = 52%), biliary strictures (RR = 0.99; 95% CI = 0.43-1.88; I2 = 27%), or postoperative death (RR = 0.51; 95% CI = 0.25-1.05; I2 = 0%). Among recipients, the incidence of major complications (RR = 0.85; 95% CI = 0.68-1.06; I2 = 21%), biliary complications (RR = 1.10; 95% CI = 0.91-1.33; I2 = 8%), and vascular complications (RR = 0.79; 95% CI = 0.44-1.43; I2 = 0%) was similar. Although the rate of small for size syndrome (RR = 0.47; 95% CI = 0.30-0.74; I2 = 0%) and postoperative deaths (RR = 0.62; 95% CI = 0.44-0.87; I2 = 0%) was lower among RL-LDLT recipients, no differences were observed in long-term graft (hazard ratio = 0.87; 95% CI = 0.55-1.38; I2 = 74%) and overall survival (hazard ratio = 0.86; 95% CI = 0.60-1.22; I2 = 44%). CONCLUSIONS: LL donors experience fewer complications than RL donors, and LL-LDLT recipients had similar outcomes to RL-LDLT recipients. These findings suggest that LL-LDLT offers the best outcomes for living donors and similar outcomes for recipients when measures are taken to prevent small for size syndrome.

Incidence, risk factors, outcomes, and clinical management of BK viremia in the modern era of kidney transplantation.

BK viremia is endemic among kidney transplant recipients (KTRs). Incidence, risk factors, outcomes, and clinical management of detectable versus high BK viremia have not been considered previously in KTR in the modern era. This observational study examined KTR transplanted between January 1, 2009 and December 31, 2016. Any BK viral load in the serum constituted detectable BK viremia and ≥103 copies/ml constituted high viremia. Among 1193 KTRs, the cumulative probability of developing detectable and high BK viremia within 2 years posttransplant were 27.8% and 19.6%, respectively. Significant risk factors for detectable BK viremia included recipient age (HR 1.02 [95% CI: 1.01, 1.03]) and donor age (HR 1.01 [95% CI: 1.00, 1.02]). Recipient age also predicted high BK viremia (HR 1.02 [95% CI: 1.01, 1.03]), whereas White race (HR 0.70 [95% CI: 0.52, 0.95]), nondepleting induction therapy (HR 0.61 [95% CI: 0.42, 0.89]), and delayed graft function (HR 0.61 [95% CI: 0.42, 0.88]) were protective. Mean estimated glomerular filtration rates were 4.28 ml/min/1.72 m2 (95% CI: 2.71, 5.84) lower with detectable BK viremia. Although low viral load was usually not acted upon at first presentation, antiproliferative dose reductions were the most common initial management. BK viremia remains a common early complication in a modern cohort of KTRs. These findings highlight the benefit of early BKV monitoring in addition to intensive clinical management. Clinical responses beyond first positive BK viremia tests, and their implications for graft outcomes, merit further investigation.

Sample Preparation using a Lipid Monolayer Method for Electron Crystallographic Studies.

Electron crystallography is a powerful tool for high-resolution structure determination. Macromolecules such as soluble or membrane proteins can be grown into highly ordered two-dimensional (2D) crystals under favorable conditions. The quality of the grown 2D crystals is crucial to the resolution of the final reconstruction via 2D image processing. Over the years, lipid monolayers have been used as a supporting layer to foster the 2D crystallization of peripheral membrane proteins as well as soluble proteins. This method can also be applied to 2D crystallization of integral membrane proteins but requires more extensive empirical investigation to determine detergent and dialysis conditions to promote partitioning to the monolayer. A lipid monolayer forms at the air-water interface such that the polar lipid head groups remain hydrated in the aqueous phase and the non-polar, acyl chains, tails partition into the air, breaking the surface tension and flattening the water surface. The charged nature or distinctive chemical moieties of the head groups provide affinity for proteins in solution, promoting binding for 2D array formation. A newly formed monolayer with the 2D array can be readily transfer into an electron microscope (EM) on a carbon-coated copper grid used to lift and support the crystalline array. In this work, we describe a lipid monolayer methodology for cryogenic electron microscopic (cryo-EM) imaging.

The Impact of Riluzole on Neurobehavioral Outcomes in Preclinical Models of Traumatic and Nontraumatic Spinal Cord Injury: Results From a Systematic Review of the Literature.

STUDY DESIGN: Systematic review. OBJECTIVE: To evaluate the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI). METHODS: An extensive search of the literature was conducted in Medline, EMBASE, and Medline in Process. Studies were included if they evaluated the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI. Extensive data were extracted from relevant studies, including sample characteristics, injury model, outcomes assessed, timing of evaluation, and main results. The SYRCLE checklist was used to assess various sources of bias. RESULTS: The search yielded a total of 3180 unique citations. A total of 16 studies were deemed relevant and were summarized in this review. Sample sizes ranged from 14 to 90, and injury models included traumatic SCI (n = 9), degenerative cervical myelopathy (n = 2), and spinal cord-ischemia (n = 5). The most commonly assessed outcome measures were BBB (Basso, Beattie, Besnahan) locomotor score and von Frey filament testing. In general, rats treated with riluzole exhibited significantly higher BBB locomotor scores than controls. Furthermore, riluzole significantly increased withdrawal thresholds to innocuous stimuli and tail flick latency following application of radiant heat stimuli. Finally, rats treated with riluzole achieved superior results on many components of gait assessment. CONCLUSION: In preclinical models of traumatic and nontraumatic SCI, riluzole significantly improves locomotor scores, gait function, and neuropathic pain. This review provides the background information necessary to interpret the results of clinical trials on the impact of riluzole in traumatic and nontraumatic SCI.

The discrepancy between functional outcome and self-reported health status after surgery for degenerative cervical myelopathy.

INTRODUCTION: Surgery for degenerative cervical myelopathy has shown not only to halt neurologic deterioration, but also to improve functional impairments. Despite these improvements, some patients may be dissatisfied with their outcomes. This study aims to (1) investigate discrepancies between postoperative clinical measures and self-reported health status, and (2) identify important predictors of such discrepancies. METHODS: Four hundred and seventy-nine surgical patients were prospectively enrolled in the CSM-International study at 16 global sites. At 1-year post-op, patients rated their general health status compared with their immediate preoperative status (much better, somewhat better, the same, somewhat worse, much worse). Descriptive analyses were conducted to evaluate the agreement between achieving a clinically important improvement (MCID) in function (modified Japanese Orthopedic Association [mJOA] scale) and self-reported health status. Agreement was defined as achieving the MCID on the mJOA and reporting general health as somewhat better or much better, whereas disagreement was defined as achieving MCID on the mJOA and reporting general health as the same, somewhat worse or much worse. Logistic regression analysis was used to determine factors that influence agreement between self-report of health status and functional outcomes. RESULTS: A total of 395 patients had complete follow-up data at 1-year and were included in this analysis. Based on patient self-reports, 56 (14.2%) were somewhat or much worse than a year ago, 80 (20.2%) patients were the same and 259 (65.6%) patients were somewhat or much better. Thirty percent of patients who reported being somewhat or much worse were found to achieve the MCID on the mJOA; 57.5% of patients who indicated their health status were the same as before surgery also exhibited clinically meaningful improvements in functional impairment. Based on multivariate analysis, there was an increased odds of observing an agreement between self-reports of health status and functional outcomes if the patient exhibited greater improvement in mJOA upper extremity motor function at 1-year (odds ratio [OR]: 1.41, 95% confidence interval [CI] 1.03-1.93, p=.033) and reduced odds of agreement with increased age (OR for every decade: 0.66, 95% CI 0.50-0.87, p=.0035) and increased bodily pain at 1-year (OR: 0.62, 95% CI 0.49-078, p<.0001). CONCLUSIONS: There was a discrepancy between changes in mJOA and self-reports of health status in patients undergoing surgery for degenerative cervical myelopathy. Increased bodily pain at 1-year, smaller improvements in postoperative upper extremity score and increased age were associated with worsened or unchanged general health status, despite clinically significant improvements in overall postoperative function.

Efficacy, safety, and economics of bracing after spine surgery: a systematic review of the literature.

BACKGROUND CONTEXT: Bracing is often used after spinal surgery to immobilize the spine, improve fusion, and relieve pain. However, controversy exists regarding the efficacy, necessity, and safety of various bracing techniques in the postsurgical setting. PURPOSE: In this systematic review, we aimed to compare the effectiveness, safety, and cost-effectiveness of postoperative bracing versus no postoperative bracing after spinal surgery in patients with several common operative spinal pathologies. STUDY DESIGN/SETTING: A systematic review was carried out to compare postoperative bracing and no postoperative bracing. METHODS: A systematic search was conducted of MEDLINE, Embase, and the Cochrane Collaboration Library from 1970 to May 2017, supplemented by manual searching of the reference list of relevant studies and previously published reviews. Studies were included if they compared disability, quality of life, functional impairment, radiographic outcomes, cost-effectiveness, or complications between patients treated with postoperative bracing and patients not receiving any postoperative bracing. Each article was critically appraised independently by two reviewers, and the overall body of evidence was rated using guidelines outlined by the Grading of Recommendation Assessment, Development and Evaluation (GRADE) Working Group. RESULTS: Of the 858 retrieved citations, 5 studies met the inclusion criteria and were included in this review, consisting of 4 randomized controlled trials and 1 prospective cohort study. Low to moderate evidence suggests that there are no significant differences in most measures of disability, pain, quality of life, functional impairment, radiographic outcomes, and safety between groups. Isolated studies reported statistically significant and inconsistent differences between groups with respect to Neck Disability Index at 6 weeks postoperatively or Short Form-36 Physical Component Score at 1.5, 3, 6, and 12 months postoperatively. CONCLUSIONS: Based on limited evidence, postoperative bracing does not result in improved outcomes after spinal surgery. Future high-quality randomized trials will be required to confirm these findings.

Identification of a single base-pair mutation of TAA (Stop codon) → GAA (Glu) that causes light chain extension in a CHO cell derived IgG1.

We describe here the identification of a stop codon TAA (Stop) → GAA (Glu) = Stop221E mutation on the light chain of a recombinant IgG1 antibody expressed in a Chinese hamster ovary (CHO) cell line. The extended light chain variants, which were caused by translation beyond the mutated stop codon to the next alternative in-frame stop codon, were observed by mass spectra analysis. The abnormal peptide peaks present in tryptic and chymotryptic LC-MS peptide mapping were confirmed by N-terminal sequencing as C-terminal light chain extension peptides. Furthermore, LC-MS/MS of Glu-C peptide mapping confirmed the stop221E mutation, which is consistent with a single base-pair mutation in TAA (stop codon) to GAA (Glu). The light chain variants were approximately 13.6% of wild type light chain as estimated by RP-HPLC analysis. DNA sequencing techniques determined a single base pair stop codon mutation, instead of a stop codon read-through, as the cause of this light chain extension. To our knowledge, the stop codon mutation has not been reported for IgGs expressed in CHO cells. These results demonstrate orthogonal techniques should be implemented to characterize recombinant proteins and select appropriate cell lines for production of therapeutic proteins because modifications could occur at unexpected locations.

A chemical genomics screen to discover genes that modulate neural stem cell differentiation.

The authors designed a chemical genomics screen with the aim of understanding genes and pathways that modulate neural stem/precursor cell differentiation. Multipotent mouse neural precursor cells isolated from cortices of embryonic day 12 (E12) embryos were subjected to spontaneous differentiation triggered by growth factor withdrawal. A quantitative whole-well immunofluorescence assay was set up to screen tool compound sets to identify small molecules with potent, dose-dependent, and reproducible effects on increasing neural stem cell differentiation toward neuronal lineage. Among the pro-neuronal compounds, kinase inhibitors were shown to exert pro-neuronal effect via a signaling pathway associated with the kinase. The global effect of hit compounds on modulating neuronal differentiation was confirmed by an in vivo mouse study and human neural stem cells culture. This study demonstrates that a phenotypic assay using cell type-specific antibody markers can be used for a large-scale compound screen to discover targets and pathways with impacts on differentiation of lineage-restricted precursor cells toward specific lineages.