Divalent triazole‐linked carbohydrate mimetics: Synthesis by click chemistry and evaluation as selectin ligands

Starting from an enantiopure 3‐amino‐substituted pyran derivative, the synthesis of a series of divalent 1,2,3‐triazole‐linked carbohydrate mimetics is described. The preparation of the required 3‐azido‐substituted pyran proceeds smoothly by copper‐catalyzed diazo transfer. Using different conditions for the Huisgen‐Meldal‐Sharpless cycloaddition, this azide reacts with several diynes to furnish the desired divalent carbohydrate mimetics bearing rigid or flexible linker units. The in situ generation of the 3‐azidopyran in the presence of Cu/C as catalyst followed by the reaction with the alkyne allows a direct one‐pot transformation from the 3‐aminopyran to the desired click products. We also examined the Sakai‐Westermann method that transfers primary amines with the aid of α,α‐dichlorotosylhydrazones into 1,2,3‐triazoles. These copper‐free click conditions were applied for the first time to the preparation of a divalent compound. The O‐sulfation of the carbohydrate mimetics was achieved using the SO3‐DMF complex under careful 1H‐NMR control. Five polysulfated compounds could be obtained in pure form and these were tested by surface plasmon resonance spectroscopy as inhibitors of L‐selectin giving IC50 values between 45 nm and 50 µm

Does the Spine Surgeon’s Experience Affect Fracture Classification, Assessment of Stability, and Treatment Plan in Thoracolumbar Injuries?

Study Design: Prospective survey-based study. Objectives: The AO Spine thoracolumbar injury classification has been shown to have good reproducibility among clinicians. However, the influence of spine surgeons’ clinical experience on fracture classification, stability assessment, and decision on management based on this classification has not been studied. Furthermore, the usefulness of varying imaging modalities including radiographs, computed tomography (CT) and magnetic resonance imaging (MRI) in the decision process was also studied. Methods: Forty-one spine surgeons from different regions, acquainted with the AOSpine classification system, were provided with 30 thoracolumbar fractures in a 3-step assessment: first radiographs, followed by CT and MRI. Surgeons classified the fracture, evaluated stability, chose management, and identified reasons for any changes. The surgeons were divided into 2 groups based on years of clinical experience as \u3c10 years (n = 12) and \u3e10 years (n = 29). Results: There were no significant differences between the 2 groups in correctly classifying A1, B2, and C type fractures. Surgeons with less experience hadmore correct diagnosis in classifyingA3 (47.2% vs 38.5%in step 1, 73.6% vs 60.3% in step 2 and 77.8% vs 65.5% in step 3), A4 (16.7% vs 24.1% in step 1, 72.9% vs 57.8% in step 2 and 70.8% vs 56.0%in step3) and B1 injuries (31.9% vs 20.7% in step 1, 41.7% vs 36.8% in step 2 and 38.9% vs 33.9% in step 3). In the assessment of fracture stability and decision on treatment, the less and more experienced surgeons performed equally. The selection of a particular treatment plan varied in all subtypes except in A1 and C type injuries. Conclusion: Surgeons’ experience did not significantly affect overall fracture classification, evaluating stability and planning the treatment. Surgeons with less experience had a higher percentage of correct classification in A3 and A4 injuries. Despite variations between them in classification, the assessment of overall stability and management decisions were similar between the 2 groups. © The Author(s) 2017

Modulating Myeloid Immune Cell Migration Using Multivalently Presented Monosaccharide Ligands for Advanced Immunotherapy

Due to their importance for the outcome of the inflammatory response, the motile myeloid cells are a focus of novel treatment options. The interplay of selectins and their ligands with leukocytes and endothelial cells, which mediate endothelial attachment and transmigration of immune cells, can be modulated by selectin‐binding structures. Here, a library of selectin‐targeting ligands coupled to either gold, silver, iron oxide nanospheres, or quantum dots of 5–10 nm in size is used to systematically study their impact on immune cell motility. The multivalent presentation of the carbohydrate mimetics results in very low sub‐nanomolar binding to L ‐selectin. Using human primary monocytes, granulocytes, lymphocytes, and macrophages, it is shown that the ligands exhibit only minor effects on uptake, whereas the motility of leukocytes is critically affected as observed in migration assays evaluated by flow cytometry. The carbohydrate mimetic ring structure, sulfation, in particular, and the degree of ligand presentation, are constituents which cohere in this process. Specific carbohydrate ligands can thus selectively regulate leukocyte subsets. These data form the basis for advanced immunotherapy which inhibits the amplification of inflammation by restricting leukocyte influx to injured tissue sites. Furthermore, the targeting ligands may complement existing treatment options for inflammatory diseases

AOSpine—Spine Trauma Classification System: The Value of Modifiers: A Narrative Review With Commentary on Evolving Descriptive Principles

Study Design: Narrative review. Objectives: To describe the current AOSpine Trauma Classification system for spinal trauma and highlight the value of patient-specific modifiers for facilitating communication and nuances in treatment. Methods: The classification for spine trauma previously developed by The AOSpine Knowledge Forum is reviewed and the importance of case modifiers in this system is discussed. Results: A successful classification system facilitates communication and agreement between physicians while also determining injury severity and provides guidance on prognosis and treatment. As each injury may be unique among different patients, the importance of considering patient-specific characteristics is highlighted in this review. In the current AOSpine Trauma Classification, the spinal column is divided into 4 regions: the upper cervical spine (C0-C2), subaxial cervical spine (C3-C7), thoracolumbar spine (T1-L5), and the sacral spine (S1-S5, including coccyx). Each region is classified according to a hierarchical system with increasing levels of injury or instability and represents the morphology of the injury, neurologic status, and clinical modifiers. Specifically, these clinical modifiers are denoted starting with M followed by a number. They describe unique conditions that may change treatment approach such as the presence of significant soft tissue damage, uncertainty about posterior tension band injury, or the presence of a critical disc herniation in a cervical bilateral facet dislocation. These characteristics are described in detail for each spinal region. Conclusions: Patient-specific modifiers in the AOSpine Trauma Classification highlight unique clinical characteristics for each injury and facilitate communication and treatment between surgeons

Effect of local TGF-β1 and IGF-1 release on implant fixation: comparison with hydroxyapatite coating: A paired study in dogs

Background and purpose Hydroxyapatite (HA) coating stimulates the osseointegration of cementless orthopedic implants. Recently, locally released osteogenic growth factors have also been shown experimentally to stimulate osseointegration so that bone fills gaps around orthopedic implants. Here, we have compared the effect of local release of TGF-β 1 and IGF-1 with that of hydroxyapatite coating on implant fixation

Variation in global treatment for subaxial cervical spine isolated unilateral facet fractures.

PURPOSE To determine the variation in the global treatment practices for subaxial unilateral cervical spine facet fractures based on surgeon experience, practice setting, and surgical subspecialty. METHODS A survey was sent to 272 members of the AO Spine Subaxial Injury Classification System Validation Group worldwide. Questions surveyed surgeon preferences with regard to diagnostic work-up and treatment of fracture types F1-F3, according to the AO Spine Subaxial Cervical Spine Injury Classification System, with various associated neurologic injuries. RESULTS A total of 161 responses were received. Academic surgeons use the facet portion of the AO Spine classification system less frequently (61.6%) compared to hospital-employed and private practice surgeons (81.1% and 81.8%, respectively) (p = 0.029). The overall consensus was in favor of operative treatment for any facet fracture with radicular symptoms (N2) and for any fractures categorized as F2N2 and above. For F3N0 fractures, significantly less surgeons from Africa/Asia/Middle East (49%) and Europe (59.2%) chose operative treatment than from North/Latin/South America (74.1%) (p = 0.025). For F3N1 fractures, significantly less surgeons from Africa/Asia/Middle East (52%) and Europe (63.3%) recommended operative treatment than from North/Latin/South America (84.5%) (p = 0.001). More than 95% of surgeons included CT in their work-up of facet fractures, regardless of the type. No statistically significant differences were seen in the need for MRI to decide treatment. CONCLUSION Considerable agreement exists between surgeon preferences with regard to unilateral facet fracture management with few exceptions. F2N2 fracture subtypes and subtypes with radiculopathy (N2) appear to be the threshold for operative treatment

Health professionals’ perspective on the applicability of AO Spine PROST (patient reported outcome Spine trauma) in people with a motor-complete traumatic or non-traumatic spinal cord injury

Purpose: The AO Spine PROST (Patient Reported Outcome Spine Trauma) was developed for people with spine trauma and minor or no neurological impairment. The purpose is to investigate health professionals’ perspective on the applicability of the AO Spine PROST for people with motor-complete traumatic or non-traumatic spinal cord injury (SCI), using a discussion meeting and international survey study. Methods: A discussion meeting with SCI rehabilitation physicians in the Netherlands was performed, followed by a worldwide online survey among the AO Spine International community, involved in the care of people with SCI. Participants rated the comprehensibility, relevance, acceptability, feasibility and completeness of the AO Spine PROST on a 1–5 point scale (5 most positive). Comments could be provided per question. Results: The discussion meeting was attended by 13 SCI rehabilitation physicians. The survey was completed by 196 participants. Comprehensibility (mean ± SD: 4.1 ± 0.8), acceptability (4.0 ± 0.8), relevance (3.9 ± 0.8), completeness (3.9 ± 0.8), and feasibility (4.1 ± 0.7) of the AO Spine PROST were rated positively for use in people with motor-complete traumatic or non-traumatic SCI. Only a few participants questioned the relevance of items on the lower extremities (e.g., walking) or missed items on pulmonary functioning and complications. Some recommendations were made for improvement in instructions, terminology and examples of the tool. Conclusion: Health professionals found the AO Spine PROST generally applicable for people with motor-complete traumatic or non-traumatic SCI. This study provides further evidence for the use of the AO Spine PROST in spine trauma care, rehabilitation and research, as well as suggestions for its further development.</p

An international validation of the AO spine subaxial injury classification system.

PURPOSE To validate the AO Spine Subaxial Injury Classification System with participants of various experience levels, subspecialties, and geographic regions. METHODS A live webinar was organized in 2020 for validation of the AO Spine Subaxial Injury Classification System. The validation consisted of 41 unique subaxial cervical spine injuries with associated computed tomography scans and key images. Intraobserver reproducibility and interobserver reliability of the AO Spine Subaxial Injury Classification System were calculated for injury morphology, injury subtype, and facet injury. The reliability and reproducibility of the classification system were categorized as slight (ƙ = 0-0.20), fair (ƙ = 0.21-0.40), moderate (ƙ = 0.41-0.60), substantial (ƙ = 0.61-0.80), or excellent (ƙ = > 0.80) as determined by the Landis and Koch classification. RESULTS A total of 203 AO Spine members participated in the AO Spine Subaxial Injury Classification System validation. The percent of participants accurately classifying each injury was over 90% for fracture morphology and fracture subtype on both assessments. The interobserver reliability for fracture morphology was excellent (ƙ = 0.87), while fracture subtype (ƙ = 0.80) and facet injury were substantial (ƙ = 0.74). The intraobserver reproducibility for fracture morphology and subtype were excellent (ƙ = 0.85, 0.88, respectively), while reproducibility for facet injuries was substantial (ƙ = 0.76). CONCLUSION The AO Spine Subaxial Injury Classification System demonstrated excellent interobserver reliability and intraobserver reproducibility for fracture morphology, substantial reliability and reproducibility for facet injuries, and excellent reproducibility with substantial reliability for injury subtype

The Influence of Regional Differences on the Reliability of the AO Spine Sacral Injury Classification System.

STUDY DESIGN Global cross-sectional survey. OBJECTIVE To explore the influence of geographic region on the AO Spine Sacral Classification System. METHODS A total of 158 AO Spine and AO Trauma members from 6 AO world regions (Africa, Asia, Europe, Latin and South America, Middle East, and North America) participated in a live webinar to assess the reliability, reproducibility, and accuracy of classifying sacral fractures using the AO Spine Sacral Classification System. This evaluation was performed with 26 cases presented in randomized order on 2 occasions 3 weeks apart. RESULTS A total of 8320 case assessments were performed. All regions demonstrated excellent intraobserver reproducibility for fracture morphology. Respondents from Europe (k = .80) and North America (k = .86) achieved excellent reproducibility for fracture subtype while respondents from all other regions displayed substantial reproducibility. All regions demonstrated at minimum substantial interobserver reliability for fracture morphology and subtype. Each region demonstrated >90% accuracy in classifying fracture morphology and >80% accuracy in fracture subtype compared to the gold standard. Type C morphology (p2 = .0000) and A3 (p1 = .0280), B2 (p1 = .0015), C0 (p1 = .0085), and C2 (p1 =.0016, p2 =.0000) subtypes showed significant regional disparity in classification accuracy (p1 = Assessment 1, p2 = Assessment 2). Respondents from Asia (except in A3) and the combined group of North, Latin, and South America had accuracy percentages below the combined mean, whereas respondents from Europe consistently scored above the mean. CONCLUSIONS In a global validation study of the AO Spine Sacral Classification System, substantial reliability of both fracture morphology and subtype classification was found across all geographic regions

Development of Online Technique for International Validation of the AO Spine Subaxial Injury Classification System.

STUDY DESIGN Global cross-sectional survey. OBJECTIVE To develop and refine the techniques for web-based international validation of fracture classification systems. METHODS A live webinar was organized in 2018 for validation of the AO Spine Subaxial Injury Classification System, consisting of 35 unique computed tomography (CT) scans and key images with subaxial spine injuries. Interobserver reliability and intraobserver reproducibility was calculated for injury morphology, subtype, and facet injury according to the classification system. Based on the experiences from this webinar and incorporating rater feedback, adjustments were made in the organization and techniques used and in 2020 a repeat validation webinar was performed, evaluating images of 41 unique subaxial spine injuries. RESULTS In the 2018 session, the AO Spine Subaxial Injury Classification System demonstrated fair interobserver reliability for fracture subtype (κ = 0.35) and moderate reliability for fracture morphology and facet injury (κ=0.45, 0.43, respectively). However, in 2020, the interobserver reliability for fracture morphology (κ = 0.87) and fracture subtype (κ = 0.80) was excellent, while facet injury was substantial (κ = 0.74). Intraobserver reproducibility for injury morphology (κ =0.49) and injury subtype/facet injury were moderate (κ = 0.42) in 2018. In 2020, fracture morphology and subtype reproducibility were excellent (κ =0.85, 0.88, respectively) while reproducibility for facet injuries was substantial (κ = 0.76). CONCLUSION With optimized webinar-based validation techniques, the AO Spine Subaxial Injury Classification System demonstrated vast improvements in intraobserver reproducibility and interobserver reliability. Stringent fracture classification methodology is integral in obtaining accurate classification results