Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Technique for Application of an External Fixator to the Lateral Column of the Foot

Summary: High-energy torsional injuries to the forefoot may result in severe disruption of the lateral column of the foot. Compression fractures of the cuboid or distallateral calcaneus are commonly associated with ligament injuries represented as joint subluxations and/or dislocations. Restoration of the lateral column may be achieved with the application of an external fixator device and adjunctive internal fixation. The details of this surgical technique are presented, as well as indications and contraindication

The Effect of Price on Surgeons' Choice of Implants: A Randomized Controlled Survey

Surgical costs are under scrutiny and surgeons are being held increasingly responsible for cost containment. In some instances, implants are the largest component of total procedure cost, yet previous studies reveal that surgeons' knowledge of implant prices is poor. Our study aims to (1) understand drivers behind implant selection and (2) assess whether educating surgeons about implant costs affects implant selection. We surveyed 226 orthopedic surgeons across 6 continents. The survey presented 8 clinical cases of upper extremity fractures with history, radiographs, and implant options. Surgeons were randomized to receive either a version with each implant's average selling price ("price-aware" group), or a version without prices ("price-naïve" group). Surgeons selected a surgical implant and ranked factors affecting implant choice. Descriptive statistics and univariate, multivariable, and subgroup analyses were performed. For cases offering implants within the same class (eg, volar locking plates), price-awareness reduced implant cost by 9% to 11%. When offered different models of distal radius volar locking plates, 25% of price-naïve surgeons selected the most expensive plate compared with only 7% of price-aware surgeons. For cases offering different classes of implants (eg, plate vs external fixator), there was no difference in implant choice between price-aware and price-naïve surgeons. Familiarity with the implant was the most common reason for choosing an implant in both groups (35% vs 46%). Price-aware surgeons were more likely to rank cost as a factor (29% vs 21%). Price awareness significantly influences surgeons' choice of a specific model within the same implant class. Merely including prices with a list of implants leads surgeons to select less expensive implants. This implies that an untapped opportunity exists to reduce surgical expenditures simply by enhancing surgeons' cost awareness. Economic/Decision Analyses

Foot and Ankle Fellowship Websites

Category: Other Introduction/Purpose: The Internet has been reported to be the first informational resource for many fellowship applicants. Despite being a popular resource, no accessibility or quality standards exist for fellowship websites. The objective of this study was to assess the accessibility of orthopaedic foot and ankle fellowship websites and to evaluate the quality of information provided via program websites. Methods: The American Orthopaedic Foot and Ankle Society (AOFAS) and the Fellowship and Residency Electronic Interactive Database (FREIDA) fellowship databases were accessed to generate a comprehensive list of orthopaedic foot and ankle fellowship programs. The databases were reviewed for links to fellowship program websites and compared with program websites accessed from a Google search. Accessible fellowship websites were then analyzed for the quality of recruitment and educational content pertinent to fellowship applicants. Results: Forty-seven orthopaedic foot and ankle fellowship programs were identified. The AOFAS database featured direct links to 7 (15%) fellowship websites with the independent Google search yielding direct links to 29 (62%) websites. No direct website links were provided in the FREIDA database. Thirty-six accessible websites were analyzed for content. Program websites featured a mean 44% (range, 5-75%) of the total assessed content. The most commonly presented recruitment content was a program description featured on 94% of fellowship websites. The most commonly presented educational content was a description of fellow operative experience featured on 83% of websites. Conclusion: There is substantial variability in the accessibility and quality of orthopaedic foot and ankle fellowship websites. Comparison of the results of our study with those of similar investigations indicates a paucity of fellowship websites presenting comprehensive program information to applicants. Recognition of deficits in accessibility and content quality may assist foot and ankle fellowships in improving program information online