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Objective: Fenestrated endografts are customized, patient-specific endovascular devices with potential to reduce morbidity and mortality of complex aortic aneurysm repair. With approval from the U.S. Food and Drug Administration, our center began performing fenestrated endovascular aneurysm repair through a physician-sponsored investigational device exemption (IDE #G130210), using both physician-modified endografts (PMEGs) and company-manufactured devices (CMDs). Because these techniques are associated with specific advantages and disadvantages, we sought to investigate differences in outcomes between PMEG and CMD cases., Methods: A single-institution retrospective review of all fenestrated endovascular aneurysm repairs was performed. The cohort was analyzed by device type (PMEG or CMD) after matching of cases on the basis of (1) number of target vessels intended for treatment, (2) extent of aneurysm, (3) aneurysm diameter, (4) device configuration, and (5) date of operation. Outcomes of ruptures, common iliac artery aneurysms, and aortic arch aneurysms were excluded. Demographics, operative details, perioperative complications, length of stay, and reinterventions were compared. For patients with >1 year of follow-up time, survival, type I or type III endoleak rate, target artery patency, and reintervention rate were estimated using the Kaplan-Meier method., Results: Between November 30, 2010, and July 30, 2016, 82 patients were identified and matched. The cohort included 41 PMEG and 41 CMD patients who underwent repair of 38 juxtarenal (PMEG, 17; CMD, 21; P = .38), 14 pararenal (PMEG, 6; CMD, 8; P = .56), and 30 thoracoabdominal type I to type IV (PMEG, 18; CMD, 12; P = .17) aneurysms. There were significant differences in presentation requiring urgent aneurysm repair (PMEG, 9; CMD, 0; P = .002), total fluoroscopy time (PMEG, 76 minutes; CMD, 61 minutes; P = .02), volume of contrast material used (PMEG, 88 mL; CMD, 70 mL; P = .02), in-operating room to out-of-operating room time (PMEG, 391 minutes; CMD, 319 minutes; P = .001), incision to surgery end time (PMEG, 276 minutes; CMD, 224 minutes; P = .002), and 1-year reintervention rate (PMEG, 37%; CMD, 13%; log-rank P = .04). No differences in perioperative complications, overall length of stay, type I or type III endoleak, or survival were observed between PMEG and CMD. For the entire cohort including both PMEG and CMD, the overall rate of any 30-day postoperative complication was 39%, and the Kaplan-Meier estimate of survival at 1 year was 86%., Conclusions: In this single-institution experience of fenestrated endovascular aneurysm repair, the primary differences between PMEG and CMD related only to operative metrics and the need for postoperative reinterventions. No statistically significant advantage was found for one approach over the other; we therefore cannot conclude that one approach is better than the other. Both remain viable options that may compare favorably with open repair of complex aortic aneurysms. Further studies are necessary to determine whether this relative equivalence represents a type II error or lack of long-term durability data or whether true equivalence between PMEG and CMD approaches exists., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Ectopic thymic tissue can arise as an asymptomatic neck mass, which may be detected on imaging studies. The aim of this study was to determine the incidence of ectopic thymic tissue in paediatric FNAs and to the correlate clinical, radiological and cytomorphological findings., Methods: FNAs in children with neck and mediastinal lesions performed between January 2012 and July 2016 were reviewed for cases of ectopic thymus. These were then evaluated and correlated with the cytology findings., Results: Of 739 FNAs, 13 (1.8%) cases from 11 patients showed ectopic thymic tissue. The targeted lesions were in the thyroid (n = 7), submandibular region (n = 1), superior mediastinum (n = 1) and paratracheal region (n = 1). The most common indication was for microcalcifications concerning for papillary thyroid carcinoma on ultrasound (n = 6). Imaging findings included fusiform lesions with linear and punctuate bright echoes. The cytology evaluation showed small lymphocytes with discohesive epithelioid cells in most cases, and proteinaceous fluid in the cystic case. There were rare macrophages and Hassall's corpuscles. Flow cytometry and/or immunostains were performed in all cases, supporting thymic origin., Conclusion: Ectopic thymic tissue is rarely present as a neck mass or thyroid nodule on FNA biopsy. The ultrasound imaging findings reveal a well-defined fusiform lesion with punctate bright echoes that could be misinterpreted as papillary thyroid carcinoma. The aspirates show a small lymphoid population, immunophenotypically compatible with thymic T-cells, in addition to scattered epithelial cells. Therefore, knowledge of the typical ultrasonographic and cytopathological features can help make a definitive diagnosis and avoid more invasive procedures in paediatric patients., (© 2018 John Wiley & Sons Ltd.)

Objective: The demand for vascular surgeons is expected to far exceed the current supply. In an attempt to decrease the training duration and to address the impending shortage, integrated vascular surgery residencies were approved and have expanded nationally. Meanwhile, vascular fellowships have continued to matriculate approximately 120 trainees annually. We sought to evaluate the supply and demand for integrated vascular residency positions as well as changes in the quality of applicants., Methods: We conducted a retrospective review of national data compiled by the Association of American Medical Colleges and the National Resident Matching Program regarding integrated vascular surgery residency programs (2008-2015) and fellowships (2007-2016). Variables reviewed included the total number of applicants, sex, U.S. vs international medical school enrollment, applications per program, and applicants per position. In addition, we conducted a retrospective review of applicants to the University of Massachusetts Medical School integrated vascular surgery residency program from 2008 to 2015 to examine these variables and United States Medical Licensing Examination Step 1 and Step 2 CK scores over time., Results: The number of vascular surgery integrated residency positions increased from 4 in 2008 to 56 in 2015. Concurrently, the number of integrated residency applicants grew from 112 in 2008 to 434 in 2015. This increase has been predominantly driven by a 575% increase in U.S. graduate applicants and a 170% increase in women applicants. The percentage of international medical graduates has decreased by 17% during the study period. The total number of applicants per residency position increased from 5.9 to 7.8. Meanwhile, the number of vascular surgery fellowship positions remained stable with an applicant to position ratio near 1:1. At the University of Massachusetts Medical School, the mean United States Medical Licensing Examination Step 1 (226 to 235) and Step 2 CK (237 to 243) scores among integrated residency applicants have improved annually and typically exceed the national average among U.S. applicants who have matched in their preferred specialty., Conclusions: Since the approval of a primary certificate in vascular surgery and the subsequent rollout of integrated vascular residency programs, the number of residency programs and the quality of residency applicants have continued to increase. Demand from medical school applicants vastly outweighs the current supply of training positions by eightfold. In contrast, demand from fellowship applicants matches the supply of fellowship positions. The matriculation of additional trainees must be met with continued expansion of the integrated vascular surgery residency pathway to manage future public health needs., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The goal of this study is to measure the quality and readability of websites related to laryngomalacia, and to compare the quality and readability scores for the sites accessed through the most popular search engines., Introduction: Laryngomalacia is a common diagnosis in children but is often difficult for parents to comprehend. As information available on the internet is unregulated, the quality and readability of this information may vary., Methods: An advanced search on Google, Yahoo, and Bing was conducted using the terms "laryngomalacia" OR "soft larynx" OR "floppy voice box." The first ten websites meeting inclusion and exclusion criteria were evaluated, for each search engine. Quality and readability were assessed using the DISCERN criteria and the Flesch reading ease scoring (FRES) and Flesch-Kincaid grade level (FKGL) tests, respectively., Results: The top 10 hits on each search engine yielded 15 unique web pages. The median DISCERN score (out of a possible high-score of 80) was 48.5 (SD 12.6). The median USA grade-level estimated by the FKGL was 11.3 (SD 1.4). Only one website (6.7%), had a readability score in the optimal range of 6th to 8th grade reading level. DISCERN scores did not correlate with FKGL scores (r = 0.10)., Conclusion: Online information discussing laryngomalacia often varies in quality and may not be easily comprehensible to the public. It is important for healthcare professionals to understand the quality of health information accessible to patients as it may influence medical decision-making by patient families., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: More than 80% of infrarenal aortic aneurysms are treated by endovascular repair. However, adoption of fenestrated and branched endovascular repair for complex aortic aneurysms has been limited, despite high morbidity and mortality associated with open repair. There are few published reports of consecutive outcomes, inclusive of all fenestrated and branched endovascular repairs, starting from the inception of a complex aortic aneurysm program. Therefore, we examined a single center's consecutive experience of fenestrated and branched endovascular repair of complex aortic aneurysms., Methods: This is a single-center, prospective, observational cohort study evaluating 30-day and 1-year outcomes in all consecutive patients who underwent fenestrated and branched endovascular repair of complex aortic aneurysms (definition: requiring one or more fenestrations or branches). Data were collected prospectively through an Institutional Review Board-approved registry and a physician-sponsored investigational device exemption clinical trial (G130210)., Results: We performed 100 consecutive complex endovascular aortic aneurysm repairs (November 2010 to March 2016) using 58 (58%) commercially manufactured custom-made devices and 42 (42%) physician-modified devices to treat 4 (4%) common iliac, 42 (42%) juxtarenal, 18 (18%) pararenal, and 36 (36%) thoracoabdominal aneurysms (type I, n = 1; type II, n = 4; type III, n = 12; type IV, n = 18; arch, n = 1). The repairs included 309 fenestrations, branches, and scallops (average of 3.1 branch arteries/case). All patients had 30-day follow-up for 30-day event rates: three (3%) deaths; six (6%) target artery occlusions; five (5%) progressions to dialysis; eight (8%) access complications; one (1%) paraparesis; one (1%) bowel ischemia; and no instances of myocardial infarction, paralysis, or stroke. Of 10 type I or type III endoleaks, 8 resolved (7 with secondary intervention, 1 without intervention). Mean follow-up time was 563 days (interquartile range, 156-862), with three (3%) patients lost to follow-up. On 1-year Kaplan-Meier analysis, survival was 87%, freedom from type I or type III endoleak was 97%, target vessel patency was 92%, and freedom from aortic rupture was 100%. Average lengths of intensive care unit stay and inpatient stay were 1.4 days (standard deviation, 3.3) and 3.6 days (standard deviation, 3.6), respectively., Conclusions: These results show that complex aortic aneurysms can now be treated with minimally invasive fenestrated and branched endovascular repair. Endovascular technologies will likely continue to play an increasingly important role in the management of patients with complex aortic aneurysm disease., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Fenestrated endografts are customized, patient-specific, endovascular devices with potential to significantly reduce morbidity and mortality of short-neck infrarenal and juxtarenal abdominal aortic aneurysm repair. The Zenith fenestrated endovascular graft (ZFEN) for abdominal aortic aneurysms (Cook Medical, Bloomington, Ind), Food and Drug Administration-approved in 2012, remains the only fenestrated device available in the United States. This technology is among the most technically complex catheter-based procedures and, therefore, inherently associated with serious risk for device-related complications. We sought to define patterns of physician and hospital adoption of ZFEN., Methods: Deidentified datasets containing numbers of physicians trained, orders by physicians and hospitals, and designs (fenestration/scallop configuration) was provided for U.S. ZFEN devices ordered (April 2012-August 2015). We evaluated the number of physicians trained, the number of devices ordered, hospital characteristics, and fenestration/scallop design configurations. Cook Medical assembled the datasets but played no role in study design, analysis, or interpretation of data., Results: Between April 2012 and August 2015, 553 physicians attended formal ZFEN training sessions, 388 (70%) of whom ordered a total of 2669 devices. An increase in orders per month (nine in June 2012 and 91 in August 2015, 911% growth; P < .001) and in number of physicians ordering per month (eight in June 2012 and 62 in August 2015, 675% growth; P < .001) was observed. Teaching hospitals, representing all U.S. regions (Midwest 927, 35%; South 799, 30%; Northeast 547, 20%; West 396, 15%), accounted for 1703 (64%) ZFEN orders. Of 553 trained physicians, 165 (30%) ordered no devices, 116 (21%) ordered 1 device, 144 (26%) ordered 2-5 devices, 61 (11%) ordered 6-10 devices, 39 (7%) ordered 11-20, and 28 (5%) ordered >20 devices. For physicians contributing >6 months of data (n = 336), the average number of devices ordered per year was three (standard deviation, 4); 272 (81%) ordered ≤ 5 devices/year, 15 (4.5%) ordered 11-20 devices/year, and 3 (0.9%) ordered >20 devices/year. Of devices with design details available (2618 of 2669; 98%), most common designs were 2 small fenestrations/1 scallop (1443; 55%), 2 small fenestrations/1 large fenestration (568; 22%), 1 small fenestration/1 scallop (173, 6.6%), and 2 small fenestrations (169; 6.5%). The average number of target vessels incorporated in each design was 2.7/device; 2071 (79%) incorporated three, 398 (15%) incorporated two., Conclusions: Since 2012, ZFEN has demonstrated a ninefold increase in monthly orders, with 553 physicians trained. Unlike the experience of rapid dissemination seen with infrarenal endografts, only 28 (5%) physicians have ordered >20, whereas 165 (30%) have ordered none, and 272 (81%) ordered ≤ 5 devices/year. Assuming that volume, in general, correlates with outcomes, this adoption pattern raises questions whether fenestrated technology should be regionalized to high-volume centers., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β 2 -microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type β 2 -microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The β 2 -microglobulin -binding nanobody, Nb24, more potently inhibits D76N β 2 -microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In β 2 -microglobulin knock out mice, the D76N β 2 -microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type β 2 -microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis.

Background: The Vascular Study Group of New England (VSGNE) requires documentation of follow-up for >80% of patients at least 9 months postprocedure. However, many participating groups fall short of this goal. We sought to identify factors independently associated with loss to long-term follow-up (LTF)., Methods: The VSGNE was queried from 2008 to 2012, for all carotid endarterectomy (CEA), endovascular aneurysm repair (EVAR), open abdominal aortic aneurysm repair (OPEN), infrainguinal bypass (INFRA), and suprainguinal bypass (SUPRA) procedures in patients who survived greater than 9 months postprocedure. Our primary endpoint was loss to LTF, with LTF defined as documentation of a phone call or office visit ≥9 months postprocedure. Multivariable logistic regression was used to identify independent predictors of loss to LTF. Covariates included patient and procedural characteristics, and treatment center/physician. Relative contributions of covariates to the model were assessed by evaluation of the relative model Wald chi-squared values., Results: We identified 14,452 procedures (6567 CEA, 2391 EVAR, 3356 INFRA, 979 OPEN, and 1159 SUPRA). Of those, 4669 (32%) were lost to LTF. Rates of loss to LTF varied by center, and ranged from 9.8% to 100%. Independent predictors of loss to LTF were history of coronary artery disease or percutaneous coronary artery intervention (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1-1.7), procedure type (OPEN, OR 1.4, 95% CI: 1.2-1.7; CEA, OR 1.2, 95% CI: 1.1-1.4; referent, EVAR), and discharge to rehab (OR 1.2, 95% CI: 1.1-1.4; referent, home). Center variation was the strongest determinant of loss to LTF with a model χ 2 over 40 times as large as the second strongest determinant., Conclusions: LTF is central to outcome reporting and is vital to the success of any registry effort. In the VSGNE experience, center variation is the strongest predictor of loss to LTF, outweighing patient and procedural factors. Other predictors of loss to LTF included history of coronary revascularization, procedure type, no prior history of congestive heart failure, and discharge location. High performing centers likely have specific process measures that decrease loss to LTF. As the Society for Vascular Surgery Vascular Quality Initiative continues to roll out nationally, high performing centers in VSGNE should be studied to document and propagate best practices for minimizing loss to LTF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Surgical skills and simulation courses are emerging to meet the demand for vascular simulation training for vascular surgical skills, but their educational effect has not yet been described. We sought to determine the effect of an intensive vascular surgical skills and simulation course on the procedural knowledge and self-rated procedural competence of vascular trainees and to assess participant feedback regarding the course., Methods: Participants underwent a 1.5-day course covering open and endovascular procedures on high-fidelity simulators and cadavers. Before and after the course, participants completed a written test that assessed procedural knowledge concerning index open vascular and endovascular procedures. Participants also assessed their own procedural competence in open and endovascular procedures on a 5-point Likert scale (1: no ability to perform, 5: performs independently). Scores before and after the course were compared among postgraduate year (PGY) 1-2 and PGY 3-7 trainees. Participants completed a survey to rate the relevance and realism of open and endovascular simulations., Results: Fifty-eight vascular integrated residents and vascular fellows (PGY 1-7) completed the course and all assessments. After course participation, procedural knowledge scores were significantly improved among PGY 1-2 residents (50% correct before vs 59% after; P < .0001) and PGY 3-7 residents (52% correct before vs 63% after; P = .003). Self-rated procedural competence was significantly improved among PGY 1-2 (2.2 ± 0.1 before vs 3.1 ± 0.1 after; P < .0001) and PGY 3-7 (3.0 ± 0.1 before vs 3.7 ± 0.1 after; P ≤ .0001). Self-rated procedural competence significantly improved for both endovascular (2.4 ± 0.1 before vs 3.3 ± 0.1 after; P < .0001) and open procedures (2.7 ± 0.1 before vs 3.5 ± 0.1 after; P < .0001). More than 93% of participants reported they were "satisfied" or "very satisfied" with the relevance and realism of the open and endovascular simulations. All participants reported they would recommend the course to other trainees., Conclusions: This intensive vascular surgical skills and simulation course improved procedural knowledge concerning index open vascular and endovascular procedures among PGY 1-2 and PGY 3-7 trainees. The course also improved self-rated procedural competence across all levels of training for open and endovascular procedures. Trainees rated the value of a surgical skills and simulation course highly. These results support strong consideration for the implementation of similar intensive simulation and surgical skills courses with ongoing objective assessment of their educational effect., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

During the course of normal aging, certain populations of nerve growth factor (NGF)-responsive neurons become selectively vulnerable to cell death. Studies using dissociated neurons isolated from neonates have shown that c-Jun N-terminal kinases (JNKs) are important in regulating the survival and neurite outgrowth of NGF-responsive sympathetic neurons. Unlike neonatal neurons, adult sympathetic neurons are not dependent on NGF for their survival. Moreover, the NGF precursor, proNGF, is neurotoxic for aging but not young adult NGF-responsive neurons. Because of these age-related differences, the effects of JNK inhibition on the survival and growth of sympathetic neurons isolated from aged mice were studied. Aged neurons, as well as glia, were found to be dependent on JNK for their growth but not their survival. Conversely, proNGF neurotoxicity was JNK-dependent and mediated by the p75-interacting protein NRAGE, whereas neurite outgrowth was independent of NRAGE. These results have implications for the potential use of JNK inhibitors as therapies for ameliorating age-related neurodegenerative disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To examine the sensitivity and specificity of history, physical examination, and radiologic studies as predictors of foreign body aspiration in children., Study Design: Case series with chart review., Setting: Tertiary care children's hospital., Subjects and Methods: Medical records were reviewed for 102 children who presented to our institution from 2006 to 2013 with suspected foreign body aspiration and who underwent endoscopy. Data included symptoms, physical examination, radiologic, and endoscopy findings. Descriptive statistics, sensitivity and specificity, and univariate and multivariable analyses were performed., Results: A total of 102 patients were included (62% male). The mean age was 3.3 years (SD, 3.7). A foreign body was identified on endoscopy in 69 cases (68%). The most common presenting symptoms were cough (88%), choking/gagging (67%), and wheezing (57%). Decreased breath sounds and wheezing on examination were independently associated with increased odds of foreign body. The most common abnormal radiographic finding was air trapping (33%). The most frequent items retrieved were fragments of seeds and nuts (49%). There were no serious complications related to endoscopy. The sensitivity and specificity of any finding on history, physical examination, and imaging were 100% and 3%, 90% and 33%, 61% and 77%, respectively. Having a positive history, examination, and chest radiograph combined was 46% sensitive and 79% specific., Conclusions: Patients with airway foreign bodies have varied presentations. The presence of any radiologic finding suggests that endoscopy should be performed, as a foreign body is probable. The absence of any history or physical examination finding was associated with a low likelihood of a foreign body., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Mycotic abdominal aortic aneurysms are rare and present unique challenges when potential treatment options are considered. Although aortic resection with in situ grafting techniques or extra-anatomic reconstruction are the treatments of choice, endovascular aortic repair has emerged as a suitable alternative in critically ill patients. We report the successful endovascular repair of a symptomatic, mycotic juxtarenal aortic aneurysm using a physician-modified fenestrated endograft. In this patient, with >6 months of follow-up, the aneurysm has completely regressed, illustrating that in select patients with complex mycotic aneurysms, endovascular repair combined with appropriate medical management is a viable treatment strategy., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Vascular surgery procedural reimbursement depends on accurate procedural coding and documentation. Despite the critical importance of correct coding, there has been a paucity of research focused on the effect of direct physician involvement. We hypothesize that direct physician involvement in procedural coding will lead to improved coding accuracy, increased work relative value unit (wRVU) assignment, and increased physician reimbursement., Methods: This prospective observational cohort study evaluated procedural coding accuracy of fistulograms at an academic medical institution (January-June 2014). All fistulograms were coded by institutional coders (traditional coding) and by a single vascular surgeon whose codes were verified by two institution coders (multidisciplinary coding). The coding methods were compared, and differences were translated into revenue and wRVUs using the Medicare Physician Fee Schedule. Comparison between traditional and multidisciplinary coding was performed for three discrete study periods: baseline (period 1), after a coding education session for physicians and coders (period 2), and after a coding education session with implementation of an operative dictation template (period 3). The accuracy of surgeon operative dictations during each study period was also assessed. An external validation at a second academic institution was performed during period 1 to assess and compare coding accuracy., Results: During period 1, traditional coding resulted in a 4.4% (P = .004) loss in reimbursement and a 5.4% (P = .01) loss in wRVUs compared with multidisciplinary coding. During period 2, no significant difference was found between traditional and multidisciplinary coding in reimbursement (1.3% loss; P = .24) or wRVUs (1.8% loss; P = .20). During period 3, traditional coding yielded a higher overall reimbursement (1.3% gain; P = .26) than multidisciplinary coding. This increase, however, was due to errors by institution coders, with six inappropriately used codes resulting in a higher overall reimbursement that was subsequently corrected. Assessment of physician documentation showed improvement, with decreased documentation errors at each period (11% vs 3.1% vs 0.6%; P = .02). Overall, between period 1 and period 3, multidisciplinary coding resulted in a significant increase in additional reimbursement ($17.63 per procedure; P = .004) and wRVUs (0.50 per procedure; P = .01). External validation at a second academic institution was performed to assess coding accuracy during period 1. Similar to institution 1, traditional coding revealed an 11% loss in reimbursement ($13,178 vs $14,630; P = .007) and a 12% loss in wRVU (293 vs 329; P = .01) compared with multidisciplinary coding., Conclusions: Physician involvement in the coding of endovascular procedures leads to improved procedural coding accuracy, increased wRVU assignments, and increased physician reimbursement., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Weibel-Palade bodies (WPBs) are endothelial storage organelles that mediate the release of molecules involved in thrombosis, inflammation and angiogenesis, including the pro-thrombotic glycoprotein von Willebrand factor (VWF). Although many protein components required for WPB formation and function have been identified, the role of lipids is almost unknown. We examined two key phosphatidylinositol kinases that control phosphatidylinositol 4-phosphate levels at the trans-Golgi network, the site of WPB biogenesis. RNA interference of the type II phosphatidylinositol 4-kinases PI4KIIα and PI4KIIβ in primary human endothelial cells leads to formation of an increased proportion of short WPB with perturbed packing of VWF, as exemplified by increased exposure of antibody-binding sites. When stimulated with histamine, these cells release normal levels of VWF yet, under flow, form very few platelet-catching VWF strings. In PI4KIIα-deficient mice, immuno-microscopy revealed that VWF packaging is also perturbed and these mice exhibit increased blood loss after tail cut compared to controls. This is the first demonstration that lipid kinases can control the biosynthesis of VWF and the formation of WPBs that are capable of full haemostatic function., (© 2016. Published by The Company of Biologists Ltd.)

Objectives: Fine-needle aspiration biopsy (FNAB) has a well-established role in the evaluation of an adult head and neck mass (HNM) but remains underused in children. The objectives of this study were to assess the diagnostic accuracy, safety profile, use of anesthesia, and influence on surgical decision making of FNAB of HNM in the pediatric population., Study Design: Case series with chart review., Setting: Tertiary care children's hospital., Subjects and Methods: In total, 257 consecutive patients with HNM who underwent 338 FNABs from July 2007 to July 2014 were reviewed. Patients ranged in age from 0 to 21 years (mean, 9.3 years); lesions ranged in size from 0.3 to 12.5 cm (mean, 2.4cm). Fine-needle aspiration biopsies were performed in the interventional radiology suite, operating room, clinic, or ward., Results: The most common patient final diagnoses included reactive lymphadenopathy (n = 99, 38.5%), benign thyroid colloid nodule (n = 31, 12.1%), malignancies (n = 21, 8.2%), and atypical mycobacterial infection (n = 15, 5.8%). On surgical histopathologic and clinical follow-up, overall sensitivity of FNAB was 94.6% and specificity was 97.7%. The complication rate was 2.1%, and general anesthesia or sedation was used for 73% of FNAB. Surgery occurred only 9 times following the 191 patients with negative FNAB results, indicating that 95.3% of unnecessary surgeries were avoided with the assistance of the FNAB result., Conclusions: Fine-needle aspiration biopsy is an accurate and safe diagnostic tool for guiding management of persistent lymphadenopathy, thyroid nodules, and other HNM in pediatric patients. Negative FNABs can often obviate the need for surgical intervention., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Objectives/hypothesis: To examine aspects of laryngomalacia and correlate findings with quality of life (QOL)., Study Design: Prospective cross-sectional study., Methods: Seventy-two patients with laryngomalacia were examined; the mean age was 8.8 weeks. Parents answered questions from the Infant and Toddler Quality of Life Questionnaire-47 (ITQOL-SF47). Fiberoptic laryngoscopy and endoscopic examination of swallowing (FEES) were performed. The presence of laryngomalacia-associated characteristics and swallowing status were recorded. Patient age, sex, presence of reflux, clinical severity, anatomical findings, and swallowing results were evaluated through logistic regression. Independent sample t tests were used to compare responses on the ITQOL-SF47. Overall laryngomalacia ITQOL-SF47 scores were compared to the scores of a large healthy sample population., Results: Forty-three (60%) patients had mild laryngomalacia, and 61 (85%) patients had findings suggesting gastroesophageal reflux disease. The most common abnormality was shortened aryepiglottic folds. Ten patients failed FEES. Patients with moderate laryngomalacia (χ = 7.62; P = .006) or prolapsing cuneiforms (χ = 4.79; P = .029) were more likely to fail FEES. Laryngomalacia severity impacted parental perception of their child's health (P < .05). Parents of children who demonstrated aspiration or penetration reported significant emotional impact (mean = 56.9; t = 2.74; P = .008). The mean ITQOL-SF47 scores of patients were significantly lower in certain sections than the reported general sample population., Conclusions: Epiglottal prolapse correlated with severity of laryngomalacia and cuneiform prolapse with swallowing dysfunction. Perceptions of worsening health and physical ability were related to severity of disease. Swallowing dysfunction had a significant emotional impact on parental daily life. Infants with laryngomalacia have a lower QOL LEVEL OF EVIDENCE: 3 Laryngoscope, 126:1232-1235, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Providing patients and payers with publicly reported risk-adjusted quality metrics for the purpose of benchmarking physicians and institutions has become a national priority. Several prediction models have been developed to estimate outcomes after lower extremity revascularization for critical limb ischemia, but the optimal model to use in contemporary practice has not been defined. We sought to identify the highest-performing risk-adjustment model for amputation-free survival (AFS) at 1 year after lower extremity bypass (LEB)., Methods: We used the national Society for Vascular Surgery Vascular Quality Initiative (VQI) database (2003-2012) to assess the performance of three previously validated risk-adjustment models for AFS. The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL), Finland National Vascular (FINNVASC) registry, and the modified Project of Ex-vivo vein graft Engineering via Transfection III (PREVENT III [mPIII]) risk scores were applied to the VQI cohort. A novel model for 1-year AFS was also derived using the VQI data set and externally validated using the PIII data set. The relative discrimination (Harrell c-index) and calibration (Hosmer-May goodness-of-fit test) of each model were compared., Results: Among 7754 patients in the VQI who underwent LEB for critical limb ischemia, the AFS was 74% at 1 year. Each of the previously published models for AFS demonstrated similar discriminative performance: c-indices for BASIL, FINNVASC, mPIII were 0.66, 0.60, and 0.64, respectively. The novel VQI-derived model had improved discriminative ability with a c-index of 0.71 and appropriate generalizability on external validation with a c-index of 0.68. The model was well calibrated in both the VQI and PIII data sets (goodness of fit P = not significant)., Conclusions: Currently available prediction models for AFS after LEB perform modestly when applied to national contemporary VQI data. Moreover, the performance of each model was inferior to that of the novel VQI-derived model. Because the importance of risk-adjusted outcome reporting continues to increase, national registries such as VQI should begin using this novel model for benchmarking quality of care., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: (1) To describe clinical and radiologic findings in patients with esophageal foreign bodies. (2) To examine the sensitivity and specificity of history, physical examination, and radiologic studies in children with suspected foreign body ingestion., Methods: A retrospective cohort study was performed evaluating all children who underwent esophagoscopy for suspected foreign body ingestion at our institution from 2006 to 2013., Results: Five hundred forty-three patients were included (54% male). Average age was 4.7 years (SD = 4.1 years). Foreign bodies were identified on esophagoscopy in 497 cases (92%). Ingestion was witnessed in 23% of cases. Most common presenting symptoms were choking/gagging (49%), vomiting (47%), and dysphagia/odynophagia (42%). Most patients with foreign bodies had a normal exam (76%). Most foreign bodies were radiopaque (83%). In 59% of patients with normal chest radiographs, a foreign body was present. Sensitivity and specificity of 1 or more findings on history, physical examination, and imaging were 99% and 0%, 21% and 76%, and 83% and 100%, respectively., Conclusions: Most patients with esophageal foreign bodies are symptomatic. Although many patients will have a normal physical examination, an abnormal exam should increase suspicion for a foreign body. Most esophageal foreign bodies are radiopaque, but a normal chest radiograph cannot rule out a foreign body., (© The Author(s) 2015.)

Objective: Repeated percutaneous interventions on failing arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) for hemodialysis are common, but the outcomes are largely unknown. We sought to determine the results of the second percutaneous intervention on failing AVGs and AVFs and to identify factors associated with loss of patency., Methods: For the purpose of this study, the second percutaneous intervention was identified as the index procedure. We reviewed the second percutaneous interventions on failing AVFs and AVGs at a single institution between 2007 and 2013. Patient comorbidities, graft or fistula configuration, lesion characteristics, and procedural characteristics of the intervention performed were analyzed with respect to technical success, primary patency, primary assisted patency, and secondary patency. Patency was defined per Society for Vascular Surgery recommended reporting standards and was determined from the time of the index procedure. Cox proportional hazards multivariable modeling was performed to identify independent determinants of loss of patency., Results: Among 91 patients, 96 second-time percutaneous interventions were performed on 52 AVFs and 44 AVGs. Patients included 56% men and 44% women with a mean age of 64 ± 17 years. The lesions intervened on were primarily located along the accessed portion of the outflow in AVFs and within the length of the graft and at the venous anastomosis in AVGs. Transluminal angioplasty alone was performed in 82 procedures (85%), and uncovered or covered stents were placed in 15 procedures (16%). Pharmacomechanical thrombectomy was performed in 32 patients (34%) and was more commonly performed in AVGs compared with AVFs (53% vs 17%; P = .0002). Technical success was achieved in 90 procedures (97%; n = 92). One-year primary patency, assisted primary patency, and secondary patency rates were 35%, 86%, and 86%, respectively. One-year primary patency did not differ between AVFs and AVGs, but secondary patency was lower for AVG in comparison to AVF (P = .04). On multivariable analysis, only the need for pharmacomechanical thrombectomy significantly predicted failure of primary patency (hazard ratio, 2.6; 95% confidence interval, 1.6-4.3). The presence of an AVG rather than an AVF independently predicted failure of secondary patency (hazard ratio, 2.9; 95% confidence interval, 1.0-8.2)., Conclusions: The second percutaneous interventions on AVFs and AVGs are associated with excellent technical success but poor primary patency. The need for pharmacomechanical thrombectomy predicts the need for additional percutaneous intervention to maintain patency. With additional interventions, acceptable secondary patency out to 5 years can be achieved, although AVGs have inferior secondary patency to AVFs. To develop optimal practice management algorithms, the effectiveness of repeated percutaneous interventions for failing AVGs and AVFs vs creation of a new access should be further investigated., (Copyright © 2016. Published by Elsevier Inc.)

Objective: Endovascular aneurysm repair (EVAR) of ruptured abdominal aortic aneurysms (RAAAs) reduces in-hospital mortality compared with open repair (OR), but it is unknown whether EVAR reduces long-term mortality. We hypothesized that EVAR of RAAA would independently reduce long-term mortality compared with OR., Methods: The Vascular Quality Initiative database (2003-2013) was used to determine Kaplan-Meier 1-year and 5-year mortality after EVAR and OR of RAAA. Multivariate analysis was performed to identify patient and operative characteristics associated with mortality at 1 year and 5 years after RAAA repair., Results: Among 590 patients who underwent EVAR and 692 patients who underwent OR of RAAA, the lower mortality seen in the hospital after EVAR (EVAR 23% vs OR 35%; P < .001) persisted at 1 year (EVAR 34% vs OR 42%; P = .001) and 5 years (EVAR 50% vs OR 58%; P = .003) after repair. After adjusting for patient and operative characteristics, EVAR did not independently reduce mortality at 1 year (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.7-1.1) or 5 years (HR, 0.95; 95% CI, 0.77-1.2) compared with OR. Dialysis dependence (HR, 3.9; 95% CI, 1.8-8.6), home oxygen use (HR, 1.9; 95% CI, 1.3-2.7), cardiac ejection fraction <50% (HR, 1.5; 95% CI, 1.03-2.1), female gender (HR, 1.3; 95% CI, 1.04-1.6), and age (HR, 1.06; 95% CI, 1.05-1.08 per 5 years) as well as cardiac arrest (HR, 3.4; 95% CI, 2.5-4.5), loss of consciousness (HR, 1.7; 95% CI, 1.3-2.2), and preoperative systolic blood pressure <90 mm Hg (HR, 1.4; 95% CI, 1.1-1.8) on admission predicted mortality at 1 year and 5 years after RAAA repair. Type I endoleak (HR, 2.2; 95% CI, 1.2-3.8) also predicted mortality at 1 year., Conclusions: EVAR does not independently reduce long-term mortality compared with OR. Patient comorbidities and indices of shock on admission are the primary independent determinants of long-term mortality. However, the lower early mortality observed in the Vascular Quality Initiative for patients selected to undergo EVAR of RAAA compared with patients selected for OR is sustained over time, suggesting that EVAR for RAAA is beneficial in appropriate candidates. Better elucidation of the key selection factors, including aneurysm anatomy, is needed to best select patients for EVAR and OR to reduce long-term mortality., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.

Human amyloid deposits always contain the normal plasma protein serum amyloid P component (SAP), owing to its avid but reversible binding to all amyloid fibrils, including the amyloid β (Aβ) fibrils in the cerebral parenchyma plaques and cerebrovascular amyloid deposits of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). SAP promotes amyloid fibril formation in vitro, contributes to persistence of amyloid in vivo and is also itself directly toxic to cerebral neurons. We therefore developed (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), a drug that removes SAP from the blood, and thereby also from the cerebrospinal fluid (CSF), in patients with AD. Here we report that, after introduction of transgenic human SAP expression in the TASTPM double transgenic mouse model of AD, all the amyloid deposits contained human SAP. Depletion of circulating human SAP by CPHPC administration in these mice removed all detectable human SAP from both the intracerebral and cerebrovascular amyloid. The demonstration that removal of SAP from the blood and CSF also removes it from these amyloid deposits crucially validates the strategy of the forthcoming 'Depletion of serum amyloid P component in Alzheimer's disease (DESPIAD)' clinical trial of CPHPC. The results also strongly support clinical testing of CPHPC in patients with CAA., (© 2016 The Authors.)

Objectives/hypothesis: 1) To determine the prevalence of dysphagia in children with laryngomalacia, 2) To ascertain whether severity of laryngomalacia influences the presence of swallowing dysfunction, and 3) To examine whether patients with medical comorbidities and laryngomalacia have a higher prevalence of swallowing dysfunction., Study Design: Retrospective cohort study., Methods: All patients seen in the aerodigestive center at our institution between January 2007 and December 2012 with the diagnosis of laryngomalacia were included. Swallowing function was assessed by symptoms, clinical swallowing evaluations (CSE) performed by speech pathologists, modified barium swallow (MBS) studies, and fiberoptic endoscopic evaluations of swallowing (FEES)., Results: There were 324 patients with laryngomalacia identified (41.4% female, 58.6% male). Severity of laryngomalacia was categorized in 279 patients, with 62.7% mild, 28.7% moderate, and 8.6% severe. Gastroesophageal reflux disease (GERD) was diagnosed in 69.8% of patients. Other medical comorbidities included Down syndrome (3.1%), neurological impairment (6.5%), and congenital heart disease (0.9%). Symptoms of dysphagia or feeding difficulty were present in 163/324 (50.3%), and failure to thrive was present in 31/324 patients (9.6%). At least one abnormal swallowing assessment was present in 97/120 (80.8%) patients presenting with subjective dysphagia and 43/65 (66.2%) patients without subjective dysphagia. A total of 140/185 (75.7%) patients had at least one abnormal baseline swallowing assessment. There was no significant relationship between severity of laryngomalacia and presence of abnormal swallowing function based on symptoms, CSE, MBS, or FEES. However, patients with greater severity were more likely to have failure to thrive. There was not a significant association between the presence of swallowing dysfunction or disease severity and medical comorbidities such as Down syndrome, neurological impairment, or congenital heart disease. However, GERD was more likely to be present in patients with moderate and severe laryngomalacia than in patients with mild disease., Conclusions: Swallowing dysfunction is common in children with laryngomalacia regardless of disease severity or other medical comorbidities. Swallowing studies are frequently abnormal in laryngomalacia patients presenting both with and without subjective symptoms of dysphagia. Dysphagia assessment should be considered as part of the evaluation of infants with laryngomalacia., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Systemic amyloidoses are a group of debilitating and often fatal diseases in which fibrillar protein aggregates are deposited in the extracellular spaces of a range of tissues. The molecular basis of amyloid formation and tissue localization is still unclear. Although it is likely that the extracellular matrix (ECM) plays an important role in amyloid deposition, this interaction is largely unexplored, mostly because current analytical approaches may alter the delicate and complicated three-dimensional architecture of both ECM and amyloid. We describe here a decellularization procedure for the amyloidotic mouse liver which allows high-resolution visualization of the interactions between amyloid and the constitutive fibers of the extracellular matrix. The primary structure of the fibrillar proteins remains intact and the amyloid fibrils retain their amyloid enhancing factor activity.

Background: Fine-needle aspiration (FNA) coupled with flow cytometry (FC) can be helpful in suspicious pediatric lymph nodes or masses to exclude a lymphoproliferative disorder. The aim of this study was to analyze FC findings in a series of pediatric FNAs and to correlate abnormal findings with follow-up information., Materials and Methods: All pediatric FNAs performed at a tertiary-care children's hospital over a 46-month period that had FC performed were retrospectively analyzed and correlated with follow-up., Results: A total of 163 FNA procedures were performed in children (age ≤21 years), and 47 (28.8%) of these cases had FC performed. Specimens were mostly obtained from the head and neck (72.3% of cases). Nine cases (19.1%) had abnormal FC findings, including double-negative T cells (n = 3; 33.3%), double-positive T cells (n = 3; 33.3%), excess λ light chains (n = 1; 11.1%), weak CD34 positivity (n = 1; 11.1%), and T-lymphoblastic lymphoma (n = 1; 11.1%)., Conclusion: Unusual FC results that are not diagnostic of malignancy can be seen in lymph node FNA in a minority of young patients. In our series, these findings were seen mainly in small populations of T cells and occurred primarily in the setting of reactive lymphoid hyperplasia or ectopic thymic tissue. Cytopathologists performing FNA on children should be aware of these abnormalities and, although they may warrant further investigation and follow-up, they are unlikely to be associated with malignancy., (© 2016 S. Karger AG, Basel.)

Objective: (1) To determine the incidence and severity of subglottic stenosis on endoscopic evaluation in a pediatric population of patients with recurrent croup. (2) To determine the incidence of abnormal findings on bronchoalveolar lavage and esophageal biopsy in a pediatric population with recurrent croup., Methods: Case series with historical chart review of clinical data for pediatric patients (age ≤18 years) at a tertiary care children's hospital who underwent endoscopic evaluation of the upper aerodigestive tract with a diagnosis of recurrent croup over a ten-year period (2002-2012). Subglottic stenosis was graded on Myer-Cotton scale. Lipid-laden macrophages on bronchoalveolar lavage were noted as none/small/moderate/large with evidence of reflux noted as moderate or large. Esophageal biopsy specimens were evaluated for evidence of esophagitis. Data is expressed as mean±SEM., Results: 1825 charts were reviewed of which 197 met inclusion criteria. Mean age at endoscopy was 53±3 months. Subglottic stenosis was noted in 41 patients (20.8%) with 95.1% being mild or Grade I. Abnormal findings on bronchoalveolar lavage were noted on 9.5% of bronchoalveolar lavage specimens. Abnormal esophageal biopsies were noted on 19.9% of specimens. Esophagitis was noted on 8.8% of biopsy specimens., Conclusions: Subglottic stenosis is a risk factor for recurrent croup. Evidence suggestive of reflux may be noted on bronchoalveolar lavage or esophageal biopsy, but these findings may not correlate with subglottic stenosis in recurrent croup patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Children with a button battery impaction present with nonspecific symptoms that may account for a delay in medical care. We conducted a retrospective study of the clinical presentation, management, and complications associated with button battery ingestion in the pediatric aerodigestive tract and to evaluate the associated long-term morbidity. We reviewed the medical records of 23 patients who were treated for button battery impaction at our tertiary care children's hospital from Jan. 1, 2000, through July 31, 2013. This population was made up of 14 boys and 9 girls, aged 7 days to 12 years (mean: 4 yr). Patients were divided into three groups based on the site of impaction; there were 9 impactions in the esophagus and 7 each in the nasal cavity and stomach. We compiled information on the type and size of each battery, the duration of the impaction, presenting symptoms, treatment, and outcomes. The mean duration of battery impaction was 40.6, 30.7, and 21.0 hours in the esophagus, nasal cavity, and stomach, respectively. We were able to identify the specific type of battery in 13 cases; 11 of these cases (85%) involved a 3-V 20-mm lithium ion battery, including all cases of esophageal impaction in which the type of battery was identified. The most common presenting signs and symptoms were vomiting (n = 7 [30%]), difficulty feeding (n = 5 [22%]), cough (n = 5), and bloody nasal discharge (n = 5); none of the presenting signs and symptoms predicted the severity of the injury or the outcome. The median length of hospital stay was far greater in the esophageal group (12 days) than in the nasal and stomach groups (1 day each; p = 0.006). Battery impaction in the esophagus for more than 15 hours was associated with a significantly longer postoperative hospital stay than impaction for less than 15 hours (p = 0.04). Esophageal complications included strictures (n = 5), perforation (n = 3), and tracheoesophageal fistula formation (n = 2). Clinicians should consider battery impaction in the upper aerodigestive tract as an emergency that can lead to significant long-term morbidity, and therefore immediate surgical intervention is required.

Objective: Carotid endarterectomy (CEA) for asymptomatic carotid artery stenosis is among the most common procedures performed in the United States. However, consensus is lacking regarding optimal preoperative imaging, carotid duplex ultrasound criteria, and ultimately, the threshold for surgery. We sought to characterize national variation in preoperative imaging, carotid duplex ultrasound criteria, and threshold for surgery for asymptomatic CEA., Methods: The Society for Vascular Surgery Vascular Quality Initiative (VQI) database was used to identify all CEA procedures performed for asymptomatic carotid artery stenosis between 2003 and 2014. VQI currently captures 100% of CEA procedures performed at >300 centers by >2000 physicians nationwide. Three analyses were performed to quantify the variation in (1) preoperative imaging, (2) carotid duplex ultrasound criteria, and (3) threshold for surgery., Results: Of 35,695 CEA procedures in 33,488 patients, the study cohort was limited to 19,610 CEA procedures (55%) performed for asymptomatic disease. The preoperative imaging modality used before CEA varied widely, with 57% of patients receiving a single preoperative imaging study (duplex ultrasound imaging, 46%; computed tomography angiography, 7.5%; magnetic resonance angiography, 2.0%; cerebral angiography, 1.3%) and 43% of patients receiving multiple preoperative imaging studies. Of the 16,452 asymptomatic patients (89%) who underwent preoperative duplex ultrasound imaging, there was significant variability between centers in the degree of stenosis (50%-69%, 70%-79%, 80%-99%) designated for a given peak systolic velocity, end diastolic velocity, and internal carotid artery-to-common carotid artery ratio. Although 68% of CEA procedures in asymptomatic patients were performed for an 80% to 99% stenosis, 26% were performed for a 70% to 79% stenosis, and 4.1% were performed for a 50% to 69% stenosis. At the surgeon level, the range in the percentage of CEA procedures performed for a <80% asymptomatic carotid artery stenosis is from 0% to 100%. Similarly, at the center level, institutions range in the percentage of CEA procedures performed for a <80% asymptomatic carotid artery stenosis from 0% to 100%., Conclusions: Despite CEA being an extremely common procedure, there is widespread variation in the three primary determinants-preoperative imaging, carotid duplex ultrasound criteria, and threshold for surgery-of whether CEA is performed for asymptomatic carotid stenosis. Standardizing the approach to care for asymptomatic carotid artery stenosis will mitigate the significant downstream effects of this variation on health care costs., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine and quantify changes in both central and obstructive sleep apnea in patients with Down syndrome (DS) after adenotonsillectomy (AT)., Study Design: Case series with chart review., Setting: Tertiary care children's hospital., Subjects and Methods: The records of all patients with DS who underwent AT for sleep-disordered breathing between November 2008 and December 2014 were examined. In total, 113 patients were identified, and 36 of these patients had pre- and postoperative polysomnograms (PSGs) that were analyzed for obstructive and central components. Wilcoxon signed-rank test, paired t test, and McNemar test were used to examine pre- and postoperative PSG differences. Logistic regression and multivariate analysis of variance of patient characteristics (between subjects) and PSG results (within subjects) were conducted., Results: The mean (SD) patient age was 5.5 (4.0) years (range, 0.9-15 years); 50.0% were male. After AT, significant reductions were identified in both obstructive apnea-hypopnea index (AHI) (P < .001) and overall AHI (P < .001). Among the 15 patients with severe obstructive sleep apnea, 86.7% experienced a significant AHI reduction to moderate or mild disease (P < .001). In addition, of the 15 patients with central sleep apnea (central apnea index [CAI] >1), 66.7% had resolution of central sleep apnea postoperatively (P = .004). There was also a significant interaction identified between CAI reduction, preoperative CO2 retention, and adenoid size, F(2, 20) = 6.87, P = .05., Conclusion: Children with DS who underwent AT demonstrated significant reductions in both obstructive and central apneic indices on PSG. A significant number of patients with central sleep apnea demonstrated resolution postoperatively. Additional analysis demonstrated a significant interaction between CO2 retention, adenoid size, and postoperative CAI reduction., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.)

Importance: Supraglottoplasty is a common procedure performed without evidence-based postoperative management plans. Patients are routinely admitted to the intensive care unit (ICU) postoperatively, but this may not be necessary in all cases., Objective: To determine (1) whether routine admission to the ICU after supraglottoplasty is warranted in all patients who undergo this procedure and (2) which factors predict requirement for ICU-level care., Design, Setting, and Participants: Retrospective case series and analysis of immediate postoperative outcomes of all children aged 1 month to 18 years who underwent supraglottoplasty at 1 tertiary-care children's hospital from January 1, 2008, through January 31, 2014. Exclusion criteria included preoperative admission to the ICU, preoperative need for positive-pressure ventilation, history of major airway reconstruction, or any concomitant other major procedure., Exposure: Supraglottoplasty., Main Outcomes and Measures: Need for ICU-level care as defined by need for intubation, positive-pressure ventilation, multiple doses of racemic epinephrine, or oxygen via nasal cannula at greater than 4 L/min within the first 24 hours., Results: Of 223 patients identified, 25 (11.2%) met our criteria for ICU-level care. Nine patients required intubation. Twenty of the 25 patients met ICU criteria within 4 hours of surgery. Univariate analysis was performed on 38 risk factors. Risk factors for ICU requirement that remained statistically significant on multivariable analysis (P < .05) included surgical duration longer than 30 minutes (odds ratio [OR], 4.48 [95% CI, 1.51-13.19]; P = .007), nonwhite race (OR, 4.42 [95% CI, 1.54-12.66]; P = .006), and a preoperative diagnosis of gastroesophageal reflux disease (OR, 0.10 [95% CI, 0.09-0.36]; P < .001)., Conclusions and Relevance: Our study suggests that most children undergoing supraglottoplasty do not require ICU-level care postoperatively. Those who require ICU-level care are likely to be identified within the first 4 hours after surgery. Consideration for routine ICU admission should be given to those with longer surgical duration and those of nonwhite race.

Papillary thyroid carcinoma (PTC) is rare in children, although it is a known secondary malignancy after treatment for neuroblastoma (NB). The interval between NB treatment completion and PTC is usually more than 5 years. A 4-year-old, female patient with a high risk adrenal NB was found to have a 2.9-cm, right thyroid nodule on surveillance chest computed tomography (CT) 6 months after completion of her NB treatment (induction chemotherapy, tumor resection, autologous stem cell transplantation, external beam radiation to the abdominal tumor site, immunotherapy, and retinoic acid). Posttreatment surveillance included iodine-123-metaiodobenzylguanidine scans and CT scans. Fine-needle aspiration of the thyroid nodule diagnosed a follicular neoplasm, which was negative for BRAF, NRAS, KRAS, HRAS, PAX8/PPARg, and RET/PTC mutations, without evidence of metastatic NB. Nodule histology demonstrated an encapsulated follicular variant of PTC (FVPTC). Next-generation sequence analysis for a 46 cancer-gene profile was performed on both tumors with subsequent peripheral blood DNA testing. A heterozygous missense mutation in STK11 (F354L) was identified in both the NB and FVPTC. This mutation was also detected in peripheral blood mononuclear cells. Two additional heterozygous somatic missense mutations of uncertain significance were identified: KDR/VEGF receptor 2 (Q472H) on chromosome 4 and MET (N375S) on chromosome 7. To our knowledge, this is the shortest reported duration from completion of NB treatment to detection of thyroid cancer. The association of the STK11 gene with Peutz-Jeghers syndrome, lung adenocarcinomas, and medullary thyroid cancer leads to a possible association between this genetic variant and our patient's tumors.

Objective: Previous studies have reported that endovascular repair (EVAR) of ruptured abdominal aortic aneurysms (RAAAs) has lower postoperative mortality than open repair (OR). However, comparisons involved heterogeneous populations that lacked adjustment for preoperative risk. We hypothesize that for RAAA patients stratified by a validated measure of preoperative mortality risk, EVAR has a lower in-hospital mortality and morbidity than does OR., Methods: In-hospital mortality and morbidity after EVAR and OR of RAAA were compared in patients from the Vascular Quality Initiative (2003-2013) stratified by the validated Vascular Study Group of New England RAAA risk score into low-risk (score 0-1), medium-risk (score 2-3), and high-risk (score 4-6) groups., Results: Among 514 patients who underwent EVAR and 651 patients who underwent OR of RAAA, EVAR had lower in-hospital mortality (25% vs 33%, P = .001). In risk-stratified patients, EVAR trended toward a lower mortality in the low-risk group (n = 626; EVAR, 10% vs OR, 15%; P = .07), had a significantly lower mortality in the medium-risk group (n = 457; EVAR, 37% vs OR, 48%; P = .02), and no advantage in the high-risk group (n = 82; EVAR, 95% vs OR, 79%; P = .17). Across all risk groups, cardiac complications (EVAR, 29% vs OR, 38%; P = .001), respiratory complications (EVAR, 28% vs OR, 46%; P < .0001), renal insufficiency (EVAR, 24% vs OR, 38%; P < .0001), lower extremity ischemia (EVAR, 2.7% vs OR, 8.1%; P < .0001), and bowel ischemia (EVAR, 3.9% vs OR, 10%; P < .0001) were significantly lower after EVAR than after OR. Across all risk groups, median (interquartile range) intensive care unit length of stay (EVAR, 2 [1-5] days vs OR, 6 [3-13] days; P < .0001) and hospital length of stay (EVAR, 6 [4-12] days vs OR, 13 [8-22] days; P < .0001) were lower after EVAR., Conclusions: This novel risk-stratified comparison using a national clinical database showed that EVAR of RAAA has a lower mortality and morbidity compared with OR in low-risk and medium-risk patients and that EVAR should be used to treat these patients when anatomically feasible. For RAAA patients at the highest preoperative risk, there is no benefit to using EVAR compared with OR., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Thyroid nodules are less common in children than adults, but the risk of malignancy in thyroid nodules is much higher in children. The ability to characterize pediatric thyroid nodules has improved with the use of ultrasound-guided fine-needle aspiration, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) classification system, and expanded molecular testing. Nevertheless, stratification criteria to predict thyroid malignancy in children are poorly defined. Our objective was to determine if clinical presentation and molecular genetics could predict malignancy in pediatric thyroid nodules., Methods: Retrospective chart review of patients ≤18 years of age at the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center with the diagnosis of a thyroid nodule from January 2007 to January 2012 was conducted. Eighty-nine subjects fulfilled the inclusion criteria: 1) thyroid nodule ≥0.8 cm and biopsy (n=76), or 2) thyroid nodule ≥0.8 cm, no biopsy, and ultrasound follow-up for at least 2 years (n=13)., Results: Twenty-four (27%) of 89 patients were diagnosed with thyroid cancer (50% papillary thyroid carcinoma [PTC], 50% follicular variant of papillary thyroid carcinoma [FVPTC]). Features associated with malignancy included larger nodule size, palpable nodule, or palpable lymphadenopathy. There were no differences in presenting features between patients with PTC and those with FVPTC. Thyroid malignancy was diagnosed in all nine patients with a molecular abnormality (BRAF, RAS, RET/PTC, PAX8/PPARγ)., Conclusions: Clinical features, FNA cytology, and molecular genetics are valuable tools to discriminate benign from malignant nodules in pediatric patients. This information is important to direct subsequent clinical management.

In 2008, the top priority in our division's 5-year strategic plan was "to become an internationally recognized center of excellence for the endovascular treatment of complex aortic pathology extending from the aortic valve to the external iliac artery." Five components were identified as "most critical" to achieve this strategic priority: (1) training at centers of excellence in complex endovascular repair; (2) industry partnership to improve access to developing technologies; (3) a fully integrated team approach with one leader involved in all steps of all cases; (4) prospective data collection; and (5) development and implementation of a physician-sponsored investigational device exemption for juxtarenal, pararenal, and thoracoabdominal aneurysms. We have now performed 49 repairs (16 commercially manufactured devices, 33 physician-modified devices) for 3 common iliac, 20 juxtarenal, 9 pararenal, and 17 thoracoabdominal aneurysms, using 142 fenestrations, branches, and scallops. All patients had complete 30-day follow-up for calculation of 30-day events. Kaplan-Meier analysis was used to calculate 1-year events. In 5 years, we developed a successful complex endovascular aortic program that uses fenestrated/branched repair techniques. A focused team strategic planning approach to program development is an effective way for vascular surgery divisions to gain experience and expertise with new complex technologies while ensuring acceptable patient outcomes., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe the use of fiberoptic endoscopic evaluation of swallowing (FEES) as an adjunct in the management of children presenting with psychogenic dysphagia, defined as food avoidance and excessive fear of eating without identifiable anatomic or functional swallowing abnormalities., Methods: Case series of patients presenting to the otolaryngology clinic of a tertiary pediatric teaching hospital between 2007 and 2008 that were evaluated and managed with the utilization of FEES. The outcomes measured were age, gender, duration of symptoms, findings of FEES, additional work-up and resolution of symptoms at follow-up., Results: Five patients (4 males, 1 female) with ages ranging from 5 to 13 years old (mean=8.6). The median duration of symptoms before presentation was 3 weeks. Four families described refusal of solids starting after choking episode and variable estimated weight loss (mean 2.8kg). One child presented with vague complaints of intermittent odynophagia and food refusal. Fiberoptic endoscopic evaluation of swallowing was performed on all patients. No abnormalities of the oropharyngeal swallow were appreciated. Additional management included different combinations of modified barium swallow study, esophagastroduodenoscopy (EGD), upper GI series, antibiotics, and psychotherapy. Mean follow-up with clinic visit was 4.2 months. Three of the five children reported complete resolution of symptoms after FEES at follow-up visit., Conclusion: Fiberoptic endoscopic evaluation of swallowing can be a useful management tool in children with psychogenic dysphagia as it provides direct visualization of the oropharyngeal swallowing mechanism. This can be used to provide visual reassure and biofeedback to patients and parents. Additional workup should be decided on an individual basis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To examine the role of polysomnography (PSG) in helping determine readiness of tracheostomized patients for decannulation., Study Design: Case series with chart review of pediatric patients who underwent PSG with tracheostomy tube in place with the goal of decannulation., Setting: Tertiary care pediatric center., Subjects and Methods: Twenty-eight tracheostomized patients who underwent PSG from January 2006 to March 2012 were included. Outcome measures were successful decannulation, PSG results, surgical procedures, and medical comorbidities., Results: Of the 28 patients, 20 (71.4%) were decannulated and 8 (28.6%) were not. One (3.6%) patient failed long-term decannulation. The average apnea-hypopnea index (AHI) with a capped tracheostomy for those successfully decannulated was 2.75 (range, 0.6-7.6), while the AHI for those not decannulated was 15.99 (range, 3.2-62). Factors associated with success or failure to decannulate were assessed, and an algorithm was developed to plan for successful decannulation. Laryngotracheal reconstruction was a significant factor in those successfully decannulated. Those who were not decannulated had multiple medical comorbidities, multilevel airway obstruction, need for additional surgery, or chronic need for pulmonary toilet., Conclusions: Polysomnography may be a useful adjunctive study in the process of determining a patient's readiness for decannulation. Our current algorithm for decannulation includes upper airway endoscopy with identification of levels of obstruction, followed by surgical correction of those obstructions; capped PSG to determine patency of the airway and help assess lung function; and overnight intensive care unit admission for capping trial, with decannulation the following day if well tolerated., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2014.)

Objective: Lifelong imaging follow-up is essential to the safe and appropriate management of patients who undergo endovascular abdominal aortic aneurysm repair (EVAR). We sought to evaluate the rate of compliance with imaging follow-up after EVAR and to identify factors associated with being lost to imaging follow-up., Methods: We identified a 20% sample of continuously enrolled Medicare beneficiaries who underwent EVAR between 2001 and 2008. Using data through 2010 from Medicare Inpatient, Outpatient, and Carrier files, we identified all abdominal imaging studies that may have been performed for EVAR follow-up. Patients were considered lost to annual imaging follow-up if they did not undergo any abdominal imaging study within their last 2 years of follow-up. Multivariable models were constructed to identify independent factors associated with being lost to annual imaging follow-up., Results: Among 19,962 patients who underwent EVAR, the incidence of loss to annual imaging follow-up at 5 years after EVAR was 50%. Primary factors associated with being lost to annual imaging follow-up were advanced age (age 65-69 years, reference; age 75-79 years: hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.15-1.32; age 80-85 years: HR, 1.45; 95% CI, 1.35-1.55; age >85 years: HR, 2.03; 95% CI, 1.88-2.20) and presentation with an urgent/emergent intact aneurysm (HR, 1.27; 95% CI, 1.20-1.35) or ruptured aneurysm (HR, 1.84; 95% CI, 1.63-2.08). Additional independent factors included several previously diagnosed chronic diseases and South and West regions of the United States., Conclusions: Annual imaging follow-up compliance after EVAR in the United States is significantly below recommended levels. Quality improvement efforts to encourage improved compliance with imaging follow-up, especially in older patients with multiple comorbidities and in those who underwent EVAR urgently or for rupture, are necessary., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Actinomyces is a rare pathogen that can be the cause of infections in the digestive and urinary tracts, skin, genitalia, and lungs, which generally have an indolent clinical course. However, in some cases these can be locally destructive and become generalized infections. Actinomyces has been previously implicated in infections of the middle ear, nasopharynx, and sinuses, occasionally causing complications such as chronic mastoiditis. Here we describe the case of a 10-year-old-male presenting with nausea, vomiting, and headache who developed intracranial complications of actinomycotic mastoiditis.

Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions., (© 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

No deficiency of human C-reactive protein (CRP), or even structural polymorphism of the protein, has yet been reported so its physiological role is not known. Here we show for the first time that CRP-deficient mice are remarkably susceptible to Streptococcus pneumoniae infection and are protected by reconstitution with isolated pure human CRP, or by anti-pneumococcal antibodies. Autologous mouse CRP is evidently essential for innate resistance to pneumococcal infection before antibodies are produced. Our findings are consistent with the significant association between clinical pneumococcal infection and non-coding human CRP gene polymorphisms which affect CRP expression. Deficiency or loss of function variation in CRP may therefore be lethal at the first early-life encounter with this ubiquitous virulent pathogen, explaining the invariant presence and structure of CRP in human adults., (© 2014 The Authors. Immunology published by John Wiley & Sons Ltd.)

Importance: Tracheocutaneous fistula (TCF) can be repaired using various techniques. This research is an outcomes and health care use comparative analysis of 2 commonly used techniques to repair TCF., Objectives: To compare outcomes and health care use for 2 techniques of TCF repair., Design, Setting, and Participants: Retrospective cohort study at a tertiary care children's hospital. The study population comprised 50 consecutive patients aged 11 to 216 months who underwent surgical treatment for persistent TCF between January 2007 and August 2012., Interventions: Tracheocutaneous fistula closure was achieved using excision of the TCF alone and healing by secondary intent or excision of the TCF plus primary closure over a drain., Main Outcomes and Measures: Differences in perioperative and postoperative outcomes., Results: In total, 30 patients underwent excision of a TCF plus primary closure over a drain (closure group), and 20 patients underwent excision of a TCF alone and healing by secondary intent (excision group). Statistically, the closure and excision groups were not significantly different regarding gestational age, age at tracheotomy, duration between decannulation and TCF repair, and duration of tracheostomy. The mean (SD) procedure durations were 9.7 (3.7) minutes for the excision group and 37.4 (25.1) minutes for the closure group (P < .001). The mean (SD) lengths of hospital stay were 0.3 (0.5) day for the excision group and 1.1 (0.9) days for the closure group (P = .001). The mean (SD) lengths of intensive care unit stay were 0.0 (0.0) day for the excision group and 1.0 (1.5) day for the closure group (P = .001). Closure success rates were 20 of 22 for the excision group and 30 of 30 for the closure group (P = .17). Complication rates were 0 of 22 for the excision group and 2 of 30 for the closure group (P = .50)., Conclusions and Relevance: The rates of success and complications were not significantly different between TCF closure and excision groups. Excision of a TCF alone with healing by secondary intent requires less operating room time and shorter hospital stay, which may suggest more efficient health care use.

To form extracellular aggregates, amyloidogenic proteins bypass the intracellular quality control, which normally targets unfolded/aggregated polypeptides. Human D76N β2-microglobulin (β2m) variant is the prototype of unstable and amyloidogenic protein that forms abundant extracellular fibrillar deposits. Here we focus on the role of the class I major histocompatibility complex (MHCI) in the intracellular stabilization of D76N β2m. Using biophysical and structural approaches, we show that the MHCI containing D76N β2m (MHCI76) displays stability, dissociation patterns, and crystal structure comparable with those of the MHCI with wild type β2m. Conversely, limited proteolysis experiments show a reduced protease susceptibility for D76N β2m within the MHCI76 as compared with the free variant, suggesting that the MHCI has a chaperone-like activity in preventing D76N β2m degradation within the cell. Accordingly, D76N β2m is normally assembled in the MHCI and circulates as free plasma species in a transgenic mouse model.

Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.