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Objectives/HypothesisMicronized AlloDerm is a commonly used injectable material for injection laryngoplasty; however, the histologic response to laryngeal implantation and resorption rate over time have not been elucidated. This study aimed to evaluate the in vivo response of micronized AlloDerm over time after laryngeal implantation using a rabbit model.Study DesignAnimal model.MethodsThe left recurrent laryngeal nerve was sectioned in five New Zealand White rabbits to create a vocal cord paralysis. Two weeks later, injection laryngoplasty was performed with 100 μL of micronized AlloDerm. Animals were sacrificed 4 (two rabbits) and 12 (three rabbits) weeks after injection. Histologic sections were stained and evaluated by a single pathologist. Volume estimates were made by assuming the implant took an ellipsoid shape using dimensions calculated from histologic slides.ResultsIn all cases, histological analysis revealed a lymphocytic inflammatory response infiltrating the peripheral margins of injection. After 4 weeks, the volume of injected material remaining in two rabbits was 404 and 278 mm3 (average 341 mm3). After 12 weeks, the volume of injected material remaining in three rabbits was 0, 61, and 124 mm3 (average 62 mm3), an 82% difference in volume of material between animals sacrificed at 4 weeks versus 12 weeks.ConclusionsInjection laryngoplasty using micronized AlloDerm induces a lymphocytic inflammatory response after injection in a rabbit model. Though a significant amount of material remains after 4 weeks, by 12 weeks the majority has been reabsorbed.Level of EvidenceNA Laryngoscope, 127:E166–E169, 2017

AbstractThe identification of a hexanucleotide repeat expansion in a non‐coding region of C9orf72 as a major cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) drastically changed the field of research on both of these conditions. Yet, despite the vast amount of work aimed at elucidating the molecular mechanisms underlying the role of this repeat in disease, the exact pathomechanisms are still unclear. A reduction in the expression of the C9orf72 gene is observed in patients, but a gain‐of‐function model is now preferred. The hexanucleotide repeat expansion forms RNA foci in the central nervous system (CNS) of repeat‐positive FTD and ALS patients, and these foci are believed to sequester RNA‐binding proteins (RBPs) and impair their function in RNA processing. At the same time, the repeat undergoes repeat‐associated non‐ATG translation to produce dipeptide repeat proteins that also form inclusions in the patient CNS. Studies from cells and flies suggest that these proteins may also be an important factor in the disease. Finally, the hexanucleotide repeat also induces the mislocalization and aggregation of TAR DNA‐binding protein 43 (TDP‐43) through an as yet unknown mechanism. This review covers the different potential pathogenic factors that have been put forth for C9orf72‐repeat‐associated FTD and ALS (C9‐FTD/ALS), while highlighting some remaining questions. image A repeat expansion in C9orf72 is a common cause of both frontal temporal dementia and amyotrophic lateral sclerosis. Although there is a decrease in C9orf72 expression in patients, this repeat is believed to induce disease primarily through an unknown gain‐of‐function mechanism involving the RNA, repeat‐associated non‐AUG translation, or both. This review summarizes and discusses current knowledge on C9orf72 repeat‐associated pathophysiology.This article is part of the Frontotemporal Dementia special issue.

Abstract Background The scheduling of residents for rotation assignments and on-call responsibilities is a time-consuming process that challenges the resources of residency programs. Assignment of schedules is traditionally done by chief residents or program administration with variable input from the residents involved. Intervention We introduced an innovative point-based scheduling system to increase transparency in the scheduling process, foster a sense of fairness and equality in scheduling, and increase resident ownership for making judicious scheduling choices. Methods We devised a point-based system in which each resident in our 40-member program was allocated an equal number of points. The residents assigned these points to their preferred choices of rotations. Residents were then surveyed anonymously on their perceptions of this new scheduling system and were asked to compare it with their traditional scheduling system. Results The schedule was successfully implemented, and it allowed residents to express their scheduling preferences using an innovative point-based approach. Residents were generally satisfied with the new system, would recommend it to other programs, and perceived a greater sense of involvement. However, resident satisfaction with the new system was not significantly greater compared with the previous approach to scheduling (P = .20). Chief residents expressed satisfaction with the new scheduling model. Conclusions Residents were equally satisfied with the traditional preference-based scheduling approach and the new point-based system. Chief residents' feedback on the new system reflected reduced stress and time commitment in the new point-based system.

Abstract Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

Abstract Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.

Background— QRS prolongation is associated with adverse outcomes in mostly white populations, but its clinical significance is not well established for other groups. We investigated the association between QRS duration and mortality in African Americans. Methods and Results— We analyzed data from 5146 African Americans in the Jackson Heart Study stratified by QRS duration on baseline 12-lead ECG. We defined QRS prolongation as QRS≥100 ms. We assessed the association between QRS duration and all-cause mortality using Cox proportional hazards models and reported the cumulative incidence of heart failure hospitalization. We identified factors associated with the development of QRS prolongation in patients with normal baseline QRS. At baseline, 30% (n=1528) of participants had QRS prolongation. The cumulative incidences of mortality and heart failure hospitalization were greater with versus without baseline QRS prolongation: 12.6% (95% confidence interval [CI], 11.0–14.4) versus 7.1% (95% CI, 6.3–8.0) and 8.2% (95% CI, 6.9–9.7) versus 4.4% (95% CI, 3.7–5.1), respectively. After risk adjustment, QRS prolongation was associated with increased mortality (hazard ratio, 1.27; 95% CI, 1.03–1.56; P =0.02). There was a linear relationship between QRS duration and mortality (hazard ratio per 10 ms increase, 1.06; 95% CI, 1.01–1.12). Older age, male sex, prior myocardial infarction, lower ejection fraction, left ventricular hypertrophy, and left ventricular dilatation were associated with the development of QRS prolongation. Conclusions— QRS prolongation in African Americans was associated with increased mortality and heart failure hospitalization. Factors associated with developing QRS prolongation included age, male sex, prior myocardial infarction, and left ventricular structural abnormalities.

Mitral Valve Injury with Catheter AblationIntroductionAn increasing number of catheter ablations involve the mitral annular region and valve apparatus, increasing the risk of catheter interaction with the mitral valve (MV) complex. We review our experience with catheter ablation‐related MV injury resulting in severe mitral regurgitation (MR) to delineate mechanisms of injury and outcomes.MethodsWe searched the Mayo Clinic MV surgical database over a 19‐year period (1993–2012) and the electrophysiologic procedures database over a 23‐year period (1990–2013) and identified 9 patients with catheter ablation related MV injury requiring clinical intervention.ResultsIndications for ablation included atrial fibrillation (AF) [n = 4], ventricular tachycardia (VT) [n = 3], and left‐sided accessory pathways [n = 2]. In all 4 AF patients, a circular mapping catheter entrapped in the MV apparatus was responsible for severe MR. In all 3 VT patients, radiofrequency energy delivery led to direct injury to the MV apparatus. In the 2 patients with accessory pathways, both mechanisms were involved (1 per patient). Six patients required surgical intervention (5 MV repair, 1 catheter removal). One patient developed severe functional MR upon successful endovascular catheter disentanglement that improved spontaneously. Two VT patients with persistent severe postablation MR were managed nonsurgically, 1 of whom died 3 months postprocedure.ConclusionCircular mapping catheter entrapment and ablation at the mitral annulus are the most common etiologies of MV injury during catheter ablation. Close surveillance of the MV is needed during such procedures and early surgical repair is important for successful salvage if significant injury occurs.