Developing a peptide to disrupt cohesin head domain interactions.

Cohesin mediates the 3-D structure of chromatin and is involved in maintaining genome stability and function. The cohesin core comprises Smc1 and Smc3, elongated-shaped proteins that dimerize through globular domains at their edges, called head and hinge. ATP binding to the Smc heads induces their dimerization and the formation of two active sites, while ATP hydrolysis results in head disengagement. This ATPase cycle is essential for driving cohesin activity. We report on the development of the first cohesin-inhibiting peptide (CIP). The CIP binds Smc3 in vitro and inhibits the ATPase activity of the holocomplex. Treating yeast cells with the CIP prevents cohesin's tethering activity and, interestingly, leads to the accumulation of cohesin on chromatin. CIP3 also affects cohesin activity in human cells. Altogether, we demonstrate the power of peptides to inhibit cohesin in cells and discuss the potential application of CIPs as a therapeutic approach.

Novel imaging classification system of nodal disease in human papillomavirus-mediated oropharyngeal squamous cell carcinoma prognostic of patient outcomes.

BACKGROUND: Matted nodes in human papillomavirus (HPV)-mediated oropharyngeal squamous cell carcinoma (OPC) is an independent predictor of distant metastases and decreased overall survival. We aimed to classify imaging patterns of metastatic lymphadenopathy, analyze our classification system for reproducibility, and assess its prognostic value. METHODS: The metastatic lymphadenopathy was classified based on radiological characteristics for 216 patients with HPV-mediated OPC. Patient outcomes were compared and inter-rater reliability was calculated. RESULTS: The presence of ≥3 abutting lymph nodes with imaging features of surrounding extranodal extension (ENE), one subtype of matted nodes, was associated with worse 5-year overall survival, overall recurrence-free survival, regional recurrence-free survival, and distant recurrence-free survival (p ≤ 0.03). Other patterns were not significantly associated with outcome measures. Overall inter-rater agreement was substantial (κ = 0.73). CONCLUSION: One subtype of matted nodes defined by ≥3 abutting lymph nodes with imaging features of surrounding ENE is the radiological marker of worst prognosis.

Effectiveness of gabapentin as a postoperative analgesic in children undergoing appendectomy.

PURPOSE: Though gabapentin is increasingly used as a perioperative analgesic, data regarding effectiveness in children are limited. The purpose of this study was to evaluate gabapentin as a postoperative analgesic in children undergoing appendectomy. METHODS: A 12-month retrospective review of children undergoing appendectomy was performed at a two-hospital children's institution. Patients receiving gabapentin (GP) were matched (1:2) with patients who did not receive gabapentin (NG) based on age, sex and appendicitis severity. Outcome measures included postoperative opioid use, pain scores, and revisits/readmissions. RESULTS: We matched 29 (33.3%) GP patients with 58 (66.6%) NG patients (n = 87). The GP group required significantly less postoperative opioids than the NG group (0.034 mg morphine equivalents/kg (ME/kg) vs. 0.106 ME/kg, p < 0.01). Groups had similar lengths of time from operation to pain scores ≤ 3 (GP 12.21 vs. NG 17.01 h, p = 0.23). GP and NG had similar rates of revisit to the emergency department (13.8 vs. 10.3%, p = 0.73), readmission (6.9 vs. 1.7%, p = 0.26), and revisits secondary to surgical pain (3.4 vs. 3.4%, p = 1.00). CONCLUSION: In this single-center, retrospective cohort study, gabapentin is associated with a reduction in total postoperative opioid use in children with appendicitis. While promising, further prospective validation of clinical effectiveness is needed.

Magnetic resonance imaging safety in nonconditional pacemaker and defibrillator recipients: A meta-analysis and systematic review.

BACKGROUND: Recommendations regarding performance of magnetic resonance imaging (MRI) in non-MRI conditional pacemaker and defibrillator recipients are evolving. Previous studies have suggested low adverse event rates with MRI in nonconditional cardiac implantable electronic device (CIED) recipients, but low power limits optimal characterization of risk. OBJECTIVE: The purpose of this study was to perform a systematic review and meta-analysis to characterize the clinical risk associated with MRI in CIED recipients in order to improve power. METHODS: PubMed and CINAHL indexed articles from 1990 to 2017 were queried. A random effects model was used for meta-analysis of continuous variables. Safety outcomes were evaluated with descriptive statistics. RESULTS: Seventy studies of non-MRI conditional devices undergoing MRI were identified, allowing for analysis of 5099 patients who underwent a total of 5908 MRI studies. Heterogeneity in lead parameter changes was observed within studies, although smaller variances were noted between studies. All lead characteristics and battery voltages showed very small, clinically insignificant changes when assessed as a pooled cohort, although cases of clinically relevant outcomes were also noted (lead failure 3, implantable cardioverter-defibrillator shock 1, electrical reset 94). Electrical resets were found only in older devices. Defibrillator function was unchanged, and inappropriate shocks were avoided with pre-MRI programming changes. CONCLUSION: This review demonstrated low lead failure and clinical event rates in non-MRI conditional pacemaker and defibrillator recipients undergoing MRI. Observed changes were small and interstudy variance was low, suggesting that the composite event rates offer a reasonable estimate of true effect. The observed adverse events reinforce the need for ongoing vigilance and caution, particularly with older devices.

Procedural outcomes and long-term survival associated with lead extraction in patients with abandoned leads.

BACKGROUND: The decision to abandon or extract superfluous sterile leads is controversial. OBJECTIVE: The purpose of this study was to compare procedural outcomes and long-term survival of patients with and those without abandoned leads undergoing lead extraction (LE). METHODS: Retrospective review of all patients who had undergone transvenous LE at our institution from January 2007 to May 2016 was performed. Patients were stratified into 2 groups based on the presence (group 1) or absence (group 2) of abandoned leads. RESULTS: Among 774 patients who had undergone LE procedures, 38 (4.9%) had abandoned leads (group 1). Dwell time of the oldest extracted lead was longer in group 1 vs group 2 (7.6 ± 4.9 years vs 5.6 ± 4.4 years; P = .017), as was infection as an indication for LE (76% vs 33%; P <.001). A bailout femoral approach was more commonly required in group 1 than in group 2 (18.4% vs 6%; P = .007). Complete procedural success rates were similar (92.1% in group 1 vs 95.0% in group 2; P = .439), but there was a trend toward lower clinical success in group 1 (92.1% vs 97.4%; P = .088), primarily due to failure to remove all hardware in the setting of infection. Major procedural complication rates were similar (2.6% in group 1 vs 1.2% in group 2; P = .397), as was long-term survival (mean follow-up 2.3 ± 2.2 years). CONCLUSION: Abandoned leads at the time of LE were associated with increased procedural complexity, including a higher rate of bailout femoral extraction, and may be associated with lower clinical success. Among appropriately selected patients, consideration should be given to LE instead of abandonment.

Procedural outcomes and long-term survival following lead extraction in octogenarians.

BACKGROUND: Octogenarians account for a significant percentage of patients with indwelling pacemakers or defibrillators. OBJECTIVES: To determine procedural outcomes and long-term survival after lead extraction (LE) in octogenarians. METHODS: We retrospectively identified all patients who underwent defibrillator or pacemaker LE at our institution between January 1, 2007 and May 31, 2016. Patients were stratified based on age into two groups: <80 years old (Group 1, n = 674) or ≥80 (Group 2, n = 100). Outcomes were determined by medical records review and query of the Social Security Death Index. RESULTS: Patients in Group 2 were more likely to be hypertensive (77% vs 61%, P = 0.02), more like to have coronary artery disease (50% vs 39%, P = 0.049), and more likely to be extracted for infectious indications (47% vs 33%, P = .009). The number of leads extracted per procedure was 2.0 ± 0.8 and the mean dwell time of the oldest extracted lead was 5.6 ± 4.3 years, without significant differences between groups. Extraction procedure success (Group 1: 94.7%, Group 2: 96%, P = 0.808) and procedural deaths (Group 1: 0.9% vs Group 2: 0%, P = 1.0) were similar. There was no significant difference in survival up to 3 years following LE between groups. CONCLUSION: At experienced centers, LE can be performed safely in octogenarians with procedural success rates and long-term survival comparable to younger individuals.

Clinical Performance of Magnetic Resonance Imaging Conditional and Nonconditional Cardiac Implantable Electronic Devices.

OBJECTIVES: This study compared risks associated with magnetic resonance imaging (MRI) in patients with non-MRI conditional and MRI conditional pacing and defibrillator systems with particular attention to clinically actionable outcomes. BACKGROUND: While recipients of new MRI conditional pacemaker and defibrillator systems may undergo MRI scanning with very low risk, safety and regulatory concerns persist regarding such scanning in recipients of non-MRI conditional systems. METHODS: Patients with any cardiac device who were referred for MRI were prospectively enrolled at a single center and underwent scanning at 1.5 Tesla. Pre- and postscan lead characteristic changes, system integrity, and symptoms were analyzed. A comparison was made between non-MRI conditional and MRI conditional devices. RESULTS: 105 patients were evaluated allowing for comparison of 97 scans with non-MRI conditional devices and 16 scans with MRI conditional devices. The cohort included those with pacemaker dependency, defibrillator, and cardiac resynchronization devices. Small, nonsignificant changes were observed in lead characteristics following scanning, and there was no significant difference when comparing non-MRI and MRI conditional devices. Lead parameter changes did not require lead revision or programming changes. No device reset, failures, or premature scan termination was observed. CONCLUSIONS: 1.5 T MRI scanning in patients with MRI conditional and non-MRI conditional cardiac devices was performed with similar, low clinical risk.

Outcomes of lead extraction in young adults.

BACKGROUND: Extraction of pacemaker and defibrillator leads in young adults may be technically challenging because of more extensive fibrosis and calcification in this patient population. OBJECTIVE: The purpose of this study was to examine outcomes of lead extraction (LE) in young adults at our institution. METHODS: We retrospectively identified all patients who underwent LE at our institution between January 1, 2007, and May 31, 2016. Patients were divided by age into 2 groups: <40 years (group 1, n = 84) or ≥40 years (group 2, n = 690). Outcomes were determined by medical records review. RESULTS: Patients in group 2 had a higher overall average number of leads extracted per procedure compared to group 1 (1.64 ± 0.80 vs 1.45 ± 0.64; P <.001). Lead dwell time was similar in the 2 groups (5.7 ± 5 years vs 5.6 ± 4.3 years; P = .95). The younger cohort tended to require femoral extraction techniques more frequently (9.5% vs 4.4%; P = .055). Extraction procedural success (group 1: 94.1%, group 2: 94.9%; P = .792), major complications (group 1: 0%, group 2: 1.3%; P = 1), and periprocedural mortality (group 1: 0%, group 2: 0.86%; P = 1) were similar in the 2 groups. CONCLUSION: LE can be performed safely and effectively in young adults. Despite the lower number of leads extracted per procedure and the similar lead dwell time, younger adults more frequently required the use of femoral extraction tools, thus highlighting the importance of performing these procedures in centers with advanced expertise in extraction techniques.

Predictors and outcomes of lead extraction requiring a bailout femoral approach: Data from 2 high-volume centers.

BACKGROUND: Lead extraction (LE) infrequently requires the use of the "bailout" femoral approach. Predictors and outcomes of femoral extraction are not well characterized. OBJECTIVE: The aim of this study was to determine the predictors of need for femoral LE and its outcomes. METHODS: Consecutive patients who underwent LE at our centers were identified. Baseline demographic characteristics, procedural outcomes, and clinical outcomes were ascertained by medical record review. Patients were stratified into 2 groups on the basis of the need for femoral extraction. RESULTS: A total of 1080 patients underwent LE, of whom 50 (4.63%) required femoral extraction. Patients requiring femoral extraction were more likely to have leads with longer dwell time (9.5 ± 6.0 years vs 5.7 ± 4.3 years; P < .001), to have more leads extracted per procedure (2.0 ± 1.0 vs 1.7 ± 0.9; P = .003), and to have infection as an indication for extraction (72% vs 37.2%; P < .001). Procedural and clinical success was lower in the femoral extraction group than in the nonfemoral group (58% and 76% vs 94.7% and 97.9 %, respectively; P < .001). Major periprocedural complications (0% vs 1.3%; P = 1.0) and periprocedural mortality (0% vs 0.8%; P = 1.0) were similar between the 2 groups. CONCLUSION: In this study, femoral extraction was needed in ~5% of LEs. Longer lead dwell time, higher number of leads extracted per procedure, and the presence of infection predicted the need for femoral extraction. Procedural success of femoral extraction was low, highlighting the fact that this approach is mostly used as a bailout strategy and thus selects for more challenging cases.

Prevalence, predictors, and outcomes of advance directives in implantable cardioverter-defibrillator recipients.

BACKGROUND: Little is known about advance directive (AD) utilization in implantable cardioverter-defibrillator (ICD) recipients. OBJECTIVE: The purpose of this study was to define the prevalence and predictors of ADs in patients with ICDs. METHODS: We identified ICD recipients with ADs at our institution. The primary end point was the prevalence of an AD documented up to 1 year after device implant and the secondary end point was the cumulative prevalence of an AD. RESULTS: Of 2549 patients with ICDs, 701 (27.5%) were followed for at least 1 year after device implant, and of those 701 patients, 164 (23.4%) had ADs documented before or within 1 year of ICD implant. The prevalence of ICD recipients with ADs increased overtime, reaching approximately 10% in the most recent years of analysis. However, only 1 AD specifically addressed the ICD as part of end-of-life decision making. In multivariable analysis, more recent year of device implant and prior cardiovascular hospitalization were positively associated with having an AD within 1 year of implant. The cumulative prevalence of an AD at any time after implant reached about 30%, with more recent implant year, prior cardiovascular hospitalization, and palliative care consultation positively associated with the presence of an AD and black race associated with a lower cumulative prevalence. CONCLUSION: In a tertiary academic medical center, most patients with ICDs still do not have ADs, and even when they do, the ICDs are rarely addressed as part of the directive. Several predictors of ADs emerged, which may provide opportunities to improve utilization of ADs in ICD recipients.

Procedural outcomes and long-term survival following trans-venous defibrillator lead extraction in patients with end-stage renal disease.

AIMS: End-stage renal disease (ESRD) increases the risk of implantable cardioverter-defibrillator (ICD) infection. We sought to define outcomes of lead extraction in patients with ESRD. METHODS AND RESULTS: Implantable cardioverter-defibrillator lead extractions at our institution from January 2006 to March 2014 were stratified by absence (Control-Ex, n = 465) or presence (ESRD-Ex, n = 43) of ESRD. Procedural outcomes and survival were determined by medical records review. Survival in the ESRD-Ex group was compared with a contemporaneous cohort with ESRD undergoing ICD lead implantation (ESRD-I, n = 127). Among extraction patients, those with ESRD were more likely to be extracted for infection (74.4% vs. 28.6%, P < 0.001). Extraction procedure success (Control-Ex: 97% vs. ESRD-Ex: 93%, P = 0.17) and procedural deaths (Control-Ex: 1.1% vs. ESRD-Ex: 2.3%, P = 0.413) were similar. Survival 1 year following extraction was worse in the ESRD-Ex group compared with the Control-Ex, with a survival rate of 65.6% vs. 92.6% (P < 0.001); these curves continued to diverge through year 3. One-year survival in the ESRD-Ex group was worse than among ESRD patients undergoing ICD implant (ESRD-I), but these curves converged and survival was similar by year 3. CONCLUSIONS: Implantable cardioverter-defibrillator lead extraction can be performed safely and effectively in patients with ESRD. However, despite high rates of procedural success, long-term mortality following extraction in ESRD patients is substantial. Much of the long-term mortality risk appears to be accounted for by the presence of ESRD and an indication for an ICD.

Improving ultrasound for appendicitis through standardized reporting of secondary signs.

OBJECTIVE: Our aim was to implement a standardized US report that included secondary signs of appendicitis (SS) to facilitate accurate diagnosis of appendicitis and decrease the use of computed tomography (CT) and admissions for observation. METHODS: A multidisciplinary team implemented a quality improvement (QI) intervention in the form of a standardized US report and provided stakeholders with monthly feedback. Outcomes including report compliance, CT use, and observation admissions were compared pretemplate and posttemplate. RESULTS: We identified 387 patients in the pretemplate period and 483 patients in the posttemplate period. In the posttemplate period, the reporting of SS increased from 5.4% to 79.5% (p<0.001). Despite lower rates of appendix visualization (43.9% to 32.7%, p<0.001) with US, overall CT use (8.5% vs 7.0%, p=0.41) and the negative appendectomy rate remained stable (1.0% vs 1.0%, p=1.0). CT utilization for patients with an equivocal ultrasound and SS present decreased (36.4% vs 8.9%, p=0.002) and admissions for observations decreased (21.5% vs 15.3%, p=0.02). Test characteristics of RLQ US for appendicitis also improved in the posttemplate period. CONCLUSION: A focused QI initiative led to high compliance rates of utilizing the standardized US report and resulted in lower CT use and fewer admissions for observation. Study of a Diagnostic Test Level of Evidence: 1.

Secondary signs may improve the diagnostic accuracy of equivocal ultrasounds for suspected appendicitis in children.

INTRODUCTION: Ultrasound (US) is the preferred imaging modality for evaluating appendicitis. Our purpose was to determine if including secondary signs (SS) improve diagnostic accuracy in equivocal US studies. METHODS: Retrospective review identified 825 children presenting with concern for appendicitis and with a right lower quadrant (RLQ) US. Regression models identified which SS were associated with appendicitis. Test characteristics were demonstrated. RESULTS: 530 patients (64%) had equivocal US reports. Of 114 (22%) patients with equivocal US undergoing CT, those with SS were more likely to have appendicitis (48.6% vs 14.6%, p<0.001). Of 172 (32%) patients with equivocal US admitted for observation, those with SS were more likely to have appendicitis (61.0% vs 33.6%, p<0.001). SS associated with appendicitis included fluid collection (adjusted odds ratio (OR) 13.3, 95% confidence interval (CI) 2.1-82.8), hyperemia (OR=2.0, 95%CI 1.5-95.5), free fluid (OR=9.8, 95%CI 3.8-25.4), and appendicolith (OR=7.9, 95%CI 1.7-37.2). Wall thickness, bowel peristalsis, and echogenic fat were not associated with appendicitis. Equivocal US that included hyperemia, a fluid collection, or an appendicolith had 96% specificity and 88% accuracy. CONCLUSION: Use of SS in RLQ US assists in the diagnostic accuracy of appendicitis. SS may guide clinicians and reduce unnecessary CT and admissions.

The use of bedside ultrasound in the evaluation of patients presenting with signs and symptoms of pulmonary embolism.

Evaluation of patients that present to the emergency department with concerns for the diagnosis of pulmonary embolism can be difficult. Modalities including computerized tomography (CT) of the chest, pulmonary angiography, and ventilation perfusion scans can expose patients to large quantities of radiation especially if the study has to be repeated due to poor quality. This is particularly a concern in the pregnant population that has an increased incidence of pulmonary embolism and may not be able to undergo multiple radiographic studies due to fetal radiation exposure. This paper presents a case of a pregnant patient with signs and symptoms concerning pulmonary embolism. The paper discusses the use of bedside ultrasound in the evaluation of patients with pulmonary embolism.

Genes affecting the cell cycle, growth, maintenance, and drug sensitivity are preferentially regulated by anti-HER2 antibody through phosphatidylinositol 3-kinase-AKT signaling.

The molecular mechanisms by which the anti-HER2 antibodies trastuzumab and its murine equivalent 4D5 inhibit tumor growth and potentiate chemotherapy are not fully understood. Inhibition of signaling through the phosphatidylinositol 3-kinase (PI3K)-AKT pathway may be particularly important. Treatment of breast cancer cells that overexpress HER2 with trastuzumab inhibited HER2-HER3 association, decreased PDK1 activity, reduced Thr-308 and Ser-473 phosphorylation of AKT, and reduced AKT enzymatic activity. To place the role of PI3K-AKT in perspective, gene expression was studied by using Affymetrix microarrays and real time reverse transcription-PCR. Sixteen genes were consistently down-regulated 2.0-4.9-fold in two antibody-treated breast cancer cell lines. Fourteen of the 16 genes were involved in three major functional areas as follows: 7 in cell cycle regulation, particularly of the G(2)-M; 5 in DNA repair/replication; and 2 in modifying chromatin structure. Of the 16 antibody-regulated genes, 64% had roles in cell growth/maintenance and 52% contributed to the cell cycle. Direct inhibition of PI3K with an inhibitor markedly reduced expression of 14 genes that were also affected by the antibody. Constitutive activation of AKT1 blocked the effect of the anti-HER2 antibody on cell cycle arrest and on eight differentially expressed genes. The antibody enhanced docetaxel-induced growth inhibition but did not increase the fraction of apoptotic cells induced with docetaxel alone. In contrast, the antibody plus docetaxel markedly down-regulated two genes, HEC and DEEPEST, required for passage through G(2)-M. Thus, anti-HER2 antibody preferentially affects genes contributing to cell cycle progression and cell growth/maintenance, in part through the PI3K-AKT signaling. Transcriptional regulation by anti-HER2 antibody through PI3K-AKT pathway may potentiate the growth inhibitory activity of docetaxel by affecting cell cycle progression.