Citations

Purpose: The purpose of this study was to establish the test-retest reliability and concurrent validity of the Modified Brief Fatigue Inventory (MBFI) and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-Fatigue) scale in a population of patients treated for cancers of the head and neck. Methods: The MBFI and the FACIT-Fatigue were administered to 65 participants in a tertiary medical center with a diagnosis of head and neck cancer (HNC), skin cancer, and thyroid cancer who had undergone surgery within the past 3 months and/or were currently receiving radiation and/or chemotherapy treatments. Test-retest reliability, internal consistency, and concurrent validity are reported. Results: For the HNC group, the MBFI had an intraclass correlation coefficient (ICC) of 0.825 (0.68-0.91) and an internal consistency of 0.828. The FACIT-Fatigue ICC was 0.866 (0.75-0.93) and internal consistency was 0.874. The MBFI ICC for the skin and thyroid cancer groups was 0.932 (0.76-0.98) and 0.880 (0.60-0.97), and internal consistency of 0.929 and 0.880, respectively. The FACIT-Fatigue ICC for the skin and thyroid cancer groups was 0.945 (0.81-0.99) and 0.941 (0.81-0.98), and the internal consistency was 0.945 and 0.941, respectively. The Spearman ρ correlation coefficient for concurrent validity of the MBFI and FACIT-Fatigue was −0.871 for HNC, −0.838 for skin cancer, and −0.903 for thyroid cancer. Conclusions: The MBFI and the FACIT-Fatigue demonstrate good test-retest reliability, internal consistency, and concurrent validity for all subgroups. The FACIT-Fatigue demonstrates a slight advantage over the MBFI with respect to test-retest reliability and internal consistency.

BACKGROUND: The use of cognitive aids, such as emergency manuals (EMs), improves team performance on critical steps during crisis events. In our large academic anesthesia practice, we sought to broadly implement an EM and subsequently evaluate team member performance on critical steps. METHODS: We observed the phases of implementing an EM at a large academic anesthesia practice from 2013 to 2016, including the formation of the EM implementation team, identification of preferred EM characteristics, consideration of institution-specific factors, selection of the preferred EM, recognition of logistical barriers, and staff education. Utilization of the EM was tested in a regular clinical environment with all available resources using a standardized verbal simulation of 3 crisis events both preimplementation and 6 months postimplementation. Individual members of the anesthesia team were asked to verbalize interventions for specific crisis events over 60 seconds. RESULTS: We introduced a customized version of the Stanford Emergency Manual on January 26, 2015. Fifty-nine total participants (equal proportion of anesthesiology attending physicians, resident physicians, certified registered nurse anesthetists, and student registered nurse anesthetist staff) were surveyed in the preimplementation phase and 60 in the 6-month postimplementation phase. In the postimplementation phase, a minority (41.7%) utilized the EM for the verbal-simulated crisis events. Those who used the EM performed better than those who did not (median 21.0 critical steps out of a possible 30 total steps [70.0%], interquartile range 19–25 vs 18.0 critical steps verbalized [60.0%], interquartile range 16–20; P < .001). Among all subjects, the median number of critical steps verbalized was 16 (53.3%) preimplementation and 19.5 critical steps (65.0%) postimplementation. CONCLUSIONS: Implementation of an EM in a large academic anesthesia practice is not without challenges. While full integration of the EM was not achieved 6 months after implementation, verbalization of critical steps on 3 simulated crisis events improved when the EM was utilized.

Background: Patients with end-stage kidney disease (ESKD) on dialysis were excluded from clinical trials of direct oral anticoagulants for atrial fibrillation (AF). Recent data have raised concerns regarding the safety of dabigatran and rivaroxaban, but apixaban has not been evaluated despite current labeling supporting its use in this population. The goal of this study was to determine patterns of apixaban use and its associated outcomes in dialysis-dependent patients with ESKD and AF. Methods: We performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System (October 2010 to December 2015). Eligible patients were those with ESKD and AF undergoing dialysis who initiated treatment with an oral anticoagulant. Because of the small number of dabigatran and rivaroxaban users, outcomes were only assessed in patients treated with apixaban or warfarin. Apixaban and warfarin patients were matched (1:3) based on prognostic score. Differences between groups in survival free of stroke or systemic embolism, major bleeding, gastrointestinal bleeding, intracranial bleeding, and death were assessed using Kaplan–Meier analyses. Hazard ratios (HRs) and 95% CIs were derived from Cox regression analyses. Results: The study population consisted of 25 523 patients (45.7% women; 68.2±11.9 years of age), including 2351 patients on apixaban and 23 172 patients on warfarin. An annual increase in apixaban prescriptions was observed after its marketing approval at the end of 2012, such that 26.6% of new anticoagulant prescriptions in 2015 were for apixaban. In matched cohorts, there was no difference in the risks of stroke/systemic embolism between apixaban and warfarin (HR, 0.88; 95% CI, 0.69–1.12; P =0.29), but apixaban was associated with a significantly lower risk of major bleeding (HR, 0.72; 95% CI, 0.59–0.87; P <0.001). In sensitivity analyses, standard-dose apixaban (5 mg twice a day; n=1034) was associated with significantly lower risks of stroke/systemic embolism and death as compared with either reduced-dose apixaban (2.5 mg twice a day; n=1317; HR, 0.61; 95% CI, 0.37–0.98; P =0.04 for stroke/systemic embolism; HR, 0.64; 95% CI, 0.45–0.92; P =0.01 for death) or warfarin (HR, 0.64; 95% CI, 0.42–0.97; P =0.04 for stroke/systemic embolism; HR, 0.63; 95% CI, 0.46–0.85; P =0.003 for death). Conclusions: Among patients with ESKD and AF on dialysis, apixaban use may be associated with a lower risk of major bleeding compared with warfarin, with a standard 5 mg twice a day dose also associated with reductions in thromboembolic and mortality risk.

Background and Purpose— Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. Methods— We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P <5×10 − 8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0–2 versus 3–6) modified Rankin Scale using ordinal and logistic regression, respectively. Results— The discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P =4.4×10 −8 ) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P =4.3×10 −8 ) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 ( P =0.04; meta-analysis P =2.5×10 −9 ; heterogeneity, P =0.16) but not for 22q13 ( P =0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P =0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P =0.045). Conclusions— We identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.

We investigated the effect of candidate variants in AS3MT (arsenic (III) methyltransferase) with urinary arsenic metabolites and their principal components in a subset of 264 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Urinary arsenic species, including inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), and arsenobetaine (Ab), were measured using high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS) and corrected for organic sources from seafood consumption by regressing Ab on arsenic species using a validated method. Principal components of arsenic metabolism were also used as independent phenotypes. We conducted linear regression of arsenic traits with allelic dosage of candidate single nucleotide polymorphisms (SNPs) rs12768205 (G > A), rs3740394 (A > G), and rs3740393 (G > C) measured using Illumina MetaboChip. Models were stratified by non-Hispanic white vs. all other race/ethnicity and adjusted for age, sex, arsenic exposure, study site, and population stratification. Consistent with previous studies, rs12768205 showed evidence for strongest association (non-Hispanic white: iAs% −0.14 (P 0.83), MMA% −0.66 (0.49), DMA% 0.81(0.49); other race/ethnicity: 0.13 (0.71), −1.21 (0.09), 1.08 (0.20)). No association, however, passed the strict Bonferroni p-value. This was a novel study among an ethnically diverse population exposed to low arsenic levels.

Pump thrombosis is a major adverse event in patients supported on continuous-flow left ventricular assist devices (CF-LVAD). The aim of this systematic review and meta-analysis was to determine the outcomes of various treatment approaches for pump thrombosis, including surgical as compared to medical therapy. Electronic search was performed to identify all studies in the English literature addressing surgical and medical management of pump thrombosis in the modern CF-LVAD era. All identified articles were systematically assessed for inclusion and exclusion criteria. In the meta-analysis, because of significant overlap of the data, reports based on trials, registries, and individual cohort studies were analyzed separately. Forty-three studies were included in the analysis (2 trials, 4 registry reports, and 37 individual cohort studies). 2,281/28,728 (10.6%) patients developed pump thrombosis, of which 44.4% and 55.1% were supported on the HeartWare and HeartMate II, respectively. To avoid overlap in studies and to seek more granular data, pooled individual cohort studies were found to be representative of the entire population, and further in-depth analysis of this category was performed. Of the 610/5,545 (11.8%) patients with pump thrombosis in these individual cohort studies, 225 patients had surgical pump exchange, and 186 were treated medically. Surgical therapy resulted in higher success as compared to medical therapy (81.3% vs. 45.4%; p < 0.001), lower 30 day mortality rate (16.7% vs. 34.5%; p = 0.013) and recurrence rate (11.8% vs. 38.3%; p < 0.001). Meta-regression of all studies demonstrates a possible temporal increase of pump thrombosis rate (p = 0.040). Surgical pump exchange is superior to medical therapy with a higher success rate of pump thrombosis resolution, lower mortality rate, and lower recurrence rate. Randomized controlled prospective studies are needed to compare these clinical approaches and their resultant outcomes to guide decision-making for the management of CF-LVAD thrombosis.

Abstract Purpose: Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for the manipulability and tolerance of transgenes. Poor tumor selectivity, off-target sequestration, and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumor-selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but nondetectable in healthy tissues. Experimental Design: Ad5NULL-A20 harbors mutations in each major capsid protein to preclude uptake via all native pathways. Tumor-tropism via αvβ6 targeting was achieved by genetic insertion of A20 peptide (NAVPNLRGDLQVLAQKVART) within the fiber knob protein. The vector's selectivity in vitro and in vivo was assessed. Results: The tropism-ablating triple mutation completely blocked all native cell entry pathways of Ad5NULL-A20 via coxsackie and adenovirus receptor (CAR), αvβ3/5 integrins, and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced αvβ6+ cell lines and primary clinical ascites-derived EOC ex vivo, including in the presence of preexisting anti-Ad5 immunity. In vivo biodistribution of Ad5NULL-A20 following systemic delivery in non–tumor-bearing mice was significantly reduced in all off-target organs, including a remarkable 107-fold reduced genome accumulation in the liver compared with Ad5. Tumor uptake, transgene expression, and efficacy were confirmed in a peritoneal SKOV3 xenograft model of human EOC, where oncolytic Ad5NULL-A20–treated animals demonstrated significantly improved survival compared with those treated with oncolytic Ad5. Conclusions: Oncolytic Ad5NULL-A20 virotherapies represent an excellent vector for local and systemic targeting of αvβ6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors. Clin Cancer Res; 24(17); 4215–24. ©2018 AACR.