Citations

AbstractWhile most Radiation Oncology clinics have adopted electronic charting in one form or another, no consensus document exists that provides guidelines for safe and effective use of the Radiation Oncology electronic medical records (RO‐EMR). Task Group 262 was formed to provide these guidelines as well as to provide recommendations to vendors for improving electronic charting functionality in future. Guidelines are provided in the following areas: Implementation and training for the RO‐EMR, acceptance testing and quality assurance (QA) of the RO‐EMR, use of the RO‐EMR as an information repository, use of the RO‐EMR as a workflow manager, electronic charting for brachytherapy and nonstandard treatments, and information technology (IT) considerations associated with the RO‐EMR. The report was based on a literature search by the task group, an extensive survey of task group members on their respective RO‐EMR practices, an AAPM membership survey on electronic charting, as well as group consensus.

Together, single-cell technologies and systems biology have been used to investigate previously unanswerable questions in biomedicine with unparalleled detail. Despite these advances, gaps in analytical capacity remain. Machine learning, which has revolutionized biomedical imaging analysis, drug discovery, and systems biology, is an ideal strategy to fill these gaps in single-cell studies. Machine learning additionally has proven to be remarkably synergistic with single-cell data because it remedies unique challenges while capitalizing on the positive aspects of single-cell data. In this review, we describe how systems-biology algorithms have layered machine learning with biological components to provide systems level analyses of single-cell omics data, thus elucidating complex biological mechanisms. Accordingly, we highlight the trifecta of single-cell, systems-biology, and machine-learning approaches and illustrate how this trifecta can significantly contribute to five key areas of scientific research: cell trajectory and identity, individualized medicine, pharmacology, spatial omics, and multi-omics. Given its success to date, the systems-biology, single-cell omics, and machine-learning trifecta has proven to be a potent combination that will further advance biomedical research.

AbstractThis first Guideline for Reasonable and Appropriate Care in the Emergency Department (GRACE‐1) from the Society for Academic Emergency Medicine is on the topic: Recurrent, Low‐risk Chest Pain in the Emergency Department. The multidisciplinary guideline panel used The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding eight priority questions for adult patients with recurrent, low‐risk chest pain and have derived the following evidence based recommendations: (1) for those >3 h chest pain duration we suggest a single, high‐sensitivity troponin below a validated threshold to reasonably exclude acute coronary syndrome (ACS) within 30 days; (2) for those with a normal stress test within the previous 12 months, we do not recommend repeat routine stress testing as a means to decrease rates of major adverse cardiac events at 30 days; (3) insufficient evidence to recommend hospitalization (either standard inpatient admission or observation stay) versus discharge as a strategy to mitigate major adverse cardiac events within 30 days; (4) for those with non‐obstructive (<50% stenosis) coronary artery disease (CAD) on prior angiography within 5 years, we suggest referral for expedited outpatient testing as warranted rather than admission for inpatient evaluation; (5) for those with no occlusive CAD (0% stenosis) on prior angiography within 5 years, we recommend referral for expedited outpatient testing as warranted rather than admission for inpatient evaluation; (6) for those with a prior coronary computed tomographic angiography within the past 2 years with no coronary stenosis, we suggest no further diagnostic testing other than a single, normal high‐sensitivity troponin below a validated threshold to exclude ACS within that 2 year time frame; (7) we suggest the use of depression and anxiety screening tools as these might have an effect on healthcare use and return emergency department (ED) visits; and (8) we suggest referral for anxiety or depression management, as this might have an impact on healthcare use and return ED visits.

Introduction: The T peak - T end interval (Tpe) is a measure of transmural dispersion of repolarisation with prolongation of this interval linked to an increased risk of ventricular arrhythmias and sudden death. Patients with cardiac amyloid experience a high rate of sudden cardiac death. Objective: To determine the prognostic utility of the Tpeak-Tend interval in patients with transthyretin (TTR) cardiac amyloidosis. Methods: Of the 240 patients who underwent evaluation for TTR amyloidosis at our tertiary referral center from 1966 to 2010, 39 met inclusion criteria (65 excluded for AF, 66 BBB/Paced Rhythm, 25 CAD, 21 other). Inclusion criteria were presence of histological diagnosis of TTR amyloid and confirmed cardiac involvement by echocardiogram or biopsy and absence of atrial fibrillation (AF) or bundle branch block/paced rhythm on the index surface ECG, or history of coronary heart disease (CAD). Tpe was measured in leads V3 and V5. Cox proportional hazards model were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Kaplan-Meier curves were used to estimate overall survival and differences between curves were estimated using log rank. Primary endpoints were death or heart transplantation. Results: Of the 39 patients, 85% were male, and 69% were mTTR. Mean age 66.4 ± 13.9 years. Mean follow up period of 4.2 ± 3.2 years, 25 died and 5 received heart transplants. Median survival was 3.8 years, with 5 year survival 34%. On univariate analysis, Tpe in lead V3 was predictive of adverse outcome, HR per 10msec, 1.195 (1.051-1.370). Further multivariate analysis, in a model accounting for age, gender, Lead V3 Tpe was independently associated with survival, HR per 10msec, 1.207, (1.094-1.411, p=0.009). Conclusions: The Tpe interval in Lead V3 at diagnosis is a novel, noninvasive independent predictor of survival in transthyretin cardiac amyloidosis patients in sinus rhythm.

Introduction: Appropriate selection of patients (pts) with heart failure (HF) who may benefit from cardiac resynchronization therapy (CRT) is difficult. We sought to identify a clinical risk score to better risk stratify patients prior to CRT implantation. Methods: Pts undergoing CRT at Mayo Clinic from 2000 –2005 were included. Multiple clinical variables (age, gender, anemia (Hgb <10g/dL), RF (creatinine clearance ≤ 60ml/min/1.73m 2 ), hyponatremia (Na ≤130mEq/L), elevated BNP level (>500pg/ml), etiology, EF ≤20%, and advanced HF (NYHA functional class III–IV) were assessed with outcomes following CRT. Multivariate analysis was used to determine a clinical risk score. Results: A total of 496 patients (80% males) age 68 ± 12 years (62% ischemic cardiomyopathy, EF 22% ± 8%) were included. In univariate analysis relative risk (RR) was > 1 for RF (RR 1.8, CI 1.3–2.8; p = 0.002), anemia (RR 3.3, CI 1.8 –5.5; p = 0.001), hyponatremia (RR 3.4, CI 1.4 – 6.9; p = 0.008), elevated BNP (RR 2.9, CI 1.6 –5.7; p < 0.001), ischemic cardiomyopathy (ICM) (RR 1.8, CI 1.2–2.7; p < 0.002), EF ≤ 20% (RR 1.5, CI 1.0 –2.1; p = 0.033), and advanced HF (RR 2.5, CI 1.5– 4.9; p < 0.001). Following multivariate analysis RF, anemia, ICM, and advanced HF remained significant predictors of poor outcome (p >0.01 for all). Survival with 3 or more of these clinical risk factors was significantly worse than with less risk factors (p <0.01, Figure ). Conclusions: Pre-implant clinical risk factors including anemia, RF, ICM and advanced HF predict worse outcome following CRT with ≥3 variables predicting >2-fold increased risk of death or heart transplantation. These factors should be considered when selecting pts prior to CRT.

Background: Atrial fibrillation (AF) is common in HCM yet the mechanisms are poorly understood but are likely secondary to either the consequences of left atrial structural remodeling (LASR) or myopathy, or triggers arising from pulmonary and other thoracic veins. The presence and severity of LASR as characterized by left atrial strain (LA ϵ), and its relationship to AF in HCM, has not been determined. Therefore, we measured LA ϵ and strain rate (SR) in Pts with HCM both with (AF+) and without (AF−) prior AF and compared these measures to those in age and gender matched controls without HCM or AF. Methods: Two-dimensional speckle-derived LA longitudinal peak ϵ, SR during systole (SR S ), early (SR E ) and late diastole (SR A ) were measured at the basal and mid portions of the lateral, septal, and posterior LA walls using Vector Velocity Imaging during sinus rhythm and were averaged. Results: Mean age of Pts in each of the matched groups was 56 ± 2 years (16 males; 59%). Significant left ventricular outflow tract obstruction was present in all Pts with HCM. Diastolic dysfunction was similar in both HCM groups and worse when compared to controls. Peak LA 3 , SR S , SR E , and SR A for each group is shown (table 1 ). HCM was associated with significantly lower LA ϵ and SR compared to controls. Although LA size was increased in Pts with HCM when compared to controls there was no correlation between LA size and ϵ or SR (p>0.05 for all). No differences in LA ϵ and SR were found between AF+ versus AF− Pts. Conclusion: HCM is associated with LASR as determined by decreased LA ϵ and SR. However, LA ϵ and SR were similar in AF+ versus AF− Pts suggesting that the occurrence of AF in HCM is not due to LASR alone. Table 1. Left Atrial Strain and Strain Rate in Hypertrophic Cardiomyopathy

Background: Cardiac resynchronization therapy (CRT) improves global systolic function in left ventricle. However, the impact of CRT on regional myocardial function is less clear. The aim of this study, therefore, is to evaluate regional changes in myocardial strain after CRT. Methods: Speckle tracking echocardiography (STE) was performed in 91 patients before and 6 month after CRT. Peak longitudinal strain was measured in 18 segments at base, mid and apex in three apical views. Left ventricular end-systolic volume (ESV) was measured by biplane Simpson’s method and reverse remodeling was defined as 10 % reduction in ESV at 6 month after CRT. Results: Peak strain improved in basal and mid segments of medial walls (basal inferoseptal, anteroseptal and inferior segments, p<0.05, mid inferoseptal and inferior segments: p<0.01) in entire group after CRT, with a greater degree of improvement in CRT responders than in nonresponders (Figure ). There was no significant improvement in free wall strain, with significant reduction in basal inferolateral segment after CRT (P=0.047) in entire group. Nonresponders had significant reduction in strain at the mid anterolateral segment (P=0.004) (Figure ). Strain of the apical segments also did not improve. Conclusions: CRT induces reverse remodeling by enhancing regional myocardial function in the septum, but suppresses the function in the free wall. Lack of reverse remodeling after CRT was characterized by the reduced function in lateral segments without improvement in septal function..

Introduction: Whether echocardiographic (echo) markers of left ventricular (LV) remodeling and diastolic dysfunction contribute incremental and independent prognostic information to clinical risk markers in patients (Pts) with coronary artery disease and severe LV systolic dysfunction is unclear. We sought to determine which echo variables provide the greatest prognostic value in the Surgical Treatment for Ischemic Heart Failure (STICH) population. Methods: Pts enrolled in STICH for whom transmitral Doppler (E/A ratio) was available on a baseline echo interpreted by an echo core laboratory blinded to treatment and outcomes formed the analysis cohort. Comprehensive datasets to account for missing echo data were created by multiple imputation and the impact on all-cause mortality was determined with the Cox’s regression model. Results: E/A ratio could be measured in 1511 of the 2136 Pts enrolled in STICH. Amongst markers of diastolic dysfunction, E/A ratio was the most significant predictor of mortality (χ 2 41.05, p <0.001) with a non-linear, u-shaped, relationship. Mortality was lowest with E/A ratio = 1.0, and increased for E/A ratio <0.6 and >1.0 up to 2.3, beyond which there was no further increase in risk. The combination of larger LV end-systolic volume index (LVESVI), low or high E/A ratio, and mitral regurgitation severity grade, had highly significant incremental negative effects on mortality (χ 2 69.65, p<0.001) when added to a multivariable model with clinical risk markers. Overall, creatinine (χ 2 30.00, p <0.001), followed by LVESVI (χ 2 27.26, p<0.001), age, and E/A ratio (χ 2 12.46, p<0.001) were among the most significant predictors of mortality and accounted for 74% of the total prognostic information. LVESVI and E/A ratio were stronger predictors of poor prognosis than New York Heart Association (NYHA) functional class, hemoglobin, diabetes, stroke, or atrial fibrillation. Conclusions: Echo markers of advanced LV remodeling and diastolic dysfunction add incremental prognostic value to clinical risk markers and are more predictive of poor prognosis than advanced NYHA functional class or anemia. LVESVI and E/A ratio outperformed other echo markers and should be considered standard in assessing risk in Pts with ischemic LV dysfunction.

Increasing age is a major risk factor for calcific aortic valve disease (CAVD). Interestingly, SIRT6 knockout mice have a marked progeroid phenotype, and we recently reported that sirtuin enzyme expression is dramatically reduced with aging and that SIRT6 expression is reduced further in valves from patients with end-stage CAVD. It is unknown, however, whether experimentally reducing SIRT6 promotes osteogenic signaling in the valve and ultimately accelerates progression of CAVD. Thus, we used cultured mouse aortic valve interstitial cells and ldlr-deficient, apolipoprotein B100-only mice (LA) that were SIRT6 wild-type (LA-SIRT6 +/+ ) or heterozygous (LA-SIRT6 +/- ) and fed a Western diet for 3 or 12 months to determine the role of SIRT6 in valve calcification. In vitro , reduction of SIRT6 increased histone acetylation and significantly increased mRNA and protein levels of the osteogenic genes Runx2 and Sp7 in response to bone morphogenetic protein 2 (100ng/ml BMP2 for 18 hours), and siRNA knockdown of SIRT6 increased mRNA levels of Sp7 even in the absence of exogenous bone morphogens. Using high-resolution ultrasound to evaluate aortic valve function in vivo, we found that 3 month old LA-SIRT6 +/- mice did not have significant impairments in valve function compared to LA-SIRT6 +/+ mice. In contrast, 12 month old LA-SIRT6 +/- had dramatically worsened aortic valve dysfunction and stenosis compared to LA-SIRT6 +/+ mice, which was also associated with reductions in left ventricular ejection fraction. Collectively, our data strongly suggest SIRT6 plays a critical role in the tonic repression of osteogenic signaling in the aortic valve, and that age-related reductions in SIRT6 are likely to increase susceptibility to valve calcification in response to risk factors for CAVD such as hypercholesterolemia. Collectively, increasing activity of SIRT6 or reducing acetylation of its targets may serve as viable therapeutic strategies to slow progression of age-related valvular calcification and stenosis.

Marfan syndrome (MFS) is a genetic disease with a mutation for the microfibrillar constituent protein fibrillin-1 being the most prevalent. MFS is often associated with progressive aortic root dilation, ultimately progressing to aortic aneurysm and dissection. While recent work has shown that increased angiotensin-II receptor type-1 and transforming growth factor beta (TGF-β) signaling contributes to aneurysm formation in aorta, efficacious therapeutic targets remain elusive. Given previous reports of progeriod phenotypes in a subset of Marfan patients, we sought to determine whether there are molecular changes that are consistent with accelerated aging in a mouse model of Marfan syndrome. In mice carrying a loss-of-function mutation in fibrillin-1, we assessed aortic root dimensions by echocardiography and gene expression levels of TGF-β1-3, runt related transcription factor 2 (RUNX2), and the cellular senescent marker CDKN2A by quantitative real time PCR at 3 and 14 months of age. As expected, aortic sinus dimensions did not change significantly with aging in wild type mice, but increased dramatically in fibrillin-1 mutant mice compared to wild-type littermate controls and with age (p < 0.05 for both). TGF-β1 ligand expression paralleled age and disease-dependent changes in aortic dimensions, however TGF-β2 and TGF-β3 mRNA levels did not. Aortic dilatation was associated with increased gene expression of RUNX2 with aging and in marfanoid mice. Interestingly, fibrillin-1 mutant mice demonstrated marked increases in expression of the anti-proliferative cell-cycle checkpoint protein CDKN2A at both time points, and correlated with changes in TGF-β1 (R 2 =0.54) and RUNX2 (R 2 =0.69) mRNA. CDNK2A gene expression patterns, however, demonstrated a poor correlation with expression of TGF-β2 and TGF-β3 (R 2 =0.04 and 0.06. respectively). Collectively, these data lend insight into novel mechanisms that may regulate development of aortic root dilation in patients MFS and are the first to implicate increased senescent cell burden in Marfan syndrome. Furthermore, we propose that clearance of senescent cells could be a viable therapeutic intervention to slow progression aortic root-dilation and aneurysm in patients with Marfan syndrome.