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Heart failure with preserved ejection fraction (HFpEF) represents a prototypical cardiovascular condition in which machine learning may improve targeted therapies and mechanistic understanding of pathogenesis. Machine learning, which involves algorithms that learn from data, has the potential to guide precision medicine approaches for complex clinical syndromes such as HFpEF. It is therefore important to understand the potential utility and common pitfalls of machine learning so that it can be applied and interpreted appropriately. Although machine learning holds considerable promise for HFpEF, it is subject to several potential pitfalls, which are important factors to consider when interpreting machine learning studies.

Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors. Here, we describe a method to harness this abnormal splicing activity to drive splicing factor mutation-dependent gene expression to selectively eliminate tumor cells. We engineered synthetic introns that were efficiently spliced in cancer cells bearing SF3B1 mutations, but unspliced in otherwise isogenic wild-type cells, to yield mutation-dependent protein production. A massively parallel screen of 8,878 introns delineated ideal intronic size and mapped elements underlying mutation-dependent splicing. Synthetic introns enabled mutation-dependent expression of herpes simplex virus-thymidine kinase (HSV-TK) and subsequent ganciclovir (GCV)-mediated killing of SF3B1-mutant leukemia, breast cancer, uveal melanoma and pancreatic cancer cells in vitro, while leaving wild-type cells unaffected. Delivery of synthetic intron-containing HSV-TK constructs to leukemia, breast cancer and uveal melanoma cells and GCV treatment in vivo significantly suppressed the growth of these otherwise lethal xenografts and improved mouse host survival. Synthetic introns provide a means to exploit tumor-specific changes in RNA splicing for cancer gene therapy.

Objectives This study aimed to investigate mitral annular dynamics in atrial fibrillation (AF) and after sinus rhythm restoration, and to assess the relationship between annular dynamics and mitral regurgitation (MR). Background AF can be associated with MR that improves after sinus rhythm restoration. Mechanisms underlying this atrial functional MR (AFMR) are ill-understood and generally attributed to left atrial remodeling. Methods Fifty-three patients with persistent AF and normal left ventricular ejection fraction were prospectively examined by means of 3-dimensional transesophageal echocardiography before, immediately after, and 6 weeks after electric cardioversion to sinus rhythm. Annular motion was assessed during AF and in sinus rhythm with the use of 3-dimensional analysis software, and the relationship with MR severity was explored. Results During AF and immediately after sinus rhythm restoration, the mitral annulus behaved relatively adynamically, with an overall change in annular area of 10.3% (95% CI: 8.7%-11.8%) and 12.2% (95% CI: 10.6%-13.8%), respectively. At follow-up, a significant increase in annular dynamics (19.0%; 95% CI: 17.4%-20.6%; P Conclusions Mitral annular dynamics are impaired in AF, with blunted presystolic narrowing that contributes to AFMR. Sinus rhythm restoration allows gradual recovery of presystolic annular dynamics. Improved annular dynamics decrease AFMR severity by optimizing annular-leaflet imbalance, regardless of LA remodeling.

Background The current standard of care for the treatment of patients with primary mitral regurgitation (MR) is surgical mitral valve repair. Transcatheter edge‐to‐edge repair with the MitraClip device provides a less invasive treatment option for patients with both primary and secondary MR. Worldwide, >150 000 patients have been treated with the MitraClip device. However, in the United States, MitraClip is approved for use only in primary patients with MR who are at high or prohibitive risk for mitral valve surgery. The REPAIR MR (Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery) trial is designed to compare early and late outcomes associated with transcatheter edge‐to‐edge repair with the MitraClip and surgical repair of primary MR in older or moderate surgical risk patients. Methods and Results The REPAIR MR trial is a prospective, randomized, parallel‐controlled, open‐label multicenter, noninferiority trial for the treatment of severe primary MR (verified by an independent echocardiographic core laboratory). Patients with severe MR and indications for surgery because of symptoms (New York Heart Association class II–IV), or without symptoms with left ventricular ejection fraction ≤60%, pulmonary artery systolic pressure >50 mm Hg, or left ventricular end‐systolic diameter ≥40 mm are eligible for the trial provided they meet the moderate surgical risk criteria as follows: (1) ≥75 years of age, or (2) if Conclusions The REPAIR MR trial will determine the safety and effectiveness of transcatheter edge‐to‐edge repair with the MitraClip in patients with primary MR who are at moderate surgical risk and are candidates for surgical MV repair. The trial will generate contemporary comparative clinical evidence for the MitraClip device and surgical MV repair. Registration https://clinicaltrials.gov/ct2/show/NCT04198870 ; NCT04198870.

BACKGROUND Pulmonary thromboendarterectomy (PTE) is a curative procedure for chronic thromboembolic pulmonary hypertension (CTEPH). Right ventricular free wall strain (RV FWS) and right atrial strain (RAS) are not well studied in a CTEPH population. We sought to determine temporal trends in RAS and RV FWS in patients post-PTE. METHODS 28 patients undergoing PTE for CTEPH were prospectively enrolled in a surgical database. Comprehensive echocardiographic assessment of the right heart was performed including RV FWS, right atrial volume, and the three components of RAS: reservoir, conduit, and booster strain. RESULTS Patients undergoing PTE demonstrated improvement in NYHA functional class (P

PurposeGrounded in hydrodynamic theory, proximal isovelocity surface area (PISA) is a simplistic and practical technique widely used to quantify valvular regurgitation flow. PISA provides a relatively reasonable, though slightly underestimated flow rate for circular orifices. However, for elliptical orifices frequently seen in functional mitral regurgitation, PISA underestimates the flow rate. Based on data obtained with computational fluid dynamics (CFD) and in vitro experiments using systematically varied orifice parameters, we hypothesized that flow rate underestimation for elliptical orifices by PISA is predictable and within a clinically acceptable range.MethodsWe performed 45 CFD simulations with varying orifice areas 0.1, 0.3 and 0.5 cm2, orifice aspect ratios 1:1, 2:1, 3:1, 5:1, and 10:1, and peak velocities (Vmax) 400, 500 and 600 cm/s. The ratio of computed effective regurgitant orifice area to true effective area (EROAC/EROA) against the ratio of aliasing velocity to peak velocity (VA/Vmax) was analyzed for orifice shape impact. Validation was conducted with in vitro imaging in round and 3:1 elliptical orifices.ResultsPlotting EROAC/EROA against VA/Vmax revealed marginal flow underestimation with 2:1 and 3:1 elliptical axis ratios against a circular orifice (A/Vmax), rising to ≤35% for 10:1 ratio. In vitro modeling confirmed CFD findings; there was a 8.3% elliptical EROA underestimation compared to the circular orifice estimate.ConclusionPISA quantification for regurgitant flow through elliptical orifices produces predictable, but generally small, underestimation deemed clinically acceptable for most regurgitant orifices.

Grounded in hydrodynamic theory, proximal isovelocity surface area (PISA) is a simplistic and practical technique widely used to quantify valvular regurgitation flow. PISA provides a relatively reasonable, though slightly underestimated flow rate for circular orifices. However, for elliptical orifices frequently seen in functional mitral regurgitation, PISA underestimates the flow rate. Based on data obtained with computational fluid dynamics (CFD) and in vitro experiments using systematically varied orifice parameters, we hypothesized that flow rate underestimation for elliptical orifices by PISA is predictable and within a clinically acceptable range. We performed 45 CFD simulations with varying orifice areas 0.1, 0.3 and 0.5 cm

Aims There is a wide spectrum of diseases associated with pulmonary hypertension, pulmonary vascular remodelling, and right ventricular dysfunction. The NIH-sponsored PVDOMICS network seeks to perform comprehensive clinical phenotyping and endophenotyping across these disorders to further evaluate and define pulmonary vascular disease. Methods and results Echocardiography represents the primary non-invasive method to phenotype cardiac anatomy, function, and haemodynamics in these complex patients. However, comprehensive right heart evaluation requires the use of multiple echocardiographic parameters and optimized techniques to ensure optimal image acquisition. The PVDOMICS echo protocol outlines the best practice approach to echo phenotypic assessment of the right heart/pulmonary artery unit. Conclusion Novel workflow processes, methods for quality control, data for feasibility of measurements, and reproducibility of right heart parameters derived from this study provide a benchmark frame of reference. Lessons learned from this protocol will serve as a best practice guide for echocardiographic image acquisition and analysis across the spectrum of right heart/pulmonary vascular disease.

OBJECTIVE: While American and European consensus statements advocate employing the ratio of the transmitral E velocity and tissue Doppler early diastolic mitral annular velocity (E/e’) in the assessment of left heart filling pressures, recent reports have questioned the reliability of this ratio to predict left atrial pressures in a variety of disease states. We hypothesized that there is a clinically significant correlation between E/e’ and pulmonary capillary wedge pressure (PCWP) in patients with severe aortic stenosis. DESIGN: Retrospective cohort study PARTICIPANTS: 733 consecutive patients with severe aortic stenosis who underwent Transcatheter Aortic Valve Replacement (TAVR) for severe aortic stenosis INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: PCWP and E/e’(ave) (average of the lateral and medial annulus tissue Doppler velocities) were measured using pulmonary artery catheter and transthoracic echocardiography during pre-procedural evaluation. Patients were grouped by left ventricular ejection fraction (LVEF) ≥ 50% and LVEF < 50%. Spearman rank correlation, anova, t-tests and chi squared tests were used to analyze the data. 79 patients met the inclusion criteria. There was no significant correlation between E/e’(ave) and PCWP (n=79, spearman, r=0.096 p=0.3994). This correlation did not improve when ventricular function was considered (LVEF < 50%: n=11, spearman, r=−0.097, p=0.776; LVEF≥ 50%: n=68, spearman, r=0.116, p=0.345). There was no statistically significant difference in mean PCWP between each range of E/e’(ave). CONCLUSION: We did not find a clinically relevant relationship between E/e’ and PCWP in patients with severe aortic stenosis.

OBJECTIVES This study was conducted to determine if gender bias explains the worse outcomes in women than in men who undergo mitral valve surgery for degenerative mitral regurgitation. METHODS Patients who underwent mitral valve surgery for degenerative mitral regurgitation with or without concomitant ablation surgery for atrial fibrillation were identified from the Cardiovascular Research Database of the Clinical Trial Unit of the Bluhm Cardiovascular Institute at Northwestern Memorial Hospital and were defined according to the Society of Thoracic Surgery National Adult Cardiac Surgery Database. Of the 1004 patients (33% female, mean age 62.1 ± 12.4 years; 67% male, mean age 60.1 ± 12.4 years) who met this criteria, propensity score matching was utilized to compare sex-related differences. RESULTS Propensity score matching of 540 patients (270 females, mean age 61.0 ± 12.2; 270 males, mean age 60.9 ± 12.3) demonstrated that 98% of mitral valve surgery performed in both groups was mitral valve repair and 2% was mitral valve replacement. Preoperative CHA2DS2-VASc scores were higher in women and fewer women were discharged directly to their homes. Before surgery, women had smaller left heart chambers, lower cardiac outputs, higher diastolic filling pressures and higher volume responsiveness than men. However, preoperative left ventricular and right ventricular strain values, which are normally higher in women, were similar in the 2 groups, indicating worse global strain in women prior to surgery. CONCLUSIONS The worse outcomes reported in women compared to men undergoing surgery for degenerative mitral regurgitation are misleading and not based on gender bias except in terms of referral patterns. Men and women who present with the same type and degree of mitral valve disease and similar comorbidities receive the same types of surgical procedures and experience similar postoperative outcomes. Speckle-tracking echocardiography to assess global longitudinal strain of the left and right ventricles should be utilized to monitor for myocardial dysfunction related to chronic mitral regurgitation.

Immune checkpoint blockade therapy has revolutionized cancer care, including the treatment of advanced metastatic disease. However, most patients derive little or no clinical benefit from these therapies and many cancer types are notoriously non-responsive. Motivated by (1) the correlation between tumor neoantigen abundance and anti-tumor immunity and (2) that most cancers are characterized by widespread dysregulation of RNA processing, we reasoned that pharmacologic modulation of RNA splicing might increase cancer cell immunogenicity via the generation of splicing-derived neoantigens. We demonstrated that two compounds which modulate RNA splicing via distinct mechanisms, inhibited tumor growth and enhanced response to immune checkpoint blockade in a manner dependent on host T cells and peptides presented on tumor MHC class I. Critical for their clinical translatability, therapeutic doses of splicing inhibitors were non-toxic, tolerated by the host immune system, and did not affect T cell activation, proliferation, and anti-cancer killing activities. Mechanistically, splicing modulation induced stereotyped, dose-dependent “splicing failure” — dramatic intron retention, alternative exon skipping, etc. — that was consistent across multiple mouse and human tumor types. By combining RNA-seq-based peptide predictions and mass spectrometry of the MHC I-bound immunopeptidome, we identified drug-induced, splicing-derived peptides that promote the expansion of antigen-specific CD8+ T cells and trigger anti-tumor T cell responses in vivo. These data definitively identify splicing modulation as an untapped source of immunogenic peptides and provide a means to enhance response to checkpoint blockade that is readily translatable to the clinic. Citation Format: James D. Thomas, Sydney X. Lu, Emma De Neef, Erich Sabio, Benoit Rousseau, Mathieu Gigoux, David A. Knorr, Benjamin Greenbaum, Yuval Elhanati, Simon J. Hogg, Andrew Chow, Arnab Ghosh, Abigail Xie, Dmitriy Zamarin, Daniel Cui, Caroline Erickson, Michael Singer, Hana Cho, Eric Wang, Bin Lu, Benjamin H. Durham, Harshal Shah, Diego Chowell, Austin M. Gabel, Yudao Shen, Jing Liu, Jian Jin, Matthew C. Rhodes, Richard E. Taylor, Henrik Molina, Jedd D. Wolchok, Taha Merghoub, Luis A. Diaz Jr, Omar Abdel-Wahab, Robert K. Bradley. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5742.

We present the novel use of a deep learning–derived technology trained on the skilled hand movements of cardiac sonographers that guides novice users to acquire high-quality bedside cardiac ultrasound images. We illustrate its use at the point of care through a series of patient encounters in the COVID-19 intensive care unit. (Level of Difficulty: Beginner.), Graphical abstract

Functional or secondary mitral regurgitation (MR) is associated with increased cardiovascular morbidity and mortality. Mechanistically, secondary MR is attributable to an imbalance between mitral leaflet tethering and closure forces, leading to poor coaptation. The pathophysiology of functional MR is most often the result of abnormalities in left ventricular function and remodeling, seen in ischemic or nonischemic conditions. Less commonly and more recently recognized is the scenario in which left ventricular geometry and function are preserved, the culprit being mitral annular enlargement associated with left atrial dilatation, termed atrial functional mitral regurgitation (AFMR). This most commonly occurs in the setting of chronic atrial fibrillation or heart failure with preserved ejection fraction. There is variability in the published reports and in current investigations as to the definition of AFMR. This paper reviews the pathophysiology of AFMR and focus on the need for a collective definition of AFMR to facilitate consistency in reported data and enhance much-needed research into outcomes and treatment strategies in AFMR.

Tricuspid valve (TV) degeneration after surgical repair with an annuloplasty ring is problematic as redo operation carries high mortality. This can be addressed with transcatheter therapies to implant a valve within in prior ring (tricuspid valve-in-ring). When an incomplete ring is present, paravalvular leak is commonly encountered after tricuspid valve-in-ring (TViR) implant; however, this can be addressed with paravalvular leak closure devices. Multimodality imaging including cardiac computed tomography and three-dimensional (3D) transesophageal echocardiography (TEE) are important for successful TViR implant. We report a case of tricuspid regurgitation after tricuspid repair with an incomplete annuloplasty ring and subsequent paravalvular leak closure.

While RNA-seq has enabled comprehensive quantification of alternative splicing, no correspondingly high-throughput assay exists for functionally interrogating individual isoforms. We describe pgFARM (paired guide RNAs for alternative exon removal), a CRISPR–Cas9-based method to manipulate isoforms independent of gene inactivation. This approach enabled rapid suppression of exon recognition in polyclonal settings to identify functional roles for individual exons, such as an SMNDC1 cassette exon that regulates pan-cancer intron retention. We generalized this method to a pooled screen to measure the functional relevance of ‘poison’ cassette exons, which disrupt their host genes’ reading frames yet are frequently ultraconserved. Many poison exons were essential for the growth of both cultured cells and lung adenocarcinoma xenografts, while a subset had clinically relevant tumor-suppressor activity. The essentiality and cancer relevance of poison exons are likely to contribute to their unusually high conservation and contrast with the dispensability of other ultraconserved elements for viability. pgFARM (paired guide RNAs for alternative exon removal) is a CRISPR–Cas9-based approach to manipulate alternative splicing and identify functional roles for individual exons, including poison exons with essential and tumor-suppressor roles.

PURPOSE: This study investigated the impact of bicuspid aortic valve (BAV) on valve morphology and motion as well as proximal and aortic hemodynamics using a same-day echocardiography and cardiac MRI. METHODS: Transthoracic echocardiography, two-dimensional cine MRI of the aortic valve, and aortic 4D flow MRI were performed on the same day in 9 normofunctional BAV patients (age=41±12, 3 female), 4 BAV with moderate to severe aortic stenosis (AS) (age=63±5, 1 female), and 36 healthy tricuspid aortic valve controls (age=52±10, 21 female). Valve opening and closing timings and transvalvular peak velocity were measured using B-mode and Doppler echocardiogram, respectively. Valve orifice morphology at fully-opened state was characterized using cine MRI. Ascending aortic (AAo) wall shear stress (WSS) was measured using 4D flow MRI data. RESULTS: Valve motion timings were similar between BAV and controls. BAV was associated with increased orifice aspect ratio (1.44±0.11 vs. 1.10±0.13, PCONCLUSION: A same-day echo and MRI imaging allows for comprehensive assessment of the impact of aortic valve disease on valve function and hemodynamics. In this pilot application to BAV, we found increased orifice aspect ratio may be responsible for increased transvalvular peak velocity and maximum AAo WSS.

Cardiomyopathy is a general term used to describe a heterogeneous group of diseases that result in impairment of ventricular function. Clinical manifestations of these diseases can range from an asymptomatic state to heart failure or arrhythmias to sudden cardiac death. Cardiac imaging, in particular echocardiography, plays a vital role in the diagnosis and management of affected individuals, and recently strain imaging has garnered great interest due to its superior ability to identify early functional abnormalities. This chapter focuses on the most common cardiomyopathies and will focus on longitudinal strain (LS) in the affected chamber; for most, this means left ventricular LS with the exception of arrhythmogenic right ventricular cardiomyopathy.

Introduction: Myocardial strain imaging provides a complex dataset that is often reduced to a single parameter, global longitudinal peak strain (GLPS). Raw temporal strain data is largely unexplored and restricted as studies often only save images of graphs lacking numerical data. While certain strain imaging packages do allow for the prospective export of raw data, the task is slow, rarely done, and cannot be done retrospectively. The troves of retrospective strain studies saved as images can be unlocked by reconstructing the numerical values contained in strain graphs. Such a dataset would be critical to future artificial intelligence strain analysis and morphological detection of disease modalities. This study aims to investigate the methods of extracting and reconstructing strain curve graphs to raw numerical outputs. Methods: By using vendor-specific color recognition algorithms, individual curves can be isolated as scattergram type plots of pixels. These pixel locations are converted to temporal strain values by defining scale factors for the graph. Intelligence-guided filtering, interpolation, and curve overlap filling can convert the pixel scattergrams into clean and complete temporal strain data. Using a set of 21 studies each containing 3 views (2Ch, 4Ch, APLAx) with each view containing 6 regional curves, 378 unique curves were reconstructed and compared to prospectively exported temporal strain data. Results: Results demonstrate that this method reconstructs the numerical data with high accuracy and precision. The reconstructed data was compared with the exported numerical data, yielding an average R 2 of .996 with an average runtime per study of 7.32s. The minute deviation from fidelity can be attributed to the finite resolution of the pixels in the analyzed graph. Discussion: Highly accurate temporal data can be extracted from routine strain graphs in clinical studies, which may allow for more nuanced assessment and deep learning of strain.

This study aims to systematically verify if the simplified geometry and flow profile of the left ventricular outflow tract (LVOT) assumed in 2D echocardiography is appropriate while examining the utility of 4D flow MRI to assess valvular disease. This prospective study obtained same-day Doppler echocardiography and 4D flow MRI in 37 healthy volunteers (age: 51.9 ± 18.2, 20 females) and 7 aortic stenosis (AS) patients (age: 64.2 ± 9.6, 1 female). Two critical assumptions made in echocardiography for aortic valve area assessment were examined, i.e. the assumption of (1) a circular LVOT shape and (2) a flat velocity profile through the LVOT. 3D velocity and shape information obtained with 4D flow MRI was used as comparison. It was found that the LVOT area was lower (by 26.5% and 24.5%) and the velocity time integral (VTI) was higher (by 28.5% and 30.2%) with echo in the healthy and AS group, respectively. These competing errors largely cancelled out when examining individual and cohort averaged LVOT stroke volume. The LVOT area, VTI and stroke volume measured by echo and 4D flow MRI were 3.6 ± 0.7 vs. 4.9 ± 1.0 cm

PURPOSE The purpose of this study was to evaluate the accuracy of four-dimensional (4D) flow MRI for direct assessment of peak velocity, flow volume, and momentum of a mitral regurgitation (MR) flow jets using an in vitro pulsatile jet flow phantom. We systematically investigated the impact of spatial resolution and quantification location along the jet on flow quantities with Doppler ultrasound as a reference for peak velocity. METHODS Four-dimensional flow MRI data of a pulsatile jet through a circular, elliptical, and 3D-printed patient-specific MR orifice model was acquired with varying spatial resolution (1.5-5 mm isotropic voxel). Flow rate and momentum of the jet were quantified at various axial distances (x = 0-50 mm) and integrated over time to calculate Voljet and MTIjet . In vivo assessment of Voljet and MTIjet was performed on 3 MR patients. RESULTS Peak velocities were comparable to Doppler ultrasound (3% error, 1.5 mm voxel), but underestimated with decreasing spatial resolution (-40% error, 5 mm voxel). Voljet was similar to regurgitant volume (RVol) within 5 mm, and then increased linearly with the axial distance (19%/cm) because of flow entrainment. MTIjet remained steady throughout the jet (2%/cm) as theoretically predicted. Four and 9 voxels across the jet were required to measure flow volume and momentum-time-integral within 10% error, respectively. CONCLUSION Four-dimensional flow MRI detected accurate peak velocity, flow rate, and momentum for in vitro MR-mimicking flow jets. Spatial resolution significantly impacted flow quantitation, which otherwise followed predictions of flow entrainment and momentum conservation. This study provides important preliminary information for accurate in vivo MR assessment using 4D flow MRI.

To determine the prevalence of concomitant aortic regurgitation (AR) in cardiac surgery and the outcomes of treatment options.Between April 2004 and June 2018, 3289 patients underwent coronary artery bypass, mitral valve, or aortic aneurysm surgery without aortic stenosis. AR was graded none/trivial (score = 0), mild (score = 1+), or moderate (score = 2+). Patients with untreated 2+ AR were compared with those with 0 or 1+ AR, and to those with 2+ AR who had aortic valve surgery. Thirty-day and late survival, echocardiography, and clinical outcomes were compared using propensity score matching.One hundred thirty-eight patients (4.2%) had 2+ AR; and 45 (33%) received aortic valve repair (n = 9) or replacement (n = 36) in the treated group and were compared with 2765 untreated patients with 0 AR and 386 patients with 1+ AR. Valve surgery was more common with anatomic leaflet abnormalities: bicuspid aortic valve (9% vs 0%; P lt; .01), rheumatic valve disease (16% vs 3%; P lt; .01), and calcification (47% vs 27%; P = .021). In unadjusted analysis, lower preoperative AR grade was associated with increased 10-year survival (P lt; .001). At year 10, progression to more-than-moderate AR among moderate AR patients was 2.6% and late intervention rate was 3.1%. In the untreated 2+ AR group, on last follow-up echocardiogram, 58% had improvement in AR, 41% remained 2+, and only 1% progressed to severe AR.Aortic valve surgery in select patients with concomitant moderate AR can be added with minimal added risk, but untreated AR does not influence long-term survival after cardiac surgery and rarely required late intervention.

How can we best prepare students for careers in our competitive environment? This paper examines how group work or cooperative learning is beneficial in the learning process. It examines certain areas of learning that lend themselves to cooperative learning. Cooperative learning leads to benefits and potential problems in working with groups. We examine ways to prepare successful groups for a project. The paper suggests ways to monitor group work in the classroom. Finally, it reports on a group work study taking place over many semesters in an introductory accounting class. Results include a very successful semester. While subsequent semesters provided good results, results were mixed. What can we do to enhance our students’ success in group work projects? The research points to several problem areas that can be addressed. What factors can we consider to improve our results? The research points to ways to prepare students for group work. This paper adds to the research by exploring ways to make group work more successful.

Biykem Bozkurt, MD, FACC, FAHA, Chair Hani Jneid, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, FACC, FAHA H. Vernon Anderson, MD, FACC, FAHA Lauren Gilstrap, MD[∗][1] Grant N. Graham, MD[∗][1] Gail K. Jones, MD[∗][1] David Kao, MD[∗][1] Leo Lopez, MD, FACC, FAHA, FASE[∗][1

Objective The ABEM ConCert Examination is a summative examination that ABEM-certified physicians are required to pass once in every 10-year cycle to maintain certification. This study was undertaken to identify practice settings of emergency physicians, and to determine if there was a difference in performance on the 2017 ConCert between physicians of differing practice types and settings. Methods This was a mixed methods cross sectional-study, using a post-examination survey and test performance data. All physicians taking the 2017 ConCert Examination who completed three survey questions pertaining to practice type, practice locations, and teaching were included. These three questions address different aspects of academia: self-identification, an academic setting, and whether the physician teaches. Results Among 2796 test administrations of the 2017 ConCert Examination, 2693 (96.3%) completed the three survey questions about practice environment. The majority (N = 2054; 76.3%) self-identified as primarily being a community physician, 528 (19.6%) as academic, and 111 (4.1%) as other. The average ConCert Examination score for community physicians was 83.5 (95% CI, 83.3–83.8); the academic group was 84.8 (95% CI, 84.3–85.3); and the other group was 82.3 (95% CI, 81.1–83.6). After controlling for initial ability as measured by the Qualifying Examination score, there was no significant difference in performance between academic and community physicians (p = .10). Conclusions Academic emergency physicians and community emergency physicians scored similarly on the ConCert. Working at a community teaching hospital was associated with higher examination performance. Teaching medical learners, especially non-emergency medicine residents, was also associated with better examination performance.

Assessing the severity of tricuspid regurgitation remains a challenging task, and although echocardiography is the test of choice, significant limitations of the current recommendations exist. Newer methods have been used in current trials of transcatheter devices and may improve our understanding of the disease process. Cardiac magnetic resonance imaging and computed tomography angiography may play significant roles as adjunctive imaging modalities. This paper reviews the imaging modalities currently used to quantify tricuspid regurgitation severity.

Background:Multi-parameter tumour gene expression assays (MPAs) are widely used to estimate individual patient residual risk and to guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) aims to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population where prospective RCT (Randomised Controlled Trial) evidence is lacking. Methods: OPTIMA is a partially blinded multi-center RCT with an adaptive two-stage design. The main eligibility criteria are women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomisation is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumour score (ROR_PT) >60 receive standard management whilst those with a low score (≤60) are treated with endocrine therapy alone. Endocrine therapy for pre-menopausal women includes ovarian suppression. The co-primary outcomes are (1) Invasive Disease Free Survival (IDFS) and (2) cost-effectiveness of test-directed treatment. Secondary outcomes include IDFS in patients with low-score tumours and quality of life. An integrated qualitative recruitment study addresses challenges to consent and recruitment and will build on experience from the feasibility study that a multidisciplinary approach at sites is important for recruitment success. Tumour blocks will be banked to allow evaluation of additional MPA technologies. Recruitment of 4500 patients over 5 years will permit demonstration of 3% non-inferiority of test-directed treatment, assuming 5-year IDFS of 85% with standard management, equivalent to a HR of 1.22. Inclusion of patients from the feasibility study will increase the power to test for non-inferiority. Results: The OPTIMA main trial opened in January 2017. Overall recruitment (including the feasibility study) will reach 1000 in August 2018. Recruitment in Norway will commence in July 2018. Characteristics of the OPTIMA main participants recruited to 31st May 2018 are shown in the table. Main study patient characteristicsCharacteristic %Median age in years (range)57 (40-80) Menopause statusPre34 Post66 Male1Tumour size=30mm42Node statuspN04 pN1mi(sn)7 pN1(sn)20 pN155 pN214Historic grade16 258 336 Conclusion: OPTIMA is one of two large scale prospective trials validating the use of test-guided chemotherapy decisions in node-positive early breast cancer. It is expected to have a global impact on breast cancer treatment. Experience from the preliminary study and close engagement with centres will aid trial success. Funding: OPTIMA is funded by the UK NIHR HTA Programme (10/34/501). Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the DoH. Citation Format: Stein RC, Hughes-Davies L, Makris A, Macpherson IR, Conefrey C, Rooshenas L, Pinder SE, Thomas J, Hall PS, Cameron DA, Earl HM, Naume B, Poole CJ, Rea DW, MacIntosh SA, Harmer V, Morgan A, Hulme C, McCabe C, Stallard N, Higgins H, Donovan JL, Bartlett JM, Marshall A, Dunn JA. OPTIMA: A prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-05-02.

Degenerative mitral regurgitation repair using a measured algorithm could increase the precision and reproducibility of repair outcomes.Direct and echocardiographic measurements guide the repair to achieve a coaptation length of 5 to 10 mm and minimize the risk of systolic anterior motion. Leaflet reconstruction restored the normal 2 to 1 ratio of anterior to posterior leaflet length without residual prolapse or restriction. The choice of ring size was based on anterior leaflet length, the distance from the leaflet coaptation point to the septum, and the anterior-posterior ring dimension. Freedom from reoperation and mitral regurgitation recurrence were based on multistate models.One thousand fifty-one patients had mitral surgery and 1026 (97.6%) were repaired. A2 length was 27.2 ± 4.5 mm; and the reconstructed posterior leaflet was 13.9 ± 2.3 mm. Median ring size was 34 mm and strongly correlated to A2 length (R = 0.76; P .001). The coaptation length at P2 after repair was 6.4 ± 1.7 mm and 87% of measurements were between 5 and 10 mm. Results at predischarge and 10 years, respectively, included mild regurgitation (7.5% and 26.1%), moderate (0.7% and 15.6%), moderate to severe (0% and 1.4%), and severe (0% and 0%), with mean mitral gradient values 3.5 ± 1.5 and 2.9 ± 1.2 mm Hg, respectively. Systolic anterior motion at discharge and last follow-up were 0.2% and 1.1%, respectively. Ten-year freedom from mitral valve reoperation was 99.7%.A simple, reproducible, measured algorithm for degenerative mitral valve repair provides excellent early and late results and is a useful adjunct to established surgical techniques.

Background: We have recently tested an automated machine-learning algorithm that quantifies left ventricular (LV) ejection fraction (EF) from guidelines-recommended apical views. However, in the point-of-care (POC) setting, apical 2-chamber views are often difficult to obtain, limiting the usefulness of this approach. Since most POC physicians often rely on visual assessment of apical 4-chamber and parasternal long-axis views, our algorithm was adapted to use either one of these 3 views or any combination. This study aimed to (1) test the accuracy of these automated estimates; (2) determine whether they could be used to accurately classify LV function. Methods: Reference EF was obtained using conventional biplane measurements by experienced echocardiographers. In protocol 1, we used echocardiographic images from 166 clinical examinations. Both automated and reference EF values were used to categorize LV function as hyperdynamic (EF>73%), normal (53%–73%), mildly-to-moderately (30%–52%), or severely reduced ( Results: Protocol 1: the agreement with the reference EF values was good (intraclass correlation, 0.86–0.95), with biases Conclusions: The new machine-learning algorithm allows accurate automated evaluation of LV function from echocardiographic views commonly used in the POC setting. This approach will enable more POC personnel to accurately assess LV function.

Background Clinicians vary markedly in their ability to detect murmurs during cardiac auscultation and identify the underlying pathological features. Deep learning approaches have shown promise in medicine by transforming collected data into clinically significant information. The objective of this research is to assess the performance of a deep learning algorithm to detect murmurs and clinically significant valvular heart disease using recordings from a commercial digital stethoscope platform. Methods and Results Using >34 hours of previously acquired and annotated heart sound recordings, we trained a deep neural network to detect murmurs. To test the algorithm, we enrolled 962 patients in a clinical study and collected recordings at the 4 primary auscultation locations. Ground truth was established using patient echocardiograms and annotations by 3 expert cardiologists. Algorithm performance for detecting murmurs has sensitivity and specificity of 76.3% and 91.4%, respectively. By omitting softer murmurs, those with grade 1 intensity, sensitivity increased to 90.0%. Application of the algorithm at the appropriate anatomic auscultation location detected moderate‐to‐severe or greater aortic stenosis, with sensitivity of 93.2% and specificity of 86.0%, and moderate‐to‐severe or greater mitral regurgitation, with sensitivity of 66.2% and specificity of 94.6%. Conclusions The deep learning algorithm’s ability to detect murmurs and clinically significant aortic stenosis and mitral regurgitation is comparable to expert cardiologists based on the annotated subset of our database. The findings suggest that such algorithms would have utility as front‐line clinical support tools to aid clinicians in screening for cardiac murmurs caused by valvular heart disease. Registration URL: https://clinicaltrials.gov ; Unique Identifier: NCT03458806.

This study aimed to investigate mitral annular dynamics in atrial fibrillation (AF) and after sinus rhythm restoration, and to assess the relationship between annular dynamics and mitral regurgitation (MR).AF can be associated with MR that improves after sinus rhythm restoration. Mechanisms underlying this atrial functional MR (AFMR) are ill-understood and generally attributed to left atrial remodeling.Fifty-three patients with persistent AF and normal left ventricular ejection fraction were prospectively examined by means of 3-dimensional transesophageal echocardiography before, immediately after, and 6 weeks after electric cardioversion to sinus rhythm. Annular motion was assessed during AF and in sinus rhythm with the use of 3-dimensional analysis software, and the relationship with MR severity was explored.During AF and immediately after sinus rhythm restoration, the mitral annulus behaved relatively adynamically, with an overall change in annular area of 10.3% (95% CI: 8.7%-11.8%) and 12.2% (95% CI: 10.6%-13.8%), respectively. At follow-up, a significant increase in annular dynamics (19.0%; 95% CI: 17.4%-20.6%; P 0.001) was observed, owing predominantly to an increase in presystolic contraction (P 0.001). The effective regurgitant orifice area decreased from 0.15 cmMitral annular dynamics are impaired in AF, with blunted presystolic narrowing that contributes to AFMR. Sinus rhythm restoration allows gradual recovery of presystolic annular dynamics. Improved annular dynamics decrease AFMR severity by optimizing annular-leaflet imbalance, regardless of LA remodeling.

BACKGROUND Elite athletes show structural cardiac changes as an adaptation to exercise. Studies examining strain in athletes have largely analyzed images at rest only. There is little data available regarding the change in strain with exercise. Our objectives were: to investigate the feasibility of strain analysis in athletes at peak exercise, to determine the normal range of left ventricular (LV) global longitudinal strain (GLS) within this population postexercise, to describe how LV GLS changes with exercise, and to determine whether any clinical characteristics correlate with the change in GLS that occurs with exercise. METHODS We conducted a cross-sectional study on elite athletes who participated in the 2016-2018 National Basketball Association Draft Combines. Echocardiograms were obtained at rest and after completing a treadmill stress test to maximal exertion or completion of Bruce protocol. Primary outcomes included GLS obtained at rest and peak exercise. Secondary outcome was the change in GLS between rest and exercise. Univariate relationships between various clinical characteristics and our secondary outcome were analyzed. RESULTS Our final cohort (n = 111) was all male and 92/111 (82.9%) were African American. Mean GLS magnitude increased in response to exercise (-17.6 ± 1.8 vs -19.2 ± 2.6, P

Importance Artificial intelligence (AI) has been applied to analysis of medical imaging in recent years, but AI to guide the acquisition of ultrasonography images is a novel area of investigation. A novel deep-learning (DL) algorithm, trained on more than 5 million examples of the outcome of ultrasonographic probe movement on image quality, can provide real-time prescriptive guidance for novice operators to obtain limited diagnostic transthoracic echocardiographic images. Objective To test whether novice users could obtain 10-view transthoracic echocardiographic studies of diagnostic quality using this DL-based software. Design, Setting, and Participants This prospective, multicenter diagnostic study was conducted in 2 academic hospitals. A cohort of 8 nurses who had not previously conducted echocardiograms was recruited and trained with AI. Each nurse scanned 30 patients aged at least 18 years who were scheduled to undergo a clinically indicated echocardiogram at Northwestern Memorial Hospital or Minneapolis Heart Institute between March and May 2019. These scans were compared with those of sonographers using the same echocardiographic hardware but without AI guidance. Interventions Each patient underwent paired limited echocardiograms: one from a nurse without prior echocardiography experience using the DL algorithm and the other from a sonographer without the DL algorithm. Five level 3–trained echocardiographers independently and blindly evaluated each acquisition. Main Outcomes and Measures Four primary end points were sequentially assessed: qualitative judgement about left ventricular size and function, right ventricular size, and the presence of a pericardial effusion. Secondary end points included 6 other clinical parameters and comparison of scans by nurses vs sonographers. Results A total of 240 patients (mean [SD] age, 61 [16] years old; 139 men [57.9%]; 79 [32.9%] with body mass indexes >30) completed the study. Eight nurses each scanned 30 patients using the DL algorithm, producing studies judged to be of diagnostic quality for left ventricular size, function, and pericardial effusion in 237 of 240 cases (98.8%) and right ventricular size in 222 of 240 cases (92.5%). For the secondary end points, nurse and sonographer scans were not significantly different for most parameters. Conclusions and Relevance This DL algorithm allows novices without experience in ultrasonography to obtain diagnostic transthoracic echocardiographic studies for evaluation of left ventricular size and function, right ventricular size, and presence of a nontrivial pericardial effusion, expanding the reach of echocardiography to clinical settings in which immediate interrogation of anatomy and cardiac function is needed and settings with limited resources.

Funding Acknowledgements Type of funding sources: None. Background Vendors use proprietary speckle tracking software algorithms for echocardiographic strain measurements, which results in high inter-vendor variability. Little is known about potential advantages or disadvantages of using vendor-independent software in clinical practice. Purpose We therefore investigated the reproducibility, accuracy, and ability to identify scar of strain measurements on images from different vendors by using a vendor-independent software. Methods A vendor-independent software (TomTec Image Arena) was used to analyze datasets of 63 patients which were obtained on four ultrasound machines from different vendors (GE, Philips, Siemens, Toshiba). We measured the tracking feasibility, inter-vendor bias, the relative and absolute test-re-test variability of strain measurements and their ability to detect scar. Cardiac magnetic resonance delayed enhancement images were used as the reference standard of scar definition. Results Tracking feasibility differed depending on the image source (p Conclusions Vendor independent software leads to low bias among strain measurements on images from different vendors. Likewise, measurement variability and the ability to identify scar becomes similar. Our findings suggest that a vendor independent speckle tracking software could help to overcome inter-vendor bias. To which extend such measurements would be more accurate compared to vendor specific software remains to be determined. Abstract Figure 1

Synthetic lethal therapies are a promising approach to expand therapeutic options for cancer patients. Since synthetic lethal therapies target tumor cells specifically, they have fewer off-target effects than oncogene targeted approaches. To identify new cancer drug targets, we focused on paralogs, ancestrally-duplicated genes that frequently retain redundant or overlapping functions. To find synthetic lethal human paralogs, we developed paired guide RNAs for Paralog gENetic interaction mapping (pgPEN), a pooled CRISPR-Cas9 single and double knockout approach targeting over 2,000 paralogs. We applied pgPEN to two cancer cell lines and found that 12% of human paralogs exhibit synthetic lethality in at least one context. To our knowledge, pgPEN represents the largest experimental assessment of human paralog synthetic lethality to date. We next identified paralog pairs to prioritize for follow-up study. A key drawback to synthetic lethal therapies is that many genetic interactions are context-dependent. To identify likely penetrant interactions, we compared our data to other published paralog screens and computational predictions of paralog synthetic lethality. We found that over 75% (n=96) of pgPEN hits were predicted to be broadly synthetic lethal, and nearly 10% (n=10) of pairs were synthetic lethal in multiple paralog screens. Finally, we prioritized paralogs targeted by existing small molecule therapies. Of the 122 synthetic lethal pairs identified by pgPEN, 16% (n=20) are currently druggable. We mined drug repurposing data from DepMap to find pairs where a paralog-targeting drug showed a stronger effect in cell lines with low target gene copy number or expression relative to cell lines with normal target gene copy number or expression. These drugs could selectively target cancer cells in cases where one or both paralogs is lost in tumors but retained in normal tissue. We also leveraged The Cancer Genome Atlas tumor sequencing data to find paralog pairs where one member is recurrently lost in cancer. Taken together, these studies identify druggable, highly penetrant synthetic lethal paralog interactions. In combination with tumor sequencing data, we identify high-priority paralog drug targets that can be further tested and translated to the clinic. Paralog synthetic lethal therapies could provide a relatively low-toxicity therapeutic approach to improve the efficacy of cancer treatments and prevent the emergence of acquired resistance. Citation Format: Phoebe C. Parrish, James D. Thomas, Austin M. Gabel, Shriya Kamlapurkar, Robert K. Bradley, Alice H. Berger. Expanding cancer therapy options by leveraging synthetic lethal interactions between druggable paralogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2278.