Abstract

Abstract
Objectives: The purpose of this study was to investigate whether propagation velocities of naturally occurring shear waves (SWs) at mitral valve closure (MVC) increase with the degree of diffuse myocardial injury (DMI) and with invasively determined LV filling pressures as a reflection of an increase in myocardial stiffness in heart transplantation (HTx) recipients. Background: After orthotopic HTx, allografts undergo DMI that contributes to functional impairment, especially to increased passive myocardial stiffness, which is an important pathophysiological determinant of left ventricular (LV) diastolic dysfunction. Echocardiographic SW elastography is an emerging approach for measuring myocardial stiffness in vivo. Natural SWs occur after mechanical excitation of the myocardium, for example, after MVC, and their propagation velocity is directly related to myocardial stiffness, thus providing an opportunity to assess myocardial stiffness at end-diastole. Methods: A total of 52 HTx recipients who underwent right heart catheterization (all) and cardiac magnetic resonance (CMR) (n = 23) during their annual check-up were prospectively enrolled. Echocardiographic SW elastography was performed in parasternal long axis views of the LV using an experimental scanner at 1,135 ± 270 frames per second. The degree of DMI was quantified with T1 mapping. Results: SW velocity at MVC correlated best with native myocardial T1 values (r = 0.75; p < 0.0001) and was the best noninvasive parameter that correlated with pulmonary capillary wedge pressures (PCWP) (r = 0.54; p < 0.001). Standard echocardiographic parameters of LV diastolic function correlated poorly with both native T1 and PCWP values. Conclusions: End-diastolic SW propagation velocities, as measure of myocardial stiffness, showed a good correlation with CMR-defined diffuse myocardial injury and with invasively determined LV filling pressures in patients with HTx. Thus, these findings suggest that SW elastography has the potential to become a valuable noninvasive method for the assessment of diastolic myocardial properties in HTx recipients. © 2020 American College of Cardiology Foundation

Abstract
Background: Internet-based cognitive-behavioral therapy (iCBT) is more effective when it is guided by human support than when it is unguided. This may be attributable to higher adherence rates that result from a positive effect of the accompanying support on motivation and on engagement with the intervention. This protocol presents the design of a pilot randomized controlled trial that aims to start bridging the gap between guided and unguided interventions. It will test an intervention that includes automated support delivered by an embodied conversational agent (ECA) in the form of a virtual coach. Methods/design: The study will employ a pilot two-armed randomized controlled trial design. The primary outcomes of the trial will be (1) the effectiveness of iCBT, as supported by a virtual coach, in terms of improved intervention adherence in comparison with unguided iCBT, and (2) the feasibility of a future, larger-scale trial in terms of recruitment, acceptability, and sample size calculation. Secondary aims will be to assess the virtual coach's effect on motivation, users' perceptions of the virtual coach, and general feasibility of the intervention as supported by a virtual coach. We will recruitN = 70 participants from the general population who wish to learn how they can improve their mood by using Moodbuster Lite, a 4-week cognitive-behavioral therapy course. Candidates with symptoms of moderate to severe depression will be excluded from study participation. Included participants will be randomized in a 1:1 ratio to either (1) Moodbuster Lite with automated support delivered by a virtual coach or (2) Moodbuster Lite without automated support. Assessments will be taken at baseline and post-study 4 weeks later. Discussion: The study will assess the preliminary effectiveness of a virtual coach in improving adherence and will determine the feasibility of a larger-scale RCT. It could represent a significant step in bridging the gap between guided and unguided iCBT interventions.

Abstract
The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

Abstract
Gastric Cancer (GC) is one of the most common and deadliest types of cancer in the world. To improve GC prognosis, increasing efforts are being made to develop new targeted therapies. Although FGFR2 genetic amplification and protein overexpression in GC have been targeted in clinical trials, so far no improvement in patient overall survival has been found. To address this issue, we studied genetic and epigenetic events affecting FGFR2 and its splicing regulator ESRP1 in GC that could be used as new therapeutic targets or predictive biomarkers. We performed copy number variation (CNV), DNA methylation, and RNA expression analyses of FGFR2/ESRP1 across several cohorts. We discovered that both genes were frequently amplified and demethylated in GC, resulting in increased ESRP1 expression and of a specific FGFR2 isoform: FGFR2-IIIb. We also showed that ESRP1 amplification in GC correlated with a significant decreased expression of FGFR2-IIIc, an alternative FGFR2 splicing isoform. Furthermore, when we performed a survival analysis, we observed that patients harboring diffuse-type tumors with low FGFR2-IIIc expression revealed a better overall survival than patients with FGFR2-IIIc high-expressing diffuse tumors. Our results encourage further studies on the role of ESRP1 in GC and support FGFR2-IIIc as a relevant biomarker in GC.

Abstract
Aims: To determine myocardial stiffness by means of measuring the velocity of naturally occurring myocardial shear waves (SWs) at mitral valve closure (MVC) and investigate their changes with myocardial remodelling in patients with hypertensive heart disease. Methods and results: Thirty-three treated arterial hypertension (HT) patients with hypertrophic left ventricular (LV) remodelling (59 ± 14 years, 55% male) and 26 aged matched healthy controls (55±15 years, 77% male) were included. HT patients were further divided into a concentric remodelling (HT1) group (13 patients) and a concentric hypertrophy (HT2) group (20 patients). LV parasternal long-axis views were acquired with an experimental ultrasound scanner at 1266 ± 317 frames per seconds. The SW velocity induced by MVC was measured from myocardial acceleration maps. SW velocities differed significantly between HT patients and controls (5.83 ± 1.20 m/s vs. 4.04 ± 0.96 m/s; P < 0.001). In addition, the HT2 group had the highest SW velocities (P < 0.001), whereas values between controls and the HT1 group were comparable (P = 0.075). Significant positive correlations were found between SW velocity and LV remodelling (interventricular septum thickness: r = 0.786, P < 0.001; LV mass index: r = 0.761, P < 0.001). SW velocity normalized for wall stress indicated that myocardial stiffness in the HT2 group was twice as high as in controls (P < 0.001), whereas values of the HT1 group overlapped with the controls (P = 1.00). Conclusions: SW velocity as measure of myocardial stiffness is higher in HT patients compared with healthy controls, particularly in advanced hypertensive heart disease. Patients with concentric remodelling have still normal myocardial properties whereas patients with concentric hypertrophy show significant stiffening.