Global Relaxation Research Articles

Environmental averaging

Many classical examples of models of self-organized dynamics, including the Cucker–Smale, Motsch–Tadmor, multi-species, and several others, include an alignment force that is based upon density-weighted averaging protocol. Those protocols can be viewed as special cases of “environmental averaging”. In this paper we formalize this concept and introduce a unified framework for systematic analysis of alignment models.A series of studies are presented including the mean-field limit in deterministic and stochastic settings, hydrodynamic limits in the monokinetic and Maxwellian regimes, hypocoercivity and global relaxation for dissipative kinetic models, several general alignment results based on chain connectivity and spectral gap analysis. These studies cover many of the known results and reveal new ones, which include asymptotic alignment criteria based on connectivity conditions, new estimates on the spectral gap of the alignment force that do not rely on the upper bound of the macroscopic density, uniform gain of positivity for solutions of the Fokker–Planck-alignment model based on smooth environmental averaging. As a consequence, we establish unconditional relaxation result for global solutions to the Fokker–Planck-alignment model, which presents a substantial improvement over previously known perturbative results.

Relaxation dynamics in the self-propelled Voronoi model for epithelial monolayers

Cell monolayers and epithelial tissues display slow relaxation dynamics during the reversible transition between mesenchymal and epithelial cells, a phenomenon directly relevant to embryogenesis, tumor metastases, and wound healing. In active cells, persistent motion induces collective dynamics that significantly influence relaxation behavior. To better understand the role of persistence in cell relaxations, we perform extensive simulations and employ cage-relative measures to address the previously overlooked system size effects in model active cells. We identify the glass transition at various persistence values, demonstrating conventional near-equilibrium supercooled dynamics at low persistence. However, highly persistent cells exhibit distinctive intermittent dynamics associated with intermittent local T1 transitions, where cell velocity correlates over space with a characteristic length ξ. More significantly, we formulate a universal relationship predicting the global relaxation time based on the T1 transition and the spatial velocity correlation across a wide range of persistence values. Specifically, the relaxation time demonstrates a power-law dependence on the irreversible T1 transition rate, multiplied by exp(ξ). Here, ξ vanishes at small persistence in nearly equilibrated cells, and the irreversible T1 transition rate diminishes towards the mode-coupling glass transition point. Published by the American Physical Society 2024

Anthracycline therapy induces an early decline of cardiac contractility in low-risk patients with breast cancer

AimsCancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy. CTRCD most frequently appears in patients with cardiovascular risk factors (CVR) or known cardiovascular disease. However, limited data exist on incidence and course of anthracycline-induced CTRCD in patients without preexisting risk factors.We therefore aimed to longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease (NCT03940625).Methods and resultsWe enrolled 59 women with primary breast cancer and scheduled anthracycline-based therapy, but without CVR or preexisting cardiovascular disease. We conducted a longitudinal assessment before, immediately and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping.Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3% immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation, two of them were symptomatic. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired.ConclusionIn every single patient anthracyclines induce a decline of myocardial contractility, even among patients without pre-existing risk factors for CTRCD. Our data suggest to thoroughly evaluate whether this may lead to an increased risk of future cardiovascular events.Graphical Reduced myocardial contractility in low-risk patients receiving anthracycline-based cancer therapy. This study included 59 otherwise healthy women with primary breast cancer undergoing anthracycline-based chemotherapy. CMR was performed at baseline, directly and 12 months after cancer therapy. A decline in left ventricular function was observed in every single patient accompanied by transient edema. More than 50% were diagnosed with cancer therapy related cardiovascular dysfunction. LVEF: left ventricular function, CTRCD: cancer therapy related cardiovascular dysfunction, GLS = Global longitudinal strain, hs-TnT= high sensitive Troponin T, NT-pro BNP = NT-pro brain natriuretic peptide

Left ventricular structural integrity on tetralogy of Fallot patients: approach using longitudinal relaxation time mapping.

Tetralogy of Fallot (TOF) is a congenital heart disease, and patients undergo surgical repair early in their lives. The evaluation of TOF patients is continuous through their adulthood. The use of cardiac magnetic resonance imaging (CMR) is vital for the evaluation of TOF patients. We aim to correlate advanced MRI sequences [parametric longitudinal relaxation time (T1), extracellular volume (ECV) mapping] with cardiac functionality to provide biomarkers for the evaluation of these patients. A complete CMR examination with the same imaging protocol was conducted in a total of 11 TOF patients and a control group of 25 healthy individuals. A Modified Look-Locker Inversion recovery (MOLLI) sequence was included to acquire the global T1 myocardial relaxation times of the left ventricular (LV) pre and post-contrast administration. Appropriate software (Circle cmr42) was used for the CMR analysis and the calculation of native, post-contrast T1, and ECV maps. A regression analysis was conducted for the correlation between global LV T1 values and right ventricular (RV) functional indices. Statistically significant results were obtained for RV cardiac index [RV_CI= -32.765 + 0.029 × T1 native; ], RV end diastolic volume [RV_EDV/BSA = -1023.872 + 0.902 × T1 native; ], and RV end systolic volume [RV_ESV/BSA = -536.704 + 0.472 × T1 native; ]. We further support the diagnostic importance of T1 mapping as a structural imaging tool in CMR. In addition to the well-known affected RV function in TOF patients, the LV structure is also impaired as there is a strong correlation between LV T1 mapping and RV function, evoking that the heart operates as an entity.

Distributed Single-Source Shortest Path with Only Local Relaxation

Finding the shortest path from a source vertex to any other vertices on a graph (single-source shortest path, SSSP) is used in a wide range of applications. With the rapid expansion of graph data volume, graphs are too large to be stored and processed in a standalone machine. Therefore, performing SSSP distributively in the computer clusters becomes an inevitable way. We found that the performance of existing distributed SSSP algorithms is limited by the communication cost between workers, which is caused by global relaxation. To eliminate the expensive communication cost, we propose an efficient distributed SSSP algorithm LR-SSSP that replaces global relaxation with local relaxation. Furthermore, we propose two optimizations, i.e., lazy synchronization and forward relaxation, to reduce invalid synchronization and communication. Our results show that LR-SSSP can achieve up to 6–20× speedup over the state-of-the-art Δ-stepping++ algorithm.

Dapagliflozin reduces systemic inflammation in patients with type 2 diabetes without known heart failure

ObjectiveSodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis.Research and design methodsThis randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping.ResultsBetween the baseline and 12-month time point, plasma IL-1B was reduced (− 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (− 158.9 pmole/min/106 cells, P = 0.0497 vs. − 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups.Clinical Trial.gov Registration NCT03782259.

Multiscale residual stress and mechanical behavior analysis in machining of Ti-6Al-4V alloy with advanced microscopic characterization

Machining of polycrystalline metal materials results in metallurgical modifications in the machined surface, and it can introduce multiscale residual stresses (macroscale and microscale residual stress), which may be detrimental to the mechanical properties thereby interfering with the service performance of machined parts. However, most of the current studies only focus on the macroscale residual stress, the microscale residual stresses have always been neglected since the limitations of the commonly used techniques for residual stress measurement in machined surfaces. In this study, the recently developed Focused Ion Beam-digital image correlation (FIB-DIC) ring core method was employed to evaluate the time-resolved strain relaxation and multiscale residual stress of the machined surface under different cutting conditions. The quantitative evaluation of residual stress and microstructural effects on hardness of the machined surface was conducted by combining with FIB incremental milling and nanoindentation technique. It has been observed that although the global tensile strain relaxation was captured in the ring-core region, local microscale compressive strain relaxation also occurred. The hardness of the machined surface was determined by the combined effects of microstructure and residual stress induced by machining. Specifically, the grain refinement and compressive residual stress contributed to hardening, while tensile residual stress resulted in softening of the machined surface. Furthermore, it was also observed the hardening/softening effects were enhanced with increasing intensity of tension and compression.

Global solutions and relaxation limit to the Cauchy problem of a hydrodynamic model for semiconductors

In this paper, we study the Cauchy problem for the one-dimensional Euler-Poisson (or hydrodynamic) model for semiconductors, where the energy equation is replaced by a pressure-density relation. First, the existence of global entropy solutions is proved by using the vanishing artificial viscosity method, where, a special flux approximate is introduced to ensure the uniform boundedness of the electric field E and the a-priori L∞ estimate, 0<2δ≤ρε,δ≤M(t),|uε,δ|≤M(t), where M(t) could tend to infinity as the time t tends to infinity, on the viscosity-flux approximate solutions (ρε,δ,uε,δ); Second, the compensated compactness theory is applied to prove the pointwise convergence of (ρε,δ,uε,δ) as ε,δ go to zero, and that the limit (ρ(x,t),u(x,t)) is a global entropy solution; Third, a technique, to apply the maximum principle to the combination of the Riemann invariants and ∫−∞xρε,δ(x,t)−2δdx, deduces the uniform L∞ estimate, 0<2δ≤ρε,δ≤M,|uε,δ|≤M, independent of the time t and ε,δ; Finally, as a by-product, the known compactness framework [14,29] is applied to show the relaxation limit, as the relation time τ and ε,δ go to zero, for general pressure P(ρ).

Sharp uniform-in-time mean-field convergence for singular periodic Riesz flows

We consider conservative and gradient flows for N -particle Riesz energies with mean-field scaling on the torus \mathbb{T}^d , for d\geq 1 , and with thermal noise of McKean–Vlasov type. We prove global well-posedness and relaxation to equilibrium rates for the limiting PDE. Combining these relaxation rates with the modulated free energy of Bresch et al. (2019, 2019–2020, 2020) and recent sharp functional inequalities of the last two named authors for variations of Riesz modulated energies along a transport, we prove uniform-in-time mean-field convergence in the gradient case with a rate which is sharp for the modulated energy pseudo-distance. For gradient dynamics, this completes in the periodic case the range d-2\leq s&lt;d not addressed by the previous work Rosenzweig and Serfaty (2023). We also combine our relaxation estimates with the relative entropy approach of Jabin and Wang (2018) for so-called \dot{W}^{-1,\infty} kernels, giving a proof of uniform-in-time propagation of chaos alternative to Guillin et al. (2021).

Anthracycline therapy induces an early decline of cardiac contractility with transient edema in low risk patients with breast cancer

Abstract Background Cancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy in the treatment of breast cancer. CTRCD most frequently appears in patients with cardiovascular risk factors or known cardiovascular disease. There is limited evidence of incidence and prospective course of anthracycline-induced CTRCD in young patients without common risk factors for CTRCD. Purpose To longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease. Methods 59 women with first-diagnosed breast cancer and planned anthracycline regime-based therapy were enrolled. Exclusion criteria were cardiovascular risk factors or known cardiovascular disease. We conducted a longitudinal assessment before, immediately after- and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping. Results Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3 % immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation (Figure 1). LVEF reduction was accompanied by a decrease in stroke volume and cardiac power index while enddiastolic volume index remained stable. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired. Conclusion Among breast cancer patients without pre-existing risk factors for CTRCD anthracyclines induce a decline of myocardial contractility in every single patient, which may lead to an increased risk of future cardiovascular diseases in these patients. Figure 1: Patients with diagnosed CTRCD directly after CT and after 12 months follow up stratified by underlying CTRCD criteria. Boldness of arrows proportionally represents the number of patients changing between the criteria. Some patients fulfilled more than one criterium for CTRCD.Graphical Abstract Figure 1

Effect of the neutral beam injector operational regime on the Alfven eigenmode saturation phase in DIII-D plasma

The aim of this study is to analyze the effect of the neutral beam injector (NBI) operation regime on the saturation phase of the Alfven Eigenmodes (AEs) in DIII-D plasma. The analysis is done using the linear and nonlinear versions of the gyro-fluid code FAR3d. A set of parametric analyses are performed modifying the nonlinear simulation EP β (NBI injection power), EP energy (NBI voltage) and the radial location of the EP density profile gradient (NBI radial deposition). The analysis indicates a transition from the soft (local plasma relaxation) to the hard MHD (global plasma relaxation) limit if the simulation EP , leading to bursting MHD activity caused by radial AEs overlapping. MHD bursts cause an enhancement of the EP transport showing ballistic-like features as avalanche-like events. Simulations in the soft MHD limit show an increment of the EP density gradient as the EP β increases. On the other hand, there is a gradient upper limit in the hard MHD limit, consistent with the critical-gradient behavior. AEs induce shear flows and zonal current leading to the deformation of the flux surfaces and the safety factor profile, respectively, particularly strong for the simulation in the hard MHD limit. Simulations in the hard MHD regime show a decrease of the AE frequency in the saturation phase; this is caused by the destabilization of a transitional mode between a TAE and a RSAE that may explain the AE frequency down-sweeping observed in some DIII-D discharges. Reducing the EP energy in the nonlinear simulations leads to a weakening of the plasma perturbation. On the other hand, increasing the EP energy causes the opposite effect. Nonlinear simulations of off-axis NBI profiles indicate a lower plasma perturbation as the EP density gradient is located further away from the magnetic axis.

Reservoir-induced stabilization of a periodically driven classical spin chain: Local versus global relaxation.

Floquet theory is an indispensable tool for analyzing periodically driven quantum many-body systems. Although it does not universally extend to classical systems, some of its methodologies can be adopted in the presence of well-separated timescales. Here we use these tools to investigate the stroboscopic behaviors of a classical spin chain that is driven by a periodic magnetic field and coupled to a thermal reservoir. We detail and expand our previous work: we investigate the significance of higher-order corrections to the classical Floquet-Magnus expansion in both the high- and low-frequency regimes; explicitly probe the evolution dynamics of the reservoir; and further explore how the driven system and the reservoir synchronize with the applied field at low frequencies. In line with our earlier results, we find that the high-frequency regime is characterized by a local Floquet-Gibbs ensemble with the reservoir acting as a nearly-reversible heat sink. At low frequencies, the driven system rapidly enters a synchronized state, which can only be fully described in a global picture accounting for the concurrent relaxation of the reservoir in a fictitious magnetic field arising from the drive. We highlight how the evolving nature of the reservoir may still be incorporated in a local picture by introducing an effective temperature. Finally, we show that generic local-dissipation models that account for the influence of the reservoir on the driven system phenomenologically through Markovian dissipative equationsof motion can generally not reproduce the rich behavior that our microscopic simulations reveal. In particular, such models prove insufficient to account for the suppression of overall energy absorption that is induced by the here observed synchronization between driven system and reservoir.

Myocardial native T1 mapping and extracellular volume quantification in asymptomatic female carriers of Duchenne muscular dystrophy gene mutations

BackgroundFemale carriers of dystrophin gene mutations (DMD-FC) were previously considered non-manifesting, but in recent decades, cardiomyopathy associated with muscular dystrophy and myocardial fibrosis has been described. Our study aimed to assess prospectively myocardial fibrosis in asymptomatic DMD-FC compared to a sex-matched control group (CG) with similar age distribution using native T1 mapping and extracellular volume (ECV) quantification by cardiovascular magnetic resonance (CMR) imaging.Materials and methods38 DMD-FC with verified genetic mutation and 22 healthy volunteers were included. Using CMR, native T1 relaxation time and ECV quantification were determined in each group. Late gadolinium enhancement (LGE) was assessed in all cases.ResultsThere were 38 DMD-FC (mean age 39.1 ± 8.8 years) and 22 healthy volunteers (mean age 39.9 ± 12.6 years) imagined by CMR. The mean global native T1 relaxation time was similar for DMD-FC and CG (1005.1 ± 26.3 ms vs. 1003.5 ± 25.0 ms; p-value = 0.81). Likewise, the mean global ECV value was also similar between the groups (27.92 ± 2.02% vs. 27.10 ± 2.89%; p-value = 0.20). The segmental analysis of mean ECV values according to the American Heart Association classification did not show any differences between DMD-FC and CG. There was a non-significant trend towards higher mean ECV values of DMD-FC in the inferior and inferolateral segments of the myocardium (p-value = 0.075 and 0.070 respectively).ConclusionThere were no statistically significant differences in the mean global and segmental native T1 relaxation times and the mean global or segmental ECV values. There was a trend towards higher segmental mean ECV values of DMD-FC in the inferior and inferolateral walls of the myocardium.

Non-linear dynamics of the double tearing mode

3D non-linear magnetohydrodynamics simulations of a double tearing mode with the JOREK code are presented in the context of trying to better understand the benign termination of runaway electron beams observed in some experiments. It is shown that the non-linear behavior qualitatively depends on the resistivity η via its effect on how fast secondary, non-linearly destabilized, tearing modes grow relative to the primary mode. Within a certain range of η, a violent and global relaxation is observed, consistent with the “Kadomtsev-predicted” reconnection region extending from almost the very center up to the edge of the plasma.

Myocardial T1 mapping by cardiac magnetic resonance imaging shows early myocardial changes in treatment-naive patients with active rheumatoid arthritis and positive autoantibodies.

We aimed to study whether myocardial changes are already detectable by cardiac magnetic resonance (CMR) imaging at the time of rheumatoid arthritis (RA) diagnosis. This single-centre prospective study included 39 treatment-naive patients with early rheumatoid arthritis (ERA, symptom duration <1 year) without any history of heart disease, and 38 age- and sex-matched healthy volunteers. The disease severity was assessed with clinical evaluation (Disease Activity Score-28 for Rheumatoid Arthritis with CRP (DAS28-CRP) score) and serological testing (rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA)). The ERA patients were classified into group A (DAS28-CRP score ≥3.2, positive RF and ACPA; n=17) and group B (not fulfilling the group A criteria). The ERA patients and healthy controls underwent 1.5T CMR. Group A patients had significantly higher myocardial global T1 relaxation times than the healthy controls, 987 [965, 1003] ms vs. 979 [960, 991] ms (median [IQR]; p=0.041). A significant difference in T1 was found in the basal, mid inferior and mid anterolateral segments. In a multivariate analysis, prolonged global T1 relaxation time was independently associated with female sex (95% CI [5.62, 51.31] ms, p=0.016), and group A status (95% CI [4.65, 39.01] ms p=0.014). At the time of diagnosis, ERA patients with a higher disease activity (DAS28-CRP score ≥3.2) and both positive RF and ACPA showed prolonged T1 relaxation times in basal myocardial segments. These segments could be most susceptible to the development of myocardial fibrosis, and a segmental reporting style could be useful when estimating the first signs of myocardial fibrosis.

Untargeted cannabinomics reveals the chemical differentiation of industrial hemp based on the cultivar and the geographical field location

Cannabis sativa has long been harvested for industrial applications related to its fibers. Industrial hemp cultivars, a botanical class of Cannabis sativa with a low expression of intoxicating Δ9-tetrahydrocannabinol (Δ9-THC) have been selected for these purposes and scarcely investigated in terms of their content in bioactive compounds. Following the global relaxation in the market of industrial hemp-derived products, research in industrial hemp for pharmaceutical and nutraceutical purposes has surged. In this context, metabolomics-based approaches have proven to fulfill the aim of obtaining comprehensive information on the phytocompound profile of cannabis samples, going beyond the targeted evaluation of the major phytocannabinoids. In the present paper, an HRMS-based metabolomics study was addressed to seven distinct industrial hemp cultivars grown in four experimental fields in Northern, Southern, and Insular Italy. Since the role of minor phytocannabinoids as well as other phytocompounds was found to be critical in discriminating cannabis chemovars and in determining its biological activities, a comprehensive characterization of phytocannabinoids, flavonoids, and phenolic acids was carried out by LC-HRMS and a dedicated data processing workflow following the guidelines of the metabolomics Quality Assurance and Quality Control Consortium. A total of 54 phytocannabinoids, 134 flavonoids, and 77 phenolic acids were annotated, and their role in distinguishing hemp samples based on the geographical field location and cultivar was evaluated by ANOVA-simultaneous component analysis. Finally, a low-level fused model demonstrated the key role of untargeted cannabinomics extended to lesser-studied phytocompound classes for the discrimination of hemp samples.

1238-P: The Face of Diabetic Cardiomyopathy—Baseline Characteristics from the ARISE-HF Trial

Background: Diabetic Cardiomyopathy (DbCM) is a severe complication of diabetes and a cause of heart failure (HF) occurring in the absence of other causes of cardiac dysfunction. Methods and Results: ARISE-HF (NCT04083339) is a global Phase 3 randomized study evaluating the safety and efficacy of a novel highly selective aldose reductase inhibitor (AT-001) versus placebo to improve exercise capacity in individuals with DbCM (defined by elevated cardiac biomarkers or structural/functional cardiac abnormalities along with impaired exercise capacity). Table 1 details the 684 study participants with DbCM in the study: 50% female, with a mean age 67.5 years. Glycemic control at enrollment was excellent (HbA1c of 6.99%). At baseline, the median NT-proBNP was 71 ng/L and hs-cTnT was 9 ng/L. Among echocardiographic abnormalities evaluated at enrollment, the most common were abnormal global longitudinal strain and impaired diastolic relaxation. Daily physical activity was low (mean PASE score of 154.3 + 89.6). Significant impairment in cardiac functional capacity was present at enrollment with a peak VO2 of 15.7 + 3.8 ml/kg/min. Conclusion: The ARISE-HF trial is an ongoing phase 3 clinical trial evaluating the safety and efficacy of aldose reductase inhibition on exercise capacity in patients with DbCM. The baseline analysis of the study cohort provides a unique characterization of individuals with DbCM. Disclosure J.Butler: Consultant; Abbott,, Amgen, Applied Therapeutics, Array, Astra Zeneca, Bayer,, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharma,, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sequana Medical, Vifor, Speaker's Bureau; Novartis, Boehringer Ingelheim-Lilly, Astra Zeneca, Janssen. F.Zannad: Advisory Panel; BMS, Novo Nordisk, Pfizer Inc., Servier Laboratories, Other Relationship; Applied Therapeutics Inc., Bayer Inc., Boehringer Ingelheim and Eli Lilly Alliance, Merck &amp; Co., Inc., Novartis. J.L.Januzzi: Consultant; Boehringer Ingelheim Inc., Janssen Pharmaceuticals, Inc., AstraZeneca, Research Support; Applied Therapeutics Inc., Abbott, Roche Diagnostics, Novartis, Innolife Co., Ltd. S.Del prato: Advisory Panel; Abbott Diagnostics, Altimmune, Amarin Corporation, Applied Therapeutics Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S, Vertex Pharmaceuticals Incorporated, Novartis, Consultant; A. Menarini Diagnostics, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi. J.Ezekowitz: Advisory Panel; Applied Therapeutics Inc. N.E.Ibrahim: None. C.S.Lam: Other Relationship; Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research &amp; Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, Us2.ai. R.Perfetti: None. J.Rosenstock: Advisory Panel; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Intarcia Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Research Support; Applied Therapeutics Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., Sanofi, Intarcia Therapeutics, Inc. W.Tang: Consultant; Sequana Medical NV, Cardiol Therapeutics, Genomics plc, Zehna Therapeutics LLC, Renovacor, Boston Scientific Corporation, Kiniksa Pharmaceuticals Inc, WhiteSwell Inc, CardiaTec Biosciences Inc, Other Relationship; American Board of Internal Medicine, Springer Nature, Research Support; National Heart, Lung, and Blood Institute. A.Urbinati: None.

Relaxation dynamics measure the aggregation propensity of amyloid-β and its mutants.

Atomistic molecular dynamics simulations are employed to investigate the global and segmental relaxation dynamics of the amyloid-β protein and its causative and protective mutants. Amyloid-β exhibits significant global/local dynamics that span a broad range of length and time scales due to its intrinsically disordered nature. The relaxation dynamics of the amyloid-β protein and its mutants is quantitatively correlated with its experimentally measured aggregation propensity. The protective mutant has slower relaxation dynamics, whereas the causative mutants exhibit faster global dynamics compared with that of the wild-type amyloid-β. The local dynamics of the amyloid-β protein or its mutants is governed by a complex interplay of the charge, hydrophobicity, and change in the molecular mass of the mutated residue.

Magnetic resonance imaging reference values for cardiac morphology, function and tissue composition in adolescents.

Cardiovascular magnetic resonance (CMR) is a precise tool for the assessment of cardiac anatomy, function, and tissue composition. However, studies providing CMR reference values in adolescence are scarce. We aim to provide sex-specific CMR reference values for biventricular and atrial dimensions and function and myocardial relaxation times in this population. Adolescents aged 15-18 years with no known cardiovascular disease underwent a non-contrast 3-T CMR scan between March 2021 and October 2021. The imaging protocol included a cine steady-state free-precession sequence for the analysis of chamber size and function, as well as T2-GraSE and native MOLLI T1-mapping for the characterization of myocardial tissue. CMR scans were performed in 123 adolescents (mean age 16±0.5 years, 52% girls). Mean left and right ventricular end-diastolic indexed volumes were higher in boys than in girls (91.7±11.6 vs 78.1±8.3ml/m2, p<0.001; and 101.3±14.1 vs 84.1±10.5ml/m2, p<0.001), as was the indexed left ventricular mass (48.5±9.6 vs 36.6±6.0g/m2, p<0.001). Left ventricular ejection fraction showed no significant difference by sex (62.2±4.1 vs 62.8±4.2%, p=0.412), whereas right ventricular ejection fraction trended slightly lower in boys (55.4±4.7 vs. 56.8±4.4%, p=0.085). Indexed atrial size and function parameters did not differ significantly between sexes. Global myocardial native T1 relaxation time was lower in boys than in girls (1215±23 vs 1252±28ms, p<0.001), whereas global myocardial T2 relaxation time did not differ by sex (44.4±2.0 vs 44.1±2.4ms, p=0.384). Sex-stratified comprehensive percentile tables are provided for most relevant cardiac parameters. This cross-sectional study provides overall and sex-stratified CMR reference values for cardiac dimensions and function, and myocardial tissue properties, in adolescents. This information is useful for clinical practice and may help in the differential diagnosis of cardiac diseases, such as cardiomyopathies and myocarditis, in this population. Instituto de Salud Carlos III (PI19/01704).

Ultrasound beam angle-independent evaluation of left ventricular filling pressure using three-dimensional speckle-tracking echocardiography.

E/e′ is a major parameter in the algorithm for estimating left ventricular filling pressure (LVFP) by echocardiography.1 However, E and e′ can be affected by Doppler beam malalignment. Moreover, regional e′ is used as an extrapolation of global left ventricular (LV) relaxation. These limitations may cause the estimation of LVFP to be inaccurate in some conditions. In the multicentre Euro-Filling study, E/e′ was weakly correlated with LV end-diastolic pressure but was not an independent parameter correlated with end-diastolic pressure in patients with an ejection fraction (EF) <50%.2 Three-dimensional speckle-tracking echocardiography allows the simultaneous evaluation of LV volume and global myocardial strain. The early diastolic filling rate (FRe), derived from the rate of LV volume change (dV/dt), is theoretically expected to reflect transmitral E, and the early diastolic global strain rate (SRe) correlates with the time constant of global LV relaxation better than e′.3 Furthermore, FRe and SRe are independent of the ultrasound beam angle because they are not measured by the Doppler method. Therefore, FRe/SRe may be used to estimate LVFP, even under conditions where the use of E/e′ is limited. In canine models, we have reported that FRe/SRe correlates well with simultaneously measured LVFP and provides a better estimate of LVFP than E/e′;4,5 however, the utility of FRe/SRe in the clinical setting remains unclear.