Interpretable machine learning of action potential duration restitution kinetics in single-cell models of atrial cardiomyocytes.

Action potential duration (APD) restitution curve and its maximal slope (Smax) reflect single cell-level dynamic instability for inducing chaotic heart rhythms. However, conventional parameter sensitivity analysis often fails to describe nonlinear relationships between ion channel parameters and electrophysiological phenotypes, such as Smax. We explored the parameter-phenotype mapping in a population of 5000 single-cell atrial cell models through interpretable machine learning (ML) approaches.

The mean of fasting, 1-h, and 2-h plasma glucose levels is superior to each separate index in predicting diabetes.

Aims: The fasting, 1-h, and 2-h plasma glucose (PG) levels during oral glucose tolerance test represent different glucose metabolic functions. We examined whether averaging these PG indices (GLU) results in a better predictor of future type 2 diabetes (T2DM).

Methods: 7533 participants were followed up biannually for 12 years.

Pro-Arrhythmogenic Effects of Heterogeneous Tissue Curvature - A Suggestion for Role of Left Atrial Appendage in Atrial Fibrillation.

Background: The arrhythmogenic role of complex atrial morphology has not yet been clearly elucidated. We hypothesized that bumpy tissue geometry can induce action potential duration (APD) dispersion and wavebreak in atrial fibrillation (AF).

Methods and results: We simulated a 2D-bumpy atrial model by varying the degree of bumpiness, and 3D-left atrial (LA) models integrated by LA computed tomographic (CT) images taken from 14 patients with persistent AF.

In vitro and in vivo assessment of biomedical Mg-Ca alloys for bone implant applications.

Background: Magnesium (Mg)-based alloys are considered to be promising materials for implant application due to their excellent biocompatibility, biodegradability, and mechanical properties close to bone. However, low corrosion resistance and fast degradation are limiting their application. Mg-Ca alloys have huge potential owing to a similar density to bone, good corrosion resistance, and as Mg is essential for Ca incorporation into bone.

Ganglionated plexi stimulation induces pulmonary vein triggers and promotes atrial arrhythmogenecity: In silico modeling study.

Background: The role of the autonomic nervous system (ANS) on atrial fibrillation (AF) is difficult to demonstrate in the intact human left atrium (LA) due to technical limitations of the current electrophysiological mapping technique. We examined the effects of the ANS on the initiation and maintenance of AF by employing a realistic in silico human left atrium (LA) model integrated with a model of ganglionated plexi (GPs).

Methods: We incorporated the morphology of the GP and parasympathetic nerves in a three-dimensional (3D) realistic LA model.

A New Efficient Method for Detecting Phase Singularity in Cardiac Fibrillation.

Background: The point of phase singularity (PS) is considered to represent a spiral wave core or a rotor in cardiac fibrillation. Computational efficiency is important for detection of PS in clinical electrophysiology. We developed a novel algorithm for highly efficient and robust detection of PS.

Spatial reproducibility of complex fractionated atrial electrogram depending on the direction and configuration of bipolar electrodes: an in-silico modeling study.

Although 3D-complex fractionated atrial electrogram (CFAE) mapping is useful in radiofrequency catheter ablation for persistent atrial fibrillation (AF), the directions and configuration of the bipolar electrodes may affect the electrogram. This study aimed to compare the spatial reproducibility of CFAE by changing the catheter orientations and electrode distance in an in-silico left atrium (LA). We conducted this study by importing the heart CT image of a patient with AF into a 3D-homogeneous human LA model.

The Spatiotemporal Stability of Dominant Frequency Sites in In-Silico Modeling of 3-Dimensional Left Atrial Mapping of Atrial Fibrillation.

Background: We previously reported that stable rotors were observed in in-silico human atrial fibrillation (AF) models, and were well represented by dominant frequency (DF). We explored the spatiotemporal stability of DF sites in 3D-AF models imported from patient CT images of the left atrium (LA).

Methods: We integrated 3-D CT images of the LA obtained from ten patients with persistent AF (male 80%, 61.

The Contribution of Ionic Currents to Rate-Dependent Action Potential Duration and Pattern of Reentry in a Mathematical Model of Human Atrial Fibrillation.

Persistent atrial fibrillation (PeAF) in humans is characterized by shortening of action potential duration (APD) and attenuation of APD rate-adaptation. However, the quantitative influences of particular ionic current alterations on rate-dependent APD changes, and effects on patterns of reentry in atrial tissue, have not been systematically investigated. Using mathematical models of human atrial cells and tissue and performing parameter sensitivity analysis, we evaluated the quantitative contributions to action potential (AP) shortening and APD rate-adaptation of ionic current remodeling seen with PeAF.

Electrophysiological Rotor Ablation in In-Silico Modeling of Atrial Fibrillation: Comparisons with Dominant Frequency, Shannon Entropy, and Phase Singularity.

Background: Although rotors have been considered among the drivers of atrial fibrillation (AF), the rotor definition is inconsistent. We evaluated the nature of rotors in 2D and 3D in- silico models of persistent AF (PeAF) by analyzing phase singularity (PS), dominant frequency (DF), Shannon entropy (ShEn), and complex fractionated atrial electrogram cycle length (CFAE-CL) and their ablation.

Methods: Mother rotor was spatiotemporally defined as stationary reentries with a meandering tip remaining within half the wavelength and lasting longer than 5 s.

Standardization of a human organ culture model of intestinal inflammation and its application for drug testing.

Targeting early molecular events in intestinal inflammation may represent a useful therapeutic strategy for maintaining remission in inflammatory bowel disease. Recently, we established an intestinal organ culture model (LEL model), which allows to study the initiation of an intestinal inflammatory response in human tissue. In this model, EDTA-mediated depletion of epithelial cells of colonic mucosa results in an instantaneous inflammatory response in resident lamina propria cells, which shows features of intestinal inflammation in vivo.

Fibrillation number based on wavelength and critical mass in patients who underwent radiofrequency catheter ablation for atrial fibrillation.

The heart characteristic length, the inverse of conduction velocity (CV), and the inverse of the refractory period are known to determine vulnerability to cardiac fibrillation (fibrillation number, FibN) in in silico or ex vivo models. The purpose of this study was to validate the accuracy of FibN through in silico atrial modeling and to evaluate its clinical application in patients with atrial fibrillation (AF) who had undergone radiofrequency catheter ablation. We compared the maintenance duration of AF at various FibNAF values using in silico bidomain atrial modeling.

Virtual ablation for atrial fibrillation in personalized in-silico three-dimensional left atrial modeling: comparison with clinical catheter ablation.

Background: Although catheter ablation is an effective rhythm control strategy for atrial fibrillation (AF), empirically-based ablation has a substantial recurrence rate. The purposes of this study were to develop a computational platform for patient-specific virtual AF ablation and to compare the anti-fibrillatory effects of 5 different virtual ablation protocols with empirically chosen clinical ablations.

Methods: We included 20 patients with AF (65% male, 60.

Clinical application of the fibrillation number in patients with an implantable cardioverter defibrillator.

Introduction: Although ventricular tachycardia/fibrillation (VT/VF) develops suddenly with catastrophic results, its prediction is limited. We tested the fibrillation number (FibN) for potential predictor of VT/VF using clinical data of implantable cardioverter-defibrillator (ICD) patients after validating the number by computational modeling.

Methods: For clinical application of FibN, we used electrocardiography and echocardiography data: QRS width, QTc, and left ventricular (LV) end-systolic dimension (FibNVT/VF1) or LV end-diastolic dimension (FibNVT/VF2).

Isolation of human antigen-specific regulatory T cells with high suppressive function.

Adoptive transfer of regulatory T (Treg) cells could be an alternative to chronic immunosuppression for prevention of allogeneic graft rejection. While polyspecific Treg cells can prevent immune responses under lymphopenic conditions, Ag-specific Treg cells are needed to treat autoimmunity and graft rejection. Yet, reliable markers for Ag-specific Treg cells are missing.

Initiation of an inflammatory response in resident intestinal lamina propria cells -use of a human organ culture model.

Resident human lamina propria immune cells serve as powerful effectors in host defense. Molecular events associated with the initiation of an intestinal inflammatory response in these cells are largely unknown. Here, we aimed to characterize phenotypic and functional changes induced in these cells at the onset of intestinal inflammation using a human intestinal organ culture model.

Parameter sensitivity analysis of stochastic models provides insights into cardiac calcium sparks.

We present a parameter sensitivity analysis method that is appropriate for stochastic models, and we demonstrate how this analysis generates experimentally testable predictions about the factors that influence local Ca(2+) release in heart cells. The method involves randomly varying all parameters, running a single simulation with each set of parameters, running simulations with hundreds of model variants, then statistically relating the parameters to the simulation results using regression methods. We tested this method on a stochastic model, containing 18 parameters, of the cardiac Ca(2+) spark.

Decoding myocardial Ca²⁺ signals across multiple spatial scales: a role for sensitivity analysis.

Numerous studies have employed mathematical modeling to quantitatively understand release of Ca(2+) from the sarcoplasmic reticulum (SR) in the heart. Models have been used to investigate physiologically important phenomena such as triggering of SR Ca(2+) release by Ca(2+) entry across the cell membrane and spontaneous leak of Ca(2+) from the SR in quiescent heart cells. In this review we summarize studies that have modeled myocardial Ca(2+) at different spatial scales: the sub-cellular level, the cellular level, and the multicellular level.

Systems biology--biomedical modeling.

Because of the complexity inherent in biological systems, many researchers frequently rely on a combination of global analysis and computational approaches to gain insight into both (i) how interacting components can produce complex system behaviors, and (ii) how changes in conditions may alter these behaviors. Because the biological details of a particular system are generally not taught along with the quantitative approaches that enable hypothesis generation and analysis of the system, we developed a course at Mount Sinai School of Medicine that introduces first-year graduate students to these computational principles and approaches. We anticipate that such approaches will apply throughout the biomedical sciences and that courses such as the one described here will become a core requirement of many graduate programs in the biological and biomedical sciences.

Complex and rate-dependent beat-to-beat variations in Ca2+ transients of canine Purkinje cells.

Purkinje fibers play an essential role in transmitting electrical impulses through the heart, but they may also serve as triggers for arrhythmias linked to defective intracellular calcium (Ca(2+)) regulation. Although prior studies have extensively characterized spontaneous Ca(2+) release in nondriven Purkinje cells, little attention has been paid to rate-dependent changes in Ca(2+) transients. Therefore we explored the behaviors of Ca(2+) transients at pacing rates ranging from 0.

A reanalysis of competing hypotheses for the spread of the California sea otter.

From 1938 to 1972, the range of California sea otters (Enhydra lutris nereis) expanded with the northern and southern fronts spreading at rates of approximately 1.4 km/yr and 3.1 km/yr, respectively.

A clinical-decision support system for the nursing process in the ENR.

This study was conducted to develop the clinical-decision support system for the nursing process in the Electronic nursing record system. Nursing diagnoses were linked to 4 components of the nursing process (except for diagnoses) and applied to ENR in 2007.

Development and evaluation of ICNP-based Electronic Nursing Record System.

This study was conducted to cross-map nursing statements with International Classification of Nursing Practice (ICNP) Version 1 and to develop and evaluate ICNP-based Electronic Nursing Record System. Among the 7,631 nursing statements which were cross-mapped, 5,970(78.2%) nursing statements were completely expressed and 1,520(19.

A calcium-induced calcium release mechanism mediated by calsequestrin.

Calcium (Ca(2+))-induced Ca(2+) release (CICR) is widely accepted as the principal mechanism linking electrical excitation and mechanical contraction in cardiac cells. The CICR mechanism has been understood mainly based on binding of cytosolic Ca(2+) with ryanodine receptors (RyRs) and inducing Ca(2+) release from the sarcoplasmic reticulum (SR). However, recent experiments suggest that SR lumenal Ca(2+) may also participate in regulating RyR gating through calsequestrin (CSQ), the SR lumenal Ca(2+) buffer.