Un modello matematico in epidemologia

Fornisce una breve trattazione di due tipi di modelli matematici applicabili nel campo dell'epidemologia, prendendo spunto da un articolo del biologo matematico A. Korobeinikov, "Lyapunov function and global properties for SEIR and SEIS epidemic models"

Real-time whole-heart electromechanical simulations using Latent Neural Ordinary Differential Equations

Cardiac digital twins provide a physics and physiology informed framework to deliver predictive and personalized medicine. However, high-fidelity multi-scale cardiac models remain a barrier to adoption due to their extensive computational costs and the high number of model evaluations needed for patient-specific personalization. Artificial Intelligence-based methods can make the creation of fast and accurate whole-heart digital twins feasible. In this work, we use Latent Neural Ordinary Differential Equations (LNODEs) to learn the temporal pressure-volume dynamics of a heart failure patient. Our surrogate model based on LNODEs is trained from 400 3D-0D whole-heart closed-loop electromechanical simulations while accounting for 43 model parameters, describing single cell through to whole organ and cardiovascular hemodynamics. The trained LNODEs provides a compact and efficient representation of the 3D-0D model in a latent space by means of a feedforward fully-connected Artificial Neural Network that retains 3 hidden layers with 13 neurons per layer and allows for 300x real-time numerical simulations of the cardiac function on a single processor of a standard laptop. This surrogate model is employed to perform global sensitivity analysis and robust parameter estimation with uncertainty quantification in 3 hours of computations, still on a single processor. We match pressure and volume time traces unseen by the LNODEs during the training phase and we calibrate 4 to 11 model parameters while also providing their posterior distribution. This paper introduces the most advanced surrogate model of cardiac function available in the literature and opens new important venues for parameter calibration in cardiac digital twins

Evaluation of an open-source pipeline to create patient-specific left atrial models: A reproducibility study

This work presents an open-source software pipeline to create patient-specific left atrial models with fibre orientations and a fibrDEFAULTosis map, suitable for electrophysiology simulations, and quantifies the intra and inter observer reproducibility of the model creation. The semi-automatic pipeline takes as input a contrast enhanced magnetic resonance angiogram, and a late gadolinium enhanced (LGE) contrast magnetic resonance (CMR). Five operators were allocated 20 cases each from a set of 50 CMR datasets to create a total of 100 models to evaluate inter and intra-operator variability. Each output model consisted of: (1) a labelled surface mesh open at the pulmonary veins and mitral valve, (2) fibre orientations mapped from a diffusion tensor MRI (DTMRI) human atlas, (3) fibrosis map extracted from the LGE-CMR scan, and (4) simulation of local activation time (LAT) and phase singularity (PS) mapping. Reproducibility in our pipeline was evaluated by comparing agreement in shape of the output meshes, fibrosis distribution in the left atrial body, and fibre orientations. Reproducibility in simulations outputs was evaluated in the LAT maps by comparing the total activation times, and the mean conduction velocity (CV). PS maps were compared with the structural similarity index measure (SSIM). The users processed in total 60 cases for inter and 40 cases for intra-operator variability. Our workflow allows a single model to be created in 16.72 ± 12.25 min. Similarity was measured with shape, percentage of fibres oriented in the same direction, and intra-class correlation coefficient (ICC) for the fibrosis calculation. Shape differed noticeably only with users' selection of the mitral valve and the length of the pulmonary veins from the ostia to the distal end; fibrosis agreement was high, with ICC of 0.909 (inter) and 0.999 (intra); fibre orientation agreement was high with 60.63% (inter) and 71.77% (intra). The LAT showed good agreement, where the median ± IQR of the absolute difference of the total activation times was 2.02 ± 2.45 ms for inter, and 1.37 ± 2.45 ms for intra. Also, the average ± sd of the mean CV difference was -0.00404 ± 0.0155 m/s for inter, and 0.0021 ± 0.0115 m/s for intra. Finally, the PS maps showed a moderately good agreement in SSIM for inter and intra, where the mean ± sd SSIM for inter and intra were 0.648 ± 0.21 and 0.608 ± 0.15, respectively. Although we found notable differences in the models, as a consequence of user input, our tests show that the uncertainty caused by both inter and intra-operator variability is comparable with uncertainty due to estimated fibres, and image resolution accuracy of segmentation tools

The role of conduction system pacing in patients with atrial fibrillation

Conduction system pacing (CSP) has emerged as a promising novel delivery method for Cardiac Resynchronisation Therapy (CRT), providing an alternative to conventional biventricular epicardial (BiV) pacing in indicated patients. Despite increasing popularity and widespread uptake, CSP has rarely been specifically examined in patients with atrial fibrillation (AF), a cohort which forms a significant proportion of the heart failure (HF) population. In this review, we first examine the mechanistic evidence for the importance of sinus rhythm (SR) in CSP by allowing adjustment of atrioventricular delays (AVD) to achieve the optimal electrical response, and thus, whether the efficacy of CSP may be significantly attenuated compared to conventional BiV pacing in the presence of AF. We next evaluate the largest clinical body of evidence in this field, related to patients receiving CSP following atrioventricular nodal ablation (AVNA) for AF. Finally, we discuss how future research may be designed to address the vital question of how effective CSP in AF patients is, and the potential hurdles we may face in delivering such studies

Leadless biventricular left bundle and endocardial lateral wall pacing versus left bundle only pacing in left bundle branch block patients

Biventricular endocardial (BIV-endo) pacing and left bundle pacing (LBP) are novel delivery methods for cardiac resynchronization therapy (CRT). Both pacing methods can be delivered through leadless pacing, to avoid risks associated with endocardial or transvenous leads. We used computational modelling to quantify synchrony induced by BIV-endo pacing and LBP through a leadless pacing system, and to investigate how the right-left ventricle (RV-LV) delay, RV lead location and type of left bundle capture affect response. We simulated ventricular activation on twenty-four four-chamber heart meshes inclusive of His-Purkinje networks with left bundle branch block (LBBB). Leadless biventricular (BIV) pacing was simulated by adding an RV apical stimulus and an LV lateral wall stimulus (BIV-endo lateral) or targeting the left bundle (BIV-LBP), with an RV-LV delay set to 5 ms. To test effect of prolonged RV-LV delays and RV pacing location, the RV-LV delay was increased to 35 ms and/or the RV stimulus was moved to the RV septum. BIV-endo lateral pacing was less sensitive to increased RV-LV delays, while RV septal pacing worsened response compared to RV apical pacing, especially for long RV-LV delays. To investigate how left bundle capture affects response, we computed 90% BIV activation times (BIVAT-90) during BIV-LBP with selective and non-selective capture, and left bundle branch area pacing (LBBAP), simulated by pacing 1 cm below the left bundle. Non-selective LBP was comparable to selective LBP. LBBAP was worse than selective LBP (BIVAT-90: 54.2 ± 5.7 ms vs. 62.7 ± 6.5, p < 0.01), but it still significantly reduced activation times from baseline. Finally, we compared leadless LBP with RV pacing against optimal LBP delivery through a standard lead system by simulating BIV-LBP and selective LBP alone with and without optimized atrioventricular delay (AVD). Although LBP alone with optimized AVD was better than BIV-LBP, when AVD optimization was not possible BIV-LBP outperformed LBP alone, because the RV pacing stimulus shortened RV activation (BIVAT-90: 54.2 ± 5.7 ms vs. 66.9 ± 5.1 ms, p < 0.01). BIV-endo lateral pacing or LBP delivered through a leadless system could potentially become an alternative to standard CRT. RV-LV delay, RV lead location and type of left bundle capture affect leadless pacing efficacy and should be considered in future trial designs

Suicide retrograde transport of volkensin in cerebellar afferents: direct evidence, neuronal lesions and comparison with ricin

Volkensin and ricin, either free or conjugated with colloidal gold, were injected into the cerebellar cortex of rats. The inferior olive and pontine nuclei were examined to verify the retrograde axonal transport of these two toxins, and the consequent neuronal damage. No evidence was obtained of a retrograde axonal transport of ricin in these pathways. Injection of gold-conjugated volkensin in the cerebellar cortex resulted in retrogradely labelled neurones in the inferior olive after 3 h, and in the pontine nuclei after 6 h. Degenerative changes were very severe in the retrogradely labelled neurones 48 h after the gold-conjugated volkensin injection. In the Nissl-stained material, neuronal degeneration started to be evident in the inferior olive 12 h, and in pontine nuclei 6 h, after volkensin injection. The neuronal degeneration in both the inferior olive and pons increased up to 4 days after the injection. These findings provide direct evidence of the retrograde axonal transport of volkensin in the cen tral nervous system, and the time course of the consequent degenerative changes in the afferents to the cerebellar cortex