Calibration of a three-state cell death model for cardiomyocytes and its application in radiofrequency ablation.

Objective.Thermal cellular injury follows complex dynamics and subcellular processes can heal the inflicted damage if insufficient heat is administered during the procedure. This work aims to the identification of irreversible cardiac tissue damage for predicting the success of thermal treatments.Approach.Several approaches exist in the literature, but they are unable to capture the healing process and the variable energy absorption rate that several cells display. Moreover, none of the existing models is calibrated for cardiomyocytes. We consider a three-state cell death model capable of capturing the reversible damage of a cell, we modify it to include a variable energy absorption rate and we calibrate it for cardiac myocytes.Main results.We show how the thermal damage predicted by the model response is in accordance with available data in the literature on myocytes for different temperature distributions. When coupled with a computational model of radiofrequency catheter ablation, the model predicts lesions in agreement with experimental measurements. We also present additional experiments (repeated ablations and catheter movement) to further illustrate the potential of the model.Significance.We calibrated a three-state cell death model to provide physiological results for cardiac myocytes. The model can be coupled with ablation models and reliably predict lesion sizes comparable to experimental measurements. Such approach is robust for repeated ablations and dynamic catheter-cardiac wall interaction, and allows for tissue remodelling in the predicted damaged area, leading to more accurate in-silico predictions of ablation outcomes.

Blood flow but not cannula positioning influences the efficacy of Veno-Venous ECMO therapy.

Despite being vital in treating intensive-care patients with lung failure, especially COVID-19 patients, Veno-Venous Extra-Corporeal Membrane Oxygenation does not exploit its full potential, leaving ample room for improvement. The objective of this study is to determine the effect of cannula positioning and blood flow on the efficacy of Veno-Venous Extra-Corporeal Membrane Oxygenation, in particular in relationship with blood recirculation. We performed 98 computer simulations of blood flow and oxygen diffusion in a computerized-tomography-segmented right atrium and venae cavae for different positions of the returning and draining cannulae and ECMO flows of 3 L/min and [Formula: see text]. For each configuration we measured how effective Veno-Venous Extra-Corporeal Membrane Oxygenation is at delivering oxygen to the right ventricle and thus to the systemic circulation. The main finding is that VV-ECMO efficacy is largely affected by the ECMO flow (global peak blood saturation: [Formula: see text]; average inter-group saturation gain: 9 percentage points) but only scarcely by the positioning of the cannulae (mean saturation ± standard deviation for the 3 L/min case: [Formula: see text]; for the [Formula: see text] case: [Formula: see text]). An important secondary outcome is that recirculation, more intense with a higher ECMO flow, is less detrimental to the procedure than previously thought. The efficacy of current ECMO procedures is intrinsically limited and fine-tuning the positions of the cannulae, risking infections, offers very little gain. Setting a higher ECMO flow offers the biggest benefit despite mildly increasing blood recirculation.

Impact of electrode tip shape on catheter performance in cardiac radiofrequency ablation.

Background: The role of catheter tip shape on the safety and efficacy of radiofrequency (RF) ablation has been overlooked, although differences have been observed in clinical and research fields. Objective: The purpose of this study was to analyze the role of electrode tip shape in RF ablation using a computational model. Methods: We simulated 108 RF ablations through a realistic 3-dimensional computational model considering 2 clinically used, open-irrigated catheters (spherical and cylindrical tip), varying contact force (CF), blood flow, and irrigation. Lesions are defined by the 50°C isotherm contour and evaluated by means of width, depth, depth at maximum width, and volume. Ablations are deemed as safe, critical (tissue temperature >90°C), and pop (tissue temperature >100°C). Results: Tissue-electrode contact is less for the spherical tip at low CF but the relationship is inverted at high CF. At low CF, the cylindrical tip generates deeper and wider lesions and a 4-fold larger volume. With increasing CF, the lesions generated by the spherical tip become comparable to those generated by the cylindrical tip. The 2 tips feature different safety profiles: CF and power are the main determinants of pops for the spherical tip; power is the main factor for the cylindrical tip; and CF has a marginal effect. The cylindrical tip is more prone to pop generation at higher powers. Saline irrigation and blood flow effect do not depend on tip shape. Conclusion: Tip shape determines the performance of ablation catheters and has a major impact on their safety profile. The cylindrical tip shows more predictable behavior in a wide range of CF values.

Systematic Characterization of High-Power Short-Duration Ablation: Insight From an Advanced Virtual Model.

Background: High-power short-duration (HPSD) recently emerged as a new approach to radiofrequency (RF) catheter ablation. However, basic and clinical data supporting its effectiveness and safety is still scarce. Objective: We aim to characterize HPSD with an advanced virtual model, able to assess lesion dimensions and complications in multiple conditions and compare it to standard protocols. Methods: We evaluate, on both atrium and ventricle, three HPSD protocols (70 W/8 s, 80 W/6 s, and 90 W/4 s) through a realistic 3D computational model of power-controlled RF ablation, varying catheter tip design (spherical/cylindrical), contact force (CF), blood flow, and saline irrigation. Lesions are defined by the 50°C isotherm contour. Ablations are deemed safe or complicated by pop (tissue temperature >97°C) or charring (blood temperature >80°C). We compared HPSD with standards protocols (30-40 W/30 s). We analyzed the effect of a second HPSD application. Results: We simulated 432 applications. Most (79%) associated a complication, especially in the atrium. The three HPSD protocols performed similarly in the atrium, while 90 W/4 s appeared the safest in the ventricle. Low irrigation rate led frequently to charring (72%). High-power short-duration lesions were 40-60% shallower and smaller in volume compared to standards, although featuring similar width. A second HPSD application increased lesions to a size comparable to standards. Conclusion: High-power short-duration lesions are smaller in volume and more superficial than standards but comparable in width, which can be advantageous in the atrium. A second application can produce lesions similar to standards in a shorter time. Despite its narrow safety margin, HPSD seems a valuable new clinical approach.

Portable simulation framework for diffusion MRI.

The numerical simulation of the diffusion MRI signal arising from complex tissue micro-structures is helpful for understanding and interpreting imaging data as well as for designing and optimizing MRI sequences. The discretization of the Bloch-Torrey equation by finite elements is a more recently developed approach for this purpose, in contrast to random walk simulations, which has a longer history. While finite element discretization is more difficult to implement than random walk simulations, the approach benefits from a long history of theoretical and numerical developments by the mathematical and engineering communities. In particular, software packages for the automated solutions of partial differential equations using finite element discretization, such as FEniCS, are undergoing active support and development. However, because diffusion MRI simulation is a relatively new application area, there is still a gap between the simulation needs of the MRI community and the available tools provided by finite element software packages. In this paper, we address two potential difficulties in using FEniCS for diffusion MRI simulation. First, we simplified software installation by the use of FEniCS containers that are completely portable across multiple platforms. Second, we provide a portable simulation framework based on Python and whose code is open source. This simulation framework can be seamlessly integrated with cloud computing resources such as Google Colaboratory notebooks working on a web browser or with Google Cloud Platform with MPI parallelization. We show examples illustrating the accuracy, the computational times, and parallel computing capabilities. The framework contributes to reproducible science and open-source software in computational diffusion MRI with the hope that it will help to speed up method developments and stimulate research collaborations.

A computational model of open-irrigated radiofrequency catheter ablation accounting for mechanical properties of the cardiac tissue.

Radiofrequency catheter ablation (RFCA) is an effective treatment for cardiac arrhythmias. Although generally safe, it is not completely exempt from the risk of complications. The great flexibility of computational models can be a major asset in optimizing interventional strategies if they can produce sufficiently precise estimations of the generated lesion for a given ablation protocol. This requires an accurate description of the catheter tip and the cardiac tissue. In particular, the deformation of the tissue under the catheter pressure during the ablation is an important aspect that is overlooked in the existing literature, which resorts to a sharp insertion of the catheter into an undeformed geometry. As the lesion size depends on the power dissipated in the tissue and the latter depends on the percentage of the electrode surface in contact with the tissue itself, the sharp insertion geometry has the tendency to overestimate the lesion obtained, which is a consequence of the tissue temperature rise overestimation. In this paper, we introduce a full 3D computational model that takes into account the tissue elasticity and is able to capture tissue deformation and realistic power dissipation in the tissue. Numerical results in FEniCS-HPC are provided to validate the model against experimental data and to compare the lesions obtained with the new model and with the classical ones featuring a sharp electrode insertion in the tissue.

Magnusiomyces clavatus infection in a child after allogeneic hematotopoetic stem cell transplantation: Diagnostic and therapeutic implications.

Magnusiomyces clavatus is an ascomycetous fungus causing invasive disease in immuno-compromised patients. Neutropenia, contaminated venous catheters, previous antifungal treatment are risk factors for this infection. We report a case of Magnusiomyces clavatus fungemia with pulmonary, renal and skin localizations in a 6-year-old boy with prolonged neutropenia because of three allogeneic hematopoietic stem cell transplantations. The infection was controlled by aggressive and strictly monitored combination therapy with voriconazole and liposomial-ampthotericine-B along with durable recover from neutropenia.

Etanercept as Treatment of Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Patients.

Corticosteroids are the standard of care for first-line treatment of patients who develop grade II-IV of acute graft-versus-host disease (aGVHD), but the optimal second-line treatment has not yet been determined. We prospectively evaluated the use of the anti-TNFα monoclonal antibody etanercept (ET) as second-line treatment in children with steroid-refractory (SR) aGVHD. Twenty-five children with either malignant or nonmalignant diseases experiencing grade II-IV SR aGVHD received ET as second-line treatment. ET was administered after a median of 14days (range, 5 to 135 days) from the onset of aGVHD. Seventeen out of 25 patients (68%) developed a complete response (CR) or partial response (PR) to ET. The overall response rate (CR plus PR) was 78% in patients with cutaneous SR aGVHD, 78% in those with gastrointestinal aGVHD, and 57% in those with hepatic aGVHD. On day +100 after the start of ET, 52% of the children were in CR, 16% were in PR, and the remaining 32% failed to respond. Overall survival was 76.5% in responders and 16.7% in nonresponders (P = .004). Transplantation-related mortality at 5years was 34.1% (95% confidence interval, 18.6% to 57.1%). In our experience, ET has proven to be effective as second-line treatment in children with SR aGVHD.

Evaluation of Chimerism Dynamics after Allogeneic Hematopoietic Stem Cell Transplantation in Children with Nonmalignant Diseases.

It is recognized that chimerism following hematopoietic stem cell transplantation (HSCT) is a dynamic process. The aims of this study were to describe the evolution of chimerism in children with nonmalignant diseases who underwent allogeneic HSCT, and to analyze the risk factors influencing chimerism status. A total of 101 HSCTs were performed in 85 patients with nonmalignant diseases. The donor was unrelated in 62.4% of HSCTs. Reduced-intensity conditioning (RIC) regimen was administered in 48.5% of patients. Acute graft-versus-host disease (aGVHD) occurred in 51.7% and chronic GVHD (cGVHD) in 39.7% of patients. Analysis of chimerism was performed through amplification of 9 specific short tandem repeats by polymerase chain reaction at engraftment and 1, 6, and 12 months after HSCT. Upon first evaluation, complete chimerism (CC) was detected in 34.7% and mixed chimerism (MC) in 55.4%, whereas graft failure occurred in 9.9% of patients. Severe aGVHD was associated with CC (P = .031). The last chimerism evaluation showed CC in 72.1%, stable MC in 12.8%, and progressive MC in 3.5%. CC was associated with a higher incidence of aGVHD (P = .016) and cGVHD (P = .022), whereas the RIC regimen was associated with graft failure (P = .026). One- and 3-year overall survival (OS) was 87.4% and 80.5%, respectively, with a lower OS at 3 years in patients with CC compared with those with MC (P = .008). aGVHD and cGVHD represent factors favoring CC, thus close, careful follow-up of chimerism is recommended in patients affected by nonmalignant disease.

Monitoring of Busulphan Concentrations in Children Undergone Hematopoietic Stem Cell Transplantation: Unicentric Experience over 10 years.

BACKGROUND AND OBJECTIVES: The aim of this report is to describe the experience in the management of busulphan-based conditioning regimen administered before hematopoietic stem cell transplantation (HSCT) in children. METHODS: We report the values of the first dose AUC (area under the concentration-time curve, normal target between 3600 and 4800 ng·h/mL) in children treated with oral and intravenous busulphan, and we analyze the impact of some clinical variables in this cohort of patients. RESULTS: 82 children treated with busulphan before HSCT were eligible for the study: 57 received oral busulphan with a mean AUC of 3586 ng·h/mL, while 25 received intravenous busulphan with a mean AUC of 4158 ng·h/mL. Dose adjustment was based on first dose AUC. The dose was increased in 36 children (43.9%) and decreased in 26 patients (31.7%). Age at HSCT (P = 0.015), cumulative dose of busulphan as mg/m2 (P < 0.001), busulphan dose prescribed as mg/Kg (P = 0.001), intravenous busulphan administration (P < 0.001), type of stem source cells (P = 0.016), and type of HSCT (P = 0.03) were associated with AUC levels. No statistically significant differences were found between transplant-related toxicity, acute and chronic graft versus host disease, engraftment, and AUC levels. CONCLUSIONS: We concluded that older age at HSCT, intravenous administration of busulphan, cumulative, and prescribed dose of busulphan are associated with higher AUC levels. The absence of significant correlations between toxic events, graft failure, and AUC suggests the efficacy of busulphan concentrations monitoring in our patients.

Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion.

We report on the molecular characterization of a microdeletion of approximately 2.5 Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3-/- mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point.

Interstitial 7q31.1 copy number variations disrupting IMMP2L gene are associated with a wide spectrum of neurodevelopmental disorders.

BACKGROUND: Since the introduction of the array-CGH technique in the diagnostic workup of mental retardation, new recurrent copy number variations and novel microdeletion/microduplication syndromes were identified. These findings suggest that some genomic disorders have high penetrance but a wide range of phenotypic severity. RESULTS: We present the clinical and molecular description of four unrelated patients affected by neurodevelopmental disorders and overlapping 7q31.1 microdeletion/microduplication, identified by array-CGH and involving only part of the IMMP2L gene. CONCLUSION: IMMP2L encodes an inner mitochondrial membrane protease-like protein, which is required for processing of cytochromes inside mitochondria. Numerous studies reported that this gene is implicated in behavioural disorders such as autistic spectrum disorders, attention-deficit hyperactivity disorders, and Gilles de la Tourette syndrome. We discuss the functions of the gene suggesting that IMMP2L may act as risk factor for neurological disease.

Recurrent microdeletion 2q21.1: report on a new patient with neurological disorders.

Whole genome profiling such as array comparative genomic hybridization has identified novel genomic imbalances. Copy number studies led to an explosion of the discoveries of new segmental duplication-mediated deletions and duplications. These rearrangements are mostly the result of non-allelic homologous recombination (NAHR) between low-copy repeats or segmental duplications. We have identified an individual with a small, rare deletion on chromosome 2q21.1 with psychomotor delay, hyperactivity, and aggressive behavior. The rearranged region is flanked by large complex low-copy repeats and includes only five genes: GPR148, FAM123C (AMER3), ARHGEF4, FAM168B, and PLEKHB2. The comparison between our patient and the cases previously reported in the literature contributes to a better definition of genotype-phenotype correlation of 2q21.1 microdeletions.

A rare 3q13.31 microdeletion including GAP43 and LSAMP genes.

BACKGROUND: Interstitial deletions affecting the proximal long arm of chromosome 3 have been rarely reported in the literature. The deleted segments vary in localization and size with different breakpoints making genotype-phenotype correlation very difficult. Until now, a girl with a 1.9-Mb interstitial deletion of 3q13.2q13.31 and 14 novel patients with deletions in 3q11q23 have been reported. RESULTS: Here we report on a 7-year-old girl with neuropsychiatric disorders and renal, vascular and skeletal anomalies. Array-CGH analysis revealed a small rare inherited 3q13.31 deletion containing only two genes, GAP43 and LSAMP. The mutation analysis of the two genes was negative on the other non-deleted chromosome. GAP43 is considered a crucial component for an effective regenerative response in the nervous system and its mRNA is localized exclusively to nerve tissue where the protein is linked to the synaptosomal membrane. LSAMP is a 64- to 68-kD neuronal surface glycoprotein found in cortical and subcortical regions of the limbic system that acts as an adhesion molecule and guides the development of specific patterns of neuronal connection. The deleted region is adjacent to a "desert gene" region extending 2.099 Mb. CONCLUSIONS: We discuss the effects of GAP43 and LSAMP haploinsufficiency, proposing that their deletion may be responsible for the main phenotype. Further cases with similar microdeletion are expected to be diagnosed and will help to better characterize the clinical spectrum of phenotypes associated with 3q13.31 microdeletion.

Primary red ear syndrome associated with cochleo-vestibular symptomatology: a paediatric case report.

BACKGROUND: Red ear syndrome (RES), first described by Lance in 1996 in an adult series, may be primary or associated with headache syndromes, upper cervical disorders or vascular anomalies. Clinically the disease is characterised by recurrent episodes of reddening and burning pain in the auricle, usually elicited by different triggers. The prevalence of RES in the paediatric age group remains poorly understood. Several therapeutic approaches have been tried with heterogeneous clinical response. CASE RESULTS: We report a paediatric patient suffering from primary RES associated with debilitating cochleo-vestibular symptomatology causing severe discomfort. Three years after the disease onset, the patient also developed headache, with clinical features of migraine. DISCUSSION: The temporal and spatial association could suggest shared pathogenetic features between neurological (cochleo-vestibular) and vascular (red and burning ear) symptomatology, likely related to trigeminal autonomic reflex activation, although further studies are required for full comprehension of RES pathogenesis.