Search Results (59)

Hemispheric asymmetries in the cortical structure and function are well documented, but whether this asymmetry is reflected in the electrophysiological properties of the same neuron type remains unclear, particularly given the many factors that influence action potential (AP) generation. Among these factors, dendritic tree size plays a crucial role in AP generation and in forward and backward propagation, yet it is not well understood whether dendritic size affects spike generation similarly in the two hemispheres. Here, electrophysiological recordings of layer 6a corticothalamic (CT) pyramidal neurons from a mouse’s left and right primary visual cortex were analyzed to examine how apical dendrite integrity influences somatic AP properties. Neurons were divided into four groups based on hemisphere and apical dendrite status (intact vs. truncated), and the AP shape parameters were quantified in response to current stimulation. Intact CT neurons showed similar AP rapidity and width across hemispheres but differed in AP threshold and amplitude. In contrast, a comparison of the intact and truncated neurons within each hemisphere revealed significant and opposing effects of apical dendrite truncation on all AP parameters. These results suggest that the coupling between dendritic morphology and somatic AP generation differs between hemispheres, implying distinct rules for integrating dendritic load in the left and right CT neurons. Full article

Inherited cardiomyopathies represent a major cause of ventricular arrhythmias (VA) and sudden cardiac death (SCD), frequently occurring in the absence of advanced systolic dysfunction. Traditional strategies for the primary prevention of SCD have relied predominantly on left ventricular ejection fraction (LVEF), an approach that fails to capture the substantial biological and clinical heterogeneity of non-ischemic cardiomyopathies. Over the past decade, advances in cardiac genetics and cardiac magnetic resonance imaging have identified specific genotypes associated with a disproportionate arrhythmic risk, which often precedes overt ventricular remodeling. The 2023 European Society of Cardiology (ESC) Guidelines on cardiomyopathies formalize this paradigm shift by integrating etiology, myocardial substrate, and electrical phenotype into contemporary risk stratification. In this narrative review, we focus on cardiomyopathy-associated genotypes consistently linked to high arrhythmic risk—LMNA, truncating variants in FLNC, RBM20, PLN p.Arg14del, and desmosomal genes—and examine their molecular mechanisms, phenotypic trajectories, and arrhythmogenic profiles. We discuss how genotype-specific patterns of myocardial fibrosis, conduction disease, and VA inform implantable cardioverter-defibrillator (ICD) decision-making beyond LVEF-based thresholds. By synthesizing genetic, imaging, and clinical evidence in light of ESC 2023 recommendations, this review highlights the evolving role of genotype-informed strategies in the personalized prevention of SCD and underscores remaining gaps in evidence and risk prediction. Full article

Particle-in-Cell (PIC) simulations require accurate solutions of the electrostatic Poisson equation, yet accuracy often degrades near irregular Dirichlet boundaries on Cartesian meshes. While prior work has focused on left-hand-side (LHS) discretization errors, the impact of right-hand-side (RHS) inaccuracies arising from charge deposition near boundaries remains largely unexplored. This study analyzes numerical errors induced by underestimated RHS values at near-boundary nodes when using embedded finite difference schemes with linear and quadratic boundary treatments. Analytical results in one dimension and truncation error analyses in two dimensions show that RHS inaccuracies affect the two schemes in fundamentally different ways: They reduce boundary-induced errors in the linear scheme but introduce zeroth-order truncation errors in the quadratic scheme, leading to larger global errors. Numerical experiments in one, two, and three dimensions confirm these predictions. In two-dimensional tests, RHS inaccuracies reduce the $L_{\infty }$ error of the linear scheme by a factor of 2–3, while increasing the quadratic-scheme error by several times, and in some cases by nearly an order of magnitude, with both schemes retaining second-order global convergence. A simple $\overline{\delta }$-based RHS calibration is proposed and shown to effectively restore the accuracy of the quadratic scheme. Full article

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is usually caused by pathogenic variants in sarcomeric genes and is inherited in an autosomal dominant manner. Around 5% of cases are caused by variants in non-sarcomeric genes, which may involve alternative modes of inheritance. This study presents the first reported case of HCM associated with digenic contribution of heterozygous variants in two non-sarcomeric genes: ALPK3 and TRIM63. The patient was incidentally diagnosed with non-obstructive HCM in childhood and developed extreme myocardial hypertrophy with moderate heart failure at the age of 18. Rapid progressive left ventricular dysfunction promptly resulted in death at the age of 26. Genetic testing with an extended HCM panel identified no sarcomeric variants but revealed two truncating variants in the ALPK3 and TRIM63 genes. Whole-genome sequencing excluded any other causes of the disease. Heterozygous ALPK3 variants are typically associated with late-onset HCM, whereas TRIM63 variants are only considered pathogenic in a recessive state. This case, therefore, suggests a synergistic contribution of both variants to the development of a severe phenotype. The potential mechanisms of interaction between the protein products of ALPK3 and TRIM63 within the M-band of the sarcomere are discussed. Full article

Background: Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by structural and functional abnormalities, in particular left or biventricular chamber dilatation and systolic dysfunction, occurring without evidence of coronary artery disease, hypertension, valvular disease, or congenital heart defects. It is a significant cause of sudden cardiac death, particularly in young individuals, often remaining undiagnosed until autopsy. Methods: A systematic review of the literature was conducted following PRISMA guidelines to revisit the main postmortem findings (gross, microscopic, and genetic) useful to perform the postmortem diagnosis of DCM. Scientific databases (PubMed and Scopus) were searched for articles published up to February 2025 describing postmortem findings in individuals diagnosed with DCM. Inclusion criteria were focused on studies reporting macroscopic cardiac findings, and microscopic and genetic variants identified postmortem or in related familial studies. Data were extracted and categorized to identify consistent diagnostic markers and to assess the frequency and relevance of genetic findings in autopsy-confirmed DCM cases. From 2081 initial records, 30 studies met inclusion criteria. Two reviewers independently performed study selection and data extraction, and methodological limitations of the included studies were considered qualitatively to inform the synthesis. Results: Common macroscopic features included increased heart weight (often > 350 g), dilated left or biventricular chambers, and thinning of the ventricular walls. Histologically, the most consistent findings were diffuse interstitial fibrosis, myocyte hypertrophy, and nuclear atypia. Particular attention was given to morphological features essential to distinguish between genetic and nongenetic forms of DCM and, thus, useful to perform a differential diagnosis with disease having a DCM-like pattern. Notably, truncating variants in genes such as TTN, FLNC, DSP, PKP2, and MYH7 were frequently reported, particularly in young decedents with no significant history of cardiac disease. However, only about half of reviewed studies included any form of genetic analysis, reflecting a significant gap in current practice for forensic pathologists. Conclusions: DCM may cause sudden death without prior symptoms, making genetic testing essential to uncover the diagnosis, especially in cases with a negative phenotype. Therefore, molecular autopsy combined with careful macroscopic and microscopic analysis can strengthen the forensic assessment. Full article

Deep learning has demonstrated better performance than traditional regression methods in handling right-censored cancer survival data; however, its application in survival analysis remains limited due to censoring-related data loss and the lack of approaches addressing left-censored or left-truncated cases. The aim of this study is to introduce a novel deep neural network algorithm designed to incorporate left truncation in survival analysis. Building upon prior research, we propose an innovative approach that integrates deep learning with survival analysis by applying complementary and consensus statistical principles to simultaneously account for left truncation and right censoring. The cumulative hazard function was estimated using the Breslow estimator and incorporated as an output variable in the proposed model. Model performance was assessed using the integrated area under the curve (iAUC), which quantifies predictive accuracy across all time points. The proposed method demonstrated robust predictive performance with an iAUC of 0.745 (95% CI: 0.705–0.785) when applied to left-truncated and right-censored survival data. Its performance was comparable to widely recognized statistical and machine learning techniques for survival analysis, including the Cox proportional hazards model (iAUC = 0.779, 95% CI: 0.739–0.812) and random survival forests (iAUC = 0.829, 95% CI: 0.795–0.858). This study introduces a methodological extension of deep neural network models, previously restricted to right-censored survival data, to also accommodate left-truncated survival data. The validation results provide evidence that the proposed model achieves predictive performance comparable to well-established methods, thereby broadening the applicability of deep learning in survival analysis. Full article

Background: Mullegama–Klein–Martinez syndrome (MKMS; OMIM #301022) is an X-linked cohesinopathy caused by pathogenic variants in STAG2, which encodes a subunit of the cohesin complex responsible for chromosomal segregation and transcriptional regulation. Individuals typically present with developmental delay, microcephaly, dysmorphic features, and variable congenital anomalies, though complex cardiac malformations are uncommon. Case Presentation: We report a female infant presenting on the first day of life with complex congenital heart disease, including pulmonary atresia, double-outlet right ventricle, large subaortic ventricular septal defect, and patent ductus arteriosus. She exhibited intrauterine growth restriction, mild craniofacial dysmorphism, and left upper-extremity hypotonia. Stepwise genetic evaluation revealed a de novo likely pathogenic STAG2 frameshift variant, c.2972_2975dup (p.His992Glnfs*11), identified by rapid trio whole-exome sequencing. This variant truncates the C-terminal domain critical for cohesin binding. A 3D structural model generated by SWISS-MODEL demonstrated disruption of β-strand and loop conformations within this domain, consistent with loss of cohesin complex stability. Conclusions: This case expands the phenotypic spectrum of STAG2-related MKM and highlights the role of STAG2 in cardiac development. Recognition of such presentations supports the inclusion of STAG2 in the differential diagnosis for complex congenital heart disease and underscores the diagnostic utility of rapid trio exome sequencing in neonatal care. The utility of 3D protein modeling to illustrate structural consequences of truncating variants provides valuable insight into variant pathogenicity and supports precision diagnosis in cohesinopathies. Full article

A variety of methods that provide approximate piecewise- analytical solutions to initial-value problems governed by scalar, nonlinear, first-order, ordinary differential equations is presented. The methods are based on fixing the independent variable in the right-hand side of these equations and approximating the resulting term by either its first- or second-order Taylor series expansion. It is shown that the second-order Taylor series approximation results in Riccati equations with constant coefficients, whereas the first-order one results in first-order, linear, ordinary differential equations. Both approximations are shown to result in explicit finite difference equations that are unconditionally linearly stable, and their local truncation errors are determined. It is shown that, for three of the nonlinear, first-order, ordinary differential equations studied in this paper that are characterized by growing or decaying solutions, as well as by solutions that first grow and then decrease, a second-order Taylor series expansion of the right-hand side of the differential equation evaluated at each interval’s midpoint results in the most accurate method; however, the accuracy of this method degrades substantially for problems that exhibit either blowup in finite time or quadratic approximations characterized by a negative radicand. It is also shown that methods based on either first- or second-order Taylor series expansion of the right-hand side of the differential equation evaluated at either the left or the right points of each interval have similar accuracy, except for one of the examples that exhibits blowup in finite time. It is also shown that both the linear and the quadratic approximation methods that use the midpoint for the independent variable in each interval exhibits the same trends as and have errors comparable to the second-order trapezoidal technique. Full article

Genetic background is a critical determinant of disease expression, arrhythmic vulnerability, and therapeutic response in inherited cardiomyopathies. Implantable cardioverter-defibrillators (ICD) remain the cornerstone for primary prevention of sudden cardiac death, yet conventional selection based on left ventricular ejection fraction does not adequately reflect the heterogeneity of genetic substrates. Increasing evidence demonstrates that pathogenic variants differ not only in prevalence across cardiomyopathy subtypes but also in prognostic impact. Truncating variants, particularly in genes encoding structural proteins, are often associated with severe remodeling, progressive dysfunction, and high arrhythmic risk, whereas missense variants may confer variable expressivity, ranging from aggressive arrhythmogenic phenotypes to milder or late-onset disease. This variability underscores the importance of distinguishing variant classes in clinical decision-making. Integrating genetic information with advanced imaging markers, such as late gadolinium enhancement, allows refinement of arrhythmic risk stratification beyond static thresholds and supports more tailored ICD allocation. Nevertheless, translation into routine practice is limited by challenges in variant interpretation, phenotypic overlap between cardiomyopathy subtypes, and the lack of prospective validation of genotype-based models. In the precision medicine era, evolving strategies should move toward dynamic, multimodal approaches that combine genotype, phenotype, and imaging biomarkers, enabling more accurate prediction of arrhythmic risk and more cost-effective use of ICD therapy. Full article

Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of TTN-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models. Methods: We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model TTN deficiency, we silenced TTN in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (MYH6, NPPA) and fibrosis-associated genes (COL1A1, COL3A1, COL14A1). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9. Results: In both human patient data and the TTN knockdown iPSC-CM model, TTN deficiency suppressed MYH6 and NPPA while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering TTN expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing TTN and HDAC5 replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of NPPA and COL1A1, though its impact on COL3A1 and COL14A1 was not similarly enhanced. Conclusions: Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in TTN deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse TTN-deficiency-induced gene dysregulation highlights its promising translational potential for TTN-related cardiomyopathies. Full article

The process capability indices $C_p$ and $C_{pk}$ are commonly used in industry to evaluate process capability, but they usually require that quality data follow a normal distribution. However, in the actual supply–demand relationship, some suppliers artificially eliminate products that do not meet the inspection requirements in order to make buyers accept their products, and these truncated sample data have a more significant impact on process capability evaluation. Based on the left-truncated sample, two modified process capability indices, $C_p^T$ and $C_{pk}^T$, are proposed, and bootstrap confidence interval estimation methods are established for each of them. Extensive simulation experiments are conducted on the modified indices by varying the sample size and truncation location parameters, and the results are compared with those of traditional methods. The comparison reveals that the new methods outperform the traditional ones across a range of sample sizes and truncation locations. Finally, a real example is used to validate the usefulness of the new method in guiding production management. Full article

The phase-type aging model (PTAM) belongs to a class of Coxian-type Markovian models that can provide a quantitative description of well-known aging characteristics that are part of a genetically determined, progressive, and irreversible process. Due to its unique parameter structure, estimation via the MLE method presents a considerable estimability issue, whereby profile likelihood functions are flat and analytically intractable. In this study, a Markov chain Monte Carlo (MCMC)-based Bayesian methodology is proposed and applied to the PTAM, with a view to improving parameter estimability. The proposed method provides two methodological extensions based on an existing MCMC inference method. First, we propose a two-level MCMC sampling scheme that makes the method applicable to situations where the posterior distributions do not assume simple forms after data augmentation. Secondly, an existing data augmentation technique for Bayesian inference on continuous phase-type distributions is further developed in order to incorporate left-truncated data. While numerical results indicate that the proposed methodology improves parameter estimability via sound prior distributions, this approach may also be utilized as a stand-alone statistical model-fitting technique. Full article

Background/Objectives: Ventricular pre-excitation (VP) increases the risk of sudden cardiac death among children. While transcatheter ablation could potentially be therapeutic, it is not without risk, especially in smaller children. Accessory pathways (APs) may spontaneously lose anterograde conduction properties over time, making invasive treatment unnecessary. We aim to investigate the probability of spontaneous loss of VP during childhood, as well as the potential factors that may be associated with VP resolution. Methods: We conducted a retrospective study of patients with VP diagnosed before 12 years of age and referred to two Northern Italian tertiary care hospitals between 1993 and 2021. Patients with complex congenital heart disease were excluded. Our primary objective was to determine the likelihood of spontaneous resolution of VP. Results: Overall, 153 patients were included, with a median age at first diagnosis of 4.9 years (25th–75th percentile: 75 days–8.4 years) and a median follow-up of 4.9 years (25th–75th percentile: 1.8–8 years). Through left truncated Kaplan–Meier analysis, we estimated that anterograde conduction would persist in 53% and 33.8% of patients at the age of 1 and 16 years, respectively. Our findings revealed that the absence of symptoms and intermittent VP were associated with a higher likelihood of VP resolution. It is noteworthy that no major arrhythmic events were reported. Conclusions: Our study strongly supports the implementation of a conservative strategy in younger children with VP. Our findings indicate that a significant proportion of pediatric patients may experience spontaneous resolution of VP in the early years of their lives, making any invasive treatment unnecessary. Full article

Anderson–Fabry (or Fabry) disease is a rare lysosomal storage disorder caused by a functional deficiency of the enzyme alpha-galactosidase A. The partial or total defect of this lysosomal enzyme, which is caused by variants in the GLA gene, leads to the accumulation of glycosphingolipids, mainly globotriaosylceramide in the lysosomes of different cell types. The clinical presentation of Fabry disease is multisystemic and can vary depending on the specific genetic variants associated with the disease. To date, more than 1000 different variants have been identified in the human GLA gene, including missense and nonsense variants, as well as small and large insertions or deletions. The identification of novel variants in individuals exhibiting symptoms indicative of Fabry disease, expands the molecular comprehension of the GLA gene, providing invaluable insights to physicians in the diagnosis of the disease. In this article, we present the case of two members of the same family, mother and son, in whom a new pathogenic variant was identified. This variant has not been previously described in the literature and is not present in databases. The two family members presented with a number of typical clinical manifestations of the disease, including cornea verticillata, neuropathic pain, left ventricular hypertrophy, angiokeratomas and abdominal pain. The son, but not his mother, showed reduced alpha-galactosidase A activity, while high levels of Lyso-Gb3 in the blood, a specific substrate accumulation biomarker, were found in both. Sequencing of the GLA gene revealed the presence of a variant, c.484delT, which is characterised by the deletion of a single nucleotide, a thymine, in exon 3 of the gene. This results in a frameshift variant, which introduces a premature stop codon, thereby generating a truncated and consequently non-functional protein. Therefore, the clinical and laboratory data indicate that the novel p.W162Gfs*3 variant described herein is associated with the classical form of Fabry disease. Full article

We present the case of a 27-year-old man who was admitted with new-onset acute heart failure. The echocardiogram revealed biventricular dilatation with a severely reduced systolic function. A genetic study identified a truncated variant of the filamin-C (FLNC) gene. Since the systolic function did not improve under heart failure guideline-directed medical therapy, an implantable cardioverter-defibrillator was placed. After two years, the patient is currently being considered for epicardial ventricular tachycardia (VT) ablation due to the failure of appropriate therapies for monomorphic VT despite recovery of the left ventricular (LV) systolic function. Filamin C truncating variants have been recognized as one cause of an overlapping phenotype in dilated and arrhythmogenic cardiomyopathies. These patients typically present with a mildly reduced LV ejection fraction (LVEF), with or without dilatation, and extensive myocardial fibrosis, which heightens the risk of complex ventricular arrhythmias (VAs). Our patient presented a combined phenotype with biventricular dilated cardiomyopathy with a severely reduced LVEF at an unusual young age, as well as an increased incidence of VAs. With this clinical case, we aim to highlight the importance of genetic evaluation in dilated cardiomyopathy, as it can be decisive in its orientation and, consequently, in its prognosis. Full article