Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with ≥2 variants. METHODS: The phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state). RESULTS: Among 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5-12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5-6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign. CONCLUSIONS: This severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population

Three-dimensional water diffusion in impermeable cylindrical tubes: theory versus experiments

Characterizing diffusion of gases and liquids within pores is important in understanding numerous transport processes and affects a wide range of practical applications. Previous measurements of the pulsed gradient stimulated echo (PGSTE) signal attenuation, E(q), of water within nerves and impermeable cylindrical microcapillary tubes showed it to be exquisitely sensitive to the orientation of the applied wave vector, q, with respect to the tube axis in the high-q regime. Here, we provide a simple three-dimensional model to explain this angular dependence by decomposing the average propagator, which describes the net displacement of water molecules, into components parallel and perpendicular to the tube wall, in which axial diffusion is free and radial diffusion is restricted. The model faithfully predicts the experimental data, not only the observed diffraction peaks in E(q) when the diffusion gradients are approximately normal to the tube wall, but their sudden disappearance when the gradient orientation possesses a small axial component. The model also successfully predicts the dependence of E(q) on gradient pulse duration and on gradient strength as well as tube inner diameter. To account for the deviation from the narrow pulse approximation in the PGSTE sequence, we use Callaghan's matrix operator framework, which this study validates experimentally for the first time. We also show how to combine average propagators derived for classical one-dimensional and two-dimensional models of restricted diffusion (e.g. between plates, within cylinders) to construct composite three-dimensional models of diffusion in complex media containing pores (e.g. rectangular prisms and/or capped cylinders) having a distribution of orientations, sizes, and aspect ratios. This three-dimensional modeling framework should aid in describing diffusion in numerous biological systems and in a myriad of materials sciences applications

Mapping apparent eccentricity and residual ensemble anisotropy in the gray matter using angular double-pulsed-field-gradient MRI

Conventional diffusion MRI methods are mostly capable of portraying microarchitectural elements such as fiber orientation in white matter from detection of diffusion anisotropy, which arises from the coherent organization of anisotropic compartments. Double-pulsed-field-gradient MR methods provide a means for obtaining microstructural information such as compartment shape and microscopic anisotropies even in scenarios where macroscopic organization is absent. Here, we apply angular double-pulsed-gradient-spin-echo MRI in the rat brain both ex vivo and in vivo for the first time. Robust angular dependencies are detected in the brain at long mixing time (tm). In many pixels, the oscillations seem to originate from residual directors in randomly oriented media, i.e., from residual ensemble anisotropy, as corroborated by quantitative simulations. We then developed an analysis scheme that enables one to map of structural indices such as apparent eccentricity (aE) and residual phase (φ) that enables characterization of the rat brain in general, and especially the rat gray matter. We conclude that double-pulsed-gradient-spin-echo MRI may in principle become important in characterizing gray matter morphological features and pathologies in both basic and applied neurosciences

Pediatric Electrophysiology Device Needs: A Survey from the Pediatric and Congenital Electrophysiology Society Taskforce on Pediatric-Specific Devices

Background There are few US Food and Drug Administration (FDA)-approved devices specifically aimed at the pediatric patient with arrhythmia. This has led to a high off-label utilization of devices in this vulnerable population. The Pediatric and Congenital Electrophysiology Society (PACES), the international organization representing pediatric and congenital heart disease arrhythmia specialists, developed a task force to comprehensively address device development issues relevant to pediatric patients with congenital arrhythmia. Methods and Results As a first step, the taskforce developed a 26-question survey for the pediatric arrhythmia community to assess providers\u27 understanding of the FDA approval process, specifically in regard to pediatric labeling. There were 92/211 respondents (44%) with a \u3e90% completion rate. The vast majority of respondents believed there was a paucity of devices available for children (96%). More than 60% of respondents stated that they did not understand the FDA regulatory process and were not aware of whether the devices they used were labeled for pediatric use. Conclusions Pediatric electrophysiologists are keenly aware of the deficit of available pediatric devices for their patients. The majority do not understand the FDA approval process and could benefit from additional educational resources regarding this. A collaborative forum including PACES, FDA, patients and their families, and Industry would be an important next step in clarifying opportunities and priorities to serve this vulnerable population

The seroprevalence of West Nile Virus in Israel: A nationwide cross sectional study.

West Nile Virus (WNV) is endemic in Israel, affecting yearly 40-160 individuals. Israel is located on a central migratory path between Africa and Eurasia and most West Nile Fever (WNF) cases reported in recent years were among residents of the coastal plain. The aim of the study was to evaluate the seroprevalence of WNV among the Israeli population and to assess correlates for WNV infection. A cross-sectional nationwide serologic survey was conducted using 3,145 serum samples collected by the national Israeli serum bank during 2011-2014, representing all age and population groups in Israel. Prevalence rates of WNV IgG antibodies were determined. Logistic regressions models were applied to assess the associations between demographic characteristics and WNV seropositivity. 350 samples were positive to WNV (11.1%; 95%CI: 10.0-12.3%). In the multivariable analysis, there was a significant association between seropositivity and the Arab population group vs. Jews and others (OR = 1.86, 95%CI: 1.37-2.52), the time lived in Israel [50-59 years vs. 0-9 years; OR = 10.80 (95%CI: 1.03-113.46) and ≥60 years vs. 0-9 years; OR = 14.00 (1.32-148.31)] residence area] Coastal Plain, Inland Plain (Shfela) and Great Rift Valley vs. Upper Galilee; OR = 2.24 (95%CI: 1.37-3.65), OR = 2.18 (95%CI: 1.18-4.03), OR = 1.90 (95%CI: 1.10-3.30), respectively [and rural vs. urban settlement (OR = 1.65, 95%CI: 1.26-2.16). People, who reside in the Coastal Plain, Inland Plain and Great Rift Valley, should be aware of the risk of contracting WNV and reduce exposure to mosquito bites, using insect repellents, and wearing protective clothing. The Ministry of Environmental Protection should be active in reducing the mosquito population by eliminating sources of standing water, a breeding ground for mosquitoes

Catecholaminergic polymorphic ventricular tachycardia patients with multiple genetic variants in the PACES CPVT Registry.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with ≥2 variants. METHODS: The phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state). RESULTS: Among 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5-12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5-6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign. CONCLUSIONS: This severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population