Genetic variants in SCN5A gene were identified in patients with various arrhythmogenic conditions including Brugada syndrome. Despite significant progress of last decades in studying the molecular mechanism of arrhythmia-associated SCN5A mutations, the understanding of relationship between genetics, electrophysiological consequences and clinical phenotype is lacking. We have found a novel genetic variant Y739D in the SCN5A-encoded sodium channel Nav1.5 of a male patient with Brugada syndrome (BrS). The objective of the study was to characterize the biophysical properties of Nav1.5-Y739D and provide possible explanation of the phenotype observed in the patient. The WT and Y739D channels were heterologously expressed in the HEK-293T cells and the whole-cell sodium currents were recorded. Substitution Y739D reduced the sodium current density by 47 ± 2% at -20 mV, positively shifted voltage-dependent activation, accelerated both fast and slow inactivation, and decelerated recovery from the slow inactivation. The Y739D loss-of-function phenotype likely causes the BrS manifestation. In the hNav1.5 homology models, which are based on the cryo-EM structure of rat Nav1.5 channel, Y739 in the extracellular loop IIS1-S2 forms H-bonds with K1381 and E1435 and pi-cation contacts with K1397 (all in loop IIIS5-P1). In contrast, Y739D accepts H-bonds from K1397 and Y1434. Substantially different contacts of Y739 and Y739D with loop IIIS5-P1 would differently transmit allosteric signals from VSD-II to the fast-inactivation gate at the N-end of helix IIIS5 and slow-inactivation gate at the C-end of helix IIIP1. This may underlie the atomic mechanism of the Y739D channel dysfunction.

OBJECTIVE: Image-guided radiotherapy (IGRT) involves frequent in-room imaging sessions contributing to additional patient irradiation. The present work provided patient-specific dosimetric data related to different imaging protocols and anatomical sites.
METHODS: We developed a Monte Carlo based software able to calculate 3D personalized dose distributions for five imaging devices delivering kV-CBCT (Elekta and Varian linacs), MV-CT (Tomotherapy machines) and 2D-kV stereoscopic images from BrainLab and Accuray. Our study reported the dose distributions calculated for pelvis, head and neck and breast cases based on dose volume histograms for several organs at risk.
RESULTS: 2D-kV imaging provided the minimum dose with less than 1 mGy per image pair. For a single kV-CBCT and MV-CT, median dose to organs were respectively around 30 mGy and 15 mGy for the pelvis, around 7 mGy and 10 mGy for the head and neck and around 5 mGy and 15 mGy for the breast. While MV-CT dose varied sparsely with tissues, dose from kV imaging was around 1.7 times higher in bones than in soft tissue. Daily kV-CBCT along 40 sessions of prostate radiotherapy delivered up to 3.5 Gy to the femoral heads. The dose level for head and neck and breast appeared to be lower than 0.4 Gy for every organ in case of a daily imaging session.
CONCLUSIONS: This study showed the dosimetric impact of IGRT procedures. Acquisition parameters should therefore be chosen wisely depending on the clinical purposes and tailored to morphology. Indeed, imaging dose could be reduced up to a factor 10 with optimized protocols.

OBJECTIVE: To use Monte Carlo (MC) together with voxel phantoms to analyze the tissue heterogeneity effect in the dose distributions and equivalent uniform dose (EUD) for (125)I prostate implants.
BACKGROUND: Dose distribution calculations in low dose-rate brachytherapy are based on the dose deposition around a single source in a water phantom. This formalism does not take into account tissue heterogeneities, interseed attenuation, or finite patient dimensions effects. Tissue composition is especially important due to the photoelectric effect.
METHODS: The computed tomographies (CT) of two patients with prostate cancer were used to create voxel phantoms for the MC simulations. An elemental composition and density were assigned to each structure. Densities of the prostate, vesicles, rectum and bladder were determined through the CT electronic densities of 100 patients. The same simulations were performed considering the same phantom as pure water. Results were compared via dose-volume histograms and EUD for the prostate and rectum.
RESULTS: The mean absorbed doses presented deviations of 3.3-4.0% for the prostate and of 2.3-4.9% for the rectum, when comparing calculations in water with calculations in the heterogeneous phantom. In the calculations in water, the prostate D 90 was overestimated by 2.8-3.9% and the rectum D 0.1cc resulted in dose differences of 6-8%. The EUD resulted in an overestimation of 3.5-3.7% for the prostate and of 7.7-8.3% for the rectum.
CONCLUSIONS: The deposited dose was consistently overestimated for the simulation in water. In order to increase the accuracy in the determination of dose distributions, especially around the rectum, the introduction of the model-based algorithms is recommended.