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Ectopic cardiovascular calcification is a highly prevalent pathology for which there are no effective novel or repurposed pharmacotherapeutics to prevent disease progression. We created a human calcification endophenotype module (ie, the "calcificasome") by mapping vascular calcification genes (proteins) to the human vascular smooth muscle‐specific protein‐protein interactome (218 nodes and 632 edges, P < 10−5). Network proximity analysis was used to demonstrate that the calcificasome overlapped significantly with endophenotype modules governing inflammation, thrombosis, and fibrosis in the human interactome (P < 0.001). A network‐based drug repurposing analysis further revealed that everolimus, temsirolimus, and pomalidomide are predicted to target the calcificasome. The efficacy of these agents in limiting calcification was confirmed experimentally by treating human coronary artery smooth muscle cells in an in vitro calcification assay. Each of the drugs affected expression or activity of their predicted target in the network, and decreased calcification significantly (P < 0.009). An integrated network analytical approach identified novel mediators of ectopic cardiovascular calcification and biologically plausible candidate drugs that could be repurposed to target calcification. This methodological framework for drug repurposing has broad applicability to other diseases. [ABSTRACT FROM AUTHOR]

Background: Although rotors have been considered among the drivers of atrial fibrillation (AF), the rotor definition is inconsistent. We evaluated the nature of rotors in 2D and 3D in- silico models of persistent AF (PeAF) by analyzing phase singularity (PS), dominant frequency (DF), Shannon entropy (ShEn), and complex fractionated atrial electrogram cycle length (CFAE-CL) and their ablation. Methods: Mother rotor was spatiotemporally defined as stationary reentries with a meandering tip remaining within half the wavelength and lasting longer than 5 s. We generated 2D- and 3D-maps of the PS, DF, ShEn, and CFAE-CL during AF. The spatial correlations and ablation outcomes targeting each parameter were analyzed. Results: 1. In the 2D PeAF model, we observed a mother rotor that matched relatively well with DF (>9 Hz, 71.0%, p<0.001), ShEn (upper 2.5%, 33.2%, p<0.001), and CFAE-CL (lower 2.5%, 23.7%, p<0.001). 2. The 3D-PeAF model also showed mother rotors that had spatial correlations with DF (>5.5 Hz, 39.7%, p<0.001), ShEn (upper 8.5%, 15.1%, p <0.001), and CFAE (lower 8.5%, 8.0%, p = 0.002). 3. In both the 2D and 3D models, virtual ablation targeting the upper 5% of the DF terminated AF within 20 s, but not the ablations based on long-lasting PS, high ShEn area, or lower CFAE-CL area. Conclusion: Mother rotors were observed in both 2D and 3D human AF models. Rotor locations were well represented by DF, and their virtual ablation altered wave dynamics and terminated AF. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate whether the location of the hinge affects the incidence of hinge fracture during medial closing-wedge distal femoral varus osteotomy (DFVO). Twenty knees from 10 fresh-frozen human cadavers (mean age, 75 ± 17 years) were used to perform uniplanar medial closing-wedge DFVO with a 7-mm wedge. Each specimen was randomly assigned to either group A (supracondylar hinge) or group B (lateral condylar hinge). The incidence of hinge fracture and stability was compared between both groups after uniplanar medial closing-wedge DFVO. In group A, 8 of 10 knees had a lateral cortex fracture during closure of the osteotomy gap, and all fractured knees were unstable. Two knees with an intact lateral cortical hinge showed stability under manual valgus and varus forces. After intentional breakage of the lateral cortical hinge, both knees were found to be unstable under the same force. In group B, 2 of 10 knees had a lateral cortex fracture, and 8 knees had no fractures. All specimens were found to be stable under manual valgus and varus forces. After intentional breakage of the lateral cortical hinge in group B, 2 knees were unstable, while 8 knees remained stable. This study showed a significantly higher incidence of lateral cortical hinge fracture and instability in group A than in group B during closure of the osteotomy gap., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Although 3D-complex fractionated atrial electrogram (CFAE) mapping is useful in radiofrequency catheter ablation for persistent atrial fibrillation (AF), the directions and configuration of the bipolar electrodes may affect the electrogram. This study aimed to compare the spatial reproducibility of CFAE by changing the catheter orientations and electrode distance in an in-silico left atrium (LA). We conducted this study by importing the heart CT image of a patient with AF into a 3D-homogeneous human LA model. Electrogram morphology, CFAE-cycle lengths (CLs) were compared for 16 different orientations of a virtual bipolar conventional catheter (conv-cath: size 3.5 mm, inter-electrode distance 4.75 mm). Additionally, the spatial correlations of CFAE-CLs and the percentage of consistent sites with CFAE-CL<120 ms were analyzed. The results from the conv-cath were compared with that obtained using a mini catheter (mini-cath: size 1 mm, inter-electrode distance 2.5 mm). Depending on the catheter orientation, the electrogram morphology and CFAE-CLs varied (conv-cath: 11.5±0.7% variation, mini-cath: 7.1±1.2% variation), however the mini-cath produced less variation of CFAE-CL than conv-cath (p<0.001). There were moderate spatial correlations among CFAE-CL measured at 16 orientations (conv-cath: r=0.3055±0.2194 vs. mini-cath: 0.6074±0.0733, p<0.001). Additionally, the ratio of consistent CFAE sites was higher for mini catheter than conventional one (38.3±4.6% vs. 22.3±1.4%, p<0.05). Electrograms and CFAE distribution are affected by catheter orientation and electrode configuration in the in-silico LA model. However, there was moderate spatial consistency of CFAE areas, and narrowly spaced bipolar catheters were less influenced by catheter direction than conventional catheters., Competing Interests: The authors declare no conflicts of interest.