Background Epicardial adipose tissue ( EAT ) is in immediate apposition to the underlying myocardium and, therefore, has the potential to influence myocardial systolic and diastolic function or myocardial geometry, through paracrine or compressive mechanical effects. We aimed to review the association between volumetric EAT and markers of myocardial function and geometry. Methods and Results PubMed, Medline, and Embase were searched from inception to May 2018. Studies were included only if complete EAT volume or mass was reported and related to a measure of myocardial function and/or geometry. Meta‐analysis and meta‐regression were used to evaluate the weighted mean difference of EAT in patients with and without diastolic dysfunction. Heterogeneity of data reporting precluded meta‐analysis for systolic and geometric associations. In the 22 studies included in the analysis, there was a significant correlation with increasing EAT and presence of diastolic dysfunction and mean e′ (average mitral annular tissue Doppler velocity) and E/e′ (early inflow / annular velocity ratio) but not E/A (ratio of peak early (E) and late (A) transmitral inflow velocities), independent of adiposity measures. There was a greater EAT in patients with diastolic dysfunction (weighted mean difference, 24.43 mL; 95% confidence interval, 18.5–30.4 mL; P <0.001), and meta‐regression confirmed the association of increasing EAT with diastolic dysfunction ( P =0.001). Reported associations of increasing EAT with increasing left ventricular mass and the inverse correlation of EAT with left ventricular ejection fraction were inconsistent, and not independent from other adiposity measures. Conclusions EAT is associated with diastolic function, independent of other influential variables. EAT is an effect modifier for chamber size but not systolic function.

Machine-learning techniques can produce accurate disease predictability better that traditional statistical regression. These tools may prove clinically useful for the automated prediction of patients who develop early biochemical recurrence after robot-assisted prostatectomy. For these patients, appropriate individualized treatment options can improve outcomes and quality of life.

We have investigated the role of the kinesin I isoform Kif5b in the trafficking of a cardiac voltage-gated potassium channel, Kv1.5. In Kv1.5-expressing HEK293 cells and H9c2 cardiomyoblasts, current densities were increased from control levels of 389 ± 50.0 and 317 ± 50.3 pA pF −1 , respectively, to 614 ± 74.3 and 580 ± 90.9 pA pF −1 in cells overexpressing the Kif5b motor. Overexpression of the Kif5b motor increased Kv1.5 expression additively with several manipulations that reduce channel internalization, suggesting that it is involved in the delivery of the channel to the cell surface. In contrast, expression of a Kif5b dominant negative (Kif5bDN) construct increased Kv1.5 expression non-additively with these manipulations. Thus, the dominant negative acts by indirectly inhibiting endocytosis. The increase in Kv1.5 currents induced by wild-type Kif5b was dependent on Golgi function; a 6 h treatment with Brefeldin A reduced Kv1.5 currents to control levels in Kif5b-overexpressing cells but had little effect on the increase associated with Kif5bDN expression. Finally, expression of the Kif5bDN prior to induction of Kv1.5 in a tetracycline inducible system blocked surface expression of the channel in both HEK293 cells and H9c2 cardiomyoblasts. Thus, Kif5b is essential to anterograde trafficking of a cardiac voltage-gated potassium channel.

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of diseasespecific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.

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Introduction: Penile fractures have classically been thought to require immediate surgical intervention; however, recent series have described acceptable outcomes with delayed repair. In this systematic review, we compared complication rates between immediate and delayed repair of penile fractures. Methods: A systematic search of MEDLINE, Embase, CENTRAL, and Web of Science was performed with predefined search terms between 1974 and 2015. Titles and abstracts were screened prior to full-text review and quality appraisal by two independent investigators. Abstracted outcomes included postoperative erectile dysfunction (ED), tunical scar formation, and penile curvature. Only studies reporting a direct comparison of complications following immediate (<24 hours from injury to presentation/surgery) and delayed (>24 hours) repair of penile fractures were included. Results: A total of 12 studies met inclusion criteria. All were retrospective, observational studies of low or moderate methodological quality. Of the reported 502 patients, 391 underwent immediate repair and 111 delayed repair. In the immediate repair group, the percent of patients with postoperative ED, tunical scars, and curvature were 6.6%, 5.4%, and 1.8%, respectively, while in the delayed group, the rates of ED, tunical scars, and curvature were 4.5% across the board. Rates of ED and tunical scar formation following immediate compared to delayed repair trended towards favouring immediate repair, but did not differ significantly, while rates of curvature significantly favoured immediate repair. However, cases of curvature were typically reported as mild and none affected sexual functioning. Conclusions: In this systematic review, we demonstrated that ED and tunical scar formation rates between immediate and delayed repair of penile fractures were statistically similar, while immediate repair had a lower rate of penile curvature. Although this suggests that a brief delay in repair may be acceptable in select patients, the results should be interpreted with caution, as the included studies were of low or moderate methodological quality. Most importantly, this review highlights the deficiencies in the current penile fracture literature, setting the stage to improve the quality of future studies.

Crystal structures of potassium (K+) channels reveal that the selectivity filter, the narrow portion of the pore, is only ∼3-Å wide and buttressed from behind, so that its ability to expand is highly constrained, and the permeation of molecules larger than Rb+ (2.96 Å in diameter) is prevented. N-methyl-d-glucamine (NMDG+), an organic monovalent cation, is thought to be a blocker of Kv channels, as it is much larger (∼7.3 Å in mean diameter) than K+ (2.66 Å in diameter). However, in the absence of K+, significant NMDG+ currents could be recorded from human embryonic kidney cells expressing Kv3.1 or Kv3.2b channels and Kv1.5 R487Y/V, but not wild-type channels. Inward currents were much larger than outward currents due to the presence of intracellular Mg2+ (1 mM), which blocked the outward NMDG+ current, resulting in a strong inward rectification. The NMDG+ current was inhibited by extracellular 4-aminopyridine (5 mM) or tetraethylammonium (10 mM), and largely eliminated in Kv3.2b by an S6 mutation that prevents the channel from opening (P468W) and by a pore helix mutation in Kv1.5 R487Y (W472F) that inactivates the channel at rest. These data indicate that NMDG+ passes through the open ion-conducting pore and suggest a very flexible nature of the selectivity filter itself. 0.3 or 1 mM K+ added to the external NMDG+ solution positively shifted the reversal potential by ∼16 or 31 mV, respectively, giving a permeability ratio for K+ over NMDG+ (PK+/PNMDG+) of ∼240. Reversal potential shifts in mixtures of K+ and NMDG+ are in accordance with PK+/PNMDG+, indicating that the ions compete for permeation and suggesting that NMDG+ passes through the open state. Comparison of the outer pore regions of Kv3 and Kv1.5 channels identified an Arg residue in Kv1.5 that is replaced by a Tyr in Kv3 channels. Substituting R with Y or V allowed Kv1.5 channels to conduct NMDG+, suggesting a regulation by this outer pore residue of Kv channel flexibility and, as a result, permeability.