Structural variants shape the genomic landscape and clinical outcome of multiple myeloma

Deciphering genomic architecture is key to identifying novel disease drivers and understanding the mechanisms underlying myeloma initiation and progression. In this work, using the CoMMpass dataset, we show that structural variants (SV) occur in a nonrandom fashion throughout the genome with an increased frequency in the t(4;14), RB1, or TP53 mutated cases and reduced frequency in t(11;14) cases. By mapping sites of chromosomal rearrangements to topologically associated domains and identifying significantly upregulated genes by RNAseq we identify both predicted and novel putative driver genes. These data highlight the heterogeneity of transcriptional dysregulation occurring as a consequence of both the canonical and novel structural variants. Further, it shows that the complex rearrangements chromoplexy, chromothripsis and templated insertions are common in MM with each variant having its own distinct frequency and impact on clinical outcome. Chromothripsis is associated with a significant independent negative impact on clinical outcome in newly diagnosed cases consistent with its use alongside other clinical and genetic risk factors to identify prognosis

Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate

The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost 90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is inappropriate

Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A Randomized, Double-Blind, Placebo Controlled Study

Purpose: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction. Materials and Methods: This randomized, double-blind, placebo controlled, 12-week study (4-week run-in and 8-week treatment) randomized 145 men to placebo, 147 to avanafil 100 mg and 148 to avanafil 200 mg on demand. The primary efficacy variable was the per subject proportion of sexual attempts during the treatment period in which subjects achieved erection sufficient for vaginal penetration within approximately 15 minutes after dosing as measured by a stopwatch. The attempt had to enable successful completion of sexual intercourse according to SEP question 3. Results: Significantly greater mean per subject percentages of successful intercourse attempts within approximately 15 minutes after dosing were observed for avanafil 100 mg (mean 25.9%, LS mean ± SE 24.7% ± 2.9%) and 200 mg (mean 29.1%, LS mean 28.2% ± 2.9%) vs placebo (mean 14.9%, LS mean 13.8% ± 2.9%, p= 0.001 and \u3c0.001, respectively). After treatment we noted a statistically significant difference between avanafil and placebo in the average per subject proportion of successful intercourse attempts according to SEP question 3 as early as 10 minutes in the 200 mg group and 12 minutes in the 100 mg group. Treatment emergent adverse events included headache, upper respiratory tract infection andnasal congestion, and most such events were mild or moderate in severity. Conclusions: Avanafil was efficacious within approximately 15 minutes of dosing compared to placebo. Astatistically significant treatment difference in the percentage of successful sexual attempts was demonstrated as early as 10 minutes after treatment. © 2015 American Urological Association Education and Research, Inc

Comparing the Predictive Power of Preoperative Risk Assessment Tools to Best Predict Major Adverse Cardiac Events in Kidney Transplant Patients

Background. Patients undergoing kidney transplantation have increased risk of adverse cardiovascular events due to histories of hypertension, end-stage renal disease, and dialysis. As such, they are especially in need of accurate preoperative risk assessment. Methods. We compared three different risk assessment models for their ability to predict major adverse cardiac events at 30 days and 1 year after transplant. These were the PORT model, the RCRI model, and the Gupta model. We used a method based on generalized U-statistics to determine statistically significant improvements in the area under the receiver operator curve (AUC), based on a common major adverse cardiac event (MACE) definition. For the top-performing model, we added new covariates into multivariable logistic regression in an attempt to create further improvement in the AUC. Results. The AUCs for MACE at 30 days and 1 year were 0.645 and 0.650 (PORT), 0.633 and 0.661 (RCRI), and finally 0.489 and 0.557 (Gupta), respectively. The PORT model performed significantly better than the Gupta model at 1 year (p=0.039). When the sensitivity was set to 95%, PORT had a significantly higher specificity of 0.227 compared to RCRI’s 0.071 (p=0.009) and Gupta’s 0.08 (p=0.017). Our additional covariates increased the receiver operator curve from 0.664 to 0.703, but this did not reach statistical significance (p=0.278). Conclusions. Of the three calculators, PORT performed best when the sensitivity was set at a clinically relevant level. This is likely due to the unique variables the PORT model uses, which are specific to transplant patients