BET bromodomains mediate transcriptional pause release in heart failure.

Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.

The role of perioperative medications in urinary retention following midurethral sling.

AIMS: Postoperative urinary retention (PUR) is a known complication of midurethral sling (MUS) placement. The use of certain perioperative medications may influence the risk of this complication. This study aimed to investigate the association of perioperative medications with urinary retention after MUS. METHODS: This was a retrospective study of women undergoing MUS placement for stress urinary incontinence by a fellowship-trained urologic surgeon between 2015 and 2018, under approval by the Institutional Review Board. Both retropubic and transobturator approaches were included. All patients underwent an active void trial following surgery. Intraoperative medications given by the anesthesia team were retrospectively noted. The Fisher's exact test was used to compare the association of PUR with categorical variables. RESULTS: A total of 82 patients were included, 17 (21%) of whom failed postoperative void trial due to urinary retention. Of 25 patients receiving perioperative scopolamine, 40% failed the postoperative void trial, compared to 12% of patients not receiving scopolamine (p = .048). Groups were then stratified based on scopolamine use due to the observed independent association with PUR. Subgroup analysis revealed a stronger association of postoperative retention with scopolamine in patients undergoing concomitant prolapse surgery. Notably, retention rate and scopolamine use were similar whether patients underwent sling placement alone or in combination with prolapse surgery. Rate of retention was also higher for retropubic versus transobturator slings (36% vs. 9%; p = .005). CONCLUSIONS: Perioperative scopolamine may be associated with an increased risk of postoperative urinary retention following MUS, especially in the setting of a concomitant prolapse surgery.

Medical Expulsive Therapy is Underused for the Management of Renal Colic in the Emergency Setting.

PURPOSE: Although the 2007 AUA (American Urological Association) guidelines established it as first line therapy for ureteral stones less than 10 mm, widespread adoption of medical expulsive therapy has been low. We determined the current penetrance of medical expulsive therapy guideline recommendations and the efficacy of medical expulsive therapy in reducing the requirement for urological procedures after emergency department visits for ureteral stones. MATERIALS AND METHODS: In a retrospective analysis of patients seen in the emergency department we included 2,105 emergency department visits associated with an ICD-9 diagnosis of urolithiasis in which computerized tomography abdomen/pelvis scan was performed. Outcomes were reviewed for spontaneous passage or required urological procedure. RESULTS: Ureteral stones were found in 48.8% of patients, including 50.0% in whom medical expulsive therapy was prescribed. There was no significant difference between patients who did and did not receive medical expulsive therapy. Within 12 weeks of the initial emergency department visit there was no difference in the rate of urological procedures performed in those who received medical expulsive therapy or in the rate of return to the emergency department. Patients treated with medical expulsive therapy experienced a shorter time to spontaneous expulsion (7.1 vs 12.8 days, p = 0.048). CONCLUSIONS: Medical expulsive therapy for renal colic in the emergency setting remains underused. Half of the patients who met criteria for medical expulsive therapy in this study did not receive the standard of care. Patients treated with medical expulsive therapy achieved spontaneous passage more quickly but there was no difference in the requirement for a urological procedure. These results highlight the need for personnel at emergency departments to better standardize care for patients with ureteral stones.

Predicting procedural pain after ureteroscopy: does hydrodistention play a role?

PURPOSE: To identify perioperative predictors of immediate pain after ureteroscopy, specifically evaluating the impact of hydrodistention from irrigation on pain. MATERIALS AND METHODS: We retrospectively identified patients who underwent ureteroscopy for the treatment of calculi. Data recorded for these patients included their maximum pain score in the post-anesthesia care unit (PACU), average flow rate of irrigant used during the procedure, patient and stone characteristics, operative procedure, and details of patients' immediate, post-operative course. Spearman's rho was used to determine the relationship between non-parametric, continuous variables. Then, a linear regression was performed to assess which variables could predict the peak pain score. RESULTS: A total of 131 patients were included in the study. A non-parametric correlation analysis revealed that maximum pain score was negatively correlated with being male (r = -0.18, p=0.04), age (r = -0.34, p<0.001), and post-op foley placement (r = -0.20, p=0.02) but positively correlated with the preoperative pain score (r = 0.41, p<0.001), time in the PACU (r = 0.19, p = 0.03), and the morphine equivalent dose (MED) of narcotics administered in the PACU (r = 0.67, p<0.001). On linear regression, the significant variables were age, preoperative pain score, and stent placement. For every ten-year increase in age post-operative pain score decreased by 4/10 of a point (p = 0.03). For every 1 point increase in preoperative pain score there was a 3/10 of a point increase in the maximum pain score (p = 0.01), and leaving a stent in place post-operatively was associated with a 1.6 point increase in the maximum pain score. CONCLUSIONS: Hydrodistention does not play a role in post-ureteroscopy pain. Patients who are younger, have higher preoperative pain scores, or who are stented will experience more post-operative pain after ureteroscopy.

A history of chronic opioid usage prior to kidney transplantation may be associated with increased mortality risk.

Chronic opioid usage (COU) for analgesia is common among patients with end-stage renal disease. In order to test whether a prior history of COU negatively affects post-kidney transplant outcomes, we retrospectively examined clinical outcomes in adult kidney transplant patients. Among 1064 adult kidney transplant patients, 452 (42.5%) reported the presence of various body pains and 108 (10.2%) reported a prior history of COU. While the overall death or kidney graft loss was not statistically different between patients with and without a history of COU, the cumulative mortality rate at 1, 3, and 5 years after transplantation, and during the entire study period, appeared significantly higher for patients with than without a history of COU (6.5, 18.5, and 20.4 vs. 3.2, 7.5, and 12.7%, respectively). Multivariate Cox regression analysis adjusted for potential confounding factors in entire cohorts and Cox regression analysis in 1:3 propensity-score matched cohorts suggest that a positive history of COU was significantly associated with nearly a 1.6- to 2-fold increase in the risk of death (hazard ratio 1.65, 95% confidence interval 1.04-2.60, and hazard ratio 1.92, 95% confidence interval 1.08-3.42, respectively). Thus, a history of chronic opioid usage prior to transplantation appears to be associated with increased mortality risk. Additional studies are warranted to confirm the observed association and to understand the mechanisms.

"Robotic fatigue?" - The impact of case order on positive surgical margins in robotic-assisted laparoscopic prostatectomy.

PURPOSE: Multiple robotic-assisted surgeries are often performed within a single operating day; however, the impact of this practice on patient outcomes has not been examined. We aim to determine whether outcomes for robotic-assisted laparoscopic prostatectomy (RALP) differed when performed sequentially. MATERIALS AND METHODS: A multi-institutional, retrospective cohort study was conducted involving a total of 8 academic centers between years 2015 and 2018. Participants were adult males undergoing RALP for localized prostate cancer on operative days in which 2 RALP cases were performed sequentially by the same resident-attending team. The primary outcome of the study was presence of positive surgical margin (PSM). Secondary outcomes were lymph node yield, operative time, and estimated blood loss. The primary analysis was a random effects meta-analysis model for PSM. RESULTS: Overall, 898 RALP cases (449 sequential pairs) were included in the study. There was no significant difference in PSM rate (27.2% vs. 30.3%, P= 0.338) between first and second case groups, respectively. Utilizing random effects meta-analysis, the second case cohort had no increased risk of PSM (OR 0.761.231.97, P= 0.40). Higher blood loss was noted in the second case cohort (186.7 ml vs. 221.7 ml, P = 0.002). Additionally, factors associated with PSM were increasing prostate specific antigen, higher percent tumor involvement, extraprostatic extension, and seminal vesicle invasion. CONCLUSION: Case sequence was not associated with PSM, lymph node yield, or operative time for RALP. Disease specific factors and institutional experience are associated with increased risk for positive surgical margin which can aid providers in scheduling of patients.

Nephrolithiasis and Polycystic Ovary Syndrome: A Case-Control Study Evaluating Testosterone and Urinary Stone Metabolic Panels.

INTRODUCTION: Both elevated testosterone and polycystic ovary syndrome (PCOS) have been speculated as possible risk factors for kidney stone formation; however, the details of this potential relationship with regards to 24-hour urine metabolic panels and stone composition have not previously been characterized. METHODS: A total of 74 PCOS patients were retrospectively identified and matched with a cohort of female stone formers at a 3 : 1 ratio (by age and BMI). All patients had 24-hour urinary metabolic panels and stone compositions. These groups were compared using Pearson chi-square and Student t-tests. Additionally, the PCOS group was differentiated based on free testosterone using multivariate analysis. RESULTS: The case-control cohort showed that PCOS patients had significantly lower sodium excretion (p=0.015) and hypernatriuria rates (28.9% vs 50.9%, p=0.009). The PCOS-testosterone cohort demonstrated that high testosterone patients had significantly higher citrate values (p=0.041) and significantly lower odds of hypocitraturia (36.7% vs 54.2%, OR = 0.2, p=0.042). The high testosterone group also had higher sodium excretion (p=0.058) with significantly higher odds of having hypernatriuria (40.0% vs 13.6%, OR = 13.3, p=0.021). No significant patterns were revealed based on stone composition analysis. CONCLUSIONS: Compared to healthy stone formers, PCOS patients did not demonstrate significant differences in 24-hour urine and stone composition values. Elevated free testosterone in PCOS patients has a significant association with higher urinary citrate and sodium values: findings that in and of themselves do not confirm the hypothesized increased risk of stone formation. This patient cohort may provide deeper insight into the interplay between androgens and stone formation; however, further study is needed to fully characterize the possible relationship between PCOS and stone formation.

RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation.

Glioblastomas co-opt stem cell regulatory pathways to maintain brain tumor-initiating cells (BTICs), also known as cancer stem cells. NOTCH signaling has been a molecular target in BTICs, but NOTCH antagonists have demonstrated limited efficacy in clinical trials. Recombining binding protein suppressor of hairless (RBPJ) is considered a central transcriptional mediator of NOTCH activity. Here, we report that pharmacologic NOTCH inhibitors were less effective than targeting RBPJ in suppressing tumor growth. While NOTCH inhibitors decreased canonical NOTCH gene expression, RBPJ regulated a distinct profile of genes critical to BTIC stemness and cell cycle progression. RBPJ was preferentially expressed by BTICs and required for BTIC self-renewal and tumor growth. MYC, a key BTIC regulator, bound the RBPJ promoter and treatment with a bromodomain and extraterminal domain (BET) family bromodomain inhibitor decreased MYC and RBPJ expression. Proteomic studies demonstrated that RBPJ binds CDK9, a component of positive transcription elongation factor b (P-TEFb), to target gene promoters, enhancing transcriptional elongation. Collectively, RBPJ links MYC and transcriptional control through CDK9, providing potential nodes of fragility for therapeutic intervention, potentially distinct from NOTCH.

Predicting procedural pain after ureteroscopy: does hydrodistention play a role?

ABSTRACT Purpose: To identify perioperative predictors of immediate pain after ureteroscopy, specifically evaluating the impact of hydrodistention from irrigation on pain. Materials and Methods: We retrospectively identified patients who underwent ureteroscopy for the treatment of calculi. Data recorded for these patients included their maximum pain score in the post-anesthesia care unit (PACU), average flow rate of irrigant used during the procedure, patient and stone characteristics, operative procedure, and details of patients' immediate, post-operative course. Spearman's rho was used to determine the relationship between non-parametric, continuous variables. Then, a linear regression was performed to assess which variables could predict the peak pain score. Results: A total of 131 patients were included in the study. A non-parametric correlation analysis revealed that maximum pain score was negatively correlated with being male (r = −0.18, p=0.04), age (r = −0.34, p<0.001), and post-op foley placement (r = −0.20, p=0.02) but positively correlated with the preoperative pain score (r = 0.41, p<0.001), time in the PACU (r = 0.19, p = 0.03), and the morphine equivalent dose (MED) of narcotics administered in the PACU (r = 0.67, p<0.001). On linear regression, the significant variables were age, preoperative pain score, and stent placement. For every ten-year increase in age post-operative pain score decreased by 4/10 of a point (p = 0.03). For every 1 point increase in preoperative pain score there was a 3/10 of a point increase in the maximum pain score (p = 0.01), and leaving a stent in place post-operatively was associated with a 1.6 point increase in the maximum pain score. Conclusions: Hydrodistention does not play a role in post-ureteroscopy pain. Patients who are younger, have higher preoperative pain scores, or who are stented will experience more post-operative pain after ureteroscopy.