Autophagy and urothelial carcinoma of the bladder: A review.

The incidence of urothelial carcinoma of the urinary bladder (bladder cancer) remains high. While other solid organ malignancies have seen significant improvement in morbidity and mortality, there has been little change in bladder cancer mortality in the past few decades. The mortality is mainly driven by muscle invasive bladder cancer, but the cancer burden remains high even in nonmuscle invasive bladder cancer due to high recurrence rates and risk of progression. While apoptosis deregulation has long been an established pathway for cancer progression, nonapoptotic pathways have gained prominence of late. Recent research in the role of autophagy in other malignancies, including its role in treatment resistance, has led to greater interest in the role of autophagy in bladder cancer. Herein, we summarize the literature regarding the role of autophagy in bladder cancer progression and treatment resistance. We address it by systematically reviewing treatment modalities for nonmuscle invasive and muscle invasive bladder cancer

Stress Urinary Incontinence post-Holmium Laser Enucleation of the Prostate: a Single-Surgeon Experience.

PURPOSE: To identify incidence and predictors of stress urinary incontinence (SUI) following Holmium laser enucleation of the prostate (HoLEP). MATERIALS AND METHODS: We performed a retrospective review of 589 HoLEP patients from 2012-2018. Patients were assessed at pre-operative and post-operative visits. Univariate and multivariate regression analyses were performed to identify predictors of SUI. RESULTS: 52/589 patients (8.8%) developed transient SUI, while 9/589 (1.5%) developed long-term SUI. tSUI resolved for 46 patients (88.5%) within the first six weeks and in 6 patients (11.5%) between 6 weeks to 3 months. Long-term SUI patients required intervention, achieving continence at 16.4 months on average, 44 men (70.9%) with incontinence were catheter dependent preoperatively. Mean prostatic volume was 148.7mL in tSUI patients, 111.6mL in long-term SUI, and 87.9mL in others (p \u3c 0.0001). On univariate analysis, laser energy used (p \u3c 0.0001), laser on time (p=0.0204), resected prostate weight (p \u3c 0.0001), overall International Prostate Symptom Score (IPSS) (p=0.0005), and IPSS QOL (p=0.02) were associated with SUI. On multivariate analysis, resected prostate weight was predictive of any SUI and tSUI, with no risk factors identified for long-term SUI. CONCLUSION: Post-HoLEP SUI occurs in ~10% of patients, with 1.5% continuing beyond six months. Most patients with tSUI recover within the first six weeks. Prostate size \u3e100g and catheter dependency are associated with increased risk tSUI. Larger prostate volume is an independent predictor of any SUI, and tSUI

Stereochemistry of Reactive Intermediates in Organophosphorous Chemistry

A new synthetic route to produce a phosphonyl radical in the ground state has been devised. The radical is capable of maintaining its structural integrity and geometry. In polar aprotic solvents the radical can equilibrate depending upon reaction conditions. Our results are significant for they show that the homolytic cleavage of a phosphorous oxygen bond could by changing the configuration at phosphorous, influence the biological properties of naturally occurring compounds. The stereochemistry of 2-substituted-5-ch1oromethyl-5methy1-2-oxo-1,3,2-dioxaphosphorinans can be established by proton NMR spectroscopy. Methanolysis of 2-hydrazinophosphorinans has been investigated. Cis and trans 2-hydrazinophosphorinans undergo acid catalyzed methanolysis to give products of both retention and inversion. The product ratio is dependent upon the strength of the acid used. Under strong acid conditions, the product ratio is nearly identical for both the cis and trans isomers. Stereochemical evidence for the participation of a phosphacylium ion-like intermediate is presented

Zero Tolerance – Mitigating the Opioid Epidemic Amongst Minimally Invasive Urologic Patients

Introduction: Opioids are routinely prescribed following minimally invasive surgery (MIS), yet the majority of medication remains unused. However, the literature is lacking evidence for non-narcotic analgesia in MIS urologic procedures. The purpose of this study is to evaluate the efficacy of a non-narcotic postoperative pain management regimen in reducing opioid use following MIS urologic procedures. Methods: In this prospective study, 51 MIS urologic patients were recruited over two months. Patients in the first month cohort (P1) were managed with the established pain management standard-of-care, while patients in the second month (P2) followed a non-narcotic postoperative pain management protocol that included an “opt-in” requirement for opioids. Protocol efficacy was assessed using self-reported patient pain scores at three time points, total postoperative hospital opioid utilization, and the need for opioids at discharge. Data analysis included descriptive statistics and student’s t-test. Results: Total mean values revealed 27.9% reduction in morphine equivalent dose (MED) prescribed, 19.7% reduction in MED used by patients, and 70% reduction in number of patients prescribed any opioids at time of discharge in P2 patients compared to P1 patients (p-value \u3c0.001). There was no significant difference between P1 and P2 in patient pain scores at each time point. Discussion: Overall, the new non-narcotic pain management protocol reduced postoperative opioid utilization in patients undergoing urologic MIS without compromising pain control. This study demonstrates that instituting a single “opt-in” postoperative pain management protocol with appropriate patient education helped significantly reduce the use of postoperative opioids

Mortality in pulmonary arterial hypertension in the modern era: Early insights from the Pulmonary Hypertension Association Registry

Background Current mortality data for pulmonary arterial hypertension (PAH) in the United States are based on registries that enrolled patients prior to 2010. We sought to determine mortality in PAH in the modern era using the PHAR (Pulmonary Hypertension Association Registry). Methods and Results We identified all adult patients with PAH enrolled in the PHAR between September 2015 and September 2020 (N=935). We used Kaplan-Meier survival analysis and Cox proportional hazards models to assess mortality at 1, 2, and 3 years. Patients were stratified based on disease severity by 3 validated risk scores. In treatment-naïve patients, we compared survival based on initial treatment strategy. The median age was 56 years (44-68 years), and 76% were women. Of the 935 patients, 483 (52%) were ≤6 months from PAH diagnosis. There were 121 deaths (12.9%) during a median follow-up time of 489 days (281-812 days). The 1-, 2-, and 3-year mortality was 8% (95% CI, 6%-10%), 16% (95% CI, 13%-19%), and 21% (95% CI, 17%-25%), respectively. When stratified into low-, intermediate-, and high-risk PAH, the mortality at 1, 2, and 3 years was 1%, 4% to 6%, and 7% to 11% for low risk; 7% to 8%, 11% to 16%, and 18% to 20% for intermediate risk; and 12% to 19%, 22% to 38%, and 28% to 55% for high risk, respectively. In treatment-naïve patients, initial combination therapy was associated with better 1-year survival (adjusted hazard ratio, 0.43 [95% CI, 0.19-0.95]

Early intervention for lactate dehydrogenase elevation improves clinical outcomes in patients with the HeartMate II left ventricular assist device: Insights from the PREVENT study

BACKGROUND: Hemolysis, assessed by elevated serum lactate dehydrogenase (LDH), is strongly associated with HeartMate II pump thrombosis (PT). However, it is unknown whether early intervention for elevated LDH circumvents the risk of serious PT requiring pump exchange. We sought to evaluate the relationship between elevated LDH and clinical outcomes, the effectiveness of early medical intervention, and risk factors for elevated LDH. METHODS: We studied 268 patients in the prospective, multicenter PREVENT study who had 2 or more LDH measurements at ≥30 days post-implant. Elevated LDH was defined as LDH ≥2.5× upper limit of normal (ULN) for 2 consecutive measurements. RESULTS: Fourteen percent of patients had elevated LDH. Stroke-free survival at 6 months was lower in patients with elevated LDH vs patients with normal LDH (83 ± 6% vs 93 ± 2%, p = 0.035). Elevated LDH resolved without intervention in 19% of patients, with intensified medical therapy in 43% and required surgical intervention in 38%. For patients receiving only medical therapy, survival was 94 ± 6% at 6 months post-treatment. In this subgroup, resolution of symptoms with intensified medical therapy was sustained in 15 of 16 patients, with PT occurring in 1 patient at 171 days after initial treatment for elevated LDH (202 days post-implant). Early medical intervention at moderately elevated LDH (2.5× to 3.2× ULN), as compared with higher levels (>3.2× ULN), led to more sustained resolution of symptoms without subsequent PT or need for surgical intervention (91% vs 26% at 6 months post-treatment, p = 0.002). CONCLUSIONS: Early medical intervention can successfully resolve moderate LDH elevations (2.5× to 3.2× ULN) with a low incidence of death or PT at 6 months post-treatment

Non-obstetrical robotic-assisted laparoscopic surgery in pregnancy: a systematic literature review.

Urologic and gynecologic surgeons are the top utilizers of robotic surgery; however, non-obstetrical robotic-assisted laparoscopic surgery (RALS) in pregnant patients is infrequent. A systematic literature review was performed to ascertain the frequency, indication and complications of RALS in pregnancy. Results showed thirty-eight pregnancies from eleven publications between 2008-2020. Five cases were for urologic indication and thirty-three for gynecologic indication. Minimal surgical alterations were required. Although no adverse maternal-fetal outcomes were reported, there are not enough cases published to determine safety. This review demonstrates the feasibility of RALS for the pregnant population in the hands of competent robotic surgeons

Excess protein O-GlcNAcylation links metabolic derangements to right ventricular dysfunction in pulmonary arterial hypertension

The hexosamine biosynthetic pathway (HBP) converts glucose to uridine-diphosphate-N-acetylglucosamine, which, when added to serines or threonines, modulates protein function through protein O-GlcNAcylation. Glutamine-fructose-6-phosphate amidotransferase (GFAT) regulates HBP flux, and AMP-kinase phosphorylation of GFAT blunts GFAT activity and O-GlcNAcylation. While numerous studies demonstrate increased right ventricle (RV) glucose uptake in pulmonary arterial hypertension (PAH), the relationship between O-GlcNAcylation and RV function in PAH is unexplored. Therefore, we examined how colchicine-mediated AMP-kinase activation altered HBP intermediates, O-GlcNAcylation, mitochondrial function, and RV function in pulmonary artery-banded (PAB) and monocrotaline (MCT) rats. AMPK activation induced GFAT phosphorylation and reduced HBP intermediates and O-GlcNAcylation in MCT but not PAB rats. Reduced O-GlcNAcylation partially restored the RV metabolic signature and improved RV function in MCT rats. Proteomics revealed elevated expression of O-GlcNAcylated mitochondrial proteins in MCT RVs, which fractionation studies corroborated. Seahorse micropolarimetry analysis of H9c2 cardiomyocytes demonstrated colchicine improved mitochondrial function and reduced O-GlcNAcylation. Presence of diabetes in PAH, a condition of excess O-GlcNAcylation, reduced RV contractility when compared to nondiabetics. Furthermore, there was an inverse relationship between RV contractility and HgbA1C. Finally, RV biopsy specimens from PAH patients displayed increased O-GlcNAcylation. Thus, excess O-GlcNAcylation may contribute to metabolic derangements and RV dysfunction in PAH