Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production.

RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here, we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologs of phosphoribosylformylglycinamidine synthetase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homolog thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme.

Treatment at Academic Centers Decreases Insurance-Based Survival Disparities in Colon Cancer.

BACKGROUND: Although insurance and race-based survival disparities in colon cancer are well studied, little is known regarding how these survival disparities are impacted by type of treating facility. MATERIALS AND METHODS: This is a retrospective cohort study of 433,997 patients diagnosed with colon adenocarcinoma using the National Cancer Database (NCDB). Using Cox proportional hazard analyses, we assessed overall survival (OS) as a function of race, insurance status, and treating facility, after adjusting for demographic and clinical factors. We also assessed differences in OS according to race and insurance status stratified by treating facility type. RESULTS: OS was significantly diminished for blacks (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.07-1.10; P < 0.001) and increased for patients of other race (primarily Asians; HR, 0.76; 95% CI, 0.74-0.78) compared with whites. Patients with private insurance had improved OS compared with uninsured (HR, 1.28; 95% CI, 1.25-1.31; P < 0.001), Medicaid (HR, 1.35; 95% CI, 1.33-1.38; P < 0.001) and Medicare (HR, 1.13, 95% CI, 1.12-1.15; P < 0.001) patients. Compared with patients treated at comprehensive community programs, patients treated at academic centers (ACs) had improved OS (HR, 0.86; 95% CI, 0.85-0.88; P < 0.001). When stratified by type of treating facility, racial disparities were not mitigated for patients treated at ACs compared with other facilities (P = 0.266 for interaction). At ACs, patients with Medicaid had persistent OS disparities compared with patients with private insurance (HR, 1.12; 95% CI, 1.09-1.15; P < 0.001), although these disparities were significantly diminished compared with patients treated at other facilities (HR, 1.41; 95% CI, 1.38-1.45; P < 0.001). CONCLUSIONS: Other race, private insurance, and treatment at AC were independently associated with improved OS in patients with colon cancer. Medicaid-based, but not race-based, survival disparities are reduced at ACs compared with other facilities.

Postoperative Opiate Use in Urological Patients: A Quality Improvement Study Aimed at Improving Opiate Disposal Practices.

PURPOSE: We aimed to determine trends in postoperative opiate management among urological patients, identify associations with opiate keeping and foster appropriate opiate disposal after surgery via introduction of an educational handout. MATERIALS AND METHODS: We retrospectively analyzed opiate practices in 68 patients who had undergone urological surgery. In a separate consecutive cohort of 59 patients we distributed a handout detailing FDA (Food and Drug Administration) approved disposal methods. Patient opiate obtainment, use and disposal were assessed via telephone interviews with prescription filling data verified using the Tennessee CSMD (Controlled Substances Monitoring Database). Opiate keeping was defined as possessing any opiates more than 3 weeks after surgery or more than 4 times the duration of the postoperative prescription, whichever was longer. RESULTS: Opiate keeping was observed in 41 patients (72%) in our initial cohort. Of these patients 68% left the medication unsecured at home. Major barriers to opiate disposal included concern for return of disease specific pain in 44% of patients and unrelated pain in 29%. As assessed on a short test, opiate keepers were less knowledgeable about safe disposal practices compared to nonkeepers (72% vs 85%, p = 0.005). Among opiate keepers there was an improvement in knowledge scores after the intervention (66% to 77%, p = 0.03). When comparing pre-education to post-education, there was no detectable improvement in the rate of opiate keeping (72% vs 68%, p = 0.66) or proper disposal (9% vs 8%, p = 1.0). CONCLUSIONS: Opiate keeping is common following urological surgery and a major barrier to disposal is concern for the return of disease specific pain. Future interventions aimed at limiting opiate keeping should combine evidence-based prescription practices and targeted patient education.

Pelvic floor biofeedback therapy in children: Assessment of symptom scores in responders and non-responders.

INTRODUCTION: Pelvic Floor Biofeedback Therapy (PFBT) can be an effective treatment for pediatric lower urinary tract symptoms (LUTS). Due to differing perceptions of efficacy and practice patterns, we sought to further evaluate PFBT in our practice. We hypothesized that PFBT results in quiescence of EMG activity during voiding and improves questionnaire scores in patients with LUTS. METHODS: We retrospectively reviewed all patients undergoing PFBT and refined the analysis to females ≥6 years old with ≥2 sessions with completed voiding questionnaires pre- and post-treatment, active EMG during voiding, with non-neurogenic urinary tract complaints refractory to standard urotherapy. Validated Bladder Bowel Dysfunction (BBD) questionnaires were collected at each visit. Quiescence of EMG activity and changes in BBD score were the primary outcomes. RESULTS: 229 patients underwent ≥1 PFBT session, of which 64 females ≥6 years of age with ≥2 PFBT sessions and completed pre and post PFBT voiding questionnaires were identified. In this group, mean age at PFBT start was 10.1 (6.2-17.0). Patients completed 3.1 sessions (2-6). No difference was seen in post-void residual (PVR) between first and last session (23.8 vs 22.6 mL, P = 0.55). Median questionnaire score decreased from 18 (4-42) before to 13 (2-28) following PFBT (P < 0.0001). Responders, characterized by silencing of the EMG after PFBT, occurred in 31% (20/64). Non-responders were younger (P = 0.007) with higher pre-PFBT questionnaire scores. CONCLUSION: The use of PFBT appears to result in a significant reduction in symptom scores, though quiescence of EMG was observed following therapy in less than 1/3 of patients.

TRAF1 Coordinates Polyubiquitin Signaling to Enhance Epstein-Barr Virus LMP1-Mediated Growth and Survival Pathway Activation.

The Epstein-Barr virus (EBV) encoded oncoprotein Latent Membrane Protein 1 (LMP1) signals through two C-terminal tail domains to drive cell growth, survival and transformation. The LMP1 membrane-proximal TES1/CTAR1 domain recruits TRAFs to activate MAP kinase, non-canonical and canonical NF-kB pathways, and is critical for EBV-mediated B-cell transformation. TRAF1 is amongst the most highly TES1-induced target genes and is abundantly expressed in EBV-associated lymphoproliferative disorders. We found that TRAF1 expression enhanced LMP1 TES1 domain-mediated activation of the p38, JNK, ERK and canonical NF-kB pathways, but not non-canonical NF-kB pathway activity. To gain insights into how TRAF1 amplifies LMP1 TES1 MAP kinase and canonical NF-kB pathways, we performed proteomic analysis of TRAF1 complexes immuno-purified from cells uninduced or induced for LMP1 TES1 signaling. Unexpectedly, we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC), and stimulated linear (M1)-linked polyubiquitin chain attachment to TRAF1 complexes. LMP1 or TRAF1 complexes isolated from EBV-transformed lymphoblastoid B cell lines (LCLs) were highly modified by M1-linked polyubiqutin chains. The M1-ubiquitin binding proteins IKK-gamma/NEMO, A20 and ABIN1 each associate with TRAF1 in cells that express LMP1. TRAF2, but not the cIAP1 or cIAP2 ubiquitin ligases, plays a key role in LUBAC recruitment and M1-chain attachment to TRAF1 complexes, implicating the TRAF1:TRAF2 heterotrimer in LMP1 TES1-dependent LUBAC activation. Depletion of either TRAF1, or the LUBAC ubiquitin E3 ligase subunit HOIP, markedly impaired LCL growth. Likewise, LMP1 or TRAF1 complexes purified from LCLs were decorated by lysine 63 (K63)-linked polyubiqutin chains. LMP1 TES1 signaling induced K63-polyubiquitin chain attachment to TRAF1 complexes, and TRAF2 was identified as K63-Ub chain target. Co-localization of M1- and K63-linked polyubiquitin chains on LMP1 complexes may facilitate downstream canonical NF-kB pathway activation. Our results highlight LUBAC as a novel potential therapeutic target in EBV-associated lymphoproliferative disorders.

Nonopioid Pain Management Pathways for Stone Disease.

Introduction: New opioid dependency after urologic surgery is a serious adverse outcome that is well-described in the literature. Patients with stone disease often require multiple procedures because of recurrence of disease and hence are at greater risk for repeat opioid exposures. Despite this, opioid prescribing after urologic surgery remains highly variable and in an emergency setting, opioids are still used commonly in management of acute renal colic. Methods: Two literature searches were performed using PubMed. First, we searched available literature concerning opioid-sparing pathways in acute renal colic. Second, we searched available literature for opioid-sparing pathways in ureteroscopy and percutaneous nephrolithotomy (PCNL). Abstracts were reviewed for inclusion in our narrative review. Results: In the setting of acute renal colic, multiple randomized control trials have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) attain greater reduction in pain scores, decreased need for rescue medications, and decreased vomiting events in comparison with opioids. NSAIDs also form a core component in management of postureteroscopy pain and have been demonstrated in randomized trials to have equivalent to improved pain control outcomes compared with opioids. Multiple opioid-free pathways have been described for postureteroscopy analgesia with need for rescue narcotics falling under 20% in most studies, including in patients with ureteral stents. Enhanced Recovery After Surgery protocols after percutaneous nephrolithotomy are less well described but have yielded a reduction in postoperative opioid requirements. Conclusions: In select patients, both acute renal colic and after kidney stone surgery, adequate pain management can usually be obtained with minimal or no opioid medication. NSAIDs form the core of most described opioid-sparing pathways for both ureteroscopy and PCNL, with the contribution of other components to postoperative pain outcomes limited because of lack of head-to-head comparisons. However, medications aimed specifically at targeting stent-related discomfort form a key component of most multimodal postsurgical pain management pathways. Further investigation is needed to develop pathways in patients unable to tolerate NSAIDs.

Impact of sexual function domains on sexual satisfaction and quality of life: Importance across the age spectrum.

BACKGROUND: Sexual satisfaction is an important component of global quality life for many adult men. Substantial gaps exist in our appreciation of how age mediates sexual satisfaction in the context of functional sexual measures. We sought to evaluate modifiable factors associated with overall sexual satisfaction and health-related quality of life (HRQoL) in a large, age-stratified community-based sample of adult men. METHODS: A sample of adult males registered with the online research service ResearchMatch completed a 75-item online questionnaire in this cross-sectional study. Queries included demographics, general health data, and validated sexual health measures including International Index of Erectile Function-5 (IIEF-5) and Premature Ejaculation Diagnostic Tool (PEDT). Multivariable regression was performed to assess associations with self-reported sexual satisfaction (defined by "moderately satisfied" or "very satisfied" on the 5-level Likert scale) and overall HRQoL (as measured by the EQ-5D-visual analog scale (VAS) stratified by age. RESULTS: One thousand thirty-three men completed the survey and were stratified by age cohorts. IIEF-5 and PEDT scores were higher in younger cohorts. On multivariable regression analysis, higher IIEF-5, lower PEDT, better overall health-related quality of life, and the presence of a sexual partner within the last month were associated with an increased likelihood of overall sexual satisfaction. When stratified by age cohort, higher IIEF-5 scores were consistently positively associated with sexual satisfaction (Odds Ratio (OR) 1.18, 95% CI 1.15-1.22, P < 0.001), as well as independently associated with improved overall HRQoL by EQ-5D-VAS (ß = 0.71, Standard Error (SE) = 0.08, P < 0.001). CONCLUSIONS: The erectile function was independently associated with sexual satisfaction and quality of life across all age strata and predictive of both sexual satisfaction and global HRQoL. Low overall rates of sexual satisfaction across cohorts highlight the critical importance of evaluation and treatment of sexual health, regardless of age.

The Financial Burden of Nephrolithiasis and Predictors of Disease-specific Financial Toxicity.

OBJECTIVE: To characterize stone-related financial toxicity among US adults with kidney stones through validated questionnaires for financial toxicity and disease-specific health-related quality of life. MATERIALS AND METHODS: We performed a cross-sectional survey of adults with kidney stone disease from the general population ascertained through a national registry of volunteers (ResearchMatch). A computer-based survey queried stone event history and related costs for medical care, disease-specific quality of life (WISQOL), and an 11-item measure of stone-related financial toxicity (COST-11 score). Multivariable logistic regression was performed to evaluate predictors of financial toxicity, defined as having a COST-11 score ≤20. RESULTS: Of 942 responses, median COST-11 score was 29 (IQR 21-38), and 24.7% (N = 233) met criteria for disease-specific financial toxicity. Stone-formers with financial toxicity spent more out of pocket on stone-treatment in the previous year than patients with lower financial burden (P <.001) and were more likely to defer or delay recommended treatment due to anticipated cost (27% vs 3%; P <.001). Stone-specific financial toxicity was associated with poorer disease-specific health-related quality of life across all WISQOL domains (each P <.001). Multivariable logistic regression showed that female gender (OR 1.81; 95% CI 1.24-2.67), Medicaid compared to private insurance (OR 3.91; 95% CI 2.34-6.94), and stone passage in the previous year (OR 2.00; 95% CI 1.41-2.86) were independently associated with financial toxicity. CONCLUSION: Approximately 1 in 4 individuals with kidney stone disease report disease-specific financial toxicity. These data suggest the financial burden of the condition may influence decision-making and associates with poorer disease-specific quality of life.

Patient-Reported Financial Toxicity Associated With Management of Nephrolithiasis.

OBJECTIVE: To characterize stone-related financial burden among adults with nephrolithiasis through validated questionnaires for financial toxicity. METHODS: We performed a cross-sectional survey of adults with history of nephrolithiasis at an outpatient clinic. The survey contained a measure of stone-related financial toxicity (COST score), and assessed demographics, stone event history, and burden of overall, ancillary, preventative, and insurance costs. A COST score ≤21 was classified as high financial toxicity. Multivariable logistic regression was used to evaluate associations with demographic variables and stone event history. RESULTS: One hundred patients completed the survey (median age 57, IQR, 48-64). The median COST score was 30 (IQR, 23-37), and 19% reported high financial toxicity. Insurance status, household income, stone surgeries during lifetime and within the last 3 years were associated with financial toxicity on univariable analysis (P <.05). Burden of costs was significantly higher in all categories within the high financial toxicity cohort (each P <.05). On multivariable logistic regression, only income >$75,000 remained significant within the second model (OR: 0.22, 95% CI, 0.05-0.77, P = .02), however, this relationship did not persist on the final model. When asked whether providers should be mindful of their financial situation prior to making treatment recommendations, 39% responded "quite a bit" or "very much." CONCLUSION: One in 5 patients seeking care for nephrolithiasis meet criteria for high financial toxicity. Financial toxicity was associated with household income, insurance, education, and frequency of stone events. Thirty-nine percent reported that their provider should be mindful of their financial situation when making recommendations.

The Role of Alumni Networks and Career Advising in Early Career Stability of Urologists: Results of a Multi-institutional Study.

OBJECTIVE: To characterize training program and early career factors that impact decision-making and job retention following graduation in a diverse population of urologists. MATERIALS AND METHODS: We performed a computer-based survey distributed to residency graduates from 25 urology training programs. Five focus institutions were identified with a goal >30% response rate. The survey included questions about training program specifics and post-training employment characteristics. RESULTS: We obtained 180 responses from urology residency graduates of 25 programs. Overall, 72% (N = 129) remain in their initial post-training position at a median of 6years postgraduation (Interquartile Range (IQR) 3-10). On Cox-regression analysis stronger trainee-rated formal career advising was associated with lower risk of changing jobs (HR 0.77, 0.60-0.99, P = .048). Location/proximity to family was the most consistently cited as the top reason for selecting a job (41%). Sixty-three respondents (35%) joined practices employing graduates of the same residency program. Cox regression analysis showed that joining a practice with alumni of the same program was associated with lower risk of changing jobs from one's initial post-training position (HR 0.39, 95% CI 0.17-0.91, P = .03). CONCLUSION: In this multi-institutional study of urologists, we observed a high rate of job retention out to a median of 6years following completion of training, with formal career advising and joining alumni in practice being associated with job retention. Collectively, our data highlights that training programs should emphasize advising programs and alumni networking in guiding their graduates in the job search process.

How a Large Academic Training Program Influences Early Career Decision-making and Employment Stability in Urology.

OBJECTIVE: To characterize training and practice factors that influence early career stability and satisfaction in urology residency and fellowship graduates. METHODS: A computer-based survey was distributed to residency and fellowship graduates from a single, large US training program from 1992 to 2015. Queries encompassed training program specifics, post-training practice characteristics, and a validated burnout assessment. RESULTS: Of 108 surveyed individuals there were 77 (71.3%) respondents. Fifty-one (67.1%) remained in their first position after residency. While 52 (67.5%) urologists reported that the program did not formally assist in finding their first post-residency position, no respondent reported difficulty securing a position. Proximity to family was a major factor in selecting a post-residency position in 40 (51.9%) of respondents. Twenty-nine (37.7%) participants joined practices with at least one other graduate of the same urology training program on staff and 24 remain in this position (82%). CONCLUSION: Urology graduates from a large US training program did not have difficulty finding employment after training and most remain in their first post-training position. While proximity to family was a strong consideration for graduates, the perceived importance of first-position characteristics varied widely. 37.7% of our cohort took initial positions at a practice already employing a graduate from the same training program with >80% staying in this position. Surveying a broader range of programs may help future graduates and training programs better tailor their mentorship curricula and alumni networks to trainee goals.

Increasing utilization of the TWIST score in workup of patients with acute scrotal pain: Role in diagnosis and risk stratification.

INTRODUCTION: The TWIST score is a 5-component physical examination score used to aid in diagnosis of testicular torsion (TT) and could lessen need for radiologic testing in certain clinical scenarios. OBJECTIVE: TWIST use was not previously widespread at our institution. The primary objective of this quality improvement study was to achieve 100% compliance in TWIST utilization among urology and ED residents and to assess for score concordance between ED and urology assessments. Secondary goals were correlation of TWIST components with need for orchiectomy. METHODS: ED staff were educated about the TWIST score and asked to complete assessment for patients presenting with acute scrotal pain. Simultaneously, an electronic medical record-based dot phrase was introduced for urology trainees to complete an independent TWIST evaluation. Spearman correlation was performed to assess association between ED and Urology TWIST scores. Multivariable logistic regression was performed to assess association of TWIST score components and need for orchiectomy. RESULTS: 103 patients presented to the ED from 3/2018-11/2020 with a complaint of acute scrotal pain; 47 were diagnosed with torsion. As compared to our retrospective cohort, the documentation rate of complete TWIST score components on exam rose from 9% to 98% (P < 0.001) on ED evaluation and 16%-66% on urology evaluation (P < 0.001). Rates of repeat ultrasound for patient's transferred between facilities was similar (58% vs. 63%; p = 0.66) as was median time to OR (160 min vs. 145 min; p = 0.5). Using TWIST cutoff of >5 yielded a specificity of 94.5% for diagnosis of torsion, with corresponding strong correlation between ED and urology scores (rho = 0.71). A firm testicle was noted on urology evaluation in 100% of orchiectomy patients (vs. 61% of salvage patients) with persistent association after controlling for duration of symptoms (OR 28.1; P = 0.016). DISCUSSION: Through two-pronged quality improvement efforts, we significantly improved utilization of the TWIST score by ED and urology staff for workup of patients with acute testicular pain. We confirmed the high sensitivity and specificity of the TWIST score and demonstrated inter-rater reliability between ED and urology assessments. On prospective analysis, testicular firmness on exam was predictive of need for orchiectomy. CONCLUSION: The TWIST score is an accurate diagnostic tool for both ED and urology providers in workup of children with acute scrotal pain, with a normal score essentially ruling out the condition. Future work should aim at minimizing unnecessary testing in patients demonstrated to be at high risk for torsion.