Deep Phenotyping the Anterior Urethral Stricture: Characterizing the Relationship Between Inflammation, Fibrosis, Patient History, and Disease Pathophysiology.

PURPOSE: Anterior urethral stricture disease (aUSD) is a complex, heterogeneous condition that is idiopathic in origin for most men. This gap in knowledge rarely affects the current management strategy for aUSD, as urethroplasty does not generally consider etiology. However, as we transition towards personalized, minimally invasive treatments for aUSD and begin to consider aUSD prevention strategies, disease pathophysiology will become increasingly important. The purpose of this study was to perform a deep phenotype of men undergoing anterior urethroplasty for aUSD. We hypothesized that unique biologic signatures and potential targets for intervention would emerge based on stricture presence/absence, stricture etiology, and the presence/absence of stricture inflammation. MATERIALS AND METHODS: Men with aUSD undergoing urethroplasty were recruited from one of 5 participating centers. Enrollees provided urethral stricture tissue and blood/serum on the day of surgery and completed patient-reported outcome measure questionnaires both pre- and postoperatively. The initial study had 3 aims: (1) to determine pediatric and adult subacute and repeated perineal trauma (SRPT) exposures using a study-specific SRPT questionnaire, (2) to determine the degree of inflammation and fibrosis in aUSD and peri-aUSD (normal urethra) tissue, and (3) to determine levels of systemic inflammatory and fibrotic cytokines. Two controls groups provided serum (normal vasectomy patients) and urethral tissue (autopsy patients). Cohorts were based on the presence/absence of stricture, by presumed stricture etiology (idiopathic, traumatic/iatrogenic, lichen sclerosus [LS]), and by the presence/absence of stricture inflammation. RESULTS: Of 138 enrolled men (120 tissue/serum; 18 stricture tissue only), 78 had idiopathic strictures, 33 had trauma-related strictures, and 27 had LS-related strictures. BMI, stricture length, and stricture location significantly differed between cohorts (P < .001 for each). The highest BMIs and the longest strictures were observed in the LS cohort. SRPT exposures did not significantly differ between etiology cohorts, with > 60% of each reporting low/mild risk. Stricture inflammation significantly differed between cohorts, with mild to severe inflammation present in 27% of trauma-related strictures, 54% of idiopathic strictures, and 48% of LS strictures (P = .036). Stricture fibrosis did not significantly differ between cohorts (P = .7). Three serum cytokines were significantly higher in patients with strictures compared to stricture-free controls: interleukin-9 (IL-9; P = .001), platelet-derived growth factor-BB (P = .004), and CCL5 (P = .01). No differences were observed in the levels of these cytokines based on stricture etiology. However, IL-9 levels were significantly higher in patients with inflamed strictures than in patients with strictures lacking inflammation (P = .019). Degree of stricture inflammation positively correlated with serum levels of IL-9 (Spearman's rho 0.224, P = .014). CONCLUSIONS: The most common aUSD etiology is idiopathic. Though convention has implicated SRPT as causative for idiopathic strictures, here we found that patients with idiopathic strictures had low SRPT rates that were similar to rates in patients with a known stricture etiology. Stricture and stricture-adjacent inflammation in idiopathic stricture were similar to LS strictures, suggesting shared pathophysiologic mechanisms. IL-9, platelet-derived growth factor-BB, and CCL5, which were elevated in patients with strictures, have been implicated in fibrotic conditions elsewhere in the body. Further work will be required to determine if this shared biologic signature represents a potential mechanism for an aUSD predisposition.

MmcA is an electron conduit that facilitates both intracellular and extracellular electron transport in Methanosarcina acetivorans.

Methanogens are a diverse group of Archaea that obligately couple energy conservation to the production of methane. Some methanogens encode alternate pathways for energy conservation, like anaerobic respiration, but the biochemical details of this process are unknown. We show that a multiheme c-type cytochrome called MmcA from Methanosarcina acetivorans is important for intracellular electron transport during methanogenesis and can also reduce extracellular electron acceptors like soluble Fe3+ and anthraquinone-2,6-disulfonate. Consistent with these observations, MmcA displays reversible redox features ranging from -100 to -450 mV versus SHE. Additionally, mutants lacking mmcA have significantly slower Fe3+ reduction rates. The mmcA locus is prevalent in members of the Order Methanosarcinales and is a part of a distinct clade of multiheme cytochromes that are closely related to octaheme tetrathionate reductases. Taken together, MmcA might act as an electron conduit that can potentially support a variety of energy conservation strategies that extend beyond methanogenesis.

Optilume drug-coated balloon for anterior urethral stricture: 2-year results of the ROBUST III trial.

Objective: The aim of this study is to report the updated 2-year results of the intervention arm of the ROBUST III randomized trial evaluating the safety and efficacy of the Optilume drug-coated balloon (DCB) versus standard endoscopic management of recurrent male anterior urethral stricture. Materials and Methods: Eligible patients included men with recurrent anterior urethral stricture ≤3 cm in length and ≤12Fr in diameter, International Prostate Symptom Score (IPSS) ≥11 and peak flow rate (Qmax) <15 mL/s. Patients were randomized to treatment with the Optilume DCB or standard-of-care endoscopic management. Primary efficacy endpoints measured at 2 years included freedom from re-intervention and changes in IPSS, Qmax and post-void residual (PVR). Secondary endpoint was impact on sexual function using the International Index of Erectile Function (IIEF). Primary safety endpoint was freedom from serious procedure- or device-related adverse events (AEs). Results: A total of 127 patients enrolled at 22 sites in the United States and Canada (48 randomized to standard-of-care dilation and 79 to DCB dilation). Seventy-five patients in the DCB arm entered the open-label phase after 6 months. Participants averaged 3.2 prior endoscopic interventions (range 2-10); most (89.9%) had bulbar strictures with an average stricture length of 1.63 cm (SD 0.76). Significant improvements in IPSS, average Qmax and PVR were maintained at 2 years. Freedom from repeat intervention was significantly higher in the Optilume DCB arm at 2 years versus the Control arm at 1 year (77.8% vs. 23.6%, p < 0.001). During the follow-up period, there were 15 treatment failures and two non-study-related deaths. Treatment-related AEs were rare and generally self-limited (haematuria, dysuria and urinary tract infection). Conclusion: The Optilume DCB shows sustained improvement in both objective and subjective voiding parameters at 2-year follow-up. Optilume appears to provide a safe and effective endoscopic treatment alternative for short recurrent anterior urethral strictures among men who wish to avoid or delay formal urethroplasty.

External Urethral Sphincter Botulinum Toxin Injection to Treat Pseudodysynergia in Patients With Cerebral Palsy.

OBJECTIVE: To evaluate urinary outcomes following cystoscopic external urinary sphincter onabotulinumtoxinA (BTX) injections in patients with cerebral palsy (CP). Adults with CP can suffer from bladder outlet obstruction and urinary retention due to a spastic external urethral sphincter ("pseudodysynergia"). We have used BTX injections into the sphincter to relieve the obstruction and allow patients to maintain spontaneous voiding rather than intermittent catheterization. METHODS: Patients were included in this retrospective cohort study if they had a diagnosis of CP, were at least 18 years of age, and underwent a urethral external sphincter BTX injection between 2016-2023. The procedure included 100 u or 200 u of BTX mixed in 4cc of saline. Primary outcomes were subjective, patient or caregiver reported changes in retention, lower urinary tract symptoms (LUTS), frequency of recurrent urinary tract infections (UTIs), and hydronephrosis or bladder stones/debris on ultrasound. RESULTS: Fifty patients were included; the majority were male (60%), lived at home with assistance (58%), and had a Gross Motor Function Classification System level of V (50%; ie, severe CP). The most common indications for BTX were retention (96%), LUTS (48%), hydronephrosis (18%), and recurrent UTIs (22%). Post-BTX improvement was seen in 67% of those with LUTS, 65% with retention, 67% with hydronephrosis, and 73% with recurrent UTIs. Most patients underwent repeat injections (60%). There were no significant complications associated with injections. CONCLUSION: External urethral sphincter BTX is a safe, effective option for treating pseudodysynergia in adults with CP.

PROPOSED REVISION OF THE AMERICAN ASSOCIATION FOR SURGERY OF TRAUMA RENAL TRAUMA ORGAN INJURY SCALE: SECONDARY ANALYSIS OF THE MULTI-INSTITUTIONAL GENITOURINARY TRAUMA STUDY.

BACKGROUND: This study updates the American Association for Surgery of Trauma (AAST) Organ Injury Scale (OIS) for renal trauma using evidence-based criteria for bleeding control intervention. METHODS: This was a secondary analysis of a multi-center retrospective study including patients with high grade renal trauma from 7 Level-1 trauma centers from 2013-2018. All eligible patients were assigned new renal trauma grades based on revised criteria. The primary outcome used to measure injury severity was intervention for renal bleeding. Secondary outcomes included intervention for urinary extravasation, units of packed red blood cells (PRBCs) transfused within 24 hours, and mortality. To test the revised grading system, we performed mixed effect logistic regression adjusted for multiple baseline demographic and trauma covariates. We determined the area under the receiver-operator curve (AUC) to assess accuracy of predicting bleeding interventions from the revised grading system and compared this to 2018 AAST organ injury scale. RESULTS: based on the 2018 OIS grading system, we included 549 patients with AAST Grade III-V injuries and CT scans (III: 52% (n = 284), IV: 45% (n = 249), and V: 3% (n = 16)). Among these patients, 89% experienced blunt injury (n = 491) and 12% (n = 64) underwent intervention for bleeding. After applying the revised grading criteria, 60% (n = 329) of patients were downgraded and 4% (n = 23) were upgraded; 2.8% (n = 7) downgraded from grade V to IV, and 69.5% (n = 173) downgraded from IV to III. The revised renal trauma grading system demonstrated improved predictive ability for bleeding interventions (2018 AUC = 0.805, revised AUC = 0.883; p = 0.001) and number of units of PRBCs transfused. When we removed urinary injury from the revised system, there was no difference in its predictive ability for renal hemorrhage intervention. CONCLUSIONS: A revised renal trauma grading system better delineates the need for hemostatic interventions than the current AAST OIS renal trauma grading system. LEVEL OF EVIDENCE: II.

Bladder management is the top health concern among adults with a spinal cord injury.

INTRODUCTION AND OBJECTIVE: Individuals with spinal cord injury (SCI) commonly experience secondary complications though it is not known how they prioritize these different health domains. Using the Neurogenic Bladder Research Group (NBRG) SCI registry, our objective was to identify the top health concerns of individuals with SCI and identify factors that may be associated with these choices with particular focus on urologic issues that participants face. METHODS: Participants in the NBRG registry were asked: "What are the top 3 problems that affect you on a daily basis?" Urinary symptoms and QoL were assessed with the Neurogenic Bladder Symptom Score (NBSS). Multivariate regression was used to identify factors related to selecting a top ranked health issue. RESULTS: Among our 1461 participants, 882 (60.4%) were men and the median age was 45.1 years (IQR 25.3-64.9). Bladder management was the most commonly top ranked primary issue (39%) followed by pain (16.4%) and bowel management (11.6%). Factors associated with ranking bladder management as the primary concern included years since injury (OR 1.01 [1.00-1.02], p = 0.042), higher (worse) total NBSS (OR 1.05 [1.03-1.06], p < 0.001), and higher (worse) NBSS QoL (OR 1.25 [1.12-1.41], p < 0.001). Reporting chronic pain on a daily basis was associated with ranking pain as the primary health concern (OR 41.7 [15.7-170], p < 0.001). CONCLUSIONS: In this cohort, bladder management was ranked as the top health issue and increasing time from injury was associated with increased concern over bladder management. More bladder symptoms were also associated with ranking bladder management as a primary concern while bladder management method and urinary tract infections rate were not.

Impact of Virtual Care on Outpatient Urinary Tract Infection Management.

OBJECTIVE: To examine the effect of virtual care on urine testing, antibiotic prescription patterns, and outcomes of care in urinary tract infection (UTI) management. METHODS: We conducted retrospective analysis of adults treated for UTI in an ambulatory setting across a large health system from March 2020-2021. Outcomes included urine testing, antibiotic prescription, and retreatment or hospitalization, stratified by in-person vs virtual visit. Multivariable logistic regression was performed to examine factors contributing to outcomes. RESULTS: Significantly fewer patients seen virtually had urine testing as compared to those seen in-person (19% vs 69%, P <.001). On multivariable logistic regression analysis, virtual visit was the most significant predictor of urine testing, associated with an 86% reduction in the odds of urine testing (odds ratio (OR) 0.14, P <.001). Having a complicated UTI did not affect the likelihood of urine testing (OR 1.0, P = .95). Patients seen virtually were more likely to have a subsequent repeat ambulatory UTI visit (OR 1.16) or repeat antibiotic prescription (1.06) more than 2 weeks after the index encounter, though no more likely to be hospitalized for UTI (OR 1.00). CONCLUSION: Virtual care for UTI is associated with a significant reduction in urine testing and an increase in repeat UTI encounters and additional antibiotics among patients with complicated and uncomplicated UTIs.

The assessment and management of voiding dysfunction in adults living with cerebral palsy.

PURPOSE: Improvements in life expectancy have resulted in an increasing number of adults with cerebral palsy, of which over a third will have neurogenic lower urinary tract dysfunction (NLUTD). This review explores urinary dysfunction in adults with cerebral palsy. METHODS: Relevant literature on NLUTD in adults with cerebral palsy was identified using an unrestricted search of PubMed. RESULTS: Urinary incontinence is the most common complaint, often accompanied by frequency and urgency. Special consideration should be given to women and in those with worse motor or cognitive dysfunction as they have been shown to have more severe urologic symptoms. NLUTD can have significant morbidity and impact quality of life. Hospital admission, urinary tract infections, and hydronephrosis are common urologic complications, with poor urinary function associated with decreased quality of life (QOL). Neurogenic detrusor overactivity is the most common urodynamic abnormality, with elevated detrusor leak point pressure and reduced bladder capacity. Detrusor sphincter dyssynergy is present in some patients and maybe secondary to generalized spasticity or incomplete upper motor neuron injury. Elevated bladder capacity is also present in a portion of patients, and becomes particularly relevant in adults as a result of increased spasticity of the urinary sphincter. Conservative management like functional toileting strategies, medications, and incontinence aids are successful in most patients. Medical management with anticholinergics is well described, and frequently the only intervention required, particularly in children. Intermittent clean catheterization has mixed results with this population, as its efficacy is limited by pelvic spasticity and patient factors. Surgical intervention, while often successful, should be restricted to select patients, as it is associated with significant morbidity in this population. CONCLUSION: Management of NLUTD in adults with CP involves conservative management, medications, and in rare cases surgical intervention.

Outcomes of Urethroplasty for Synchronous Anterior Urethral Stricture Utilizing the Trauma and Urologic Reconstruction Network of Surgeons Length, Segment and Etiology Anterior Urethral Stricture Classification System.

OBJECTIVE: To describe the characteristics, management, and functional outcomes of patients with synchronous urethral stricture disease (SUSD) utilizing a multi-institutional cohort. METHODS: Data were collected and assessed from a prospectively maintained, multi-institutional database. Patients who underwent anterior urethroplasty for urethral stricture disease (USD) were included and stratified by the presence or absence of SUSD. USD location and etiology were classified according to the Trauma and Urologic Reconstruction Network of Surgeons Length, Segment and Etiology Anterior Urethral Stricture Classification System. Anterior urethroplasty techniques were recorded for both strictures. Functional failure was compared between groups. RESULTS: One thousand nine hundred eighty-three patients were identified, of whom, 137/1983 (6.9%) had SUSD. The mean primary stricture length for patients with SUSD was 3.5 and 2.6 cm for the secondary stricture. Twelve anterior urethroplasty technique combinations were utilized in treating the 27 different combinations of SUSD. Functional failure was noted in 18/137 (13.1%) patients with SUSD vs 192/1846 (10.4%) patients with solitary USD, P = .3. SUSD was not associated with increased odds of functional failure. S classifications: S1b, P = .003, S2a, P = .001, S2b, P = .01 and S2c, P = .02 and E classifications: E3a, P = .004 and E6, P = .03, were associated with increased odds of functional failure. CONCLUSION: Repair of SUSD in a single setting does not increase the risk of functional failure compared to patients with solitary USD. Increasing S classification, S1b through S2c and E classifications E3a and E6 were associated with increased functional failure. This reinforces the importance of the Trauma and Urologic Reconstruction Network of Surgeons Length, Segment and Etiology Anterior Urethral Stricture Classification System as a necessary tool in large-scale multi-institutional analysis when assessing highly heterogenous patient populations.