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.

The Impact of Social Deprivation on Anterior Urethral Stricture Recurrence After Urethroplasty - A Trauma and Urologic Reconstructive Network of Surgeons (TURNS) Analysis.

INTRODUCTION AND OBJECTIVES: Several factors influence recurrence after urethral stricture repair. The impact of socioeconomic factors on stricture recurrence after urethroplasty is poorly understood. This study aims to assess the impact that social deprivation, an area-level measure of disadvantage, has on urethral stricture recurrence after urethroplasty. METHODS: We performed a retrospective review of patients undergoing urethral reconstruction by surgeons participating in a collaborative research group. Home zip code was used to calculate Social Deprivation Indices (SDI; 0-100), which quantifies the level of disadvantage across several sociodemographic domains collected in the American Community Survey. Patients without zip code data were excluded from the analysis. The Cox Proportional Hazards model was used to study the association between SDI and the hazard of functional recurrence, adjusting for stricture characteristics as well as age and body mass index. RESULTS: Median age was 46.0 years with a median follow up of 367 days for the 1452 men included in the study. Patients in the fourth SDI quartile (worst social deprivation) were more likely to be active smokers with traumatic and infectious strictures compared to the first SDI quartile. Patients in the fourth SDI quartile had 1.64 times the unadjusted hazard of functional stricture recurrence vs patients in the first SDI quartile (95% CI 1.04-2.59). Compared to anastomotic ± excision, substitution only repair had 1.90 times the unadjusted hazard of recurrence. The adjusted hazard of recurrence was 1.08 per 10-point increase in SDI (95% CI 1.01-1.15, P = .027). CONCLUSIONS: Patient social deprivation identifies those at higher risk for functional recurrence after anterior urethral stricture repair, offering an opportunity for preoperative counseling and postoperative surveillance. Addressing these social determinants of health can potentially improve outcomes in reconstructive surgery.

Ecological momentary assessment of pelvic pain and urinary urgency variability in urologic chronic pelvic pain syndrome and their association with illness impact and quality of life: Findings from the multidisciplinary approach to the study of chronic pelvic pain symptom patterns study.

PURPOSE: This study tested the hypothesis that ecological momentary assessment (EMA) of pelvic pain (PP) and urinary urgency (UU) would reveal unique Urologic Chronic Pelvic Pain Syndrome (UCPPS) phenotypes that would be associated with disease specific quality of life (QOL) and illness impact metrics (IIM). MATERIALS AND METHODS: A previously validated smart phone app (M-app) was provided to willing Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) participants. M-app notifications were sent 4-times daily for 14 days inquiring about PP and UU severity. A clustering algorithm that accounted for variance placed participants into PP and UU variability? clusters. Associations between clusters and QOL and IIM were then determined. RESULTS: A total of 204 participants enrolled in the M-app study (64% female). M-app compliance was high (median 63% of surveys). Cluster analysis revealed k = 3 (high, low, none) PP clusters and k = 2 (high, low) UU clusters. When adjusting for baseline pain severity, high PP variability, but not UU variability, was strongly associated with QOL and IIM; specifically worse mood, worse sleep and higher anxiety. UU and PP clusters were associated with each other (p < 0.0001), but a large percentage (33%) of patients with high PP variability had low UU variability. CONCLUSIONS: PP variability is an independent predictor of worse QOL and more severe IIM in UCPPS participants after controlling for baseline pain severity and UU. These findings suggest alternative pain indices, such as pain variability and unpredictability, may be useful adjuncts to traditional measures of worst and average pain when assessing UCPPS treatment responses.

Haemorrhagic cystitis: a review of management strategies and emerging treatments.

Haemorrhagic cystitis (HC) is characterised by persistent haematuria and lower urinary tract symptoms following radiotherapy or chemotherapy. Its pathogenesis is poorly understood but thought to be related to acrolein toxicity following chemotherapy or fibrosis/vascular remodelling after radiotherapy. There is no standard of care for patients with HC, although existing strategies including fulguration, hyperbaric oxygen therapy, botulinum toxin A, and other intravesical therapies have demonstrated short-term efficacy in cohort studies. Novel agents including liposomal tacrolimus are promising targets for further research. This review summarises the incidence and pathogenesis of HC as well as current evidence supporting its different management strategies.

Grade V renal trauma management: results from the multi-institutional genito-urinary trauma study.

PURPOSE: To investigate management trends for American Association for the Surgery of Trauma (AAST) grade V renal trauma with focus on non-operative management. METHODS: We used prospectively collected data as part of the Multi-institutional Genito-Urinary Trauma Study (MiGUTS). We included patients with grade V renal trauma according to the AAST Injury Scoring Scale 2018 update. All cases submitted by participating centers with radiology images available were independently reviewed to confirm renal trauma grade. Management was classified as expectant, conservative (minimally invasive, endoscopic or percutaneous procedures), or operative (renal-related surgery). RESULTS: Eighty patients were included, 25 of whom had complete imaging and had independent confirmation of AAST grade V renal trauma. Median age was 35 years (Interquartile range (IQR) 25-50) and 23 (92%) had blunt trauma. Ten patients (40%) were managed operatively with nephrectomy. Conservative management was used in nine patients (36%) of which six received angioembolization and three had a stent or drainage tube placed. Expectant management was followed in six (24%) patients. Transfusion requirements were progressively higher with groups requiring more aggressive treatment, and injury characteristics differed significantly across management groups in terms of hematoma size and laceration size. Vascular contrast extravasation was more likely in operatively managed patients though a statistically significant association was not found. CONCLUSION: Successful use of nonoperative management for grade V injuries is used for a substantial subset of patients. Lower transfusion requirement and less severe injury radiologic phenotype appear to be important characteristics delineating this group.

Understanding the Prodromal Period of Necrotizing Soft Tissue Infections of the Genitalia (Fournier's Gangrene) and the Incidence, Duration, and Risk Factors Associated With Potential Missed Opportunities for an Earlier Diagnosis: A Population-based Longitudinal Study.

PURPOSE: The purpose of this paper was to investigate patterns of health care utilization leading up to diagnosis of necrotizing soft tissue infections of the genitalia and to identify risk factors associated with potential diagnostic delay. MATERIALS AND METHODS: IBM MarketScan Research Databases (2001-2020) were used to identify index cases of necrotizing soft tissue infections of the genitalia. We identified health care visits for symptomatically similar diagnoses (eg, penile swelling, cellulitis) that occurred prior to necrotizing soft tissue infections of the genitalia diagnosis. A change-point analysis identified the window before diagnosis where diagnostic opportunities first appeared. A simulation model estimated the likelihood symptomatically similar diagnosis visits represented a missed opportunity for earlier diagnosis. Patient and provider characteristics were evaluated for their associations with delay. RESULTS: We identified 8,098 patients with necrotizing soft tissue infections of the genitalia, in which 4,032 (50%) had a symptomatically similar diagnosis visit in the 21-day diagnostic window, most commonly for "non-infectious urologic abnormalities" (eg, genital swelling; 64%): 46% received antibiotics; 16% saw a urologist. Models estimated that 5,096 of the symptomatically similar diagnosis visits (63%) represented diagnostic delay (mean duration 6.2 days; mean missed opportunities 1.8). Risk factors for delay included urinary tract infection history (OR 2.1) and morbid obesity (OR 1.6). Visits to more than 1 health care provider/location in a 24-hour period significantly decreased delay risk. CONCLUSIONS: Nearly 50% of insured patients who undergo debridement for, or die from, necrotizing soft tissue infections of the genitalia will present to a medical provider with a symptomatically similar diagnosis suggestive of early disease development. Many of these visits likely represent diagnostic delay. Efforts to minimize logistic and cognitive biases in this rare condition may lead to improved outcomes if they lead to earlier interventions.

The Lived Experience of Patients with Adult Acquired Buried Penis.

PURPOSE: We describe the lived experience of adults with acquired buried penis (AABP) through thematic analysis of patient interviews. We examine the challenges that patients face and the impacts of surgery. MATERIALS AND METHODS: This mixed-methods study utilized validated instruments and semi-structured interviews to capture pre- and postsurgical outcomes. Semi-structured interviews were conducted with open-ended questions to elicit the impact of AABP on a patient's quality of life in several domains including urinary function, sexual function, interpersonal relationships and mental health. Recruitment was completed once we achieved thematic saturation. RESULTS: Twenty patients participated in the study; 11 underwent surgical treatment for AABP. Semi-structured interviewee responses were coded into 12 different themes and 39 subthemes. The most common themes were problems with urinary (19/20, 95%) and sexual function (19/20, 95%). Most participants (16/20, 80%) reported negative impacts of AABP on social life. Interviewees struggled with relationships (8/20, 40%) and mental health (11/20, 55%), often avoiding romantic relationships and reporting fear of rejection with concomitant depression and/or anxiety. The majority (70%, 14/20) experienced difficulties accessing care. Among patients who underwent surgery, the majority discussed improvement in urinary and sexual function (82% [9/11] and 73% [8/11], respectively). Though weight gain was a precipitating factor, weight loss did not result in symptom improvement. Rather, in 4/20 (20%), weight loss made their condition worse. CONCLUSIONS: Patients living with AABP experience profound negative impacts on quality of life including their urinary and sexual function, social life and mental health. Many patients face issues with access to care.

Defining Success after Anterior Urethroplasty: An Argument for a Universal Definition and Surveillance Protocol.

PURPOSE: A successful urethroplasty has been defined in different ways across studies. This variety in the literature makes it difficult to compare success rates and techniques across studies. We aim to evaluate the success of anterior urethroplasty based on different definitions of success in a single cohort. MATERIALS AND METHODS: Data were collected from a multi-institutional, prospectively maintained database. We included men undergoing first-time, single-stage, anterior urethroplasty between 2006 and 2020. Exclusion criteria included lack of followup, hypospadias, extended meatotomy, perineal urethrostomy, posterior urethroplasty and staged repairs. We compared 5 different ways to define a "failed" urethroplasty: 1) stricture retreatment, 2) anatomical recurrence on cystoscopy, 3) peak flow rate <15 ml/second, 4) weak stream on questionnaire and 5) failure by any of these measures. Kaplan-Meier survival curves were generated for each of the definitions. We also compared outcomes by stricture length, location and etiology. RESULTS: A total of 712 men met inclusion criteria, including completion of all types of followup. The 1- and 5-year estimated probabilities of success were "retreatment," 94% and 75%; "cystoscopy," 88% and 71%; "uroflow," 84% and 58%; "questionnaire," 67% and 37%; and "any failure," 57% and 23%. This pattern was inconsistent across stricture length, location and etiology. CONCLUSIONS: The estimated probability of success after first-time, anterior urethroplasty is highly dependent on the way success is defined. The variability in definitions in the literature has limited our ability to compare urethroplasty outcomes across studies.

Minimizing Antibiotic Use in Urethral Reconstruction.

PURPOSE: There are no established guidelines regarding management of antibiotics for patients specifically undergoing urethral reconstruction. Our aim was to minimize antibiotic use by following a standardized protocol in the pre-, peri- and postoperative setting, and adhere to American Urological Association antibiotic guidelines. We hypothesized that prolonged suppressive antibiotics post-urethroplasty does not prevent urinary tract infection and/or wound infection rates. MATERIALS AND METHODS: We prospectively treated 900 patients undergoing urethroplasty or perineal urethrostomy at 11 centers over 2 years. The first-year cohort A received prolonged postoperative antibiotics. Year 2, cohort B, did not receive prolonged antibiotics. A standardized protocol following the American Urological Association guidelines for perioperative antibiotics was used. The 30-day postoperative infectious complications were determined. We used chi-square analysis to compare the cohorts, and multivariate logistic regression to identify risk factors. RESULTS: The mean age of participants in both cohorts was 49.7 years old and the average stricture length was 4.09 cm. Overall, the rate of postoperative urinary tract infection and wound infection within 30 days was 5.1% (6.7% in phase 1 vs 3.9% in phase 2, p=0.064) and 3.9% (4.1% in phase 1 vs 3.7% in phase 2, p=0.772), respectively. Multivariate logistic regression analysis of patient characteristics and operative factors did not reveal any factors predictive of postoperative infections. CONCLUSIONS: The use of a standardized protocol minimized antibiotic use and demonstrated no benefit to prolonged antibiotic use. There were no identifiable risk factors when considering surgical characteristics. Given the concern of antibiotic over-prescription, we do not recommend prolonged antibiotic use after urethral reconstruction.

Impact of Sleep Disturbance, Physical Function, Depression and Anxiety on Male Lower Urinary Tract Symptoms: Results from the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN).

PURPOSE: The impact of nonurological factors on male lower urinary tract symptoms (LUTS) remains unclear. We investigated cross-sectional and longitudinal associations among anxiety, depression, physical function, sleep quality and urinary symptom subdomains. MATERIALS AND METHODS: Data from 518 men in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study were analyzed to identify associations between Patient-Reported Outcomes Measurement Information System® (PROMIS®) depression, anxiety, sleep disturbance and physical function measures and LUTS subdomains, as derived from the American Urological Association Symptom Index and LUTS Tool. Multivariable linear regression was used to assess the relationships between PROMIS measures and LUTS subdomains at baseline and at 3- and 12-month followup. RESULTS: Baseline depression and anxiety were associated with urinary incontinence (p <0.001), voiding symptoms (p <0.001) and quality of life (p=0.002), whereas baseline sleep disturbance was associated with voiding and storage symptoms and quality of life (p <0.001 for all). Urinary symptom severity improved in all subdomains at 3 and 12 months. Similar associations between PROMIS measures and LUTS subdomains were observed at all time points, but baseline depression, anxiety, sleep disturbance and physical function measures were not associated with longitudinal trajectories of LUTS. CONCLUSIONS: Urinary symptom subdomains are independently associated with modifiable clinical variables including sleep quality and depression at all time points, but these variables do not predict the degree of improvement in LUTS following urological evaluation and treatment over the medium term. Bidirectional assessment and randomized experiments may improve our understanding of these relationships.

Urethroscopic Findings following Urethroplasty Predict the Need for Secondary Intervention in the Long Term: A Multi-Institutional Study from Trauma and Urologic Reconstructive Network of Surgeons.

PURPOSE: Postoperative surveillance urethroscopy has been shown to be an effective tool to predict reoperation within 1 year after urethroplasty. We aimed to evaluate early surveillance urethroscopy findings and long-term outcomes among urethroplasty patients in order to define the value of surveillance urethroscopy to predict failure. MATERIALS AND METHODS: We evaluated 304 patients with at least 4 years of followup after urethroplasty performed at 10 institutions across the United States and Canada. All patients were surveilled using a flexible 17Fr cystoscope and were categorized into 3 groups: 1) normal lumen, 2) large-caliber stricture (≥17Fr) defined as the ability of the cystoscope to easily pass the narrowing and 3) small-caliber stricture (<17Fr) that the cystoscope could not be passed. Failure was stricture recurrence requiring a secondary intervention. RESULTS: The median followup time was 64.4 months (range 55.3-80.6) and the time to initial surveillance urethroscopy was 3.7 months (range 3.1-4.8) following urethroplasty. Secondary interventions were performed in 29 of 194 (15%) with normal lumens, 11 of 60 (18.3%) with ≥17Fr strictures and 32 of 50 (64%) with <17Fr strictures (p <0.001). The 1-, 3- and 9-year cumulative probability of intervention was 0.01, 0.06 and 0.23 for normal, 0.05, 0.17 and 0.18 for ≥17Fr, and 0.32, 0.50 and 0.73 for <17Fr lumen groups, respectively. Patient-reported outcome measures performed poorly to differentiate the 3 groups. CONCLUSIONS: Early cystoscopic visualization of scar recurrence that narrows the lumen to <17Fr following urethroplasty is a significant long-term predictor for patients who will eventually undergo a secondary intervention.

Warmer Weather and the Risk of Urinary Tract Infections in Women.

PURPOSE: The incidence of urinary tract infections is seasonal, peaking in summer months. One possible mechanism for the observed seasonality of urinary tract infections is warmer weather. MATERIALS AND METHODS: We identified all urinary tract infection cases located in approximately 400 metropolitan statistical areas in the contiguous United States between 2001 and 2015 using the Truven Health MarketScan® databases. A total of 167,078,882 person-years were included in this data set and a total of 15,876,030 urinary tract infection events were identified by ICD-9 code 599.0. Weather data for each metropolitan statistical area and date were obtained from the National Centers for Environmental Information. We computed the mean temperature during the period 0 to 7 days prior to the urinary tract infection diagnosis. We used a quasi-Poisson generalized linear model. The primary outcome was the number of urinary tract infections each day in a metropolitan statistical area in each age group. Covariates considered included age group, day of week, year and the temperature during the previous 7 days. RESULTS: Warmer weather increases the risk of urinary tract infections among women treated in outpatient settings in a dose-response fashion. On days when the prior week's average temperature was between 25 and 30C, the incidence of urinary tract infections was increased by 20% to 30% relative to when the prior week's temperature was 5 to 7.5C. CONCLUSIONS: The incidence of urinary tract infections increases with the prior week's temperature. Our results indicate that warmer weather is a risk factor for urinary tract infections. Furthermore, as temperatures rise, the morbidity attributable to urinary tract infections may increase.

Current Management of Extraperitoneal Bladder Injuries: Results from the Multi-Institutional Genito-Urinary Trauma Study (MiGUTS).

PURPOSE: We studied the current management trends for extraperitoneal bladder injuries and evaluated the use of operative repair versus catheter drainage, and the associated complications with each approach. MATERIALS AND METHODS: We prospectively collected data on bladder trauma from 20 level 1 trauma centers across the United States from 2013 to 2018. We excluded patients with intraperitoneal bladder injury and those who died within 24 hours of hospital arrival. We separated patients with extraperitoneal bladder injuries into 2 groups (catheter drainage vs operative repair) based on their initial management within the first 4 days and compared the rates of bladder injury related complications among them. Regression analyses were used to identify potential predictors of complications. RESULTS: From 323 bladder injuries we included 157 patients with extraperitoneal bladder injuries. Concomitant injuries occurred in 139 (88%) patients with pelvic fracture seen in 79%. Sixty-seven patients (43%) initially underwent operative repair for their extraperitoneal bladder injuries. The 3 most common reasons for operative repair were severity of injury or bladder neck injury (40%), injury found during laparotomy (39%) and concern for pelvic hardware contamination (28%). Significant complications were identified in 23% and 19% of the catheter drainage and operative repair groups, respectively (p=0.55). The only statistically significant predictor for complications was bladder neck or urethral injury (RR 2.69, 95% 1.21-5.97, p=0.01). CONCLUSIONS: In this large multi-institutional cohort, 43% of patients underwent surgical repair for initial management of extraperitoneal bladder injuries. We found no significant difference in complications between the initial management strategies of catheter drainage and operative repair. The most significant predictor for complications was concomitant urethral or bladder neck injury.

Multicenter analysis of posterior urethroplasty complexity and outcomes following pelvic fracture urethral injury.

PURPOSE: To analyze outcomes of posterior urethroplasty following pelvic fracture urethral injuries (PFUI) and to determine risk factors for surgical complexity and success. METHODS: Patients who underwent posterior urethroplasty following PFUI were identified in the Trauma and Urologic Reconstructive Network of Surgeons (TURNS) database. Demographics, injury patterns, management strategies, and prior interventions were evaluated. Risk factors for surgical failure and the impact of ancillary urethral lengthening maneuvers (corporal splitting, pubectomy and supracrural rerouting) were evaluated. RESULTS: Of the 436 posterior urethroplasties identified, 122 were following PFUI. 83 (68%) patients were acutely managed with suprapubic tubes, while 39 (32%) underwent early endoscopic realignment. 16 (13%) patients underwent pelvic artery embolization in the acute setting. 116 cases (95%) were completed via a perineal approach, while 6 (5%) were performed via an abdominoperineal approach. The need for one or more ancillary maneuvers to gain urethral length occurred in 4 (36%) patients. Of these, 44 (36%) received corporal splitting, 16 (13%) partial or complete pubectomy, and 2 (2%) supracrural rerouting. Younger patients, those with longer distraction defects, and those with a history of angioembolization were more likely to require ancillary maneuvers. 111 patients (91%) did not require repeat intervention during follow-up. Angioembolization (p = 0.03) and longer distraction defects (p = 0.01) were associated with failure. CONCLUSIONS: Posterior urethroplasty provides excellent success rates for patients following PFUI. Pelvic angioembolization and increased defect length are associated with increased surgical complexity and risk of failure. Surgeons should be prepared to implement ancillary maneuvers when indicated to achieve a tension-free anastomosis.

Cystitis-induced bladder pain is Toll-like receptor 4 dependent in a transgenic autoimmune cystitis murine model: a MAPP Research Network animal study.

Altered Toll-like receptor (TLR)4 activation has been identified in several chronic pain conditions but has not been well studied in interstitial cystitis/bladder pain syndrome (IC/BPS). Our previously published human studies indicated that patients with IC/BPS present altered systemic TLR4-mediated inflammatory responses, which were significantly correlated with reported pain severity. In the present study, we sought to determine whether altered TLR4 activation plays a role in pelvic/bladder pain seen in patients with IC/BPS using our validated IC/BPS-like transgenic autoimmune cystitis model (URO-OVA). URO-OVA mice developed responses consistent with pelvic and bladder pain after cystitis induction, which was associated with increased splenocyte production of TLR4-mediated proinflammatory cytokines IL-1ß, IL-6, and TNF-α. Increased spinal expression of mRNAs for proinflammatory cytokines IL-6 and TNF-α, glial activation markers CD11b and glial fibrillary acidic protein, and endogenous TLR4 ligand high mobility group box 1 was also observed after cystitis induction. Compared with URO-OVA mice, TLR4-deficient URO-OVA mice developed significantly reduced nociceptive responses, although similar bladder inflammation and voiding dysfunction, after cystitis induction. Intravenous administration of TAK-242 (a TLR4-selective antagonist) significantly attenuated nociceptive responses in cystitis-induced URO-OVA mice, which was associated with reduced splenocyte production of TLR4-mediated IL-1ß, IL-6, and TNF-α as well as reduced spinal expression of mRNAs for IL-6, TNF-α, CD11b, glial fibrillary acidic protein, and high mobility group box 1. Our results indicate that altered TLR4 activation plays a critical role in bladder nociception independent of inflammation and voiding dysfunction in the URO-OVA model, providing a potential mechanistic insight and therapeutic target for IC/BPS pain.

Nontransecting Techniques Reduce Sexual Dysfunction after Anastomotic Bulbar Urethroplasty: Results of a Multi-Institutional Comparative Analysis.

PURPOSE: The purpose of this multi-institutional study was to compare outcomes of transecting and nontransecting anastomotic bulbar urethroplasty. MATERIALS AND METHODS: We performed a retrospective, multi-institutional review of the records of 352 patients who underwent transecting or nontransecting anastomotic bulbar urethroplasty performed by 1 of 4 reconstructive urologists from September 2003 to March 2017. Study outcomes were urethroplasty success, defined as urethral patency greater than 16Fr on cystoscopy; de novo sexual dysfunction assessed at 6 months, defined as a 5-point or greater change in the SHIM (Sexual Health Inventory for Men) or a patient reported adverse change; and 90-day complications, defined as Clavien 2 or greater. When appropriate, comparisons were made between the transecting and nontransecting cohorts using the Mantel-Cox test, the t-test or the chi-square test. RESULTS: Of the 352 patients with a mean stricture length of 1.7 cm (range 0.5 to 5) 258 and 94 underwent transecting and nontransecting anastomotic bulbar urethroplasty, respectively. The overall success rate was 94.9% at a mean followup of 64.2 months (range 6 to 170). Of the patients 7.1% experienced a 90-day complication and 11.6% reported sexual dysfunction. When comparing transecting and nontransecting techniques, there was no difference in success (93.8% vs 97.9%, Mantel-Cox test p = 0.18) or postoperative complications (8.1% vs 4.3%, p = 0.25). Patients treated with transecting anastomotic urethroplasty were more likely to report an adverse change in sexual function (14.3% vs 4.3%, p = 0.008). On multivariate analysis only transecting urethroplasty was associated with sexual dysfunction (p = 0.01) while age (p = 0.29), stricture length (p = 0.42), etiology (p = 0.99) and surgeon (p = 0.88) were not. CONCLUSIONS: Anastomotic urethroplasty is a highly effective surgery with relatively minimal associated morbidity. Nontransecting anastomotic urethroplasty compares quite favorably to the transecting technique and likely reduces the risk of associated sexual dysfunction.

Histopathology of Anterior Urethral Strictures: Toward a Better Understanding of Stricture Pathophysiology.

PURPOSE: Histopathology can provide insights into disease mechanisms but to date it has been poorly described for urethral stricture. The purpose of this study was to comprehensively describe histopathological findings of stricture specimens obtained at the time of anterior urethroplasty. MATERIALS AND METHODS: All pathological specimens of men who underwent anterior urethroplasty of urethral stricture disease from 2010 to 2017 at a single institution were rereviewed by a single blinded pathologist directed to rule out lichen sclerosus and then describe inflammatory cell type and severity when present. Cohorts comprising strictures with no inflammation, minimal to mild inflammation or moderate to severe inflammation were developed and stricture, patient and surgical outcome characteristics were compared. RESULTS: Histopathology slides from 100 anterior urethroplasty cases were reviewed. Two or more lichen sclerosus characteristics were present in 21% of specimens and 44% of specimens showed chronic inflammation, which was minimal in 20%, mild in 39%, moderate in 39% and severe in 2%. Lymphocytes in 86% of specimens and plasma cells in 12% were the predominant cell types. Patients with inflammatory stricture reported worse overall health. Inflammation was largely absent from isolated bulbomembranous strictures (9%) and more common in lichen sclerosus strictures (100%). The 11% overall failure rate was not affected by the presence (7%) or absence (14%) of inflammation. CONCLUSIONS: Chronic inflammation is prevalent in a significant percent of urethral stricture disease specimens. Associations with worse overall health suggest systemic mediators. Absent inflammation in bulbomembranous strictures suggests a unique pathophysiology in this region. The presence of inflammation did not affect surgical outcomes at mid-term followup.

Urinary and Sexual Function after Perineal Urethrostomy for Urethral Stricture Disease: An Analysis from the TURNS.

PURPOSE: Perineal urethrostomy is a viable option for many complex urethral strictures. However, to our knowledge no comparison with anterior urethroplasty regarding patient reported outcome measures has been published. We compared these groups using a large multi-institution database. MATERIALS AND METHODS: We performed a retrospective study of anterior urethroplasty in the TURNS (Trauma and Urologic Reconstructive Network of Surgeons) database. The anterior urethroplasty cohort was defined by long strictures greater than 6 cm. We compared demographic, clinical, urinary and sexual characteristics using validated patient reported outcome measures between patients treated with long stricture anterior urethroplasty and those who underwent perineal urethrostomy. RESULTS: Of the 131 patients 92 treated with long stricture anterior urethroplasty and 39 treated with perineal urethrostomy met study inclusion criteria. The cumulative incidence of failure at 2 years was 30.2% (95% CI 18.3-47.3) for long stricture anterior urethroplasty and 14.5% (95% CI 4.8-39.1) for perineal urethrostomy (p = 0.09). Compared to baseline metrics, patients who underwent long stricture anterior urethroplasty and perineal urethrostomy had similar improvements in urinary function and stable sexual function after surgery. CONCLUSIONS: Patients reported improvement in urinary function after perineal urethrostomy with no deleterious effect on sexual function. These patient reported outcome measures were comparable to those of long stricture anterior urethroplasty. Perineal urethrostomy failure rates were similar to those of long stricture anterior urethroplasty.

Symptom Based Clustering of Men in the LURN Observational Cohort Study.

PURPOSE: Conventional classification of patients with lower urinary tract symptoms into diagnostic categories based on a predefined symptom complex or predominant symptom appears inadequate. This is due to the frequent presentation of patients with multiple urinary symptoms which could not be perfectly categorized into traditional diagnostic groups. We used a novel clustering method to identify subtypes of male patients with lower urinary tract symptoms based on detailed multisymptom information. MATERIALS AND METHODS: We analyzed baseline data on 503 care seeking men in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Observational Cohort Study. Symptoms and symptom severity were assessed using the LUTS (Lower Urinary Tract Symptoms) Tool and the AUA SI (American Urological Association Symptom Index), which include a total of 52 questions. We used a resampling based consensus clustering algorithm to identify patient subtypes with distinct symptom signatures. RESULTS: Four distinct symptom clusters were identified. The 166 patients in cluster M1 had predominant symptoms of frequency, nocturia, hesitancy, straining, weak stream, intermittency and incomplete bladder emptying suggestive of bladder outlet obstruction. The 93 patients in cluster M2 mainly endorsed post-micturition symptoms (eg post-void dribbling and post-void leakage) with some weak stream. The 114 patients in cluster M3 reported mostly urinary frequency without incontinence. The 130 patients in cluster M4 reported severe frequency, urgency and urgency incontinence. Most other urinary symptoms statistically differed between cluster pairs. Patient reported outcomes of bowel symptoms, mental health, sleep dysfunction, erectile function and urological pain significantly differed across the clusters. CONCLUSIONS: We identified 4 data derived clusters among men seeking care for lower urinary tract symptoms. The clusters differed from traditional diagnostic categories. Further subtype refinement will be done to incorporate clinical data and nonurinary patient reported outcomes.