VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center in 2023.

The Eukaryotic Pathogen, Vector and Host Informatics Resource (VEuPathDB, https://veupathdb.org) is a Bioinformatics Resource Center funded by the National Institutes of Health with additional funding from the Wellcome Trust. VEuPathDB supports >600 organisms that comprise invertebrate vectors, eukaryotic pathogens (protists and fungi) and relevant free-living or non-pathogenic species or hosts. Since 2004, VEuPathDB has analyzed omics data from the public domain using contemporary bioinformatic workflows, including orthology predictions via OrthoMCL, and integrated the analysis results with analysis tools, visualizations, and advanced search capabilities. The unique data mining platform coupled with >3000 pre-analyzed data sets facilitates the exploration of pertinent omics data in support of hypothesis driven research. Comparisons are easily made across data sets, data types and organisms. A Galaxy workspace offers the opportunity for the analysis of private large-scale datasets and for porting to VEuPathDB for comparisons with integrated data. The MapVEu tool provides a platform for exploration of spatially resolved data such as vector surveillance and insecticide resistance monitoring. To address the growing body of omics data and advances in laboratory techniques, VEuPathDB has added several new data types, searches and features, improved the Galaxy workspace environment, redesigned the MapVEu interface and updated the infrastructure to accommodate these changes.

Identifying Bladder Phenotypes After Spinal Cord Injury With Unsupervised Machine Learning: A New Way to Examine Urinary Symptoms and Quality of Life.

PURPOSE: Patients with spinal cord injuries (SCIs) experience variable urinary symptoms and quality of life (QOL). Our objective was to use machine learning to identify bladder-relevant phenotypes after SCI and assess their association with urinary symptoms and QOL. MATERIALS AND METHODS: We used data from the Neurogenic Bladder Research Group SCI registry. Baseline variables that were previously shown to be associated with bladder symptoms/QOL were included in the machine learning environment. An unsupervised consensus clustering approach (k-prototypes) was used to identify 4 patient clusters. After qualitative review of the clusters, 2 outcomes of interest were assessed: the total Neurogenic Bladder Symptom Score (NBSS) and the NBSS-satisfaction question (QOL). The NBSS and NBSS-satisfaction question at baseline and after 1 year were compared between clusters using analysis of variance and linear regression. RESULTS: Among the 1263 included participants, the 4 identified clusters were termed "female predominant," "high function, low SCI complication," "quadriplegia with bowel/bladder morbidity," and "older, high SCI complication." Using outcome data from baseline, significant differences were observed in the NBSS score, with the female predominant group exhibiting worse bladder symptoms. After 1 year, the overall bladder symptoms (NBSS Total) did not change significantly by cluster; however, the QOL score for the high function, low SCI complication group had more improvement (ß = -0.12, P = .005), while the female predominant group had more deterioration (ß = 0.09, P = .047). CONCLUSIONS: This study demonstrates the utility of machine learning in uncovering bladder-relevant phenotypes among SCI patients. Future research should explore cluster-based targeted strategies to enhance bladder-related outcomes and QOL in SCI.

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.

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.

Sex Differences in Bladder Management, Symptoms, and Satisfaction After Spinal Cord Injury.

PURPOSE: We sought to characterize sex-stratified differences in bladder management and bladder symptoms and satisfaction after spinal cord injury. MATERIALS AND METHODS: This study was a prospective, cross-sectional, observational study; eligibility included: age ≥18 years and acquired spinal cord injury. Bladder management was grouped as (1) clean intermittent catheterization, (2) indwelling catheter, (3) surgery, and (4) voiding. Primary outcome was Neurogenic Bladder Symptom Score. Secondary outcomes were subdomains of the Neurogenic Bladder Symptom Score and bladder-related satisfaction. Multivariable regression was used in sex-stratified models to establish associations between participant characteristics and outcomes. RESULTS: A total of 1,479 participants enrolled in the study. Of the patients 843 (57%) were paraplegic and 585 (40%) were women. Median age and time from injury were 44.9 (IQR 34.3, 54.1) and 11 (IQR 5.1, 22.4) years. Women utilized clean intermittent catheterization at a lower rate (42.6% vs 56.5%) and surgery at a higher rate (22.6% vs 7.0%), especially catheterizable channel creation with or without augmentation cystoplasty (11.0% vs 1.9%). Women had worse measures of bladder symptoms and satisfaction across all outcomes. In adjusted analyses, women and men utilizing indwelling catheters had fewer associated overall symptoms (Neurogenic Bladder Symptom Score), less incontinence, and fewer storage and voiding symptoms. Surgery was associated with fewer bladder symptoms (Neurogenic Bladder Symptom Score) and less incontinence in women, and was also associated with better satisfaction in both sexes. CONCLUSIONS: There are significant sex-stratified differences in bladder management after spinal cord injury, which included a much higher use of surgery. Bladder symptoms and satisfaction are worse across all measurements in women. Women have a substantial associated benefit with surgery, while both sexes have fewer bladder symptoms with indwelling catheters compared to clean intermittent catheterization.

Role for Conservative Management in Grade V Renal Trauma.

PURPOSE: We assessed the use of conservative management for American Association for the Surgery of Trauma grade V renal trauma in the National Trauma Databank. MATERIALS AND METHODS: We used data of grade V renal trauma patients in the 2017-2019 National Trauma Databank. Conservative management was defined by the absence of surgical or procedural intervention except for ureteral stent or percutaneous drain placement. We initially analyzed patients who survived to final hospital discharge and reported the percent utilization of conservative management. We then repeated our analysis in the overall grade V population and in all those who did not die in the emergency department. RESULTS: Of 1,474 who survived to discharge, 557 (37.8%) patients were managed conservatively. In the adjusted analysis, penetrating trauma mechanism (OR 0.13, 95% CI 0.09-0.19, P < .001) and receiving transfusion (OR 0.22, 95% CI 0.17-0.29, P < .001) were associated with decreased odds of receiving conservative management. Overall, there were 1,919 patients with grade V injury, of whom 731 (38.1%) were managed conservatively. Mortality rate was 22.8% in those managed conservatively vs 23.8% in those who had intervention. After excluding 110 patients who died in the emergency department, there were 1,809 patients, of whom 625 (34.6%) were managed conservatively. Mortality rate was 22.6% in the operatively managed group and 10.9% in the conservatively managed group. CONCLUSIONS: A substantial portion of grade V renal trauma cases were managed successfully without intervention in the National Trauma Databank. Further research is needed to identify radiological phenotypes suitable for nonoperative management and to overcome possible renal trauma grade misclassification.

Decision making in metoidioplasty and phalloplasty gender-affirming surgery: a mixed methods study.

BACKGROUND: Gender-affirming surgical procedures, such as metoidioplasty and phalloplasty for those assigned female at birth, are complex and multistaged and involve risks. Individuals considering these procedures experience greater uncertainty or decisional conflict, compounded by difficulty finding trustworthy information. AIM: (1) To explore the factors contributing to decisional uncertainty and the needs of individuals considering metoidioplasty and phalloplasty gender-affirming surgery (MaPGAS) and (2) to inform development of a patient-centered decision aid. METHODS: This cross-sectional study was based on mixed methods. Adult transgender men and nonbinary individuals assigned female at birth at various stages of MaPGAS decision making were recruited from 2 study sites in the United States to participate in semistructured interviews and an online gender health survey, which included measures of gender congruence, decisional conflict, urinary health, and quality of life. Trained qualitative researchers conducted all interviews with questions to explore constructs from the Ottawa decision support framework. OUTCOMES: Outcomes included goals and priorities for MaPGAS, expectations, knowledge, and decisional needs, as well as variations in decisional conflict by surgical preference, surgical status, and sociodemographic variables. RESULTS: We interviewed 26 participants and collected survey data from 39 (24 interviewees, 92%) at various stages of MaPGAS decision making. In surveys and interviews, affirmation of gender identity, standing to urinate, sensation, and the ability to "pass" as male emerged as highly important factors for deciding to undergo MaPGAS. A third of survey respondents reported decisional conflict. Triangulation of data from all sources revealed that conflict emerged most when trying to balance the strong desire to resolve gender dysphoria through surgical transition against the risks and unknowns in urinary and sexual function, appearance, and preservation of sensation post-MaPGAS. Insurance coverage, age, access to surgeons, and health concerns further influenced surgery preferences and timing. CLINICAL IMPLICATIONS: The findings add to the understanding of decisional needs and priorities of those considering MaPGAS while revealing new complexities among knowledge, personal factors, and decisional uncertainty. STRENGTHS AND LIMITATIONS: This mixed methods study was codeveloped by members of the transgender and nonbinary community and yielded important guidance for providers and individuals considering MaPGAS. The results provide rich qualitative insights for MaPGAS decision making in US contexts. Limitations include low diversity and sample size; both are being addressed in work underway. CONCLUSIONS: This study increases understanding of the factors important to MaPGAS decision making, and results are being used to guide development of a patient-centered surgical decision aid and informed survey revision for national distribution.

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.

Time-Related Changes in Patient Reported Bladder Symptoms and Satisfaction after Spinal Cord Injury.

PURPOSE: Increased time after spinal cord injury (SCI) is associated with a migration to bladder managements with higher morbidity such as indwelling catheter (IDC). Still, it is unclear how this affects bladder-related quality of life (QoL). We hypothesized that time from injury (TFI) would be associated with changes in bladder management, symptoms and satisfaction. MATERIALS AND METHODS: Cross-sectional analysis of time-related changes in patient-reported bladder management, symptoms and satisfaction using the Neurogenic Bladder Research Group SCI Registry. Outcomes included Neurogenic Bladder Symptom Score (NBSS) and bladder-related satisfaction (NBSS-satisfaction). Multivariable regression was performed to assess associations between TFI and outcomes, adjusting for participant characteristics, injury specifics, and psychosocial aspects of health-related QoL. Participants with TFI <1 year were excluded and TFI was categorized 1-5 (reference), 6-10, 11-15, 16-20 and >20 years. RESULTS: Of 1,420 participants mean age at injury was 29.7 years (SD 13.4) and mean TFI was 15.2 years (SD 11.6). Participants grouped by TFI included 298 (21%) 1-5, 340 (24%) 6-10, 198 (14%) 11-15, 149 (10%) 16-20 and 435 (31%) >20 years. As TFI increased, clean intermittent catheterization (CIC) declined (55% 1-5 vs 45% >20 years, p <0.001) and IDC increased (16% 1-5 vs 21% >20 years, p <0.001). On multivariable analysis, increased TFI was associated with fewer bladder symptoms at >20 years from injury (-3.21 [CI -1.29, -5.14, p <0.001]) and better satisfaction (6-10 years -0.20 [CI -0.41, 0.01, p=0.070], 11-15 years -0.36 [CI -0.60, -0.11, p=0.002], 16-20 years -0.59 [CI -0.86, -0.32, p <0.001], >20 years -0.85 [CI -1.07, -0.63, <0.001]). CONCLUSIONS: After SCI, CIC decreases and IDC increases over time; however, increasing TFI is associated with reduced urinary symptoms and improved bladder-related satisfaction.

Nephrectomy Is Not Associated with Increased Risk of Mortality or Acute Kidney Injury after High-Grade Renal Trauma: A Propensity Score Analysis of the Trauma Quality Improvement Program (TQIP).

PURPOSE: Patients with high-grade renal trauma (HGRT) undergoing nephrectomy may be at higher risk for mortality compared to those treated conservatively. However, no study has controlled for degree of hemorrhage as a measure of shock. We hypothesized that after controlling for blood transfusions and other factors, nephrectomy after HGRT would be associated with increased mortality and acute kidney injury (AKI). MATERIALS AND METHODS: We identified adult patients with HGRT (American Association for the Surgery of Trauma grade III-V) in TQIP (2013-2017). Propensity scoring was used to adjust for the probability of nephrectomy. Conditional logistic regression was used to analyze the association between nephrectomy and mortality and AKI. We adjusted for patient characteristics, injury specifics, and physiological factors including blood transfusions. RESULTS: There were 12,780 patients with HGRT, and 1,014 (7.9%) underwent nephrectomy. Mortality was 10.6% and 4.2% in the nephrectomy and nonnephrectomy groups, respectively (p <0.001). In nephrectomy patients, 8.6% experienced AKI vs 2.4% of nonnephrectomy patients (p <0.001). In the adjusted analysis, there was no association between nephrectomy and mortality (OR=0.367, 95% CI 0.09-1.497, p=0.162). There was also no association between nephrectomy and AKI. Increasing age, nonCaucasian race, increasing Injury Severity Score, decreasing Glasgow Coma Score and blood transfusions were associated with higher mortality. For AKI, independent predictors included increasing age, male sex, and blood transfusions. CONCLUSIONS: After adjusting for volume of blood transfused in the first 24 hours, nephrectomy after HGRT was not associated with increased mortality or AKI. As a clinical principle, trauma nephrectomy should be avoided when possible.

Risk of Postoperative Thromboembolism in Men Undergoing Urological Prosthetic Surgery: An Assessment of 21,413 Men.

PURPOSE: We assessed venous thromboembolism (VTE) and associated risk factors following artificial urinary sphincter (AUS) and inflatable penile prosthesis (IPP) surgery. MATERIALS AND METHODS: Using IBM® MarketScan, a commercial claims database, patients undergoing AUS and IPP surgery were identified using CPT® and ICD (International Classification of Diseases)-10 procedure codes between 2008 and 2017. ICD-9 and -10 codes were used to identify health care visits associated with lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) within 90 days of surgery. Covariates were assessed using a multivariable model to determine association with outcome of DVT and/or PE. RESULTS: A total of 21,413 men underwent AUS (4,870) or IPP (16,543) surgery between 2008 and 2017 with a median age of 62 years and 68 years, respectively. DVT and PE events following AUS and IPP surgery occurred in 1.54% and 1.04%, respectively. A history of varicose veins (HR 2.76; 95% CI 1.11-6.79), prior history of DVT (HR 13.65; 95% CI 7.4-25.19), or PE (HR 7.65; 95% CI 4.01-14.6) in those undergoing AUS surgery was highly associated with development of postoperative VTE. Likewise, prior history of DVT (HR 12.6; 95% CI 7.99-19.93) and PE (HR 8.9; 95% CI 5.6-14.13) was strongly associated with a VTE event following IPP surgery. CONCLUSIONS: In a large cohort of men undergoing AUS and IPP surgery, 1.54% and 1.04% of men experienced a VTE event within 90 days of surgery, respectively. Prior history of varicose veins, DVT, and PE was associated with an increased likelihood of developing a postoperative DVT or PE.

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.

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.

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.

General and bladder-related quality of life: A focus on women living with spinal cord injury.

OBJECTIVE: To compare bladder symptoms, and urinary and overall quality of life (QOL) among women and men after Spinal cord injury (SCI), and to describe specific aspects of QOL among women with SCI. METHODS: We used data from a prospective, multi-center, and cross-sectional study that was carried out from May 2019 to September 2020. Clinical and demographic details were obtained and participants completed two patient reported outcomes: the neurogenic bladder symptoms score-short form (NBSS-SF, which measures bladder symptoms and QOL) and the SF-12 (which measures overall physical and mental health QOL). RESULTS: Our cohort included 135 women and 210 men with SCI. Among the women, the median age was 50, and 40% had a cervical SCI. For general QOL, women with SCI had physical functioning scores similar to men, but lower mental health scores on the SF-12 (46.85 vs. 49.76, p = 0.01). Women had significantly worse overall NBSS (10.76 vs. 9.08, p < 0.001) and NBSS continence domain scores (4.71 vs. 3.66, p < 0.001) compared to men. There were significant differences between overall QOL measures, and bladder symptoms based on bladder management techniques among the women. NBSS-SF symptom scores were better among women who used overactive bladder medications compared to women who did not (8.43 vs. 11.9, p = 0.02) and NBSS-SF QOL domain scores were significantly better among women who underwent surgery and those that used overactive bladder medications. CONCLUSIONS: Women have more bladder symptoms (specifically incontinence) compared to men. Symptom burden and overall QOL vary among women who use different bladder management techniques and treatments.

Association of stone surgery with patient-reported complications after spinal cord injury.

AIMS: To determine if a history of urinary stone surgery in individuals with spinal cord injury (SCI) is associated with an increased incidence of SCI-related complications and lower quality of life (QOL). METHODS: The Neurogenic Bladder Research Group (NBRG) registry is a multicenter, prospective, observational study which measures QOL after acquired SCI. Over 1.5 years, 1479 participants were enrolled and grouped according to history of stone surgery. We evaluated SCI-related complications, QOL, and associations between patient factors and prior stone surgery using multivariable regression. RESULTS: Participants were a median of 11 years post-SCI and 189 (12.8%) reported prior bladder or kidney stone surgery; 95.8% of these occurred after the SCI. Median time between SCI and first stone was 5.6 years (IQR: 1.8-12.8). Hospitalizations were higher for those with prior stone surgery, with common reasons including UTIs, blood clots, pressure ulcers, and pneumonia (p < 0.001). During the year of observation, the incidence of stone surgery was 17% in those with a prior history of stone surgery and 2% per year in those without prior stone surgery (p < 0.001). Controlling for covariates, bladder management strategy, age, BMI, and years since SCI were associated with history of stone surgery. CONCLUSIONS: People with SCI and a history of surgical stone disease are at high risk for episodes of recurrent stones and increased hospitalizations, particularly those with kidney stones and indwelling catheter use. Identification of high-risk patients may guide tailored surveillance for complications and stone prevention strategies.

PINCER: improved CRISPR/Cas9 screening by efficient cleavage at conserved residues.

CRISPR/Cas9 functional genomic screens have emerged as essential tools in drug target discovery. However, the sensitivity of available genome-wide CRISPR libraries is impaired by guides which inefficiently abrogate gene function. While Cas9 cleavage efficiency optimization and essential domain targeting have been developed as independent guide design rationales, no library has yet combined these into a single cohesive strategy to knock out gene function. Here, in a massive reanalysis of CRISPR tiling data using the most comprehensive feature database assembled, we determine which features of guides and their targets best predict activity and how to best combine them into a single guide design algorithm. We present the ProteIN ConsERvation (PINCER) genome-wide CRISPR library, which for the first time combines enzymatic efficiency optimization with conserved length protein region targeting, and also incorporates domains, coding sequence position, U6 termination (TTT), restriction sites, polymorphisms and specificity. Finally, we demonstrate superior performance of the PINCER library compared to alternative genome-wide CRISPR libraries in head-to-head validation. PINCER is available for individual gene knockout and genome-wide screening for both the human and mouse genomes.

Cystine-glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity.

T cell-invigorating cancer immunotherapies have near-curative potential. However, their clinical benefit is currently limited, as only a fraction of patients respond, suggesting that these regimens may benefit from combination with tumor-targeting treatments. As oncogenic progression is accompanied by alterations in metabolic pathways, tumors often become heavily reliant on antioxidant machinery and may be susceptible to increases in oxidative stress. The cystine-glutamate antiporter xCT is frequently overexpressed in cancer and fuels the production of the antioxidant glutathione; thus, tumors prone to redox stress may be selectively vulnerable to xCT disruption. However, systemic inhibition of xCT may compromise antitumor immunity, as xCT is implicated in supporting antigen-induced T cell proliferation. Therefore, we utilized immune-competent murine tumor models to investigate whether cancer cell expression of xCT was required for tumor growth in vivo and if deletion of host xCT impacted antitumor immune responses. Deletion of xCT in tumor cells led to defective cystine uptake, accumulation of reactive oxygen species, and impaired tumor growth, supporting a cancer cell-autonomous role for xCT. In contrast, we observed that, although T cell proliferation in culture was exquisitely dependent on xCT expression, xCT was dispensable for T cell proliferation in vivo and for the generation of primary and memory immune responses to tumors. These findings prompted the combination of tumor cell xCT deletion with the immunotherapeutic agent anti-CTLA-4, which dramatically increased the frequency and durability of antitumor responses. Together, these results identify a metabolic vulnerability specific to tumors and demonstrate that xCT disruption can expand the efficacy of anticancer immunotherapies.

Self-Reported Urological Hospitalizations or Emergency Room Visits in a Contemporary Spinal Cord Injury Cohort.

PURPOSE: Individuals with spinal cord injuries frequently use urgent and emergent medical care. We hypothesized that urological causes are a primary driver of hospitalizations/emergency room visits in a contemporary spinal cord injury cohort. MATERIALS AND METHODS: The Neurogenic Bladder Research Group spinal cord injury registry is a prospective cohort study evaluating neurogenic bladder related quality of life after traumatic spinal cord injury. Questionnaires were administered to participants querying whether a hospitalization or emergency room visit occurred during the interval 1-year followup and reason for visit. Primary outcome was the rate of urological related hospitalizations/emergency room visits in 1 year. Multivariable logistic regression was used to identify risk factors for urology related hospitalization/emergency room visit. RESULTS: Of the 1,479 participants enrolled 1,260 had 1-year followup. In all, 16.7% (211/1,260) reported at least 1 urological hospitalization/emergency room visit, and urinary tract infections were the most common reason cited. Patients with an indwelling catheter had the greatest odds of having a hospitalization/emergency room episode for a urological indication (OR 3.35, CI 1.68-6.67, p=0.001), followed by clean intermittent catheterization (OR 2.56, CI 1.36-4.84, p=0.004) as compared to those who voided spontaneously. Other predictors included SF-12 physical scores (OR 0.98, CI 0.96-0.996, p=0.014), diminished hand function (OR 1.83, CI 1.05-3.19, p=0.033), and unemployment (OR 1.64, CI 1.13-2.37, p=0.009). CONCLUSIONS: There was a high incidence of hospitalizations/emergency room visits for patients with spinal cord injuries during a 1-year followup and urological complications were the most common reason for admission. Patient self-reported physical health as well as unemployment, and bladder management strategy, particularly indwelling catheter use, were associated with increased risk of urology related hospitalization/emergency room visits.

Nephrectomy is Associated with Increased Mortality after Renal Trauma: An Analysis of the National Trauma Data Bank from 2007-2016.

PURPOSE: The majority of high grade renal trauma can be managed conservatively. However, nephrectomy is still common for acute management. We hypothesized that when controlling for multiple injury severity measures, nephrectomy would be associated with increased mortality. MATERIALS AND METHODS: We identified high grade renal trauma patients from the National Trauma Data Bank® from 2007-2016. Exclusion criteria were age <18 years, severe head injury and death within 4 hours of admission. We performed conditional logistic regression analysis to determine if nephrectomy was independently associated with mortality, controlling for age, gender, race/ethnicity, mechanism of injury, shock, blood transfusion, Glasgow Coma Scale, Revised Trauma Score and Injury Severity Score. Interaction was measured for mechanism of injury and shock with mortality. RESULTS: We identified 42,898 patients with high grade renal trauma (grade III-V), of whom 3,204 (7.5%) underwent nephrectomy. Unadjusted mortality was 16.6% in nephrectomy vs 5.7% in nonnephrectomy patients. In multivariable logistic regression, nephrectomy was associated with 82% increased odds of death (OR 1.82, 95% CI 1.63-2.03, p <0.001). Other significant associations with death included age, nonWhite race, penetrating mechanism, hypotension, blood transfusion, lower Glasgow Coma Scale, lower Revised Trauma Score and higher Injury Severity Score. The association between nephrectomy and death did not differ by mechanism of injury. However, it was slightly attenuated in patients presenting in shock. CONCLUSIONS: In the National Trauma Data Bank, nephrectomy is independently associated with increased risk of mortality after adjusting for patient demographics, injury characteristics and multiple measures of overall injury severity. Nephrectomy may impact overall survival and must be avoided when possible.