Comparison of outcomes in patients with and without neurologic diseases undergoing holmium laser enucleation of the prostate.

INTRODUCTION: We aimed to compare holmium laser enucleation of the prostate (HoLEP) outcomes in patients with and without neurologic diseases (ND). METHODS: A prospectively maintained database of patients undergoing HoLEP from January 2021 to April 2022 was reviewed. The following NDs were included: diabetes-related neuropathy/neurogenic bladder, Parkinson's disease, dementia, cerebrovascular accident, multiple sclerosis, traumatic brain injury, transient ischemic attack, brain/spinal tumors, myasthenia gravis, spinal cord injury, and other. Statistical analysis was performed using t-tests, Chi-squared, and binomial tests (p<0.05). RESULTS: A total of 118 ND patients were identified with 135 different neurologic diseases. ND patients were more likely to have indwelling catheters (57% vs. 39%, p=0.012) and urinary tract infections (UTIs) preoperatively (32% vs. 19%, p=0.002). Postoperatively, ND patients were more likely to fail initial trial of void (20% vs. 8.1%, p<0.001) and experience an episode of acute urinary retention (16% vs. 8.5%, p=0.024). Within 90 days postoperative, the overall complication rate was higher in the ND group (26% vs. 13%, p=0.001). Within the ND group, 30/118 (25%) had ≥1 UTI within 90 days preoperative, which decreased to 10/118 (8.7%) 90 days postoperative (p<0.001). At last followup (mean 6.7 months [ND] vs. 5.4 months [non-ND], p=0.03), four patients (4.4%) in the ND group required persistent catheter/clean intermittent catheterization compared to none in the non-ND group (p=0.002). CONCLUSIONS: Patients with ND undergoing HoLEP are more likely to experience postoperative retention and higher complication rates compared to non-ND patients. While UTI rates are higher in this population, HoLEP significantly reduced three-month UTI and catheterization rates.

Incidence and predictors of delays in starting fellowship training in urology.

INTRODUCTION: The completion of residency and start of fellowship training marks a critical transition for urologists in the pursuit of subspeciality training. Most graduating urology residents are under contract until June 30, and most fellowships are scheduled to begin on July 1. There has been no investigation into the practical implications of fellowship delays in urology from a trainee perspective. Our research study aimed to investigate the incidence and predictors of delays in fellowship starts. METHODS: Pediatric urology fellows that began their fellowship training between 2019 and 2023 and endourologic fellows that began their fellowship training between 2017 and 2022 were surveyed using SurveyMonkey®. A total of 250 endourology (EU) fellows and 90 pediatric urology (PU) fellows were contacted. RESULTS: A total of 26.0% and 14.3% of EU and PU fellows, respectively, experienced a delay in their training, despite many leaving their residency positions early (33.8% vs. 44.9%, p=0.2097); 11.7% and 8.2% of EU and PU fellows, respectively, experienced delays they reported to be "very stressful" and 9.1% and 4.1%, respectively, found them "somewhat stressful." Delays of 2-4 weeks were experienced by 5.2% and 6.1%, 4-6-week delays by 7.8% and 4.1%, and delays >6 weeks by 2.6% and 0% of EU and PU fellows, respectively (p=0.0007). CONCLUSIONS: Delays in fellowship training do occur at a notable rate, despite nearly half of urology fellows leaving their residency training positions early, with unclear impacts on patient care and resident colleague well-being. This research highlights the importance of fellowship programs considering delaying fellowship starts to mid-July or August, with support of the prior fellow cohorts.

Does Resectoscope Sheath Size Influence Holmium Laser Enucleation of the Prostate Outcomes? A Prospective Randomized Controlled Trial.

Introduction: Holmium laser enucleation of the prostate (HoLEP) is routinely performed with a 24F, 26F, or a 28F scope. Proponents of the larger scopes propose that a bigger sheath size allows for superior flow and visibility leading to a more efficient operation and better hemostasis. Those utilizing the smaller scopes suggest that the smaller sheath is less traumatic, resulting in lower stricture rates and temporary incontinence. We sought to compare outcomes of ambulatory HoLEP using the 24F and 28F laser scope. Materials and Methods: From May 2022 to March 2023, we randomized patients undergoing HoLEP (<200 cm3 in size) 1:1 to either a 24F or 28F scope. The primary outcome was differences in surgical duration between groups (minutes). Secondary outcomes included surgeon scope evaluation and postoperative patient results. Results: There was no difference in patient characteristics in those randomized to 28F (n = 76) vs 24F (n = 76) (p > 0.05) scopes. Procedural duration and efficiencies were not different between groups (all p > 0.05). The 28F scope was associated with improved surgeon-graded irrigation flow and visibility (p < 0.001). Patients treated with the 28F scope were more likely to achieve effective same-day trial of void (SDTOV) (28F 94.3% vs 24F 82.1%, p = 0.048) and have a shorter length of stay (LOS) (28F 7.0 vs 24F 11.9 hours, p = 0.014), however, rates of same-day discharge (SDD) were not statistically different (28F 87.8% vs 24F 78.4%, p = 0.126). There was no difference between the cohorts in rates of 90-day emergency room presentations, re-admissions, complications, or functional ouctomes (p > 0.05). Conclusions: We identified no clear advantage of scope size with regard to intraoperative or postoperative outcomes at 3-month follow-up due to scope size. However, if SDD is part of your postoperative pathway, the 28F scope may shorten LOS and increase rates of effective SDTOV. Clinicaltrials.gov: NCT05308017.

Trends of Benign Prostatic Hyperplasia Procedures in Ambulatory Surgery Settings.

Introduction: Holmium laser enucleation of the prostate (HoLEP) has evidenced-based advantages in treating benign prostatic hyperplasia (BPH) relative to other interventions. Unfortunately, the adoption of HoLEP has remained relatively low in Medicare and the National Surgical Quality Improvement Program populations. HoLEPs role as an inpatient surgical intervention is changing as advancements in the technique and systems have demonstrated the feasibility of same-day discharge. Thus, our objective was to evaluate national HoLEP trends in ambulatory surgery settings from 2016 to 2019. Materials and Methods: The Nationwide Ambulatory Surgery Sample (NASS) is the largest national all-payer database of ambulatory surgical encounters, managed by the Agency for Healthcare Research and Quality. A cross-sectional retrospective analysis of the 2016 and 2019 NASS was performed. Rates of BPH surgeries were calculated and stratified by age, census region, and primary payer to compare across time points for trends. Chi-squared tests and two-sample t-tests were completed for categorical and continuous variables, respectively. Results: The total number of ambulatory BPH surgeries fell 20% between 2016 (n = 124,538) and 2019 (n = 100,593). In 2016, HoLEP lagged behind photoselective vaporization of the prostate (PVP) and transurethral resection of prostate (TURP) with 4.7% of surgeries but rose to the second most common procedure in 2019 with 8.3% of total surgeries. TURP was the most common intervention (62.6% in 2016, 90.7% in 2019). Simple prostatectomy was the most expensive intervention. By U.S. census region, more HoLEPs were carried out in the South (43.1% in 2016, 37.5% in 2019) and Midwest (26.8% in 2016, 31.7% in 2019). Conclusions: Overall, HoLEP uptake is increasing. HoLEP has replaced greenlight PVP as the second most frequently used intervention. The rate of ambulatory HoLEPs has nearly doubled despite a general decrease in the number of surgeries.

Benign prostatic hyperplasia surgical re-treatment after prostatic urethral lift A narrative review.

INTRODUCTION: Prostatic urethral lift (PUL) accounts for approximately one-quarter of all surgical benign prostatic hyperplasia (BPH) procedures performed in the U.S. Within five years of a patient's PUL procedure, approximately 1/7 patients will require surgical BPH retreatment. We aimed to highlight the evidence of surgical BPH retreatment modalities after PUL, with a focus on safety, short-term efficacy, durability, and relative costs. METHODS: A literature review was performed using PubMed, and an exhaustive review of miscellaneous online resources was completed. The search was limited to English, human studies. Citations of relevant studies were reviewed. RESULTS: No study has examined the efficacy, safety, or durability of transurethral resection of the prostate (TURP) or repeat PUL in the post-PUL setting. Recently, groups have examined laser enucleation (n=81), water vapor thermal therapy (WVTT) (n=5), robotic simple prostatectomy (SP) (n=2), and prostatic artery embolization (PAE) (n=1) in the post-PUL setting. Holmium enucleation of the prostate (HoLEP) after PUL appears to be safe and has similar functional outcomes to HoLEP controls. Other treatment modalities examined appear safe but have limited efficacy evidence supporting their use. Photo-selective vaporization of the prostate (PVP) and robotic waterjet treatment (RWT) have no safety or efficacy studies to support their use in the post-PUL setting. CONCLUSIONS: Despite increasing numbers of patients expected to require surgical retreatment after PUL in North America, there is currently limited evidence and a lack of recommendations guiding the evaluation and management of these patients. HoLEP is associated with the strongest evidence to support its use in the post-PUL setting.

Short-Term Clinical Outcomes of Bladder Neck Incision at Time of Holmium Laser Enucleation of the Prostate.

Introduction: The effect of prophylactic bladder neck incision (BNI) at time of holmium laser enucleation of the prostate (HoLEP) is unknown. The aim of our study was to examine HoLEP outcomes with a specific focus on rates of bladder neck contractures (BNCs), with and without utilizing prophylactic BNI. Materials and Methods: We performed a retrospective review of HoLEP patients from January 2021 until January 2022. Outcomes of patients who underwent BNI at time of HoLEP were compared with those who underwent standard HoLEP alone. Student's t-tests, chi-square tests, and logistic regressions were performed using SAS Studio. Results: In total, 421 patients underwent HoLEP. BNI was concurrently performed in 74 (17.6%) HoLEP patients. BNI patients were younger (67.5 ± 9.0 years vs 71.1 ± 8.2 years, p = 0.00007) and had smaller prostates (60.7 ± 30.3 cc vs 133.2 ± 64.5 cc, p < 0.0001). Procedure, enucleation, and morcellation times were shorter in the BNI group (all p < 0.0001). There was no statistical difference in same-day discharge rates (90.4% vs 87.7%, p = 0.5), short-term functional outcomes, emergency department (ED) visits, or readmission rates between the two groups. At 14 months mean follow-up, two BNCs occurred in patients in the control group (0.6%), and no BNCs occurred in patients who underwent BNI (0.0%, p = 0.5). Conclusions: BNI at time of HoLEP did not decrease the ability to achieve same-day discharge or increase 90-day complications, ED visits, or readmission rates. No BNCs occurred in patients who underwent prophylactic BNI (0.0%) despite a smaller gland size and lower specimen weight in this cohort. Further prospective studies are required to conclude if concurrent BNI at time of HoLEP is protective against BNC.

Contemporary Use of Computed Tomography (CT) Imaging in Suspected Urolithiasis in Pregnancy.

PURPOSE OF REVIEW: We aimed to examine the role of low-dose CT (LDCT) in the diagnostic work-up for suspected urolithiasis in pregnancy. We reviewed contemporary urologic recommendations for CT in pregnancy, its utilization for suspected urolithiasis, and explored barriers to its use. RECENT FINDINGS: National urologic guidelines and the American College of Obstetricians and Gynecologists recommend the judicious use of LDCT imaging in pregnancy when necessary. We noted inconsistencies in review article management pathways and recommendations for CT imaging for suspected urolithiasis in pregnancy. Overall CT utilization in pregnancy for suspected urolithiasis is low. Proposed barriers to LDCT use in pregnancy include fears of litigation and misperceptions of the harm of diagnostic radiation. Recent advancements in imaging technologies for urolithiasis in pregnancy are limited. More specific diagnostic pathway recommendations from national urologic guideline bodies for when to use LDCT to investigate renal colic in pregnancy may reduce diagnostic and intervention delays.

Ureteral Wall Thickness Is an Effective Predictor of Ureteral Stone Impaction and Management Outcomes: A Systematic Review and Meta-analysis.

PURPOSE: Ureteral stone impaction is associated with unfavorable endourological outcomes; however, reliable predictors of stone impaction are limited. We aimed to assess the performance of ureteral wall thickness on noncontrast computed tomography as a predictor of ureteral stone impaction and failure rates of spontaneous stone passage, shock wave lithotripsy, and retrograde guidewire and stent passage. MATERIALS AND METHODS: This study was completed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. A search was conducted in April 2022 for all adult, human, and English language studies investigating ureteral wall thickness using PROSPERO, OVID Medline, OVID EMBASE, Wiley Cochrane Library, Proquest Dissertations & Theses Global, and SCOPUS. A systematic review and meta-analysis using random effects model was conducted. Risk of bias was assessed using the MINORS (Methodological Index for Non-randomized Studies) score. RESULTS: Fourteen studies with a pooled population of 2,987 patients were included for quantitative analysis, and 34 studies were included in our qualitative review. Meta-analysis findings suggest that a thinner ureteral wall thickness is associated with more favorable subgroup stone outcomes. Thinner ureteral wall thickness suggests a lack of stone impaction and was associated with improved rates of spontaneous stone passage, successful retrograde guidewire and stent placement, and improved shock wave lithotripsy outcomes. Studies lack a standardized ureteral wall thickness measurement protocol. CONCLUSIONS: Ureteral wall thickness is a noninvasive measure that predicts ureteral stone impaction, and thin measurements are predictive of successful outcomes. Variability in measurement methods confirms that a standardized ureteral wall thickness protocol is needed, and the clinical utility of ureteral wall thickness is yet to be determined.

Quality Improvement of Surgical Team Communication of Required Percutaneous Nephrolithotomy Equipment.

OBJECTIVE: To evaluate if implementation of a percutaneous nephrolithotomy (PCNL) equipment whiteboard can improve communication accuracy of surgical equipment, streamline operative efficiency, and decrease unnecessary case equipment costs. METHODS: A real-time editable equipment whiteboard was designed and implemented for all PCNL cases between October and December 2021. The relative difference in pre- and post-intervention surgical equipment accuracy as well as overall case costing was compared from 90 days prior to implementation to the period after intervention. RESULTS: Quality assessment surveys were completed prior to whiteboard implementation (N = 25) and cost implementation (n = 15). Pre- and postoperative assessment of equipment communication, assessed on a 10-point scale, improved after implementation of the communication whiteboard (Pre-op: 6.7/10 vs. 8.9/10, P < .001. Post-op: 7.0/10 vs. 9.3/10, P < .001). On average 64% (3.2/5) of items were accurate on preintervention cases. Postintervention accuracy improved to 88% (4.4/5 items) (P = .049). There was a significant relative case cost improvement after implementing the PCNL equipment whiteboard with an average of $436.81 USD savings per case (P = .001) and $488.22 USD per renal moiety (P = .002). CONCLUSION: Our baseline quality assessment of surgical team communication regarding PCNL equipment identified an area for improvement. Multidisciplinary feedback resulted in the development of a real-time editable PCNL equipment whiteboard which improved team perception of equipment communication, case item accuracy and resulted in a relative average cost savings for PCNL.

Intradetrusor OnabotulinumtoxinA Injections at the Time of Holmium Laser Enucleation of the Prostate for Men with Severe Storage Symptoms.

Introduction: Intradetrusor onabotulinumtoxinA (OTA) injection is a well-established treatment option for refractory overactive bladder; however, its use at the time of holmium laser enucleation of the prostate (HoLEP) for men with bladder outlet obstruction (BOO) and severe storage symptoms has not been previously reported. Materials and Methods: We retrospectively identified men with BOO and severe storage symptoms who underwent treatment with 200 U of intradetrusor OTA (Botox®) at the time of HoLEP. Patients were propensity score matched to a cohort of HoLEP-only patients based on age, Michigan Incontinence Symptom Index (M-ISI) score, preoperative urinary retention, urge incontinence, and prostate size. Perioperative, postoperative, and patient-reported outcomes were examined between groups. Results: We identified 82 men who underwent HoLEP, including 41 patients in the OTA group and 41 patients in the control group. There was no difference in operative times (59 minutes OTA vs 55 minutes control, p = 0.2), rates of same-day trial of void (TOV) (92% OTA vs 94% control, p = 0.7), or rates of same-day discharge (88% OTA vs 85% control, p = 0.6) between groups. There was no difference in temporary postoperative urinary retention (7% OTA vs 2% control, p = 0.3) between groups. Patients who received OTA injections had a significant reduction in their incontinence scores at 3-month follow-up (M-ISI -8, interquartile range [IQR]: -13 to 0, p < 0.001), whereas control patients did not (M-ISI -5, IQR: -8 to -1, p = 0.2). There was no difference in rates of 90-day complications between groups (OTA 10% vs control 5%, p = 0.7). Conclusions: Intradetrusor OTA at the time of HoLEP is safe and is associated with improved urinary incontinence scores and AUA Symptom Score. Rates of same-day discharge and same-day TOV after HoLEP were not affected by OTA. These findings support the role of OTA as an adjunct to surgical intervention in men with incontinence in the presence of BOO.

Percutaneous management of caliceal diverticula: a narrative review.

PURPOSE OF REVIEW: Caliceal diverticula are relatively uncommon within urologic practice and may be difficult to diagnose and treat. We aim to highlight contemporary studies examining surgical interventions for patients with caliceal diverticula, with a focus on percutaneous intervention, and provide updated practical recommendations for the management of these patients. RECENT FINDINGS: Studies within the last 3 years examining surgical treatment options for caliceal diverticular calculi are limited. When flexible ureteroscopy (f-URS) and percutaneous nephrolithotomy (PCNL) are examined within the same observational cohorts, PCNL is associated with improved stone-free rates (SFRs), lower requirement for re-intervention, and longer lengths of stay (LOS). Retrograde f-URS for the treatment of caliceal diverticula and diverticular calculi is associated with satisfactory safety and efficacy outcomes. There are no studies in the last 3 years that provide supporting evidence to use shock wave lithotripsy to treat caliceal diverticular calculi. SUMMARY: Recent studies examining surgical interventions for patients with caliceal diverticula are limited to small observational studies. Heterogeneity in LOS and follow-up protocol limits comparisons between series. Despite technological advancements in f-URS, PCNL appears to be associated with more favorable and definitive outcomes. PCNL continues to be the preferred treatment strategy for patients with symptomatic caliceal diverticula when deemed technically feasible.

Lipid pathway dysfunction is prevalent in patients with Parkinson's disease.

Many genetic risk factors for Parkinson's disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson's disease. Moreover, the hallmark Parkinson's disease pathological protein, α-synuclein, has lipid membrane function and pathways dysregulated in Parkinson's disease such as the endosome-lysosome system and synaptic signalling rely heavily on lipid dynamics. Despite the potential role for lipids in Parkinson's disease, most research to date has been protein-centric, with large-scale, untargeted serum and CSF lipidomic comparisons between genetic and idiopathic Parkinson's disease and neurotypical controls limited. In particular, the extent to which lipid dysregulation occurs in mutation carriers of one of the most common Parkinson's disease risk genes, LRRK2, is unclear. Further, the functional lipid pathways potentially dysregulated in idiopathic and LRRK2 mutation Parkinson's disease are underexplored. To better determine the extent of lipid dysregulation in Parkinson's disease, untargeted high-performance liquid chromatography-tandem mass spectrometry was performed on serum (n = 221) and CSF (n = 88) obtained from a multi-ethnic population from the Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium. The cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with Parkinson's disease and Parkinson's disease patients without a LRRK2 mutation. Age and sex were adjusted for in analyses where appropriate. Approximately 1000 serum lipid species per participant were analysed. The main serum lipids that distinguished both Parkinson's disease patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine and lysophosphatidylethanolamine. Significant alterations in sphingolipids and glycerolipids were also reflected in Parkinson's disease and LRRK2 mutation carrier CSF, although no correlations were observed between lipids identified in both serum and CSF. Pathway analysis of altered lipid species indicated that sphingolipid metabolism, insulin signalling and mitochondrial function were the major metabolic pathways dysregulated in Parkinson's disease. Importantly, these pathways were also found to be dysregulated in serum samples from a second Parkinson's disease cohort (n = 315). Results from this study demonstrate that dysregulated lipids in Parkinson's disease generally, and in LRRK2 mutation carriers, are from functionally and metabolically related pathways. These findings provide new insight into the extent of lipid dysfunction in Parkinson's disease and therapeutics manipulating these pathways may be beneficial for Parkinson's disease patients. Moreover, serum lipid profiles may be novel biomarkers for both genetic and idiopathic Parkinson's disease.

Fistulae involving the appendix: a systematic review of the literature.

BACKGROUND: The appendix has a unique place in surgical history. Although the first ever appendicectomy involved a fistula to the skin, fistulae involving the appendix remain uncommon and can lead to unique surgical considerations. METHODS: A systematic review of the literature was performed for case reports of appendiceal fistulae. We excluded cases in which the patient had a history of appendicectomy. Cases were categorized by site and aetiology, with information regarding relative frequency and demographics obtained. RESULTS: A total of 301 case reports of fistula involving the appendix were found. The most common sites of these fistulae were to the bladder (148 cases), skin (40 cases), vasculature (19 cases), umbilicus (16 cases) and to the gastrointestinal tract. The most common aetiology in sub-analysis was appendicitis alone (150 cases), with less common causes including appendiceal adenocarcinoma (32 cases) and congenital abnormalities (18 cases). There were significantly more appendiceal fistulae in males than in females, with a ratio of 1.7:1. In patients with appendiceal adenocarcinoma as a cause for fistula, there were significantly more females than males with a ratio of 2.3:1. CONCLUSION: In conducting a systematic review of case reports of fistulae involving the appendix, we identified 301 unique case reports, with a range of different sites and aetiologies.

Correction: Are viral-infections associated with Ménière's Disease? A systematic review and meta-analysis of molecular-markers of viral-infection in case-controlled observational studies of MD.

[This corrects the article DOI: 10.1371/journal.pone.0225650.].

Are viral-infections associated with Ménière's Disease? A systematic review and meta-analysis of molecular-markers of viral-infection in case-controlled observational studies of MD.

Despite considerable research, it remains controversial as to whether viral-infections are associated with Meniere's Disease (MD), a clinically heterogeneous set of chronic inner-ear disorders strongly associated with endolymphatic hydrops. Here, we investigated whether viral-infections are associated with MD through a systematic review and meta-analysis of observational clinical studies using molecular-diagnostics. Eligible for inclusion were case-controlled studies which ascertained molecular-determinants of past or present viral-infection through either viral nucleic acids or host serological marker in MD cases and non-MD controls. Across online databases and grey literature, we identified 210 potentially relevant articles in the English language, from which a total of 14 articles fully satisfied our eligibility criteria such that meta-groups of 611 MD-cases and 373 controls resulted. The aggregate quality of the modest-sized (14 studies) body of evidence was limited and varied considerably with regards to participant selection, matching, and ascertainment(s) and determinant(s) of viral-infection. Most data identified concerned the human cytomegalovirus (CMV), and meta-analysis of eligible studies revealed that evidence of CMV-infection was associated approximately three-fold with MD compared to controls, however the timing of the infections was indeterminate as the pooled analyses combined antiviral serological markers with viral nucleic acid markers. No association was found for any of HSV-1, -2, VZV, or EBV. Associative analyses of any viral species not aforementioned were precluded by limited data, and thus potential associations between other viral species and MD, especially other than Herpesviridae, are yet to be characterised. Overall, we have found a small association between CMV-infection and MD, however it is to be determined for what sub-groups of MD this finding may be relevant, and ideally the reported association remains would be reproduced by a greater volume of higher quality evidence.

Incidence and Predictors of Complications due to Urethral Stricture in Patients Awaiting Urethroplasty.

PURPOSE: We examined the incidence and predictors of complications due to urethral stricture in patients awaiting urethroplasty. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients who underwent urethroplasty from 2009 to 2013. The primary outcome was complications, defined as any unplanned interaction with the health care system due to urethral stricture during the period between the decision to perform surgery and urethroplasty. RESULTS: A total of 276 patients were identified for analysis. Median stricture length was 4.0 cm and 67.4% of strictures were in the bulbar urethra. The most common stricture etiologies were idiopathic in 47.8% of cases and traumatic in 15.9%. Overall 15.9% of patients presented with a complication with a median time to complication of 43 days. Median surgical wait time was 151 days. Complications included urinary tract infections in 56.8% of patients, acute urinary retention in 20.5%, genitourinary pain in 5.8% and catheter related issues in 15.9%. Univariate analysis suggested that catheter dependent status, number of prior endoscopic treatments, a hypospadias and/or trauma etiology, and prior urethroplasty were potential significant predictors of complications. Multivariate analysis yielded only catheter dependent status (HR 5.2, 95% CI 2.4-11.3, p <0.0001) and prior failed urethroplasty (HR 1.6, 95% CI 1.1-2.3, p = 0.03) as significantly associated with complications. CONCLUSIONS: To our knowledge our study is the first to examine and quantify the morbidity of urethroplasty wait time. Approximately 16% of patients experienced a complication while awaiting urethroplasty. The optimal wait time should be less than 43 days. Patients with prior urethroplasty and catheters at the time of the surgical decision should be prioritized as they may be more likely to experience complications.

Evolution of the vertebrate claudin gene family: insights from a basal vertebrate, the sea lamprey.

Claudins are major constituents of tight junctions, contributing both to their intercellular sealing and selective permeability properties. While claudins and claudin-like molecules are present in some invertebrates, the association of claudins with tight junctions has been conclusively documented only in vertebrates. Here we report the sequencing, phylogenetic analysis and comprehensive spatiotemporal expression analysis of the entire claudin gene family in the basal extant vertebrate, the sea lamprey. Our results demonstrate that clear orthologues to about half of all mammalian claudins are present in the lamprey, suggesting that at least one round of whole genome duplication contributed to the diversification of this gene family. Expression analysis revealed that claudins are expressed in discrete and specific domains, many of which represent vertebrate-specific innovations, such as in cranial ectodermal placodes and the neural crest; whereas others represent structures characteristic of chordates, e.g. pronephros, notochord, somites, endostyle and pharyngeal arches. By comparing the embryonic expression of claudins in the lamprey to that of other vertebrates, we found that ancestral expression patterns were often preserved in higher vertebrates. Morpholino mediated loss of Cldn3b demonstrated a functional role for this protein in placode and pharyngeal arch morphogenesis. Taken together, our data provide novel insights into the origins and evolution of the claudin gene family and the significance of claudin proteins in the evolution of vertebrates.

Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death.

UNLABELLED: Fostriecin is a natural product purified from Sterptomyces extracts with antitumor activity sufficient to warrant human clinical trials. Unfortunately, difficulties associated with supply and stable drug formulation stalled further development. At a molecular level, fostriecin is known to act as a catalytic inhibitor of four PPP-family phosphatases, and reports describing the design of molecules in this class suggest derivatives targeting enzymes within the fostriecin-sensitive subfamily can be successful. However, it is not clear if the tumor-selective cytotoxicity of fostriecin results from the inhibition of a specific phosphatase, multiple phosphatases, or a limited subset of fostriecin sensitive phosphatases. How the inhibition of sensitive phosphatases contributes to tumor-selective cytotoxicity is also not clear. Here, high-content time-lapse imaging of live cells revealed novel insight into the cellular actions of fostriecin, showing that fostriecin-induced apoptosis is not simply induced following a sustained mitotic arrest. Rather, apoptosis occurred in an apparent second interphase produced when tetraploid cells undergo mitotic slippage. Comparison of the actions of fostriecin and antisense-oligonucleotides specifically targeting human fostriecin-sensitive phosphatases revealed that the suppression PP4C alone is sufficient to mimic many actions of fostriecin. Importantly, targeted suppression of PP4C induced apoptosis, with death occurring in tetraploid cells following mitotic slippage. This effect was not observed following the suppression of PP1C, PP2AC, or PP5C. These data clarify PP4C as a fostriecin-sensitive phosphatase and demonstrate that the suppression of PP4C triggers mitotic slippage/apoptosis. IMPLICATIONS: Future development of fostriecin class inhibitors should consider PP4C as a potentially important target. Mol Cancer Res; 11(8); 845-55. ©2013 AACR.

Antisense inhibition of connective tissue growth factor (CTGF/CCN2) mRNA limits hypertrophic scarring without affecting wound healing in vivo.

Augmented expression of connective tissue growth factor (CTGF/CCN2) is observed in healing wounds and in a variety of fibrotic disorders. It appears to enhance many of the effects of transforming growth factor-beta and has been shown to have independent fibrogenic functions. Despite these observations, its importance to dermal wound healing and the transition from wound to scar remains poorly defined. In this study, we use established rabbit models to evaluate the roles of CTGF in dermal wound healing and hypertrophic scarring. We show that CTGF mRNA demonstrates persistent up-regulation in hypertrophic scars. Treatment of wounds with antisense oligonucleotides to CTGF has no measurable effect on early wound closure. However, antisense therapy significantly limits subsequent hypertrophic scarring. Inhibition of CTGF is associated with a marked reduction in the number of myofibroblasts in scars and decreased transcription of TIMP-1 and types I and III collagen. These findings confirm CTGF to be a key mediator of hypertrophic scarring in this model. Its effect on myofibroblasts in this setting suggests a mechanism whereby it plays this role. Its limited participation in early healing implies that it may be a useful and specific target for modulating hypertrophic scarring following injury.