Destroyed bladders: Characterization of progressive inflammatory cystitis.

PURPOSE: We identified a subset of patients with noninfectious cystitis who develop refractory symptoms marked by diffuse inflammatory changes, reduced bladder capacity, and vesicoureteral reflux (VUR), termed here as "progressive inflammatory cystitis" (PIC). Our objective was to describe the phenotype, disease outcomes, and pathologic findings of PIC. MATERIAL AND METHODS: A single institution retrospective cohort study of patients with PIC. Patients with a history of pelvic radiation, urologic malignancy, or neurogenic bladder were excluded. We describe cohort characteristics and use bivariate analyses to compare subgroups. Kaplan-Meier methods estimate time to urinary diversion. RESULTS: From 2008 to 2020, 46 patients with PIC were identified. The median age of symptom onset was 63 years old (interquartile range [IQR]: 56, 70) and the most common presenting symptoms were urinary urgency/frequency (54%) and incontinence (48%). Urodynamics showed a median maximum bladder capacity of 80 mL (IQR: 34, 152), commonly with VUR (68%) and hydronephrosis (59%). Ultimately 36 patients (78%) underwent urinary diversion at a median of 4.5 years (IQR: 2, 6.5) after symptom onset. Significant pathologic findings include presence of ulceration (52%), acute and chronic inflammation (68%), including eosinophils (80%), lymphoid follicles (56%), and mast cells in both lamina and muscularis propria (76%). CONCLUSIONS: PIC is a newly defined entity characterized by significantly diminished bladder capacity, upper tract changes, and relatively quick progression to urinary diversion. Larger prospective cohort studies are required to further characterize this severe phenotype of chronic noninfectious cystitis, aid earlier diagnosis, and guide management decisions.

Urologic oncology patient perspectives during COVID-19 treatment delays.

PURPOSE: We sought to describe patient experiences during COVID-19 related delays in urologic cancer treatment. METHODS: We conducted a mixed methods study with an explanatory-sequential design. Survey findings are presented here. Patients from a Midwestern Cancer Center and the Bladder Cancer Advocacy Network (BCAN) self-reported via survey their experience of treatment delay, patient-provider communication, and coping strategies. We quantified patient distress with an ordinal scale (0-10), based on the National Comprehensive Cancer Network Distress Thermometer (NCCN-DT). RESULTS: Forty-four patients with bladder, prostate, and kidney cancers consented to the survey. Most individuals were male (n = 29; 66%) and older than 61 years of age (n = 34; 77%). Median time since diagnosis was 6 months. Dominant reactions to treatment delay included fear that cancer would progress (n = 22; 50%) and relief at avoiding COVID-19 exposure (n = 19; 43%). Most patients reported feeling that their providers acknowledged their emotions (n = 31; 70%), yet 23 patients (52%) did not receive follow-up phone calls and only 24 (55%) felt continually supported by their providers. Patients' median distress level was 5/10 with 68% (n = 30) of patients reaching a clinically significant level of distress (≥ 4). Thematically grouped suggestions for providers included better communication, more personalized support, and better patient education. CONCLUSION: During the COVID-19 pandemic, a high proportion of urologic cancer patients reached a clinically significant level of distress. While they felt concern from providers, they desired more engagement and personalized care.

SKOPE-Study of Ketorolac vs Opioid for Pain after Endoscopy: A Double-Blinded Randomized Control Trial in Patients Undergoing Ureteroscopy.

PURPOSE: Pain is the leading cause of unplanned emergency department visits and readmissions after ureteroscopy, making postoperative analgesic stewardship a priority given the current opioid epidemic. We conducted a double-blinded, randomized controlled trial, with noninferiority design, comparing nonsteroidal anti-inflammatory drugs to opiates for postoperative pain control in patients undergoing ureteroscopy for urolithiasis. MATERIALS AND METHODS: Patients were randomized and blinded to either oxycodone (5 mg) or ketorolac (10 mg), taken as needed, with 3 nonblinded oxycodone rescue pills for breakthrough pain. Primary study outcome was visual analogue scale pain score on postoperative days 1-5. Secondary outcomes included medication utilization, side effects, and Ureteral Stent Symptom Questionnaire scores. RESULTS: A total of 81 patients were included (43 oxycodone, 38 ketorolac). The 2 groups had comparable patient, stone, and perioperative characteristics. No differences were found in postoperative pain scores, study medication or rescue pill usage, or side effects. Higher maximum pain scores on days 1-5 (p <0.05) and higher questionnaire score (28.1 vs 21.7, p=0.045) correlated with analgesic usage, irrespective of treatment group. Patients receiving ketorolac reported significantly fewer days confined to bed (mean±SD 1.3±1.3 vs 2.3±2.6, p=0.02). There was no difference in unscheduled postoperative physician encounters. CONCLUSIONS: This is the first double-blinded randomized controlled trial comparing nonsteroidal anti-inflammatory drugs and opiates post-ureteroscopy, and demonstrates noninferiority of nonsteroidal anti-inflammatory drugs in pain control with similar efficacy, safety profile, physician contact and notably, earlier convalescence compared to the opioid group. This provides strong evidence against routine opioid use post-ureteroscopy, justifying continued investigation into reducing postoperative opiate prescriptions.

Motor Response Matters: Optimizing Lead Placement Improves Sacral Neuromodulation Outcomes.

PURPOSE: We sought to determine the usefulness of motor responses during sacral neuromodulation lead placement by testing the hypothesis that a greater number of motor responses during intraoperative electrode testing would be associated with more durable therapy. MATERIALS AND METHODS: We retrospectively reviewed all sacral neuromodulation lead placements at a large academic center from 2010 to 2015. Included in study were all unilateral sacral lead placements for which the presence or absence of a motor response was documented discretely for each electrode. Motor responses were quantified into separate subscores, including bellows and toe response subscores (each range 0 to 4) for a possible maximum total score of 8 when combined. Revision surgery was the primary outcome. Univariate and multivariate analyses were performed for factors associated with lead revision. RESULTS: A total of 176 lead placements qualified for analysis. Mean ± SD cohort age was 58.4 ± 15.9 years, 86.4% of the patients were female and 93.2% had undergone implantation for overactive bladder. Median followup was 10.5 months (range 2 to 36). Overall 34 patients (19%) required lead revision. Revision was negatively associated with the total electrode response score (p = 0.027) and the toe subscore (p = 0.033) but not with the bellows subscore (p = 0.183). Predictors of revision on logistic regression included age less than 59 years at implantation (OR 5.5, 95% CI 2-14) and a total electrode response score less than 4 (OR 4.2, 95% CI 1.4-12.8). CONCLUSIONS: Fewer total electrode responses and specifically fewer toe responses were associated with sacral neuromodulation lead revision. These data suggest that placing a lead with more toe responses during testing may result in more durable sacral neuromodulation therapy.

Impact of Age and Comorbidities on Use of Sacral Neuromodulation.

PURPOSE: We investigated the influence of patient age on sacral nerve stimulation trial outcomes, device implantation and treatment durability. MATERIALS AND METHODS: We analyzed a database of all sacral nerve stimulation procedures performed between 2012 and 2014 at a high volume institution for associations of patient age with sacral nerve stimulation indication, trial stimulation success, device revision and device explantation. RESULTS: In a cohort of 356 patients those with nonobstructive urinary retention and urgency-frequency were younger than patients with urgency urinary incontinence. Trial stimulation success did not differ by age in stage 1 and percutaneous nerve evaluation trials (p = 0.51 and 0.84, respectively). Logistic regression identified greater odds of trial success in females compared to males (OR 2.97, 95% CI 1.32-6.04, p = 0.009) and for urgency urinary incontinence compared to urgency-frequency (OR 3.02, 95% CI 1.39-6.50, p = 0.006). In analyzed patients there were 119 surgical revisions, including battery replacement, and 53 explantations. Age was associated with a decreased risk of revision with 3% lower odds per each additional year of age (OR 0.97, 95% CI 0.95-0.98, p <0.0001). While age did not influence explantation, for each body mass index unit there was a 5% decrease in the odds of explantation (OR 0.95, 95% CI 0.91-0.98). CONCLUSIONS: In contrast to previous studies, older patients experienced no difference in the sacral nerve stimulation response in stimulation trials and no difference in the implantation rate. Furthermore, age was modestly protective against device revision. This suggests that age alone should not negatively predict sacral nerve stimulation responses.

Perceived vs Actual Shared Decision-Making Behavior Among Urologists: A Convergent, Parallel, Mixed-Methods Study of Self-Reported Practice.

OBJECTIVE: To evaluate the association between self-perceived use of shared decision-making among urologists with use of validated prediction tools and self-described surgical decision-making. METHODS: This is a convergent mixed methods study of these parallel data from two modules (Shared Decision Making and Validated Prediction tools) within the 2019 American Urological Association (AUA) Annual Census. The shared decision-making (SDM) module queried aspects of SDM that urologists regularly used. The validated prediction tools module queried whether urologists regularly used, trusted, and found prediction tools helpful. Selected respondents to the 2019 AUA Annual Census underwent qualitative interviews on their surgical decision-making. RESULTS: In the weight sampled of 12,312 practicing urologists, most (77%) reported routine use of SDM, whereas only 30% noted regular use of validated prediction tools. On multivariable analysis, users of prediction tools were not associated with regular SDM use (31% vs 28%, P = .006) though was associated with use of decision aids f (32% vs 26%, P < .001). Shared decision-making emerged thematically with respect to matching treatment options, prioritizing goals, and navigating challenging decisions. However, the six specific components of shared decision-making ranged in their mentions within qualitative interviews. CONCLUSION: Most urologists report performing SDM as supported by its thematic presence in surgical decision-making. However, only a minority use validated prediction tools and urologists infrequently mention specific SDM components. This discrepancy provides an opportunity to explore how urologists perform SDM and can be used to support integrated strategies to implement SDM more effectively in clinical practice.

Endoscopic management of a spontaneous rectus sheath hematoma causing bladder perforation.

Rarely pelvic hemorrhage events can lead to bladder perforation. We present a 48-year-old female who developed a spontaneous rectal sheath hematoma which perforated her bladder. Her case was monitored with serial MRI imaging and managed with two endoscopic clot resections which demonstrated new epithelialization of the bladder wall across the hematoma point of entry. We conclude that the bladder has an impressive potential to heal and select cases of symptomatic invasive bladder hematomas may be monitored with serial imaging and managed endoscopically.

Aging astrocytes metabolically support aging axon function by proficiently regulating astrocyte-neuron lactate shuttle.

The astrocyte-neuron lactate shuttle (ANLS) is an essential metabolic support system that uptakes glucose, stores it as glycogen in astrocytes, and provides glycogen-derived lactate for axonal function. Aging intrinsically increases the vulnerability of white matter (WM) to injury. Therefore, we investigated the regulation of this shuttle to understand vascular-glial metabolic coupling to support axonal function during aging in two different WM tracts. Aging astrocytes displayed larger cell bodies and thicker horizontal processes in contrast to thinner vertically oriented processes of young astrocytes. Aging axons recovered less following aglycemia in mouse optic nerves (MONs) compared to young axons, although providing lactate during aglycemia equally supported young and aging axonal function. Incubating MONs in high glucose to upregulate glycogen stores in astrocytes delayed loss of function during aglycemia and improved recovery in both young and aging axons. Providing lactate during recovery from aglycemia unmasked a metabolic switch from glucose to lactate in aging axons. Young and aging corpus callosum consisting of a mixture of myelinated and unmyelinated axons sustained their function fully when lactate was available during aglycemia and surprisingly showed a greater resilience to aglycemia compared to fully myelinated axons of optic nerve. We conclude that lactate is a universal substrate for axons independent of their myelination content and age.

Delineating the Role of the Urinary Metabolome in the Lithogenesis of Calcium-Based Kidney Stones.

OBJECTIVE: To delineate the role of the urinary metabolome in the genesis of urinary stone disease (USD). METHODS: Untargeted metabolomics was utilized in comparative analyses of calcium-based stones (CBS) and spot urine samples from patients with a history of USD with or without urinary stone activity based on radiologic imaging. Stone and urine metabolomes were stratified by composition and radiographic stone-activity, respectively. Additionally, we quantified highly abundant metabolites that were present in either calcium oxalate (CaOx) or calcium phosphate (CaPhos) stones and also significantly enriched in the urine of active stone formers (SF) compared to non-active SF. These data were used to delineate either a direct involvement of urinary metabolites in lithogenesis or the passive uptake of biomolecules within the stone matrix. RESULTS: Urinary metabolomes were distinct based on radiographic stone-activity and the 2 types of CBS. Stratification by radiologic stone activity was driven by the enrichment of 14 metabolites in the urine of active SF that were also highly abundant in both CaOx and CaPhos stones, indicative of a potential involvement of these metabolites in lithogenesis. Using the combination of these 14 metabolites in total, we generated a model that correctly classified patients as either active vs non-active SF in a prospectively recruited cohort with 73% success. CONCLUSION: Collectively, our data suggest specific urinary metabolites directly contribute to the formation of urinary stones and that active SF may excrete higher levels of lithogenic metabolites than non-active patients. Future studies are needed to confirm these findings and establish the causative mechanisms associated with these metabolites.

Delayed Urological Cancer Care during the COVID-19 Pandemic: Urologists' Experience.

INTRODUCTION: The arrival of coronavirus disrupted health care systems and forced delays in cancer treatment. We explored the experience of urologists who had to delay their patients' cancer care. METHODS: Urologists who treat prostate, bladder, and renal cancers, selected through purposive sampling, responded to a survey about cancer treatment delay. They were asked about their practice setting, decision making and interactions with patients, and they were asked to reflect on their personal experience. A 0 to 10 point scale, modeled on the National Comprehensive Cancer Network' Distress Thermometer (NCCN-DT), validated for cancer patients with cancer, was used to estimate physician distress. We used descriptive statistics to analyze survey results. RESULTS: Of the 64 participating urologists, 98% delayed surgical treatment; fewer delayed cases of advanced cancers (42% for ≥T3/T4 or Gleason ≥8 prostate cancers, 58% for muscle invasive bladder cancer, 61% for ≥T2 renal cancers). They reported feeling anxious (44%) and helpless (29%), and their median distress score was 5 (range 0-10). They relied on their own risk assessments (67%) and consulted colleagues (56%) and national guidelines (53%) when making treatment deferral decisions. They identified a number of concerns as they resumed surgeries. CONCLUSIONS: Based on a comparison to the NCCN-DT clinical cutoff distress level of 4, urologists experienced moderately high levels of distress as they delayed cancer care during the COVID-19 pandemic and expressed concerns going forward. While the focus on patient care is paramount in a pandemic, it is important to recognize physician distress and develop practical and psychological strategies for distress mitigation.

Reducing Readmissions Following Radical Cystectomy: Moving Beyond Enhanced Recovery.

OBJECTIVE: To assess readmission outcomes of a traditional ER pathway as well as a targeted postdischarge intervention aimed at reducing hospital readmissions following RC. METHODS: A prospectively maintained clinical database was used to identify patients undergoing RC before and after implementation of an ER protocol at our institution. An additional intervention aimed at reducing hospital readmission included close postdischarge follow-up and outpatient intravenous hydration (ER+). Inpatient length of stay (LOS) and readmission rates were compared between groups using Wilcoxon Rank Sum and chi-square, respectively. Univariate and multivariate logistic regression was used to identify factors associated with hospital readmission. RESULTS: A total of 320 patients underwent RC, including 111 and 209 patients before and after ER implementation. Median (IQR) LOS decreased from 8.0 (6.0-11.0) days to 5.0 (4.0-7.0) days following ER implementation (P <.0001). Readmissions, however, were unchanged following ER implementation (P = .49). An additional targeted readmission reduction intervention (ER+) was associated with significantly reduced hospital readmissions compared to traditional ER alone (ER+ 5.9%, traditional ER 20.3%, P = .017). CONCLUSION: ER protocols consistently demonstrate reductions in LOS, and should be the standard of care following RC. In order to reduce readmissions, the urologic community must expand beyond traditional ER pathways. We report significant reductions in hospital readmission among RC patients receiving a targeted postdischarge intervention beyond traditional ER alone.

Perioperative Educational Interventions and Contemporary Sexual Function Outcomes of Radical Prostatectomy.

INTRODUCTION: Men undergoing prostatectomy can have unrealistic preoperative expectations regarding sexual function after surgery and may desire more education on recovery and symptom management. AIM: To present contemporary data on recovery of sexual function after prostatectomy and characterize how it is impacted by perioperative patient educational interventions. METHODS: A comprehensive review of the English-language literature available by PubMed search. MAIN OUTCOME MEASURES: Rates of sexual function recovery after prostatectomy and the impact of educational interventions on these and related outcomes. RESULTS: Available studies describe heterogeneous educational and support interventions that differ by patient selection, content, method of delivery, timing, and duration. Interventions with group-based education or peer support benefitted sexual satisfaction metrics. Many studies included men and their partners in supportive interventions. However, the few randomized controlled trials directly analyzing the effect of partner attendance revealed no additional benefit to outcomes. Interventions within 6 weeks of prostatectomy variably aided measures of sexual recovery. Some studies with greater time between prostate cancer treatment and interventions revealed only temporary improvements in outcomes. Yet durable improvements in sexual satisfaction and sexual function were observed in some men enrolled years after prostate cancer treatment. At times, web-based interventions had lower completion rates, but sexual function outcomes were comparable to traditional in-person interventions within randomized trials. CONCLUSION: Educational interventions imparted variable benefit to sexual function and satisfaction, with group-based designs mostly benefitting satisfaction outcomes. Despite standardized interventions, men reported worse-than-expected outcomes, suggesting an emphasis on counseling regarding changes in erectile function at multiple time points before surgery and during the recovery period may be helpful. Earlier interventions may help with recovery by establishing more accurate patient expectations. Regarding accessibility, future endeavors may be improved with internet-based educational content, as such interventions appeared to provide comparable benefits to in-person sessions. Faris AER, Montague DK, Gill BC. Perioperative Educational Interventions and Contemporary Sexual Function Outcomes of Radical Prostatectomy. Sex Med Rev 2019;7:293-305.

Role of Brain Glycogen During Ischemia, Aging and Cell-to-Cell Interactions.

The astrocyte-neuron lactate transfer shuttle (ANLS) is one of the important metabolic systems that provides a physiological infrastructure for glia-neuronal interactions where specialized architectural organization supports the function. Perivascular astrocyte end-feet take up glucose via glucose transporter 1 to actively regulate glycogen stores, such that high ambient glucose upregulates glycogen and low levels of glucose deplete glycogen stores. A rapid breakdown of glycogen into lactate during increased neuronal activity or low glucose conditions becomes essential for maintaining axon function. However, it fails to benefit axon function during an ischemic episode in white matter (WM). Aging causes a remarkable change in astrocyte architecture characterized by thicker, larger processes oriented parallel to axons, as opposed to vertically-transposing processes. Subsequently, aging axons become more vulnerable to depleted glycogen, although aging axons can use lactate as efficiently as young axons. Lactate equally supports function during aglycemia in corpus callosum (CC), which consists of a mixture of myelinated and unmyelinated axons. Moreover, axon function in CC shows greater resilience to a lack of glucose compared to optic nerve, although both WM tracts show identical recovery after aglycemic injury. Interestingly, emerging evidence implies that a lactate transport system is not exclusive to astrocytes, as oligodendrocytes support the axons they myelinate, suggesting another metabolic coupling pathway in WM. Future studies are expected to unravel the details of oligodendrocyte-axon lactate metabolic coupling to establish that all WM components metabolically cooperate and that lactate may be the universal metabolite to sustain central nervous system function.

TACC3 is a microtubule plus end-tracking protein that promotes axon elongation and also regulates microtubule plus end dynamics in multiple embryonic cell types.

Microtubule plus end dynamics are regulated by a conserved family of proteins called plus end-tracking proteins (+TIPs). It is unclear how various +TIPs interact with each other and with plus ends to control microtubule behavior. The centrosome-associated protein TACC3, a member of the transforming acidic coiled-coil (TACC) domain family, has been implicated in regulating several aspects of microtubule dynamics. However, TACC3 has not been shown to function as a +TIP in vertebrates. Here we show that TACC3 promotes axon outgrowth and regulates microtubule dynamics by increasing microtubule plus end velocities in vivo. We also demonstrate that TACC3 acts as a +TIP in multiple embryonic cell types and that this requires the conserved C-terminal TACC domain. Using high-resolution live-imaging data on tagged +TIPs, we show that TACC3 localizes to the extreme microtubule plus end, where it lies distal to the microtubule polymerization marker EB1 and directly overlaps with the microtubule polymerase XMAP215. TACC3 also plays a role in regulating XMAP215 stability and localizing XMAP215 to microtubule plus ends. Taken together, our results implicate TACC3 as a +TIP that functions with XMAP215 to regulate microtubule plus end dynamics.

Growth cone-specific functions of XMAP215 in restricting microtubule dynamics and promoting axonal outgrowth.

BACKGROUND: Microtubule (MT) regulators play essential roles in multiple aspects of neural development. In vitro reconstitution assays have established that the XMAP215/Dis1/TOG family of MT regulators function as MT 'plus-end-tracking proteins' (+TIPs) that act as processive polymerases to drive MT growth in all eukaryotes, but few studies have examined their functions in vivo. In this study, we use quantitative analysis of high-resolution live imaging to examine the function of XMAP215 in embryonic Xenopus laevis neurons. RESULTS: Here, we show that XMAP215 is required for persistent axon outgrowth in vivo and ex vivo by preventing actomyosin-mediated axon retraction. Moreover, we discover that the effect of XMAP215 function on MT behavior depends on cell type and context. While partial knockdown leads to slower MT plus-end velocities in most cell types, it results in a surprising increase in MT plus-end velocities selective to growth cones. We investigate this further by using MT speckle microscopy to determine that differences in overall MT translocation are a major contributor of the velocity change within the growth cone. We also find that growth cone MT trajectories in the XMAP215 knockdown (KD) lack the constrained co-linearity that normally results from MT-F-actin interactions. CONCLUSIONS: Collectively, our findings reveal unexpected functions for XMAP215 in axon outgrowth and growth cone MT dynamics. Not only does XMAP215 balance actomyosin-mediated axon retraction, but it also affects growth cone MT translocation rates and MT trajectory colinearity, all of which depend on regulated linkages to F-actin. Thus, our analysis suggests that XMAP215 functions as more than a simple MT polymerase, and that in both axon and growth cone, XMAP215 contributes to the coupling between MTs and F-actin. This indicates that the function and regulation of XMAP215 may be significantly more complicated than previously appreciated, and points to the importance of future investigations of XMAP215 function during MT and F-actin interactions.

Neural Explant Cultures from Xenopus laevis.

The complex process of axon guidance is largely driven by the growth cone, which is the dynamic motile structure at the tip of the growing axon. During axon outgrowth, the growth cone must integrate multiple sources of guidance cue information to modulate its cytoskeleton in order to propel the growth cone forward and accurately navigate to find its specific targets(1). How this integration occurs at the cytoskeletal level is still emerging, and examination of cytoskeletal protein and effector dynamics within the growth cone can allow the elucidation of these mechanisms. Xenopus laevis growth cones are large enough (10-30 microns in diameter) to perform high-resolution live imaging of cytoskeletal dynamics (e.g.(2-4) ) and are easy to isolate and manipulate in a lab setting compared to other vertebrates. The frog is a classic model system for developmental neurobiology studies, and important early insights into growth cone microtubule dynamics were initially found using this system(5-7) . In this method(8), eggs are collected and fertilized in vitro, injected with RNA encoding fluorescently tagged cytoskeletal fusion proteins or other constructs to manipulate gene expression, and then allowed to develop to the neural tube stage. Neural tubes are isolated by dissection and then are cultured, and growth cones on outgrowing neurites are imaged. In this article, we describe how to perform this method, the goal of which is to culture Xenopus laevis growth cones for subsequent high-resolution image analysis. While we provide the example of +TIP fusion protein EB1-GFP, this method can be applied to any number of proteins to elucidate their behaviors within the growth cone.