Evaluating symptom severity and urinary cytokine levels in interstitial cystitis/bladder pain syndrome patients, with and without Hunner's lesions.

PURPOSE: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition characterized in part by urinary urgency, frequency, and pain. There is a strong interest in gathering more data to compare and assess the differences in characteristics based on the presence of Hunner's lesions in patients with IC/BPS. MATERIALS AND METHODS: Using a nationwide crowdsource effort, we collected surveys and urine samples from patients with a history of IC/BPS. Participants completed the Interstitial Cystitis Symptom Index (ICSI) and Problem Index (ICPI), Overactive Bladder questionnaire (OABq SF), and pain scores. In addition, participants reported any co-morbidities and lifestyle modifications. Urinary cytokine levels were measured and compared to symptom severity. RESULTS: 491 participants enrolled: 119 with history of ulcerative Hunner's lesions (UIC), 372 reported no lesions (NHIC), and 2 unknowns. 96.3% were female, and prevalence of UIC was equal for both genders. Average age was higher for UIC vs. NHIC group (P = 0.011), as was the duration since diagnosis (P < 0.001). Symptom scores were elevated in UIC patients (P < 0.001). Both groups widely implemented lifestyle modifications, with dietary changes being most prevalent (70.1%), followed by prescription medication usage (63.1%). More UIC compared to NHIC participants experienced co-morbidities (P = 0.010). Urine samples were analyzed for GRO, IL-6, IL-8, and MCP-1. MCP-1 levels were significantly higher in UIC patients (P = 0.044). Weak positive correlation was found between cytokines and symptom scores. CONCLUSIONS: Patients with UIC and NHIC from across the United States displayed distinct phenotypic and urine biological characteristics. These findings contribute to increased understanding of IC/BPS and may aid in improving our knowledge of the condition.

Comparison of Polymerase Chain Reaction and Urine Culture in the Evaluation of Patients with Complex Urinary Tract Infections.

To compare organism identification using polymerase chain reaction (PCR) and urine culture (UC) in patients with complex urinary tract infections (cUTIs), we reviewed the results of 3395 patients seen during 2022 with cUTI who underwent concomitant PCR and UC testing. We compared the overall positivity rates as well as the ability of each test to identify fastidious organisms (FOs) and the presence of polymicrobial infections (PMOs) and conducted concordance analysis between the tests. PCR detected 36.4% more organisms than UC and was 20 and nearly 36 times more likely to detect PMOs and FOs, respectively. PCR identified 90.6% of organisms found in UC, whereas UC identified 40.7% of organisms found in PCR testing. We found that 62.4% of organisms found in PCR were not found in urine culture, while UC found 9.4% of organisms not identified in polymerase chain reaction. All these differences were statistically significant (p < 0.05). Although we found that PCR was superior to UC in overall pathogen detection, and detection of both PMOs and FOs, both identified potentially pathogenic organisms not found in the corresponding test. Our data strongly suggest that the evaluation of patients with cUTI is best accomplished using PCR in conjunction with UC.

Risk Classification for Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) Using Machine Learning Based Predictions.

OBJECTIVES: To improve diagnosis of IC/BPS(IC) we hereby developed an improved IC risk classification using machine learning algorithms. METHODS: A national crowdsourcing resulted in 1,264 urine samples consisting of 536 IC (513 female, 21 male, 2 unspecified), and 728 age-matched controls (318 female, 402 male, 8 unspecified) with corresponding PRO pain and symptom scores. In addition, 296 urine samples were collected at three academic centers: 78 IC (71 female, 7 male) and 218 controls (148 female, 68 male, 2 unspecified). Urinary cytokine biomarker levels were determined using Luminex assay. A machine learning predictive classification model, termed the Interstitial Cystitis Personalized Inflammation Symptom (IC-PIS) Score, that utilizes PRO and cytokine levels, was generated and compared to a challenger model. RESULTS: The top-performing model using biomarker measurements and PROs (AUC=0.87) was a support vector classifier, which scored better at predicting IC than PROs alone (AUC=0.83). While biomarkers alone (AUC=0.58) did not exhibit strong predictive performance, their combination with PROs produced an improved predictive effect. CONCLUSIONS: IC-PIS represents a novel classification model designed to enhance the diagnostic accuracy of IC/BPS by integrating PROs and urine biomarkers. The innovative approach to sample collection logistics, coupled with one of the largest crowdsourced biomarker development studies utilizing ambient shipping methods across the US, underscores the robustness and scalability of our findings.

Percutaneous tibial neuromodulation initial therapy compliance and subsequent third-line treatment patterns.

PURPOSE: Percutaneous Tibial Neuromodulation (PTNM) is used to treat Overactive Bladder (OAB). This analysis summarizes patient adherence to PTNM treatment and examines trends of other third-line therapy use during and after PTNM. METHODS: Optum's deidentified Clinformatics® Data Mart Database (CDM) and CMS Research Identifiable Files were queried for adults with OAB symptoms and who underwent PTNM treatment (2019-2020). We evaluated the proportion of patients who completed 12 visits within 1 year, and defined patients as treatment compliant if 12 PTNM visits were completed within 12 weeks. We then identified the proportion of patients who used other third-line therapies after PTNM and stratified these patients based on their PTNM therapy compliance status. RESULTS: 2302 patients met selection criteria from CDM and 16,473 patients from CMS. The proportion of patients completing a full PTNM treatment course increased over time; from 16% at week 12% to 42% by week 52 (CDM) and 24% to 38% (CMS). Other third-line therapy use increased over time and was higher for PTNM noncompliant versus compliant patients at 52 weeks: onabotulinumtoxinA was 6.5% versus 5.7% for noncompliant versus compliant (CMS, p = 0.0661) and 6.4% versus 4.9% (CDM, p = 0.035), SNM trial procedure was 6.5% versus 2.5% (CDM, p = 0.002) and 4.2% versus 2.0% (CMS, p = 0.010). CONCLUSIONS: Most patients are noncompliant with recommended PTNM treatment regimen. Albeit low, third-line therapy was pursued more frequently by noncompliant patients. Given low compliance, the effectiveness of PTNM may be compromised. Alternative implantable technologies may be needed to assure effectiveness of neuromodulation.

Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing.

Pelvic cancer survivors who were treated with radiation therapy are at risk for developing (hemorrhagic) radiation cystitis (RC) many years after completion of radiation therapy. Patients with RC suffer from lower urinary tract symptoms, including frequency, nocturia, pelvic pain, and incontinence. In advanced stages, hematuria can occur, potentially escalating to life-threatening levels. Current therapeutic options for RC are limited, partly due to ethical concerns regarding bladder biopsy in patients with fragile bladder tissue. This study aimed to leverage our established preclinical model to elucidate the molecular pathways implicated in radiation-induced tissue changes in the bladder. Female C57Bl/6 mice received a single dose of 40 Gy using CT-guided imaging and a two-beam irradiation approach using the SARRP irradiator. Bladders from irradiated and age-matched littermate controls were harvested at 1 week [n = 5/group] or 6 months [n = 5/group] after irradiation, RNA was harvested, and mRNA sequencing was performed at paired-end 150bp on the Illumina NovaSeq6000 with a target of 30 million reads per sample. Following RNA sequencing, thorough bioinformatics analysis was performed using iPathwayGuide v2012 (ADVAITA Bioinformatics). Findings of the RNA sequencing were validated using qPCR analysis. At 1 week post-irradiation, altered gene expression was detected in genes involved in DNA damage response, apoptosis, and transcriptional regulation. By 6 months post-irradiation, significant changes in gene expression were observed in inflammation, collagen catabolism, and vascular health. Affected pathways included the p53, JAK-STAT, and PI3K-Akt pathways. These findings were validated in vivo in bladder tissues from our preclinical model. This is the first study to determine the molecular changes in the bladder in response to radiation treatment. We have successfully pinpointed several pathways and specific genes that undergo modification, thereby contributing to the progression of radiation cystitis. These insights enhance our understanding of the pathophysiology of radiation cystitis and may ultimately pave the way to the identification of potential new therapeutic targets.

Maternity Leave Satisfaction Among Physicians Compared with Nonphysician Professionals.

Objective: The objective of this study was to compare maternity leave satisfaction between physicians and nonphysicians. Currently, paid maternal leave is not guaranteed in the United States, resulting in palpable dissatisfaction among parents. Previous studies have shown associations between length of paid leave and career satisfaction and maternal happiness. Materials and Methods: A Qualtrics® electronic survey was distributed to female professionals through email and social media from April 2019 to March 2020. Inclusion criterion was ≥1 child by birth or adoption, or active pregnancy. Continuous and categorical data were analyzed using two-sample t-test and chi-square, respectively. Results: Of 808 respondents, 77% were physicians. Mean age at birth/adoption of first child was higher in physicians versus nonphysicians (32.1 years vs. 29.7 years; p < 0.001). Physicians took shorter maternity leave than nonphysicians (10.9 weeks vs. 12.0 weeks, p = 0.017) with half of that time paid by employers (5.4 weeks vs. 5.9 weeks, p = 0.2). Dissatisfaction was high among physicians (85.1%) and nonphysicians (92.4%) that correlates with maternity leave compensation dissatisfaction (49% vs. 71.3%, p < 0.001). Thirty-four percent of physicians versus 41% of nonphysicians stated that their health was negatively impacted by maternity leave length. Physicians and nonphysicians reported similar incidences of depression, and breastfeeding, delivery, and other postpartum complications. When queried, 38.8% of physicians and 57% of nonphysicians said they would desire >16 weeks of paid maternity leave (p < 0.001). Conclusions: In conclusion, dissatisfaction among professional women on maternity leave duration and compensation is high in the United States. Given health implications for both mother and child, this should invite further discussion and changes.

Comparing online crowdsourcing with clinic patient enrollment: Findings from the IP4IC Study on interstitial cystitis/bladder pain syndrome.

Introduction: Interstitial cystitis/bladder pain syndrome (IC/BPS) manifests as urinary symptoms including urgency, frequency, and pain. The IP4IC Study aimed to establish a urine-based biomarker score for diagnosing IC/BPS. To accomplish this objective, we investigated the parallels and variances between patients enrolled via physician/hospital clinics and those recruited through online crowdsourcing. Methods: Through a nationwide crowdsource effort, we collected surveys from patients with history of IC/BPS. Study participants were asked to complete the validated instruments of Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI), as well as provide demographic information. We then compared the survey responses of patients recruited through crowdsourcing with those recruited from three specialized tertiary care urology clinics engaged in clinical research. Results: Survey responses of 1300 participants were collected from all 50 states of the USA via crowdsourcing and 319 from a clinical setting. ICSI and ICPI were similar for IC/BPS patients diagnosed by the physicians in clinic and self-reported by subjects via crowdsourcing stating they have a history of previous physician diagnosis of IC/BPS. Surprisingly, ICSI and ICPI were significantly lower in crowdsourced control than in-clinic control subjects. Conclusion: The IP4IC Study provides valuable insights into the similarities and differences between patients recruited through clinics and those recruited through online crowdsourcing. There were no significant differences in disease symptoms among these groups. Individuals who express an interest in digital health research and self-identify as having been previously diagnosed by physicians with IC/BPS can be regarded as reliable candidates for crowdsourcing research.

Fibrin microthrombi in bladder urothelium after SARS-CoV-2 infection: Case report.

A 45-year-old male with diabetes, hypertension and hyperlipidemia was referred to urology due to persistent symptoms of urinary frequency, urgency, nocturia, erectile dysfunction, and constant pain localized to the bladder, pelvis, and perineal area, 3-4 months after SARS-CoV-2 infection. A bladder biopsy showed urothelial mucosa and submucosa with hemorrhage and fibrin microthrombi in blood vessels. Hydrodistention of the bladder and pelvic floor physical therapy resolved symptoms, though bladder and pain symptoms returned upon reinfection with SARS-CoV-2. Urinalysis revealed elevated urinary interleukin-8, which may indicate localized bladder inflammation.

Prevalence and Causes of Discontinuation of Androgen Receptor Inhibitors in Advanced Prostate Cancer Patients and Analysis of Physician Management to Increase Duration of Therapy.

OBJECTIVE: To investigate the prevalence and cause of early discontinuation (DC) of androgen receptor inhibitor (ARi) in advanced prostate cancer (PCa) patients. Additionally, to study the effect of changing ARi vs dose reduction on duration of treatment (DOT). MATERIALS AND METHODS: A retrospective cohort study of 333 patients with advanced PCa who started ARi between 2016 and 2020 was performed. ARi medication, treatment duration, reason for DC, stage of PCa, prostate specific antigen, Gleason score, and prior PCa treatments were collected. The cohort was divided into 2 subgroups, patients that stayed on one medication (Group A) vs patients who changed ARi medication (Group B). Student's t test, chi-square test, and Kaplan-Meier survival analysis were performed. RESULTS: At 1 year 28.8% of patient's had discontinued ARi. Reasons for DC were side effects (34.4%), death (34.4%), and cancer progression (18.8%). DOT was 13 months for enzalutamide, 13.7 months for abiraterone, 7.6 months for darolutamide, and 12.1 months for apalutamide. Average DOT for patients with a dose change was 13.4 months, similar to those without dose change at 13.9 months (P = .630). DOT was 12.7 months in Group A vs 19.8 months in Group B (P = .001). CONCLUSION: In our study population DC of ARi is higher than reported in the published trials. Providing patients with an alternative ARi is associated with an increase in DOT while dose reduction is not. It is important for clinicians to understand the causes of early DC to develop strategies to maximize duration of therapy for management of advanced PCa patients.

Impact of the bladder detrusor muscular ring on lower urinary tract symptoms due to benign prostatic hyperplasia: A quantitative MRI analysis.

BACKGROUND: The etiology of lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH) remains uncertain. OBJECTIVE: The purpose of our study was to quantitatively analyze anatomic characteristics on magnetic resonance imaging (MRI) to assess novel independent factors for symptoms. METHODS: This retrospective single-institution study evaluated treatment-naïve men who underwent prostate MRI within 3 months of international prostate symptom score (IPSS) scoring from June 2021 to February 2022. Factors measured on MRI included: size of the detrusor muscular ring (DMR) surrounding the bladder outlet, central gland (CG) mean apparent diffusion coefficient (ADC), levator hiatus (LH) volume, intrapelvic volume, intravesicular prostate protrusion (IPP) volume, CG volume, peripheral zone (PZ) volume, prostate urethra angle (PUA), and PZ background ordinal score. Multivariable logistic regression and receiver operating characteristic analysis were used to analyze factors for moderate/severe (IPSS ≥ 8) and severe LUTS/BPH (IPSS ≥ 20). RESULTS: A total of 303 men (mean age: 66.1 [SD: 8.1]) were included: 154 demonstrated moderate or severe symptoms with 28 severe and 149 with asymptomatic/mild symptoms. Increasing age [p = 0.02; odds ratio (OR): 1.05 (1.01-1.08)], PUA [p = 0.02; OR: 1.05 (1.01-1.09)], LH volume [p = 0.04; OR: 1.02 (1.00-1.05)], and DMR size measured as diameter [p < 0.001; OR: 5.0 (3.01-8.38)] or area [p < 0.001; OR: 1.92 (1.47-2.49)] were significantly independently associated with moderate/severe symptoms, with BMI [p = 0.02; OR: 0.93 (0.88-0.99)] inversely related. For every one cm increase in DMR diameter, patients had approximately five times the odds for moderate/severe symptoms. Increasing DMR size [diameter p < 0.001; OR: 2.74 (1.76-4.27) or area p < 0.001; OR: 1.37 (1.18-1.58)] was independently associated with severe symptoms. Optimal criterion cutoff of DMR diameter for moderate/severe symptoms was 1.2 cm [sensitivity: 77.3; specificity: 71.8; AUC: 0.80 (0.75-0.84)]. Inter-reader reliability was excellent for DMR diameter [ICC = 0.92 (0.90-0.94)]. CONCLUSION: Expansion of the DMR surrounding the bladder outlet is a novel anatomic factor independently associated with moderate and severe LUTS/BPH, taking into account prostate volumes, including quantified IPP volume, which were unrelated. Detrusor ring diameter, easily and reliably measured on routine prostate MRI, may relate to detrusor dysfunction from chronic stretching of this histologically distinct smooth muscle around the bladder neck.

Incidence of New or Worsening Overactive Bladder Among Patients with a Prior SARS-CoV-2 Infection: A Cohort Study.

Background: Literature is sparse on COVID-19-associated cystitis (CAC), a novel condition comprising frequency, urgency, and nocturia after COVID-19 infection. Objective: To determine the incidence of CAC and correlation with SARS-CoV-2 antibody levels. Design setting and participants: This was a retrospective study in which urinary symptoms were scored using the International Consultation on Incontinence Questionnaire-overactive bladder (ICIQ-OAB) at three time points: before the pandemic (January 2020), 2 mo after COVID-19 infection (if applicable), and at the time of the study (May 2021). The setting was a regional health care system. The 18 785 healthcare employees who took part in the BLAST COVID study group were invited to participate, of whom 1895 responded. Outcome measurements and statistical analysis: The outcome measured was the percentage of COVID-positive patients with a significant change on ICIQ-OAB over time. Pearson's χ2 test was used for comparison of categorical data, and one-way analysis of variance for continuous data and multivariate analysis. A sample size of 618 was calculated for power of 80% and α = 0.05. Results and limitations: Of the 1895 participants, 31.9% (n = 605) were positive for COVID-19 according to positive serology or a polymerase chain reaction (PCR) test. Of these, 492 were PCR-positive and had 2-mo postinfection data, with 36.4% (179/492) reporting an increase of ≥1 point on the ICIQ-OAB compared to baseline (before the pandemic), with de novo OAB in 22% of these cases (40/179). Comparison of symptoms between baseline and the study time revealed that 27.4% (31/113) of those with positive serology only (asymptomatic COVID) and 37.8% (186/492) of those with PCR positivity (symptomatic COVID) had an increase of ≥1 point on the ICIQ-OAB, compared to 15.8% (n = 204) of uninfected patients, with odds ratios of 2.013 (95% confidence interval [CI] 1.294-3.138; p = 0.0015) and 3.236 (95% CI 2.548-4.080; p < 0.0001), respectively. The retrospective nature of the study and the volunteer sample are limitations. Conclusions: COVID-19 infection increases the risk of developing new or worsening OAB symptoms. Patient summary: We compared overactive bladder symptoms in a large group of participants between individuals with and without a previous COVID-19 infection. We found that symptomatic infection was associated with a three times greater risk of developing new or worsening overactive bladder symptoms among COVID-19 patients.

Increased extracellular matrix stiffness accompanies compromised bladder function in a murine model of radiation cystitis.

Radiation cystitis, a long-term bladder defect due to pelvic radiation therapy, results in lower urinary tract symptoms, such as urinary frequency and nocturia, suggestive of compromised bladder compliance. The goal of this study was to identify alterations to the mechanical behavior of the urinary bladder extracellular matrix of a murine model of radiation cystitis, at 3 and 6 months after radiation exposure. The results of this study demonstrated that the extracellular matrix of irradiated bladders was significantly less distensible when compared to age matching controls. These findings coincided with functional bladder changes, including increased number of voids and decreased voided volume. Both mechanical and functional changes were apparent at 3 months post-irradiation and were statistically significant at 6 months, demonstrating the progressive nature of radiation cystitis. Overall, the results of this study indicate that irradiation exposure changes both the mechanical and physiological properties of the bladder. STATEMENT OF SIGNIFICANCE: In humans, radiation cystitis results in lower urinary tract symptoms, such as urinary frequency and nocturia, suggestive of compromised bladder compliance. This pathology can significantly affect recovery and quality of life for cancer survivors. Gaining knowledge about how alterations to the mechanical behavior of the urinary bladder extracellular matrix can affect urinary function will have a significant impact on this population. The results of this study demonstrated that the extracellular matrix of irradiated bladders was significantly less distensible when compared to age matching controls, in a mouse model of radiation cystitis. These findings were accompanied by functional voiding changes, including increased number of voids and decreased voided volume. The results of this study uncovered that irradiation exposure changes the mechanical and physiological properties of the bladder.

A Cost, Time, and Demographic Analysis of Participant Recruitment and Urine Sample Collection Through Social Media Optimization.

INTRODUCTION: Clinical research can be expensive and time consuming due to high associated costs and/or duration of the study. We hypothesized that urine sample collection using online recruitment and engagement of research participants via social medial has the potential to reach a large population in a small timeframe, at a reasonable cost. METHODS: We performed a retrospective cost analysis of a cohort study comparing cost per sample and time per sample for both online and clinically recruited participants for urine sample collection. During this time, cost data were collected based on study associated costs from invoices and budget spreadsheets. The data were subsequently analyzed using descriptive statistics. RESULTS: Each sample collection kit contained 3 urine cups, 1 for the disease sample and 2 for control samples. Out of the 3,576 (1,192 disease + 2,384 control) total sample cups mailed, 1,254 (695 control) samples were returned. Comparatively, the 2 clinical sites collected 305 samples. Although the initial startup cost of online recruitment was higher, cost per sample for online recruited was found to be $81.45 compared to $398.14 for clinic sample. CONCLUSIONS: We conducted a nationwide, contactless, urine sample collection through online recruitment in the midst of the COVID-19 pandemic. Results were compared with the samples collected in the clinical setting. Online recruitment can be utilized to collect urine samples rapidly, efficiently, and at a cost per sample that was 20% of an in-person clinic, and without risk of COVID-19 exposure.

Voiding defects in acute radiation cystitis driven by urothelial barrier defect through loss of E-cadherin, ZO-1 and Uroplakin III.

Long term-side effects from cancer therapies are a growing health care concern as life expectancy among cancer survivors increases. Damage to the bladder is common in patients treated with radiation therapy for pelvic cancers and can result in radiation (hemorrhagic) cystitis (RC). The disease progression of RC consists of an acute and chronic phase, separated by a symptom-free period. Gaining insight in tissue changes associated with these phases is necessary to develop appropriate interventions. Using a mouse preclinical model, we have previously shown that fibrosis and vascular damage are the predominant pathological features of chronic RC. The goal of this study was to determine the pathological changes during acute RC. We identified that radiation treatment results in a temporary increase in micturition frequency and decrease in void volume 4-8 weeks after irradiation. Histologically, the micturition defect is associated with thinning of the urothelium, loss of urothelial cell-cell adhesion and tight junction proteins and decrease in uroplakin III expression. By 12 weeks, the urothelium had regenerated and micturition patterns were similar to littermate controls. No inflammation or fibrosis were detected in bladder tissues after irradiation. We conclude that functional bladder defects during acute RC are driven primarily by a urothelial defect.

Prostate cancer survivors with symptoms of radiation cystitis have elevated fibrotic and vascular proteins in urine.

Radiation for pelvic cancers can result in severe bladder damage and radiation cystitis (RC), which is characterized by chronic inflammation, fibrosis, and vascular damage. RC development is poorly understood because bladder biopsies are difficult to obtain. The goal of this study is to gain understanding of molecular changes that drive radiation-induced cystitis in cancer survivors using urine samples from prostate cancer survivors with history of radiation therapy. 94 urine samples were collected from prostate cancer survivors with (n = 85) and without (n = 9) history of radiation therapy. 15 patients with radiation history were officially diagnosed with radiation cystitis. Levels of 47 different proteins were measured using Multiplex Luminex. Comparisons were made between non-irradiated and irradiated samples, and within irradiated samples based on radiation cystitis diagnosis, symptom scores or hematuria. Statistical analysis was performed using Welch's t-test. In prostate cancer survivors with history of radiation therapy, elevated levels of PAI 1, TIMP1, TIMP2, HGF and VEGF-A were detected in patients that received a radiation cystitis diagnosis. These proteins were also increased in patients suffering from hematuria or high symptom scores. No inflammatory proteins were detected in the urine, except in patients with gross hematuria and end stage radiation cystitis. Active fibrosis and vascular distress is detectable in the urine through elevated levels of associated proteins. Inflammation is only detected in urine of patients with end-stage radiation cystitis disease. These results suggest that fibrosis and vascular damage drive the development of radiation cystitis and could lead to the development of more targeted treatments.

Micturition defects and altered bladder function in the klotho mutant mouse model of aging.

INTRODUCTION AND OBJECTIVES: Symptoms associated with detrusor underactivity (DU) or underactive bladder (UAB) can severely impact a person's quality of life, and growing old is the main etiological factor of DU and UAB. The gene Klotho has been associated with suppression of several aging phenotypes, and there is moderate klotho expression in the bladder. Given this, we hypothesized that the klotho gene is involved in regulation of bladder function. Thus, we examined a premature aging rodent genetic model with hypomorphic klotho expression for alterations in bladder function. METHODS: Klotho mutant mice are established as a preclinical model of aging. Male and female klotho mice had micturition measured at weeks 4, 6, and 8 through metabolic cage and void spot assays. Histology was assessed at 4, 6, and 8 weeks. Lastly, bladder contraction was assessed using bladder strip tissue bath. All animals were gender- and age-matched with wild-type littermates for analysis. RESULTS: Void spot and bladder contraction assays revealed that klotho mutant mice, similar to other aging models, have increased voiding frequency and decreased voiding volume per micturition event. The in vitro contractile response to electrical stimulation was weaker and muscarinic receptor subtype expression was reduced in the in klotho mutant mouse bladders. These data suggest that klotho mutant mouse bladders had impaired bladder function. CONCLUSIONS: Klotho mutant mice recapitulate many characteristics of an older dysfunctional bladder, including altered bladder function. Given the short time frame to bladder dysfunction and robustness of the model, this model will provide new insights to drive aging bladder research.

Underactive Bladder; Review of Progress and Impact From the International CURE-UAB Initiative.

There is a significant need for research and understanding of underactive bladder (UAB). The International Congress of Urologic Research and Education on Aging UnderActive Bladder (CURE-UAB) was organized by Doctors Michael Chancellor and Ananias Diokno in order to address these concerns. CURE-UAB was supported, in part, by the US National Institute of Aging and National Institute of Diabetes Digestive and Kidney. Since 2014, there have been 5 successful CURE-UAB congresses. They have brought together diverse stakeholders in the UAB field to identify areas of major scientific challenge and initiated a call to action among the medical community. In this review, we will highlight current and novel treatments under development for UAB and the progress and impact from the CURE-UAB initiative.

Radiation cystitis modeling: A comparative study of bladder fibrosis radio-sensitivity in C57BL/6, C3H, and BALB/c mice.

A subset of patients receiving radiation therapy for pelvic cancer develop radiation cystitis, a complication characterized by mucosal cell death, inflammation, hematuria, and bladder fibrosis. Radiation cystitis can reduce bladder capacity, cause incontinence, and impair voiding function so severely that patients require surgical intervention. Factors influencing onset and severity of radiation cystitis are not fully known. We tested the hypothesis that genetic background is a contributing factor. We irradiated bladders of female C57BL/6, C3H, and BALB/c mice and evaluated urinary voiding function, bladder shape, histology, collagen composition, and distribution of collagen-producing cells. We found that the genetic background profoundly affects the severity of radiation-induced bladder fibrosis and urinary voiding dysfunction. C57BL/6 mice are most susceptible and C3H mice are most resistant. Irradiated C57BL/6 mouse bladders are misshapen and express more abundant collagen I and III proteins than irradiated C3H and BALB/c bladders. We localized Col1a1 and Col3a1 mRNAs to FSP1-negative stromal cells in the bladder lamina propria and detrusor. The number of collagen I and collagen III-producing cells can predict the average voided volume of a mouse. Collectively, we show that genetic factors confer sensitivity to radiation cystitis, establish C57BL/6 mice as a sensitive preclinical model, and identify a potential role for FSP1-negative stromal cells in radiation-induced bladder fibrosis.

Cancer survivorship issues with radiation and hemorrhagic cystitis in gynecological malignancies.

PURPOSE: Given that more cancers are being diagnosed earlier and that treatment of cancer is improving, health issues of cancer survivors are becoming more common and apparent. Pelvic radiation therapy for the treatment of gynecological cancers can lead to long-term collateral damage to the bladder, a condition termed radiation cystitis (RC). Late sequelae may take many years to develop and include incontinence and pain as well as hematuria. RC is a rare but potentially life-threatening condition for which there are few management and treatment options. METHODS: There are limited data in the literature regarding the effects of radiation on the bladder after gynecological cancer therapy and we hereby review the literature on cancer survivorship issues of pelvic radiation for gynecology literature. RESULTS: Treatment options are available for patients with radiation-induced hemorrhagic cystitis. However, most treatments are risky or only effective for a short timeframe and no therapy is currently available to reverse the disease progress. Furthermore, no standardized guidelines exist describing preferred management options. Common therapies include hyperbaric oxygen therapy, clot evacuation, fulguration, intravesical instillation of astringent agents, and surgery. Novel developing strategies include Botulinum Toxin injections and liposomal-tacrolimus instillations. These treatments and strategies are discussed. CONCLUSIONS: In this review, we will present current and advanced therapeutic strategies for RC to help cancer survivors deal with long-term bladder health issues.