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

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

Polycarbonate Urethane Mesh: A New Material for Pelvic Reconstruction.

OBJECTIVE: Polycarbonate urethane (PCU) is a new biomaterial, and its mechanical properties can be tailored to match that of vaginal tissue. We aimed to determine whether vaginal host immune and extracellular matrix responses differ after PCU versus lightweight polypropylene (PP) mesh implantation. METHODS: Hysterectomy and ovariectomy were performed on 24 Sprague-Dawley rats. Animals were divided into 3 groups: (1) PCU vaginal mesh, (2) PP vaginal mesh, and (3) sham controls. Vagina-mesh complexes or vaginas (controls) were excised 90 days after surgery. We quantified responses by comparing: (1) histomorphologic scoring of hematoxylin and eosin- and Masson trichrome-stained slides, (2) macrophage subsets (immunolabeling), (3) pro-inflammatory and anti-inflammatory cytokines (Luminex panel), (4) matrix metalloproteinase (MMP)-2 and -9 using an enzyme-linked immunosorbent assay, and (5) type I/III collagen using picrosirius red staining. RESULTS: There was no difference in histomorphologic score between PCU and PP (P = 0.211). Although the histomorphologic response was low surrounding all mesh fibers, groups with PCU and PP mesh had a higher histomorphologic score than the control group (P < 0.005 and P < 0.002, respectively). There were no differences between groups in terms of macrophage subsets, pro-inflammatory cytokines, anti-inflammatory cytokines, MMP-2 and MMP-9, or collagen ratio. CONCLUSIONS: Polycarbonate urethane, an elastomer with material properties similar to those of vaginal tissue, elicits minimal host inflammatory responses in a rat model. Because its implantation does not elicit more inflammation than currently used lightweight PP, using PCU for prolapse mesh warrants further investigation with larger animal models.

Evaluation of Host Immune Cellular and Extracellular Matrix Responses to Prolapse Mesh With and Without Tension in a Rat Model.

OBJECTIVES: We sought to determine whether vaginal host immune cellular and extracellular matrix responses are altered in a rat sacrocolpopexy model when lightweight polypropylene mesh is attached on tension versus without tension. METHODS: We performed hysterectomy and ovariectomy in 32 Sprague-Dawley rats. Animals were assigned to 4 groups (n = 8/group): (1) controls with sham operation only (control), (2) mesh sutured only on the vagina (vaginal mesh), (3) sacrocolpopexy without tension, and (4) sacrocolpopexy with tension. Ninety days later, we excised vagina-mesh complexes. A histomorphologic scoring system of hematoxylin/eosin and Masson trichrome stained slides was used to assess host inflammatory responses. The cellular inflammatory response was further quantified using (1) identification of M1 and M2 macrophage subsets and (2) quantification of proinflammatory and anti-inflammatory cytokines. The extracellular matrix response was evaluated by measuring (1) matrix metalloproteinase-2 and matrix metalloproteinase-9 levels and (2) type I/III collagen. RESULTS: Histomorphological tissue responses were greater in all groups with mesh compared with sham controls. Both sacrocolpopexy groups had similar scores, but each group scored significantly higher than the vaginal mesh group. Among the 4 groups, there were no statistically significant differences in M1 or M2 macrophage subsets, proinflammatory or anti-inflammatory cytokines, or extracellular matrix remodeling responses. CONCLUSIONS: Attachment of prolapse mesh resulted in an increased histologic inflammatory response independent of tension. Other markers of cellular inflammation and extracellular matrix remodeling showed no differences among experimental groups. Tension on lightweight polypropylene mesh did not significantly alter the host response in this rat sacrocolpopexy model.

Best practices for cystometric evaluation of lower urinary tract function in muriform rodents.

AIMS: Rodent cystometry has provided valuable insights into the impact of the disease, injury, and aging on the cellular and molecular pathways, neurologic processes, and biomechanics of lower urinary tract function. The purpose of this white paper is to highlight the benefits and shortcomings of different experimental methods and strategies and to provide guidance on the proper interpretation of results. METHODS: Literature search, selection of articles, and conclusions based on discussions among a panel of workers in the field. RESULTS: A range of cystometric tests and techniques used to explore biological phenomena relevant to the lower urinary tract are described, the advantages and disadvantages of various experimental conditions are discussed, and guidance on the practical aspects of experimental execution and proper interpretation of results are provided. CONCLUSIONS: Cystometric evaluation of rodents comprises an extensive collection of functional tests that can be performed under a variety of experimental conditions. Decisions regarding which approaches to choose should be determined by the specific questions to be addressed and implementation of the test should follow standardized procedures.

Timing of sacral neurostimulation is important for increasing bladder capacity in the anesthetized rat.

We assessed the effects of limited application of sacral neurostimulation (SNS) during bladder filling on bladder capacity using our previously published SNS model in rats. Female Sprague-Dawley rats (n = 24) were urethane anesthetized (1.2 g/kg sc) and implanted with jugular venous and transvesical bladder catheters. L6/S1 nerve trunks were isolated bilaterally, and two electrodes were placed on each exposed nerve. True bladder capacity (TBC) was determined using stable single-fill cystometrograms. In the first series of experiments, SNS was applied at the onset of bladder filling for 25%, 50%, 75%, and 100% of the previous control filling cycle duration (n = 10). In the second series of experiments, SNS was applied during the first, second, third, and fourth 25% and the first and second 50% of the control fill. In the first series, a significant increase in TBC was observed only when SNS was applied for 75% or 100% of the control fill duration (30% and 35%, respectively, P < 0.05). In the second series, significant increases in TBC only occurred during the fourth 25% period and second 50% period (32% and 43%, respectively, P < 0.001). Results from the second series also revealed an increase in subsequent single-fill bladder capacities (TBC) only when SNS was applied during the second 50% of the prior fill cycle. These data indicate that the application of SNS during the final 50% of the bladder fill cycle is necessary and sufficient for increasing bladder capacity.

Patient Characteristics Associated with More Bother from Lower Urinary Tract Symptoms.

PURPOSE: Some patients continue to have bothersome lower urinary tract symptoms despite treatment. We examined characteristics associated with bother from lower urinary tract symptoms in a prospective cohort. MATERIALS AND METHODS: In this 1-year prospective, observational cohort study we obtained data on patients with lower urinary tract symptoms who were seeking care at a total of 6 tertiary care centers in the United States. Participants answered the AUA-SI (American Urological Association Symptom Index) global urinary bother question at study entry and 12 months later. Multilevel logistic and linear regression was used to identify factors associated with worsening bother and bother at 12 months, respectively. RESULTS: Of the 756 participants 121 (16%) had worsened lower urinary tract symptom bother during the study period. When adjusted for other variables, worsened lower urinary tract symptom bother was more likely among men who were nonwhite (OR 1.79, 95% CI 0.94-3.40) or who had diabetes (OR 1.68, 95% CI 0.86-3.27) and among women with diabetes (OR 1.77, 95% CI 0.85-3.67), prior treatment of lower urinary tract symptoms (OR 2.58, 95% CI 1.22-5.46) or a higher depression level (OR 1.29, 95% CI 1.10-1.52). Baseline factors associated with more severe bother at 12 months in men included more severe bother at baseline, nonwhite race, worse urinary frequency and incontinence, and higher levels of stress (p <0.05). Among women more severe bother at baseline, urinary urgency and frequency, and worse physical function were associated with more severe bother at 12 months. CONCLUSIONS: Urinary symptom severity at baseline, race, depression and psychological stress were associated with the bother of lower urinary tract symptoms in a prospective cohort of men and women treated at tertiary care facilities. These findings may inform the clinical care of patients with bothersome lower urinary tract symptoms and direct providers to better prognosticate for patients with challenging lower urinary tract symptoms cases.

Chronic high-fat diet decreased detrusor mitochondrial respiration and increased nerve-mediated contractions.

AIMS: To assess the impact of chronic high-fat diet (HFD) on behavioral voiding patterns, detrusor contractility, and smooth muscle mitochondrial function in male mice. MATERIALS AND METHODS: Male C57BL/6J mice (6 weeks) were fed a control or HFD for 20 weeks. Bladder function was assessed by void spot assays. Bladders were collected and detrusor contractility to carbachol (10-9 -10-5 M), and electrical field stimulation (EFS, 0.5-32 Hz) in the presence and absence of atropine was measured. Homogenized detrusor samples were placed in oxygraphs to assess the rate of oxygen consumption of the mitochondria within the detrusor in the presence of different substrates. Mitochondrial hydrogen peroxide (H2 O2 ) emission was measured fluorometrically. Detrusor citrate synthase activity was measured via enzyme activity kit and Western blots assessed the electron transport chain (ETC) protein content. RESULTS: HFD significantly increased body weight, adiposity, and blood glucose levels. HFD mice demonstrated increased voiding frequency and increased EFS-induced detrusor contractility. There were no changes in detrusor relaxation or cholinergic-medicated contraction. Mitochondrial respiration was decreased with HFD and H2 O 2 emission was increased. The relative amount of mitochondria in the detrusor was similar between groups. However, ETC complexes V and III were increased following HFD. CONCLUSIONS: Chronic HFD increased adiposity, lead to more frequent voiding, and enhanced EFS-mediated detrusor contractions. Mitochondrial respiration was decreased and H2 O 2 emission increased following HFD. Further research is required to determine if alterations in mitochondrial function could play a role in the development of HFD-induced bladder dysfunction.

The Distribution of Post-Void Residual Volumes in People Seeking Care in the Symptoms of Lower Urinary Tract Dysfunction Network Observational Cohort Study With Comparison to Asymptomatic Populations.

OBJECTIVE: To describe the distribution of post-void residual (PVR) volumes across patients with and without lower urinary tract symptoms (LUTS) and examine relationships between self-reported voiding symptoms, storage symptoms, and PVR. METHODS: PVR and demographic data were obtained from the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) observational cohort study. Self-reported symptoms were collected using the American Urological Association Symptom Index and the LUTS Tool. PVR values were obtained from 2 other cohorts: living kidney donors with unknown LUTS from the Renal and Lung Living Donors Evaluation Study (RELIVE), and continent women in the Establishing the Prevalence of Incontinence (EPI) study, a population-based study of racial differences in urinary incontinence prevalence. RESULTS: Across the 3 studies, median PVRs were similar: 26 mL in LURN (n = 880, range 0-932 mL), 20 mL in EPI (n = 166, range 0-400 mL), and 14 mL in RELIVE (n = 191, range 0-352 mL). In LURN, males had 3.6 times higher odds of having PVR > 200 mL (95% CI = 1.72-7.48). In RELIVE, median PVR was significantly higher for males (20 mL vs 0 mL, P= .004). Among women, only the intermittency severity rating was associated with a probability of an elevated PVR. Among men, incomplete emptying and burning severity rating were associated with a higher odds of elevated PVR, but urgency severity ratings were associated with lower odds of elevated PVR. CONCLUSION: Care-seeking patients have PVRs similar to those in people with unknown history of LUTS (RELIVE) and without self-reported LUTS (EPI). Although PVR was correlated with voiding symptoms, the mean differences only explain ∼2% of the variance.

Sex differences in lower urinary tract biology and physiology.

Females and males differ significantly in gross anatomy and physiology of the lower urinary tract, and these differences are commonly discussed in the medical and scientific literature. However, less attention is dedicated to investigating the varied development, function, and biology between females and males on a cellular level. Recognizing that cell biology is not uniform, especially in the lower urinary tract of females and males, is crucial for providing context and relevance for diverse fields of biomedical investigation. This review serves to characterize the current understanding of biological sex differences between female and male lower urinary tracts, while identifying areas for future research. First, the differences in overall cell populations are discussed in the detrusor smooth muscle, urothelium, and trigone. Second, the urethra is discussed, including anatomic discussions of the female and male urethra followed by discussions of cellular differences in the urothelial and muscular layers. The pelvic floor is then reviewed, followed by an examination of the sex differences in hormonal regulation, the urinary tract microbiome, and the reticuloendothelial system. Understanding the complex and dynamic development, anatomy, and physiology of the lower urinary tract should be contextualized by the sex differences described in this review.

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

PURPOSE: Women with lower urinary tract symptoms are often diagnosed based on a predefined symptom complex or a predominant symptom. There are many limitations to this paradigm as often patients present with multiple urinary symptoms which do not perfectly fit the preestablished diagnoses. We used cluster analysis to identify novel, symptom based subtypes of women with lower urinary tract symptoms. MATERIALS AND METHODS: We analyzed baseline urinary symptom questionnaire data obtained from 545 care seeking female participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Observational Cohort Study. Symptoms were measured with the LUTS (lower urinary tract symptoms) Tool and the AUA SI (American Urological Association Symptom Index), and analyzed using a probability based consensus clustering algorithm. RESULTS: Four clusters were identified. The 138 women in cluster F1 did not report incontinence but experienced post-void dribbling, frequency and voiding symptoms. The 80 women in cluster F2 reported urgency incontinence as well as urgency and frequency but minimal voiding symptoms or stress incontinence. Cluster F3 included 244 women who reported all types of incontinence, urgency, frequency and mild voiding symptoms. The 83 women in cluster F4 reported all lower urinary tract symptoms at uniformly high levels. All but 2 of 44 LUTS Tool and 8 AUA SI questions significantly differed between at least 2 clusters (p <0.05). All clusters contained at least 1 member from each conventional group, including continence, and stress, urgency, mixed and other incontinence. CONCLUSIONS: Women seeking care for lower urinary tract symptoms cluster into 4 distinct symptom groups which differ from conventional clinical diagnostic groups. Further validation is needed to determine whether management improves using this new classification.

Bowel function, sexual function, and symptoms of pelvic organ prolapse in women with and without urinary incontinence.

AIMS: Bowel symptoms, pelvic organ prolapse, and sexual dysfunction are common, but their frequency among women with lower urinary tract symptoms (LUTS) has not been well described. Our aims were to describe pelvic floor symptoms among women with and without urinary incontinence (UI) and among subtypes of UI. METHODS: Women with LUTS seeking care at six U.S. tertiary care centers enrolled in prospective cohort study were studied. At baseline, participants completed the Pelvic Floor Distress Inventory (PFDI-20), Pelvic Organ Prolapse/Incontinence Sexual Questionnaire (PISQ-IR), and PROMIS GI Diarrhea, Constipation, and Fecal Incontinence Scales. RESULTS: Mean age among the 510 women was 56.4 ± 14.4 years. Women who reported UI (n = 420) had more diarrhea and constipation symptoms (mean scores 49.5 vs 46.2 [P = 0.01] and 51.9 vs 48.4 [P < 0.01], respectively) at baseline. Among sexually active women, mean PISQ-IR subscale scores were lower among those with UI (condition specific: 89.8 vs 96.7, P < 0.01; condition impact: 79.8 vs 92.5, P < 0.01). Women with mixed urinary incontinence (MUI) (n = 240) reported more prolapse symptoms, fecal incontinence, and worse sexual function compared to those with stress urinary incontinence (SUI) and urgency urinary incontinence (UUI). CONCLUSIONS: Women presenting with LUTS with UI reported significantly worse constipation, diarrhea, fecal incontinence, and sexual function compared to women without UI. In women with UI, sexual function and pelvic organ prolapse (POP) symptoms were worse in those with MUI compared to SUI and UUI.

Urinary bladder organ hypertrophy is partially regulated by Akt1-mediated protein synthesis pathway.

AIMS: The present study aims to investigate the role of Akt in the regulation of urinary bladder organ hypertrophy caused by partial bladder outlet obstruction (pBOO). MAIN METHODS: Male rats were surgically induced for pBOO. Real-time PCR and western blot were used to examine the levels of mRNA and protein. A phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was used to inhibit the activity of endogenous Akt. KEY FINDINGS: The urinary bladder developed hypertrophy at 2 weeks of pBOO. The protein but not mRNA levels of type I collagen and α-smooth muscle actin (αSMA) were increased in pBOO bladder when compared to sham control. The phosphorylation (activation) levels of Akt1 (p-Ser473), mammalian target of rapamycin (mTOR), p70S6 kinase (p70S6K), and 4E-BP1 were also increased in pBOO bladder. LY294002 treatment reduced the phosphorylation levels of Akt1 and 4E-BP1, and the protein levels of type I collagen and αSMA in pBOO bladder. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA) were increased in pBOO bladder, and PCNA up-regulation occurred in urothelial not muscular layer. LY294002 treatment had no effect on the mRNA and protein levels of PCNA in pBOO bladder. LY294002 treatment partially reduced the bladder weight caused by pBOO. SIGNIFICANCE: pBOO-induced urinary bladder hypertrophy is attributable to fibrosis, smooth muscle cellular hypertrophy, and urothelium cell hyper-proliferation. Akt1-mediated protein synthesis in pBOO bladder contributes to type I collagen and αSMA but not PCNA up-regulation. Target of Akt1 is necessary but not sufficient in treatment of urinary bladder hypertrophy following pBOO.

American Urogynecologic Society Prolapse Consensus Conference Summary Report.

OBJECTIVES: The 2016 American Urogynecologic Society Prolapse Consensus Conference brought together thought leaders in the field of pelvic organ prolapse (POP). The goal was to identify critical areas of need for future research. This article summarizes the findings. METHODS: Prior to the conference, 5 major focus areas were identified. Focus areas were explored over the 2-day conference. Clinicians, clinical and basic science researchers, and representatives from government agencies, industry, patient advocacy groups, and the public convened to identify the major gaps in knowledge in each of these focus areas. RESULTS: The 5 major topics were as follows: (1) mechanistic research on pelvic supportive structures and how these are altered with pregnancy, delivery, and aging; (2) novel prostheses or implants that address pathophysiology and provide mechanical support; (3) large-scale community-based research; (4) clinical trials to optimize outcomes after POP surgery; and (5) evidence-based quality measures for POP outcomes. Key recommendations were made for each topic. CONCLUSIONS: Critical gaps in our knowledge were identified. These limit scientific discovery across all 5 topic areas. Further scientific progress would be advanced by (1) developing a standardized group of POP outcomes and quality measures for large trials and community-based research, (2) creating specimen biorepositories that are integrated with robust clinical data, and (3) developing collaborative teams with expertise from a variety of disciplines, convened to tackle our most challenging and complex scientific questions.

Autonomic response during bladder hydrodistention reflects the severity of symptoms in patients with bladder pain syndrome/interstitial cystitis.

AIMS: To evaluate the correlation between symptom severity of bladder pain syndrome/interstitial cystitis (BPS/IC) and autonomic nervous system activity, we examined autonomic responses during bladder hydrodistention. METHODS: Medical records were collected from a prospective database for patients who underwent bladder hydrodistention with a fixed protocol from March 2012 to December 2013. A total of 40 patients (16 males, 24 females) were included for the analysis. Hydrodistention was performed under general anesthesia (31 patients), spinal anesthesia (six patients), and both types of anesthesia (three patients) at different times. Twenty-five patients who underwent holmium laser enucleation of the prostate served as controls. Pulse rate (PR), systolic (SBP), and diastolic blood pressure (BP) were measured pre-hydrodistention, during hydrodistention, and after drainage. RESULTS: The spinal anesthesia and control groups exhibited little change in BP and PR during hydrodistention, while a significant increase was demonstrated in the general anesthesia group (e.g., ΔSBP 4.89 ± 4.80, 10.40 ± 19.03, and 56.26 ± 30.38 mm Hg, respectively, P < 0.001). Under general anesthesia, autonomic response during hydrodistention was more prominent in patients with preoperative visual analogue scale (VAS) pain score ≥7, Hunner's lesion, and glomerulation grade 4. Preoperative maximal cystometric capacity negatively correlated with changes in SBP during hydrodistention (R2 = 0.294, P = 0.009), while VAS score and interstitial cystitis problem index demonstrated a positive correlation with the changes (R2 = 0.208, P = 0.012; R2 = 0.173, P = 0.015). CONCLUSIONS: Under general anesthesia, exaggerated autonomic responses to bladder hydrodistention were demonstrated in BPS/IC patients, which reflected the severity of symptoms. These results support the hypothesis of altered activity of autonomic system in BPS/IC. Neurourol. Urodynam. 36:677-682, 2017. © 2016 Wiley Periodicals, Inc.

A standard for terminology in chronic pelvic pain syndromes: A report from the chronic pelvic pain working group of the international continence society.

AIMS: Terms used in the field of chronic pelvic pain (CPP) are poorly defined and often confusing. An International Continence Society (ICS) Standard for Terminology in chronic pelvic pain syndromes (CPPS) has been developed with the aim of improving diagnosis and treatment of patients affected by chronic pelvic pain syndromes. The standard aims to facilitate research, enhance therapy development and support healthcare delivery, for healthcare providers, and patients. This document looks at the whole person and all the domains (organ systems) in a systematic way. METHODS: A dedicated working group (WG) was instituted by the ICS Standardisation Steering Committee according to published procedures. The WG extracted information from existing relevant guidelines, consensus documents, and scientific publications. Medline and other databases were searched in relation to each chronic pelvic pain domain from 1980 to 2014. Existing ICS Standards for terminology were utilized where appropriate to ensure transparency, accessibility, flexibility, and evolution. Consensus was based on majority agreement. RESULTS: The multidisciplinary CPPS Standard reports updated consensus terminology in nine domains; lower urinary tract, female genital, male genital, gastrointestinal, musculoskeletal, neurological aspects, psychological aspects, sexual aspects, and comorbidities. Each is described in terms of symptoms, signs and further evaluation. CONCLUSION: The document presents preferred terms and definitions for symptoms, signs, and evaluation (diagnostic work-up) of female and male patients with chronic pelvic pain syndromes, serving as a platform for ongoing development in this field. Neurourol. Urodynam. 36:984-1008, 2017. © 2016 Wiley Periodicals, Inc.

Characterizing the Bladder's Response to Onabotulinum Toxin Type A Using a Rat Model.

OBJECTIVES: The aim of this study was to characterize the response of the rat bladder neuromuscular system to intramural injection of onabotulinum toxin type A (BoNT/A) over 9 weeks using in vivo cystometry (CMG) and in vitro contractility (IVC). METHODS: Chronic bladder catheters were implanted in female Sprague-Dawley rats, and either (1) BoNT/A (10 units in 20 µL saline) or (2) saline (20 µL) was injected in 5 × 4 µL doses throughout the bladder wall. At 1, 3, 6, and 9 weeks after injection, conscious restrained CMG was performed. At each time point, 25% of each group (8 BoNT/A and 4 controls) was euthanized and bladders harvested for IVC. We measured IVC in response to electric field stimulation, carbachol, and potassium chloride. RESULTS: In total, 47 animals were included; 31 underwent BoNT/A injection, and 16 received sham (saline). Bladder capacities did not differ significantly between groups for each time point. One week after injection BoNT/A animals exhibited significantly longer bladder contraction durations and lower voiding efficiencies compared with controls. By 3 weeks these values returned to control levels. For BoNT/A animals, contractile response to carbachol stimulation was enhanced at 3 weeks. Otherwise, there were no differences in IVC responses. CONCLUSIONS: One week after BoNT/A injection, prolonged bladder contractions are noted in rats. This may reflect supraspinal compensation for denervation by increasing the duration of efferent drive during voiding. After 3 weeks postinjection, we observed no differences in either CMG or IVC responses suggesting either compensatory efferent sprouting, increased gap junction formation, or loss of BoNT/A effect.

Expert Panel Recommendations on Lower Urinary Tract Health of Women Across Their Life Span.

Urologic and kidney problems are common in women across their life span and affect their daily life, including physical activity, sexual relations, social life, and future health. Urological health in women is still understudied and the underlying mechanisms of female urological dysfunctions are not fully understood. The Society for Women's Health Research (SWHR®) recognized the need to have a roundtable discussion where researchers and clinicians would define the current state of knowledge, gaps, and recommendations for future research directions to transform women's urological health. This report summarizes the discussions, which focused on epidemiology, clinical presentation, basic science, prevention strategies, and efficacy of current therapies. Experts around the table agreed on a set of research, education, and policy recommendations that have the potential to dramatically increase awareness and improve women's urological health at all stages of life.

What is the role of combination drug therapy in the treatment of overactive bladder? ICI-RS 2014.

AIMS AND METHODS: The role of combination therapy using oral antimuscarinic medications for the treatment of overactive bladder was proposed at the 2014 International Consultation on Incontinence-Research Society in Bristol, UK to identify key factors to consider when making clinical decisions and to guide future research design. RESULTS: Combination therapy is justified if monotherapy is associated with suboptimal efficacy or bothersome side effects. Combination therapy has the potential to improve efficacy with fewer side effects than monotherapy. Two Phase 2 studies comparing combination therapy that included an antimuscarinic demonstrated improvement in mean voided volume, the primary outcome chosen, with some combinations showing improved micturition frequency and quality of life. The two studies found no evidence of an increased safety risk with combination therapy compared to monotherapy. Future studies should use clinically meaningful or patient reported outcomes such as incontinence episodes when comparing efficacy. If surrogate measures are used, a clear justification should be provided. Cost analyses should be planned for clinical research trials evaluating combination drug therapy. CONCLUSIONS: Combination therapy is reasonable when monotherapy has suboptimal efficacy or bothersome side effects. Future research studies evaluating combination therapy for urgency urinary incontinence should ideally(1) be performed as part of a randomized clinical trial,(2) evaluate non-responders to monotherapy,(3) evaluate combination therapy using medications with different mechanisms of action,(4) include clinically meaningful and patient reported outcomes when evaluating efficacy, and(5) include cost-effectiveness analyses to justify any increased cost by showing improvement in efficacy or reduction in side effects.

The effects of Ins2(Akita) diabetes and chronic angiotensin II infusion on cystometric properties in mice.

AIMS: Diabetes is associated with both dysfunction of the lower urinary tract (LUT) and overactivity of the renin-angiotensin system (RAS). Although it is well known that the RAS affects normal LUT function, very little is known about RAS effects on the diabetic LUT. Accordingly, we investigated the effects of chronic angiotensin II (AngII) treatment on the LUT in a model of type 1 diabetes. METHODS: Ins2(Akita) diabetic mice (20 weeks old) and their age-matched background controls underwent conscious cystometric evaluation after 4 weeks of chronic AngII treatment (700 ng/kg/min by osmotic pump) or vehicle (saline). RESULTS: Diabetic mice had compensated LUT function with bladder hypertrophy. Specifically, micturition volume, residual volume, and bladder capacity were all increased, while voiding efficiency and pressure generation were unchanged as bladder mass, contraction duration, and phasic urethral function were increased. AngII significantly increased voiding efficiency and peak voiding pressure and decreased phasic frequency irrespective of diabetic state and, in diabetic but not normoglycemic control mice, significantly decreased residual volume and increased contraction duration and nonphasic contraction duration. CONCLUSIONS: The Ins2(Akita) diabetic mice had compensated LUT function at 20 weeks of age. Even under these conditions, AngII had beneficial effects on LUT function, resulting in increased voiding efficiency. Future studies should therefore be conducted to determine whether AngII can rescue the decompensated LUT function occurring in end-stage diabetic uropathy.

Genetic contributions to urgency urinary incontinence in women.

PURPOSE: We identify genetic variants associated with urgency urinary incontinence in postmenopausal women. MATERIALS AND METHODS: A 2-stage genome-wide association analysis was conducted to identify variants associated with urgency urinary incontinence. The WHI GARNET substudy with 4,894 genotyped post-reproductive white women was randomly split into independent discovery and replication cohorts. Genome-wide imputation was performed using IMPUTE2 with the 1000 Genomes ALL Phase I integrated variant set as a reference. Controls reported no urgency urinary incontinence at enrollment or followup. Cases reported monthly or greater urgency urinary incontinence and leaked sufficiently to wet/soak underpants/clothes. Logistic regression models were used to predict urgency urinary incontinence case vs control status based on genotype, assuming additive inheritance. Age, obesity, diabetes and depression were included in the models as covariates. RESULTS: Following quality control, 975,508 single nucleotide polymorphisms in 2,241 cases (discovery 1,102; replication 1,133) and 776 controls (discovery 405, replication 371) remained. Genotype imputation resulted in 9,077,347 single nucleotide polymorphisms and insertions/deletions with minor allele frequency greater than 0.01 available for analysis. Meta-analysis of the discovery and replication samples identified 6 loci on chromosomes 5, 10, 11, 12 and 18 associated with urgency urinary incontinence at p <10(-6). Of the loci 3 were within genes, the zinc finger protein 521 (ZFP521) gene on chromosome 18q11, the ADAMTS16 gene on chromosome 5p15 and the CIT gene on chromosome 12q24. The other 3 loci were intergenic. CONCLUSIONS: Although environmental factors also likely contribute, this first exploratory genome-wide association study for urgency urinary incontinence suggests that genetic variants in the ZFP521, CIT and ADAMTS16 genes might account for some of the observed heritability of the condition.