Current and Emerging Pharmacological Targets and Treatments of Urinary Incontinence and Related Disorders.

Overactive bladder syndrome with and without urinary incontinence and related conditions, signs, and disorders such as detrusor overactivity, neurogenic lower urinary tract dysfunction, underactive bladder, stress urinary incontinence, and nocturia are common in the general population and have a major impact on the quality of life of the affected patients and their partners. Based on the deliberations of the subcommittee on pharmacological treatments of the 7th International Consultation on Incontinence, we present a comprehensive review of established drug targets in the treatment of overactive bladder syndrome and the aforementioned related conditions and the approved drugs used in its treatment. Investigational drug targets and compounds are also reviewed. We conclude that, despite a range of available medical treatment options, a considerable medical need continues to exist. This is largely because the existing treatments are symptomatic and have limited efficacy and/or tolerability, which leads to poor long-term adherence. SIGNIFICANCE STATEMENT: Urinary incontinence and related disorders are prevalent in the general population. While many treatments have been approved, few patients stay on long-term treatment despite none of them being curative. This paper provides a comprehensive discussion of existing and emerging treatment options for various types of incontinence and related disorders.

Involvement of Mast-Cell-Tryptase- and Protease-Activated Receptor 2-Mediated Signaling and Urothelial Barrier Dysfunction with Reduced Uroplakin II Expression in Bladder Hyperactivity Induced by Chronic Bladder Ischemia in the Rat.

We aimed to investigate the relationship between mast cell (MC) infiltration into the bladder with urothelial barrier dysfunction and bladder hyperactivity in a chronic bladder ischemia (CBI) rat model. We compared CBI rats (CBI group; n = 10) with normal rats (control group; n = 10). We measured the expression of mast cell tryptase (MCT) and protease-activated receptor 2 (PAR2), which are correlated with C fiber activation via MCT, and Uroplakins (UP Ia, Ib, II and III), which are critical to urothelial barrier function, via Western blotting. The effects of FSLLRY-NH2, a PAR2 antagonist, administered intravenously, on the bladder function of CBI rats were evaluated with a cystometrogram. In the CBI group, the MC number in the bladder was significantly greater (p = 0.03), and the expression of MCT (p = 0.02) and PAR2 (p = 0.02) was significantly increased compared to that of the control group. The 10 µg/kg FSLLRY-NH2 injection significantly increased the micturition interval of CBI rats (p = 0.03). The percentage of UP-II-positive cells on the urothelium with immunohistochemical staining was significantly lower in the CBI group than in the control group (p < 0.01). Chronic ischemia induces urothelial barrier dysfunction via impairing UP II, consequently inducing MC infiltration into the bladder wall and increased PAR2 expression. PAR2 activation by MCT may contribute to bladder hyperactivity.

Effectiveness of ultrasound-guided pelvic floor muscle training in improving prolonged urinary incontinence after robot-assisted radical prostatectomy.

Persistence of urinary incontinence (UI) after robot-assisted radical prostatectomy (RARP) is a bothersome problem because of its negative effect on the patient's quality of life (QOL). This study aimed to evaluate the effect of transperineal ultrasound (TPUS)-guided pelvic floor muscle training (PFMT) on prolonged UI after RARP. Thirty men with stress UI persisting for > 1 year after RARP underwent biofeedback PFMT using TPUS once every 2-3 weeks for 3 months. The frequency and duration of sustaining pelvic floor muscle (PFM) contractions were assessed using ultrasound imaging. The severity of UI and UI-related QOL were evaluated using a 24-hour pad test and the incontinence quality of life (I-QOL) questionnaire. Twenty-four men (mean age, 72.2 years) completed the TPUS-guided PFMT. The mean duration from RARP to PFMT was 1,228.9 days. The mean cumulative session and the total duration of TPUS-guided PFMT were 4.6 times and 73.3 days, respectively. Compared with the data before TPUS-guided PFMT, the frequency of PFM contractions and duration of sustaining contraction significantly improved after TPUS-guided PFMT (p < 0.05). Additionally, the total amount of urinary leakage after TPUS-guided PFMT was reduced significantly (248.6 ± 280.6 g vs. 397.0 ± 427.0 g, p = 0.024). The I-QOL score was significantly increased after TPUS-guided PFMT (72.1 ± 16.8 vs. 61.0 ± 19.0, p < 0.001). TPUS-guided PFMT may be effective in improving prolonged UI occurring > 1 year after RARP.

Cystectomy for patients with Hunner-type interstitial cystitis at a tertiary referral center in Japan.

OBJECTIVES: To evaluate the outcomes of partial and total cystectomy in patients with refractory Hunner-type interstitial cystitis (HIC). METHODS: Patients with end-stage HIC who underwent supratrigonal partial cystectomy with augmentation ileocystoplasty (PC-CP) or total cystectomy with ileal conduit (TC-IC) were identified retrospectively. Changes in the 11-point numerical rating scale of bladder pain and in 7-grade quality of life (QOL) scores were evaluated. Changes in the O'Leary and Sant's Symptom Index (OSSI) and O'Leary and Sant's Problem Index (OSPI) were analyzed in patients with PC-CP. Peri- and postoperative complications and patient satisfaction with overall outcomes were examined. RESULTS: Four patients (one female) underwent PC-CP and 13 (nine females) underwent TC-IC. Bladder pain persisted in three PC-CP patients, but resolved completely in all TC-IC patients. Pain scale and QOL scores improved significantly in patients with TC-IC (P < .01), but not in those with PC-CP. OSSI/OSPI scores did not improve significantly in patients with PC-CP. Three PC-CP patients required clean intermittent catheterization due to voiding dysfunction or persistent pain. Two TC-IC patients developed stricture of the ureteroileal anastomosis, resulting in permanent placement of a ureteral stent in one case and nephrostomy in the other. Satisfaction rate was higher in the TC-IC than in the PC-CP group (76.9% vs 25.0%, P < .05). CONCLUSIONS: TC-IC provided reliable pain relief and improved QOL in patients with end-stage HIC, but the small case number and limited methodology restrict interpretation of the results. Further studies are needed to identify appropriate candidates and optimal surgical procedures.

Evaluation of a Point-of-Care Ultrasound Educational Program for Nurse Educators.

BACKGROUND: The effectiveness of point-of-care ultrasound (POCUS) for nurses has been demonstrated; however, only a limited number of nurses have been trained to perform POCUS. This article reports on a POCUS train-the-trainer program for nurse educators that targets lower urinary track dysfunction. METHOD: Nurse educators (n = 38) were invited to participate in a POCUS train-the-trainer program, which comprised an e-learning module and a hands-on seminar. Acquisition of knowledge and skills were assessed after the module and seminar, respectively. RESULTS: Questions from the "Basic Knowledge of Ultrasonography" test were answered correctly at a rate of 93.0% (SD, 8.5%). Measured values of bladder urinary volume using ultrasonography were in close agreement with actual values. All of the participants indicated that the program covered the content necessary to use in practice. CONCLUSION: The POCUS train-the-trainer program equips nurse educators with the knowledge and skills needed for training nurses at their institutions. [J Contin Educ Nurs. 2021;52(8):375-381.].

Novel operative technique of advancement urethral meatoplasty utilizing buccal mucosa for Vulvar Paget's disease with urethral invasion: two case reports.

BACKGROUND: Vulvar Paget's disease (VPD) is a rare malignant disorder originating in the external genitalia. It occasionally invades into urethral or vaginal mucosa of female, making surgical treatment more complicating. In case of urethral invasion of Paget's cells, systematic mapping biopsy of urethral mucosa is the standard of care to determine the range of surgical resection. Resection of urethral mucosa and simple skin grafting often result in urethral stricture after surgery, which severely deteriorates patient's quality of life. CASE PRESENTATION: We applied a new technique of advancement urethral meatoplasty using buccal mucosa, in two Japanese cases of VPD with urethral invasion. After broad resection of vulvar skin together with the urethral mucosa, buccal mucosa was implanted between advanced urethral mucosa and skin graft. In both cases, we could prevent urethral stricture one year and two years after surgery, respectively. CONCLUSION: This technique prevented urethral stricture after surgery and could be a useful technique as part of urethroplasty for VPD.

Lacking transient receptor potential melastatin 2 attenuates lipopolysaccharide-induced bladder inflammation and its associated hypersensitivity in mice.

OBJECTIVE: To study the role of transient receptor potential melastatin 2 in bladder function and inflammation-associated hypersensitivity. METHODS: We evaluated physiological function of the bladder and intravesical lipopolysaccharide-induced inflammatory nociceptive responses in female wild-type and transient receptor potential melastatin 2-knockout mice. In vivo frequency/volume and decerebrated unanesthetized cystometry measurements, as well as in vitro detrusor strip functional studies, were carried out to evaluate bladder function. Mice received intravesical lipopolysaccharide (2.0 mg/mL) or saline instillation to evaluate responses to bladder inflammation. Voiding and bladder pain-like behaviors, cystometry measurements and histological evaluation were carried out before and after intravesical lipopolysaccharide instillation. RESULTS: Few phenotypic differences in in vivo and in vitro physiological function were found between the two genotypes. Comparison of measurements taken before and 24-48 h after intravesical lipopolysaccharide instillation showed that voiding parameters did not change in transient receptor potential melastatin 2-knockout mice, whereas an increased voiding frequency was observed in wild-type mice. At 24 h after intravesical lipopolysaccharide instillation, the numbers of bladder pain-like behaviors and of infiltrated inflammatory cells in the bladder submucosal layer were significantly increased, and the voided volume and the intercontraction interval were significantly decreased on cystometry measurements in wild-type mice compared with those in both transient receptor potential melastatin 2-knockout mice and in wild-type mice treated with saline instillation. CONCLUSIONS: Although the physiological roles of transient receptor potential melastatin 2 channels in the bladder might be limited, inflammation and associated hypersensitivity of the bladder caused by intravesical lipopolysaccharide instillation are attenuated in transient receptor potential melastatin 2-knockout mice, suggesting pathophysiological roles of transient receptor potential melastatin 2 channels in these processes.

Clinical characterization of interstitial cystitis/bladder pain syndrome in women based on the presence or absence of Hunner lesions and glomerulations.

OBJECTIVES: To compare the clinical characteristics of three groups of female patients with interstitial cystitis/bladder pain syndrome (IC/BPS) classified according to the presence or absence of Hunner lesions (HL) and glomerulations. METHODS: The clinical records of 100 female patients with IC/BPS who underwent their first bladder hydrodistension at our institution were retrospectively reviewed. They were divided into patients having (HL-IC; n = 57) or lacking (BPS; n = 43) HL. BPS patients were further classified as those with (29) and without (14) glomerulations. Among these three subtypes, demographics, comorbidities, symptom parameters including a visual analog scale for pain scores, O'Leary and Sant Symptom and Problem (OSSI/OSPI) Indices, frequency volume chart variables, and bladder capacity at hydrodistension were compared. RESULTS: HL-IC patients were older and had higher OSSI/OSPI scores, greater daytime frequency and nocturia, reduced maximum and average voided volumes, and smaller bladder capacity at hydrodistension compared with BPS patients. Pain intensity and illness duration were comparable among the three groups. HL-IC patients had autoimmune disorders as comorbidities more often, but had psychiatric disorders and irritable bowel syndrome less often compared with BPS patients. No discernible differences in clinical characteristics of symptom severity and comorbid disorders were evident between BPS patients with and without glomerulations. CONCLUSIONS: The presence of HL is associated with distinctive clinical characteristics, while glomerulations are not in female patients with IC/BPS. The presence of HL, but not glomerulations, is a robust phenotypic feature of IC/BPS in women.

Pathophysiological changes of the lower urinary tract behind voiding dysfunction in streptozotocin-induced long-term diabetic rats.

We evaluated pathophysiological characteristics of the lower urinary tract dysfunction in a streptozotocin (STZ)-induced diabetic rat model. STZ (60 mg/kg) was injected intraperitoneally into male Wistar rats. In vitro bladder muscle strip experiments, in vivo cystometry, and simultaneous recordings of bladder pressure + urethral perfusion pressure (BP + UPP) with or without intravenous administration of L-arginine (300 mg/kg) or tadalafil (0.03 mg/kg) were performed at several time points. In vitro muscle strip experiments demonstrated that diabetic rats had significantly higher contractile responses to carbachol at 4-16 weeks, and a tendency for higher contractile responses to electrical field stimulation at 4-12 weeks, but this was reversed at 16 weeks. Diabetic rats had significant increases in voided volume, residual volume, bladder capacity, maximal voiding pressure, and amplitude and frequency of non-voiding contractions at 16 weeks. Tadalafil decreased the residual volume in diabetic rats. Diabetic rats had significantly higher UPP nadir and mean UPP during high-frequency oscillation at 16 weeks, which were reversed by tadalafil or L-arginine administration. The present results suggest that urethral relaxation failure, probably related to impairment of the NO/cGMP signalling pathway, rather than bladder contractile dysfunction may be a prominent cause for voiding dysfunction in STZ-induced chronic diabetic rats.

KPR-5714, a Novel Transient Receptor Potential Melastatin 8 Antagonist, Improves Overactive Bladder via Inhibition of Bladder Afferent Hyperactivity in Rats.

Transient receptor potential (TRP) melastatin 8 (TRPM8) is a temperature-sensing ion channel mainly expressed in primary sensory neurons (Aδ-fibers and C-fibers in the dorsal root ganglion). In this report, we characterized KPR-5714 (N-[(R)-3,3-difluoro-4-hydroxy-1-(2H-1,2,3-triazol-2-yl)butan-2-yl]-3-fluoro-2-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]benzamide), a novel and selective TRPM8 antagonist, to assess its therapeutic potential against frequent urination in rat models with overactive bladder (OAB). In calcium influx assays with HEK293T cells transiently expressing various TRP channels, KPR-5714 showed a potent TRPM8 antagonistic effect and high selectivity against other TRP channels. Intravenously administered KPR-5714 inhibited the hyperactivity of mechanosensitive C-fibers of bladder afferents and dose-dependently increased the intercontraction interval shortened by intravesical instillation of acetic acid in anesthetized rats. Furthermore, we examined the effects of KPR-5714 on voiding behavior in conscious rats with cerebral infarction and in those exposed to cold in metabolic cage experiments. Cerebral infarction and cold exposure induced a significant decrease in the mean voided volume and increase in voiding frequency in rats. Orally administered KPR-5714 dose-dependently increased the mean voided volume and decreased voiding frequency without affecting total voided volume in these models. This study demonstrates that KPR-5714 improves OAB in three different models by inhibiting exaggerated activity of mechanosensitive bladder C-fibers and suggests that KPR-5714 may provide a new and useful approach to the treatment of OAB. SIGNIFICANCE STATEMENT: TRPM8 is involved in bladder sensory transduction and plays a role in the abnormal activation in hypersensitive bladder disorders. KPR-5714, as a novel and selective TRPM8 antagonist, may provide a useful treatment for the disorders related to the hyperactivity of bladder afferent nerves, particularly in overactive bladder.

Clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury.

The present article is an abridged English translation of the Japanese clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury updated as of July 2019. The patients are adult spinal cord injured patients with lower urinary tract dysfunction; special consideration of pediatric and elderly populations is presented separately. The target audience is healthcare providers who are engaged in the medical care of patients with spinal cord injury. The mandatory assessment includes medical history, physical examination, frequency-volume chart, urinalysis, blood chemistry, transabdominal ultrasonography, measurement of post-void residual urine, uroflowmetry and video-urodynamic study. Optional assessments include questionnaires on the quality of life, renal scintigraphy and cystourethroscopy. The presence or absence of risk factors for renal damage and symptomatic urinary tract infection affects urinary management, as well as pharmacological treatments. Further treatment is recommended if the maximum conservative treatment fails to improve or prevent renal damage and symptomatic urinary tract infection. In addition, management of urinary incontinence should be considered individually in patients with risk factors for urinary incontinence and decreased quality of life.

Cardiovascular safety of antimuscarinic add-on therapy in patients with overactive bladder who had a suboptimal response to mirabegron monotherapy: A post hoc analysis from the Japanese MILAI II study.

OBJECTIVE: This analysis was conducted to investigate the cardiovascular (CV) safety outcomes from the MILAI II study. MILAI II was conducted to evaluate the long-term safety and efficacy of antimuscarinic add-on therapy to mirabegron over 52 weeks in patients with overactive bladder (OAB) symptoms. METHODS: MILAI II consisted of a 2-week screening period (patients received mirabegron 50 mg once daily) plus a 52-week treatment period (patients were randomized to receive a combination of mirabegron 50 mg/d plus solifenacin 5 mg/d, propiverine 20 mg/d, imidafenacin 0.2 mg/d, or tolterodine 4 mg/d). CV safety was assessed using treatment-emergent adverse events (TEAEs), vital signs, and 12-lead electrocardiograms (ECGs). Vital signs and ECG data were evaluated for each patient using worst post-baseline values reported. RESULTS: Of 647 patients, 570 (88.1%) were female with a mean age of 65 years. CV history at baseline and CV-related concomitant medication use throughout the study were balanced between groups. The incidences of overall and drug-related CV TEAEs were ≤8.1% and ≤6.2%, respectively, for all groups. The most common TEAEs were ECG T wave amplitude decreased, ECG QT prolonged, and ventricular extrasystoles. Overall, 36 TEAEs of interest related to the CV system that were possibly/probably related to treatment were reported with similar incidences for each group. For the worst post-baseline vital signs and ECGs, no relationships were noted in terms of either timing or treatment group. CONCLUSION: A favorable CV safety profile was observed following long-term combination treatment with mirabegron and an antimuscarinic in patients with OAB symptoms.

Longitudinal change of comprehensive lower urinary tract symptoms and various types of urinary incontinence during robot-assisted radical prostatectomy.

AIMS: To clarify longitudinal change of lower urinary tract symptoms (LUTS) and various types of urinary incontinence following robot-assisted radical prostatectomy (RARP) using validated questionnaires. MATERIALS AND METHODS: The core lower urinary tract symptom score (CLSS) and the International Consultation on Incontinence Questionnaire (ICIQ)-Short Form (SF) questionnaires were administered to 607 consecutive, treatment-naïve men receiving RARP before and after surgery. The time course of comprehensive LUTS and various types of urinary incontinence, including stress-, urgency-, and urinary incontinence with no obvious reason, were evaluated. Continence recovery rates were compared for the different types of incontinence using Cox hazard regression analysis. RESULTS: After surgery, stress urinary incontinence (SUI) was reported most frequently (32% of cases) as the chief complaint with the most impact on daily life, as assessed by the CLSS questionnaire, followed by urgency urinary incontinence (UUI; 27% of cases). The rates of continence recovery differed among the different types of urinary incontinence, such as after urinating, when dressed, when asleep, when physically active or exercising, when coughing or sneezing, before reaching the toilet, and for no obvious reason. Incontinence for no obvious reason at 1 month after RARP was a strongest prognostic factor of delayed continence recovery (hazard ratio, 0.61; P < 0.0001), whereas patients reporting SUI and UUI gradually regained continence. CONCLUSIONS: Further time course on continent recovery after RARP would be more precisely predictable based on the incontinence status at one month postoperatively. Especially, incontinence with no obvious reason would be a significant factor for delayed recovery.

ß3 -Adrenoceptors in the normal and diseased urinary bladder-What are the open questions?

ß3 -Adrenoceptor agonists are used in the treatment of overactive bladder syndrome. Although the relaxant response to adrenergic stimulation in human detrusor smooth muscle cells is mediated mainly via ß3 -adrenoceptors, the plasma concentrations of the therapeutic dose of mirabegron, the only clinically approved ß3 -adrenoceptor agonist, are considerably lower than the EC50 for causing direct relaxation of human detrusor, suggesting a mechanism of action other than direct relaxation of detrusor smooth muscle. However, the site and mechanism of action of ß3 -adrenoceptor agonists in the bladder have not been firmly established. Postulated mechanisms include prejunctional suppression of ACh release from the parasympathetic nerves during the storage phase and inhibition of micro-contractions through ß3 -adrenoceptors on detrusor smooth muscle cells or suburothelial interstitial cells. Implications of possible desensitization of ß3 -adrenoceptors in the bladder upon prolonged agonist exposure and possible causes of rarely observed cardiovascular effects of mirabegron are also discussed. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

Molecular Taxonomy of Interstitial Cystitis/Bladder Pain Syndrome Based on Whole Transcriptome Profiling by Next-Generation RNA Sequencing of Bladder Mucosal Biopsies.

PURPOSE: We systematically characterized gene expression, inflammation and neovascularization in patients with interstitial cystitis/bladder pain syndrome to obtain biological evidence supporting diagnosis and classification. MATERIALS AND METHODS: We sequenced RNA obtained from bladder mucosal biopsies of 33 patients with 3 subtypes of interstitial cystitis/bladder pain syndrome, including Hunner lesions in 12, no Hunner lesions in 11 but with glomerulations and neither Hunner lesions nor glomerulations in 10, and 9 controls. Differentially expressed genes of each subtype were searched to identify subtype specific biological pathways and candidate genes important for pathogenesis. Candidate genes were validated by quantitative polymerase chain reaction and immunohistochemistry. Digital immunohistochemical quantification was performed to assess subepithelial lymphoplasmacytic cell and microvessel density. Relationships between candidate gene over expression and symptom severity were explored. RESULTS: Patients with Hunner lesions showed a distinct gene expression profile associated with significant up-regulation of biological processes involving immune responses and infection, and an increase in subepithelial lymphoplasmacytic cell and microvessel density. Over expression of 2 candidate genes, VEGF and BAFF, correlated with symptom severity. Meanwhile, the gene expression profiles of patients with the 2 subtypes without Hunner lesions were similar to those of controls. No difference in biological pathways or subepithelial lymphoplasmacytic cell and microvessel density were detected between these 2 subtypes and controls. CONCLUSIONS: Interstitial cystitis/bladder pain syndrome with Hunner lesions shows distinct genomic and histological features associated with immune responses and infection. In addition, VEGF and BAFF are potential disease biomarkers and therapeutic targets. This subtype should be considered separate from the syndrome.

Feasibility of approximate measurement of bladder volume in male patients using the Lilium α-200 portable ultrasound bladder scanner.

OBJECTIVE: This study examined the accuracy of a new portable ultrasound bladder scanner, the Lilium α-200 (Lilium Otsuka, Kanagawa, Japan), by evaluating the correlation between bladder volumes periodically measured by the Lilium α-200 and instilled volume during video-urodynamic studies (V-UDS). METHODS: Using the Lilium α-200, fluid volume was measured prospectively in the bladders of patients with lower urinary tract dysfunction during V-UDS. This was done both immediately after micturition (for assessment of post-void residual [PVR] volume) and at 1-minute intervals during filling cystometry with patients in the supine position. These measurements were then compared with the PVR volume obtained directly by catheter drainage and instilled volume during cystometry using paired t tests and Spearman's rank correlation. RESULTS: Fifteen male patients (median age 70.5 years; range 18-84 years) were included in the study. The PVR volume measured by the Lilium α-200 was strongly correlated with that obtained by catheter drainage (r = 0.94; P < 0.0001). There was a strong correlation between instilled and bladder volumes measured by the Lilium α-200 at every minute during and at the end of instillation (281 measurements in 15 patients; r = 0.86; P < 0.0001). However, the relative error of bladder volumes measured by the Lilium α-200 during cystometry showed considerable variation (mean [± SD] 5.6 ± 62.9%). CONCLUSIONS: Bladder volumes measured periodically by the Lilium α-200 during cystometry were strongly correlated with actual PVR or instilled volumes. However, they showed considerable variation and may not predict actual volume accurately. The Lilium α-200 is feasible for obtaining an approximate measure of bladder volume.

Ultrasound-assisted prompted voiding care for managing urinary incontinence in nursing homes: A randomized clinical trial.

AIMS: To determine whether ultrasound-assisted prompted voiding (USAPV) care is more efficacious than conventional prompted voiding (CPV) care for managing urinary incontinence in nursing homes. METHODS: Thirteen participating nursing homes in Japan were randomized to CPV (n = 7) or USAPV care group (n = 6). Residents of the allocated nursing homes received CPV (n = 35) or USAPV (n = 45) care for 8 weeks. In the CPV group, caregivers asked the elderly every 2-3 h whether they had a desire to void and prompted them to void when the response was yes. In the USAPV group, caregivers regularly monitored bladder urine volume by an ultrasound device and prompted them to void when the volume reached close to the individually optimized bladder capacity. Frequency-volume chart was recorded at the baseline and after the 8-week intervention to measure the daytime urine loss. RESULTS: The change in daytime urine loss was statistically greater in the USAPV (median, -80.0 g) than in the CPV (median, -9.0 g; P = .018) group. The proportion of elderly individuals whose daytime urine loss decreased by >25% was 51% and 26% in the USAPV and CPV group, respectively (P = .020). Quality-of-life measures of elderly participants showed no significant changes in both groups. The care burden scale score of caregivers was unchanged in the USAPV group (P = .59) but significantly worsened in the CPV group (P = .010) after the intervention. CONCLUSIONS: USAPV is efficacious and feasible for managing urinary incontinence in nursing homes.

RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced hyperactivity of the primary bladder afferent nerves in rats.

AIMS: To examine the effects of RQ-00434739, a novel selective TRPM8 antagonist, on deep body temperature (DBT) and normal bladder sensory function and overactivity and its associated facilitation of mechanosensitive primary bladder single-unit afferent activities (SAAs) induced by intravesical l-menthol or prostaglandin E2 (PGE2) instillation in rats. MAIN METHODS: The effect of RQ-00434739 on DBT was evaluated using intravenous administration of RQ-00434739 (1 mg/kg) or its vehicle under urethane anaesthesia. Cystometry (CMG) was performed on conscious and freely moving rats. SAAs were measured from the left L6 dorsal root under urethane anaesthesia, and the fibers were grouped as Aδ- or C-fiber based on their conduction velocity. For both CMG and SAA measurements, after baseline recording with saline instillation, further recording was performed with intravesical l-menthol (6 mM) or PGE2 (60 µM) instillation after pretreatment with intravenous RQ-00434739 (1 mg/kg) or its vehicle. KEY FINDINGS: RQ-00434739 did not significantly affect DBT. In CMG measurements, RQ-00434739 administration increased mean voided volume. Both l-menthol and PGE2 instillation decreased mean voided volume following vehicle pretreatment, whereas such effects were not observed following RQ-00434739 pretreatment. In SAA measurements, either l-menthol or PGE2 instillations increased SAAs of C-fibers, but not SAAs of Aδ-fibers, in the presence of vehicle. RQ-00434739 pretreatment significantly inhibited the l-menthol- and PGE2-induced activation of C-fiber SAAs. SIGNIFICANCE: The present results demonstrate that blockade of TRPM8 channels can inhibit the pathological activation of mechanosensitive C-fibers and suggest that RQ-00434739 may be a promising therapeutic drug candidate for bladder hypersensitive disorders without affecting DBT.

May perioperative ultrasound-guided pelvic floor muscle training promote early recovery of urinary continence after robot-assisted radical prostatectomy?

AIMS: The efficacy of perioperative pelvic floor muscle training (PFMT) for continence recovery after robot-assisted radical prostatectomy (RARP) remains unclear. Visualization of the bladder neck and urethra using transperineal ultrasound (US) may promote self-recognition of urethral closure during PFM contraction. This study aimed to examine whether transperineal US-guided PFMT promotes early recovery of post-RARP incontinence. METHODS: This prospective cohort study included 116 men undergoing RARP. All men were offered to undergo transperineal US-guided PFMT, and 36 men agreed. The protocol consisted of biofeedback PFMT using transperineal US before RARP and 1-month after RARP with verbal instruction of PFMT immediately after urethral catheter removal. The remaining 80 patients received verbal instruction for PFMT alone. Continence recovery was defined as the number of days requiring a small pad (20 g) per day by self-report. RESULTS: No differences were observed in demographic or peri-operative parameters between the two groups except the longer operative time in the US-guided PFMT group. The mean time until continence recovery was significantly shorter in the US-guided PFMT group (75.6 ± 100.0 days) than in the verbal-PFMT group (121.8 ± 132.0 days, P = 0.037). Continence recovery rates within 30 days were 52.8% (19/36) and 35.4% (28/80) in the US-guided PFMT and verbal-PFMT groups, respectively (P = 0.081). US-guided PFMT was associated with better postoperative continence status (adjusted hazard ratio [95% confidence interval]: 0.550 [0.336-0.900], P = 0.017). CONCLUSIONS: The results showed that transperineal US-guided PFMT perioperatively was associated with early recovery of urinary continence after RARP.