Recommendations of the SUFU/AUGS/ICS Female Stress Urinary Incontinence Surgical Publication Working Group: A common standard minimum data set for the literature.

INTRODUCTION AND OBJECTIVES: Relevant, meaningful, and achievable data points are critical in objectively assessing quality, utility, and outcomes in female stress urinary incontinence (SUI) surgery. A minimum data set female SUI surgery studies was proposed by the first American Urological Association guidelines on the surgical management of female SUI in 1997, but recommendation adherence has been suboptimal. The Female Stress Urinary Incontinence Surgical Publication Working Group (WG) was created from members of several prominent organizations to formulate a recommended standard of study structure, description, and minimum outcome data set to be utilized in designing and publishing future SUI studies. The goal of this WG was to create a body of evidence better able to assess the outcomes of female SUI surgery. METHODS: The WG reviewed the minimum data set proposed in the 1997 AUA SUI Guideline document, and other relevant literature. The body of literature was examined in the context of the profound changes in the field over the past 25 years. Through a DELPHI process, a standard study structure and minimum data set were generated. Care was taken to balance the value of several meaningful and relevant data points against the burden of creating an excessively difficult or restrictive standard that would disincentivize widespread adoption and negatively impact manuscript production and acceptance. RESULTS: The WG outlined standardization in four major areas: (1) study design, (2) pretreatment demographics and characterization of the study population, (3) intraoperative events, and (4) posttreatment evaluation, and complications. Forty-two items were evaluated and graded as: STANDARD-must be included; ADDITIONAL-may be included for a specific study and is inclusive of the Standard items; OPTIMAL-may be included for a comprehensive study and is inclusive of the Standard and Additional items; UNNECESSARY/LEGACY-not relevant. CONCLUSIONS: A reasonable, achievable, and clinically meaningful minimum data set has been constructed. A structured framework will allow future surgical interventions for female SUI to be objectively scrutinized and compared in a clinically significant manner. Ultimately, such a data set, if adopted by the academic community, will enhance the quality of the scientific literature, and ultimately improve short and long-term outcomes for female patients undergoing surgery to correct SUI.

Recommendations of the SUFU/AUGS/ICS Female Stress Urinary Incontinence Surgical Publication Working Group: A Common Standard Minimum Data Set for the Literature.

INTRODUCTION AND OBJECTIVES: Relevant, meaningful, and achievable data points are critical in objectively assessing quality, utility, and outcomes in female stress urinary incontinence (SUI) surgery. A minimum data set female SUI surgery studies was proposed by the first American Urological Association guidelines on the surgical management of female SUI in 1997, but recommendation adherence has been suboptimal. The Female Stress Urinary Incontinence Surgical Publication Working Group (WG) was created from members of several prominent organizations to formulate a recommended standard of study structure, description, and minimum outcome data set to be utilized in designing and publishing future SUI studies. The goal of this WG was to create a body of evidence better able to assess the outcomes of female SUI surgery. METHODS: The WG reviewed the minimum data set proposed in the 1997 AUA SUI Guideline document, and other relevant literature. The body of literature was examined in the context of the profound changes in the field over the past 25 years. Through a DELPHI process, a standard study structure and minimum data set were generated. Care was taken to balance the value of several meaningful and relevant data points against the burden of creating an excessively difficult or restrictive standard that would disincentivize widespread adoption and negatively impact manuscript production and acceptance. RESULTS: The WG outlined standardization in four major areas: 1) study design, 2) pretreatment demographics and characterization of the study population, 3) intraoperative events, and 4) post-treatment evaluation, and complications. Forty-two items were evaluated and graded as: STANDARD - must be included; ADDITIONAL - may be included for a specific study and is inclusive of the Standard items; OPTIMAL - may be included for a comprehensive study and is inclusive of the Standard and Additional items; UNNECESSARY/LEGACY - not relevant. CONCLUSIONS: A reasonable, achievable, and clinically meaningful minimum data set has been constructed. A structured framework will allow future surgical interventions for female SUI to be objectively scrutinized and compared in a clinically significant manner. Ultimately, such a data set, if adopted by the academic community, will enhance the quality of the scientific literature, and ultimately improve short and long-term outcomes for female patients undergoing surgery to correct SUI.

Trial Design for Mixed Urinary Incontinence: Midurethral Sling Versus Botulinum Toxin A.

IMPORTANCE: Mixed urinary incontinence (MUI) is common and can be challenging to manage. OBJECTIVES: We present the protocol design and rationale of a trial comparing the efficacy of 2 procedures for the treatment of women with MUI refractory to oral treatment. The Midurethral sling versus Botulinum toxin A ( MUSA) trial compares the efficacy of intradetrusor injection of 100 U of onabotulinimtoxinA (an office-based procedure directed at the urgency component) versus midurethral sling (MUS) placement (a surgical procedure directed at the stress component). STUDY DESIGN: The MUSA is a multicenter, randomized trial of women with MUI electing to undergo procedural treatment for MUI at 7 clinical centers in the NICHD Pelvic Floor Disorders Network. Participants are randomized to either onabotulinumtoxinA 100 U or MUS. OnabotulinimtoxinA recipients may receive an additional injection between 3 and 6 months. Participants may receive additional treatment (including crossover to the alternative study intervention) between 6 and 12 months. The primary outcome is change from baseline in Urogenital Distress Inventory (UDI) at 6 months. Secondary outcomes include change in UDI at 3 and 12 months, irritative and stress subscores of the UDI, urinary incontinence episodes, predictors of poor treatment response, quality of life and global impression outcomes, adverse events, use of additional treatments, and cost effectiveness. RESULTS: Recruitment and randomization of 150 participants is complete and participants are currently in the follow-up phase. CONCLUSIONS: This trial will provide information to guide care for women with MUI refractory to oral treatment who seek surgical treatment with either onabotulinumtoxinA or MUS.

Can we improve techniques and patients' selection for nerve stimulation suitable for lower urinary tract dysfunctions? ICI-RS 2023.

AIMS: Lower urinary tract dysfunctions (LUTD) are very common and, importantly, affect patients' quality of life (QoL). LUTD can range from urinary retention to urgency incontinence and includes a variety of symptoms. Nerve stimulation (NS) is an accepted widespread treatment with documented success for LUTD and is used widely. The aim of this review is to report the results of the discussion about how to improve the outcomes of NS for LUTD treatment. METHODS: During its 2023 meeting in Bristol, the International Consultation on Incontinence Research Society discussed a literature review, and there was an expert consensus discussion focused on the emerging awareness of NS suitable for LUTD. RESULTS: The consensus discussed how to improve techniques and patients' selection in NS, and high-priority research questions were identified. CONCLUSIONS: Technique improvement, device programming, and patient selection are the goals of the current approach to NS. The conditional nerve stimulation with minimally invasive wireless systems and tailored algorithms hold promise for improving NS for LUTD, particularly for patients with neurogenic bladder who represent the new extended population to be treated.

Which parameters, related to the female urethra and pelvic floor, determine therapy selection for recurrent female stress urinary incontinence: ICI-RS 2023?

INTRODUCTION: The evidence basis for therapy selection in women who have failed primary stress urinary incontinence (SUI) surgery is limited. The ICI-RS group discussed the available data at its meeting in June 2023, particularly the anatomical characteristics as assessed using magnetic resonance imaging (MRI) and ultrasound (US) modalities, functional characteristics associated with storage and voiding urodynamic assessment, as well as the patient characteristics that might influence outcomes. This paper summarizes the evidence base that supported these discussions and offers the basis for research proposals for future groups. METHODS: A literature search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was performed, and the data is presented. Research questions are based on the knowledge gaps highlighted. RESULTS: Possible MRI parameters that may influence outcomes were striated urethral sphincter volume, bladder and proximal urethral funneling, pubo-urethral ligament integrity, distance of the bladder neck below the pubococcygeal line, posterior urethra-vesical angle, and bladder neck to levator ani distance. US parameters included sling distance to the urethral lumen and pubis, sling position, bladder neck mobility, and lateral arm asymmetry, twisting, or curling. Urodynamic parameters included detrusor overactivity, Valsalva leak point pressure, maximum urethral closure pressure, and bladder outlet obstruction. Important patient parameters included body mass index, age, and previous interventions. CONCLUSIONS: Identifying and quantifying causative factors in patients with recurrent SUI, that allow clinicians to modify subsequent treatment choices and techniques may help reduce treatment failure and complications. Formulating algorithms is the next step in optimizing patient counseling, surgical selection, and healthcare allocation.

Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype.

INTRODUCTION AND OBJECTIVE: Interstitial cystitis and bladder pain syndrome (IC/BPS) presents with symptoms of debilitating bladder pain and is typically a diagnosis of exclusion. The cystoscopic detection of Hunner's lesions increases the likelihood of detecting tissue inflammation on bladder biopsy and increases the odds of therapeutic success with anti-inflammatory drugs. However, the identification of this subgroup remains challenging with the current lack of surrogate biomarkers of IC/BPS. On the path towards identifying biomarkers of IC/BPS, we modeled the dynamic evolution of inflammation in an experimental IC/BPS rodent model using computational biological network analysis of inflammatory mediators (cytokines and chemokines) released into urine. The use of biological network analysis allows us to identify urinary proteins that could be drivers of inflammation and could therefore serve as therapeutic targets for the treatment of IC/BPS. METHODS: Rats subjected to cyclophosphamide (CYP) injection (150 mg/kg) were used as an experimental model for acute IC/BPS (n = 8). Urine from each void was collected from the rats over a 12-h period and was assayed for 13 inflammatory mediators using Luminex™. Time-interval principal component analysis (TI-PCA) and dynamic network analysis (DyNA), two biological network algorithms, were used to identify biomarkers of inflammation characteristic of IC/BPS over time. RESULTS: Compared to vehicle-treated rats, nearly all inflammatory mediators were elevated significantly (p < 0.05) in the urine of CYP treated rats. TI-PCA highlighted that GRO-KC, IL-5, IL-18, and MCP-1 account for the greatest variance in the inflammatory response. At early time points, DyNA indicated a positive correlation between IL-4 and IL-1ß and between TNF-α and IL-1ß. Analysis of TI-PCA and DyNA at later time points showed the emergence of IL-5, IL-6, and IFNγ as additional key mediators of inflammation. Furthermore, DyNA network complexity rose and fell before peaking at 9.5 h following CYP treatment. This pattern of inflammation may mimic the fluctuating severity of inflammation associated with IC/BPS flares. CONCLUSIONS: Computational analysis of inflammation networks in experimental IC/BPS analysis expands on the previously accepted inflammatory signatures of IC by adding IL-5, IL-18, and MCP-1 to the prior studies implicating IL-6 and GRO as IC/BPS biomarkers. This analysis supports a complex evolution of inflammatory networks suggestive of the rise and fall of inflammation characteristic of IC/BPS flares.

Role of opioid and ß-adrenergic receptors in bladder underactivity induced by prolonged pudendal nerve stimulation in cats.

AIMS: To determine the role of opioid and ß-adrenergic receptors in bladder underactivity induced by prolonged pudendal nerve stimulation (PNS). METHODS: In α-chloralose anesthetized cats, 30-min PNS was applied repeatedly for 3-9 times to induce poststimulation or persistent bladder underactivity. Then, naloxone (opioid receptor antagonist, 1 mg/kg, IV) or propranolol (ß-adrenergic receptor antagonist, 3 mg/kg, IV) was given to reverse the bladder underactivity. After the drug treatment, an additional 30-min PNS was applied to counteract the drug effect. Repeated cystometrograms were performed by slowly (1-2 mL/min) infusing the bladder with saline via a urethral catheter to determine the bladder underactivity and the treatment effects. RESULTS: Prolonged (2-4.5 h) PNS induced bladder underactivity evident as a large bladder capacity (169 ± 49% of control) and a reduced amplitude of bladder contraction (59 ± 17% of control). Naloxone fully reversed the bladder underactivity by reducing bladder capacity to 113 ± 58% and increasing the amplitude of bladder contraction to 104 ± 34%. After administration of naloxone an additional 30-min PNS temporarily increased the bladder capacity to the underactive bladder level (193 ± 74%) without changing the amplitude of the bladder contraction. Propranolol had no effect on bladder underactivity. CONCLUSIONS: A tonic enkephalinergic inhibitory mechanism in the CNS plays a critical role in the bladder underactivity induced by prolonged PNS, while the peripheral ß-adrenergic receptor mechanism in the detrusor is not involved. This study provides basic science evidence consistent with the clinical observation that comorbid opioid usage may contribute to voiding dysfunction in patients with Fowler's syndrome.

Intraoperative Predictors of Sacral Neuromodulation Implantation and Treatment Response: Results From the ROSETTA Trial.

PURPOSE: We determined the utility of intraoperative data in predicting sacral neuromodulation outcomes in urgency urinary incontinence. MATERIALS AND METHODS: Intraoperative details of sacral neuromodulation stage 1 were recorded during the prospective, randomized, multicenter ROSETTA trial, including responsive electrodes, amplitudes, and response strengths (motor and sensory Likert scales). Stage 2 implant was performed for stage 1 success on 3-day diary with 24-month follow-up. An intraoperative amplitude response score for each electrode was calculated ranging from 0 (no response) to 99.5 (maximum response, 0.5 V). Predictors for stage 1 success and improvement at 24 months were identified by stepwise logistic regression confirmed with least absolute shrinkage and selection operator and stepwise linear regression. RESULTS: Intraoperative data from 161 women showed 139 (86%) had stage 1 success, which was not associated with number of electrodes generating an intraoperative motor and/or sensory response, average amplitude at responsive electrodes, or minimum amplitude-producing responses. However, relative to other electrodes, a best amplitude response score for bellows at electrode 3 was associated with stage 1 failure, a lower reduction in daily urgency urinary incontinence episodes during stage 1, and most strongly predicted stage 1 outcome in logistic modeling. At 24 months, those who had electrode 3 intraoperative sensory response had lower mean reduction in daily urgency urinary incontinence episodes than those who had no response. CONCLUSIONS: Specific parameters routinely assessed intraoperatively during stage 1 sacral neuromodulation for urgency urinary incontinence show limited utility in predicting both acute and long-term outcomes. However, lead position as it relates to the trajectory of the sacral nerve root appears to be important.

Does large volume of distribution of lidocaine masks its systemic uptake from bladder?

PURPOSE: To assess whether therapeutic and toxic effects of intravesical lidocaine are determined by coincident serum levels. MATERIAL AND METHODS: Published clinical trials and case studies on instilled lidocaine 1-2% that reported serum lidocaine levels were analyzed using model independent pharmacokinetic equations to compute the absorbed dose fraction (F) for linear regression with the respective dwell times. RESULTS: Rapid absorption of intravesical lidocaine is evinced by the serum levels of 0.16±0.3 mg/L at 5 min in bladder cancer patients coinciding with the rapid onset of pain relief (<5 min) and blood pressure drop (≥10 mm Hg) in spinal cord injured patients. Serum levels at 5 min are raised five-fold by alkalinization for a tertiary amine with pKa of 7.8 and a linear rise in F with longer dwell time (r2 = 0.80; P<0.005) conforms to passive, paracellular diffusion of amphiphilic lidocaine (log P of 1.68) around umbrella cell borders with absorption rate at least five times faster than the terminal elimination rate, and therefore the delay in blood sampling after instillation is unwarranted. A rapid resolution of therapeutic and toxic effects is predicated on the extensive dilution of absorbed lidocaine with a rapid distribution half-life of 3.6 min in body weight dependent Vd - 15 times larger than blood volume, 0.13-4.5 L/kg which necessitates dose adjustment in children. CONCLUSION: Whether rapid absorption of instilled lidocaine is complicated by an equally rapid and extensive dilution in body weight dependent Vd can be resolved by early blood sampling (<30 min) for: evidence-based medicine, avoidance of lidocaine toxicity in children and to educate the evolution of lidocaine solution to gel and devices.

Treating Lower Urinary Tract Symptoms in Older Adults: Intravesical Options.

This article provides an overview of the diagnosis and the treatment of lower urinary tract symptoms in older adults complicated by the neurodegenerative changes in the micturition reflex and further confounded by age-related decline in hepatic and renal clearance raising the propensity of adverse drug reactions. The first-line drug treatment for lower urinary tract symptoms, orally administered antimuscarinics, fails to reach the equilibrium dissociation constant of muscarinic receptors even at their maximum plasma concentration and tends to evoke a half-maximal response at a muscarinic receptor occupancy of just 0.206% in the bladder with a minimal difference from exocrine glands, which raises the adverse drug reaction risk. On the contrary, intravesical antimuscarinics are instilled at concentrations 1000-fold higher than the oral maximum plasma concentration and the equilibrium dissociation constant erects a downhill concentration gradient that drives passive diffusion and achieves a mucosal concentration around ten-fold lower than the instilled concentration for a long-lasting occupation of muscarinic receptors in mucosa and sensory nerves. A high local concentration of antimuscarinics in the bladder triggers alternative mechanisms of action and is supposed to engage retrograde transport to nerve cell bodies for neuroplastic changes that underlie a long-lasting therapeutic effect, while an intrinsically lower systemic uptake of the intravesical route lowers the muscarinic receptor occupancy of exocrine glands to lower the adverse drug reaction relative to the oral route. Thus, the traditional pharmacokinetics and pharmacodynamics of oral treatment are upended by intravesical antimuscarinics to generate a dramatic improvement (~ 76%) noted in a meta-analysis of studies enrolling children with neurogenic lower urinary tract symptoms on the primary endpoint of maximum cystometric bladder capacity as well as the secondary endpoints of filling compliance and uninhibited detrusor contractions. The therapeutic success of intravesical multidose oxybutynin solution or oxybutynin entrapped in the polymer for sustained release in the pediatric population bodes well for patients with lower urinary tract symptoms at the other extreme of the age spectrum. Though generally used to predict oral drug absorption, Lipinski's rule of five can also explain the ten-fold lower systemic uptake from the bladder of positively charged trospium over oxybutynin, a tertiary amine. Chemodenervation by an intradetrusor injection of onabotulinumtoxinA is merited for patients with idiopathic overactive bladder discontinuing oral treatment because of a lack of efficacy. However, age-related peripheral neurodegeneration potentiates the adverse drug reaction risk of urinary retention that motivates the quest of liquid instillation, delivering larger fraction of onabotulinumtoxinA to the mucosa as opposed to muscle by an intradetrusor injection can also probe the neurogenic and myogenic predominance of idiopathic overactive bladder. Overall, the treatment paradigm of lower urinary tract symptoms in older adults should be tailored to individual's overall health status and the risk tolerance for adverse drug reactions.

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.

Cost-effectiveness of overactive bladder treatments from a US commercial and payer perspective.

Aim: The cost-effectiveness of treatment options (anticholinergics, ß3-adrenoceptor agonists, onabotulinumtoxinA, sacral nerve stimulation and percutaneous tibial stimulation [the latter two including new rechargeable neurostimulators]) for the management of overactive bladder (OAB) were compared with best supportive care (BSC) using a previously published Markov model. Materials & methods: Cost-effectiveness was evaluated over a 15-year time horizon, and sensitivity analyses were performed using 2- and 5-year horizons. Discontinuation rates, resource utilization, and costs were derived from published sources. Results: Using Medicare and commercial costs over a 15-year time period, onabotulinumtoxinA 100U had incremental cost-effectiveness ratios (ICERs) gained of $39,591/quality-adjusted life-year (QALY) and $42,255/QALY, respectively, versus BSC, which were the lowest ICERs of all assessed treatments. The sensitivity analyses at 2- and 5-year horizons also showed onabotulinumtoxinA to be the most cost-effective of all assessed treatments versus BSC. Conclusion: OnabotulinumtoxinA 100U is currently the most cost-effective treatment for OAB.

Penile Erection Induced by Stimulation of Sacral S1/S2 Spinal Root in Cats.

OBJECTIVE: This study aimed at determining whether stimulation of sacral spinal roots can induce penile erection in cats. MATERIALS AND METHODS: In anesthetized cats, a 20-gauge catheter was inserted into the corpus cavernosum to measure the penile pressure. Stimulus pulses (5-80 Hz, 0.2 ms) were applied through bipolar hook electrodes to sacral ventral roots alone or to combined ventral and dorsal roots of a single S1-S3 segment to induce penile pressure increases and penile erection. RESULTS: Stimulation of the S1 or S2 ventral root at 30 to 40 Hz induced observable penile erection with rigidity and the largest increase (169 ± 11 cmH2O) in penile pressure. Continuous stimulation (10 minutes) of afferent and efferent axons by simultaneous stimulation of the S1 or S2 dorsal and ventral roots at 30 Hz also produced a large increase (190 ± 8 cmH2O) in penile pressure that was sustainable during the entire stimulation period. After a complete spinal cord transection at the T9-T10 level, simultaneous stimulation of the S1 or S2 dorsal and ventral roots induced large (186 ± 9 cmH2O) and sustainable increases in penile pressure. CONCLUSION: This study indicates the possibility to develop a novel neuromodulation device to restore penile erection after spinal cord injury using a minimally invasive surgical approach to insert a lead electrode through the sacral foramen to stimulate a sacral spinal root.

Vaginal Lubrication and Pressure Increase Induced by Pudendal Nerve Stimulation in Cats.

BACKGROUND: Vaginal lubrication and contractions are among the top difficulties affecting sexual intercourse in women after spinal cord injury. AIM: This study aimed at determining if pudendal nerve stimulation (PNS) can improve vaginal lubrication and induce increases in vaginal pressure. METHODS: In anesthetized cats, a small piece of cotton was inserted into the vagina for 10 minutes with or without PNS to measure vaginal wetness by the weight increase of the vaginal cotton. Then, a small balloon catheter was inserted into the vagina to measure the pressure increase induced by PNS. Intensity response of the vagina to PNS (30 Hz, 0.2 ms, 5 seconds) was determined at 1-4 times of intensity threshold (T) for PNS to induce an observable vaginal pressure increase. Frequency response was determined at 2T intensity in a range of PNS frequencies (5-50 Hz). Finally, fatigue in vaginal pressure was determined by applying PNS (30 Hz, 2T) either continuously or intermittently (5 seconds on and 5 seconds off) for 4 minutes. OUTCOMES: The effectiveness of PNS in increasing vaginal wetness and pressure is evaluated. RESULTS: PNS significantly (P = .0327) increased the measurement of vaginal wetness from 15.8 ± 3.8 mg during control without stimulation to 32.4 ± 4.7 mg after stimulation. Vaginal pressure increased as PNS intensity or frequency increased. PNS (30 Hz, 2T) induced vaginal pressure increase ≥80% of the maximal response. Intermittent PNS induced significantly (P = .0354) smaller fatigue (45.6 ± 3.7%) in vaginal pressure than continuous PNS (69.1 ± 3.0%) during the 4-minute stimulation. CLINICAL TRANSLATION: This study raises the possibility of developing a novel pudendal neuromodulation device to improve female sexual function after spinal cord injury. STRENGTHS & LIMITATIONS: This study provides preclinical data supporting the development of a novel pudendal neuromodulation device. The limitation includes the lack of chemical analysis of the vaginal secretion. CONCLUSION: PNS can improve vaginal lubrication and induce increases in vaginal pressure. Chen J, Zhong Y, Wang J, et al. Vaginal Lubrication and Pressure Increase Induced by Pudendal Nerve Stimulation in Cats. J Sex Med 2022;19:1517-1523.

Potential role of oxidative stress in the pathogenesis of diabetic bladder dysfunction.

Diabetes mellitus is a chronic metabolic disease, posing a considerable threat to global public health. Treating systemic comorbidities has been one of the greatest clinical challenges in the management of diabetes. Diabetic bladder dysfunction, characterized by detrusor overactivity during the early stage of the disease and detrusor underactivity during the late stage, is a common urological complication of diabetes. Oxidative stress is thought to trigger hyperglycaemia-dependent tissue damage in multiple organs; thus, a growing body of literature has suggested a possible link between functional changes in urothelium, muscle and the corresponding innervations. Improved understanding of the mechanisms of oxidative stress could lead to the development of novel therapeutics to restore the redox equilibrium and scavenge excessive free radicals to normalize bladder function in patients with diabetes.

Changes in brain response to urgency before and after treatment of urgency urinary incontinence with onabotulinumtoxin A.

INTRODUCTION: To better understand the role of the brain in urgency urinary incontinence (UUI), we used onabotulinumtoxin A (BoNTA) as a probe to evaluate changes in the brain's response to urgency in successful and unsuccessful treatment. Because BoNTA acts peripherally, brain changes observed should represent a reaction to changes in bladder function caused by BoNTA, or changes in the brain's compensatory mechanisms, rather than a direct effect of BoNTA on the brain. METHODS: We recruited 20 women aged over 60 years with nonneurogenic UUI who were to undergo treatment with onabotulinum A toxin injected intravesically. We performed a baseline evaluation which included a 3-day bladder diary and functional magnetic resonance imaging with an urgency provocation task; we repeated this evaluation 6 weeks posttreatment. We performed an analysis of variance on a priori selected regions of interest and post hoc voxel-wise analysis on responders and nonresponders to treatment. RESULTS: We found a significant interaction in the right insula [F(1,18) = 5.5, p = 0.031]; activity was different during urgency provocation in responders and non-responders to therapy, before and after therapy. The supramarginal gyrus (SMG) and inferior frontal gyrus (IFG) also displayed significant interactions (p < 0.005). Activity in the periaqueductal gray and prefrontal cortex was correlated with number of leakage episodes (p < 0.05). CONCLUSION: The changes seen in the brain control mechanism after therapy likely reflect reduced bladder sensation caused by BoNTA's peripheral action. We ascribe the SMG and IFG changes to a coping mechanism for urgency which is reduced in those who respond well to treatment.

Intravesical Instillation of OnabotulinumtoxinA in the Treatment of Refractory Overactive Bladder in Participants with Urinary Incontinence.

PURPOSE: Intradetrusor injections of onabotulinumtoxinA are efficacious for the treatment of overactive bladder with urgency urinary incontinence in adults refractory to or intolerant of anticholinergics. Delivery of onabotulinumtoxinA via instillation would reduce the need for intradetrusor injections. The objective of this trial was to assess the efficacy and safety of intravesical instillation of an onabotulinumtoxinA + hydrogel admixture. MATERIALS AND METHODS: After review of a stage 1 safety phase by an independent committee, participants were recruited into stage 2 and randomized to either onabotulinumtoxinA 100, 300, 400, or 500 U, or placebo, all with hydrogel admixture. End points included change from baseline to week 12 in the number of urinary incontinence episodes (primary); micturition, urgency urinary, and nocturia episodes/day; volume voided per micturition; proportion of participants with a ≥50% decrease from baseline in urinary incontinence episodes/day; and Overactive Bladder Questionnaire total score. Adverse events were reported. RESULTS: Change from baseline to week 12 in number of urinary incontinence episodes was -2.72 with placebo and ranged from -0.89 to -1.85 in the onabotulinumtoxinA + hydrogel treatment groups. No difference from placebo was observed for any efficacy end point. The proportions of participants with treatment-emergent adverse events were similar among all groups, with asymptomatic bacteriuria the highest reported (6.7%-15.5%). There were no reports of urinary retention or elevated post-void residual volume. CONCLUSIONS: Intravesical instillation of an onabotulinumtoxinA + hydrogel admixture for the treatment of refractory overactive bladder was well tolerated, but it showed no improvement over placebo.

Pharmacologic Management of Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as persistent or chronic discomfort perceived to be related to the urinary bladder accompanied by urinary urgency or frequency. Pharmacotherapies used to treat IC/BPS include oral and intravesical agents. Oral therapies include amitriptyline, hydroxyzine, cyclosporine A, and pentosan polysulfate sodium (PPS), although the recent finding of pigmented maculopathy with chronic PPS is very concerning and must be discussed with patients, many of whom will choose to either come off this medicine or not even start it. Certolizumab pegol is a pharmacologic therapy that is currently in clinical development for treatment of IC/BPS symptoms.

Role of hyperpolarization-activated cyclic nucleotide-gated channels in aging bladder phenotype.

OBJECTIVE: To assess the functional role of Hyperpolarization-activated cyclic nucleotide-gated gated channel (HCN) subtypes in the aging bladder phenotype characterized by diminished bladder volume sensation (BVS) with or without the detrusor instability (DI). METHODS: Expression of HCN subtypes was examined by quantitative RT-PCR and Western blot in aged male Fisher 344 rats (n = 15) and young rats (n = 15). Nocturnal urination and awake cystometry (CMG) were assessed in presence and absence of a steady state HCN channel blockade achieved with daily oral gavage of vehicle or Ivabradine (HCN blocker) 6 mg/kg for 7 days. RESULTS: The association of BVS with the age-related downregulation (~30%) of cAMP sensitive HCN1, HCN2 subtypes, and (~50%) upregulation of cAMP insensitive HCN3 subtype is evinced by the doubling in the mean urine volume of nocturnal voids (0.82 ± 0.22 mL vs 0.41 ± 0.12 mL; n = 10; p < 0.05) predicting an age-related rise in the micturition volume threshold (p < 0.0001) in CMG, which is raised further by Ivabradine treatment (p < 0.0005). Ivabradine also doubled non-voiding contractions (NVC) and maximum voiding pressure (MVP) in young and aged rats, respectively (p < 0.0001) to abolish the age-related, innate two -fold elevation in NVC not accompanied with MVP rise in untreated aged rats (p < 0.005). CONCLUSION: The age-related HCN downregulation is mechanistically linked to the exhibition of aging bladder phenotype with the manifestation of DI following steady state blockade of HCN channels in Ivabradine treated young rats. The amplification of MVP in aged rats mediated by FDA approved Ivabradine hints at potential repurposing opportunity in detrusor underactivity.