Who Progresses to Third-Line Therapies for Overactive Bladder? Trends From the AQUA Registry.

INTRODUCTION: Overactive bladder (OAB) patients who do not achieve satisfactory results with second-line OAB medications should be offered third-line therapies (percutaneous tibial nerve stimulation, sacral neuromodulation, onabotulinumtoxinA bladder injection [BTX-A]). We aimed to determine which clinical factors affect progression from second- to third-line OAB therapy. METHODS: Between 2014 and 2020, the AUA Quality Registry was queried for adult patients with idiopathic OAB. For the primary outcome, patient and provider factors associated with increased odds of progression from second- to third-line therapy were assessed. Secondary outcomes included median time for progression to third-line therapy and third-line therapy utilization across subgroups. RESULTS: A total of 641,122 patients met inclusion criteria and were included in analysis. Of these, only 7487 (1.2%) received third-line therapy after receiving second-line therapy. On multivariate analysis, patients aged 65 to 79, women, White race, history of dual anticholinergic and ß3 agonist therapy, metropolitan area, government insurance, and single specialty practice had the greatest odds of progressing to third-line therapy. Black and Asian race, male gender, and rural setting had lower odds of progressing to third-line therapy. BTX-A was the most common therapy overall (40% BTX-A, 32% sacral neuromodulation, 28% percutaneous tibial nerve stimulation). The median time of progression from second- to third-line therapy was 15.4 months (IQR 5.9, 32.4). Patients < 50 years old and women progressed fastest to third-line therapy. CONCLUSIONS: Very few patients received third-line therapies, and the time to progression from second- to third-line therapies is > 1 year. The study findings highlight a potential need to improve third-line therapy implementation.

Restoring both continence and micturition after chronic spinal cord injury by pudendal neuromodulation.

Neurogenic bladder management after spinal cord injury (SCI) is very challenging. Daily urethral catheterization is most commonly used to empty the bladder, which causes frequent infections of the lower urinary tract. This study reports a novel idea to restore both continence and micturition after SCI by an implantable pudendal nerve stimulator (PNS). The PNS was surgically implanted in four cats with complete SCI at T9-T10 spinal level and tested weekly for 13-14 weeks under awake conditions. These chronic SCI cats consistently exhibited large residual bladder volumes (average 40-50 ml) due to their inability to void efficiently, while urine leakage also occurred frequently. The PNS which consisted of stimulating the pudendal nerve at 20-30 Hz to trigger a spinal reflex bladder contraction and at the same time blocking the pudendal nerves bilaterally with 10 kHz stimulation to relax the external urethral sphincter and reduce the urethral outlet resistance successfully induced highly efficient (average 80-100%), low pressure (<50 cmH2O) voiding. The PNS at 5 Hz also promoted urine storage by inhibiting reflex bladder activity and increasing bladder capacity. At the end of 14-week chronic testing, low pressure efficient voiding induced by PNS was further confirmed under anesthesia by directly measuring voiding pressure using a bladder catheter inserted through the bladder dome. This study demonstrated the efficacy and safety of the PNS in awake chronic SCI cats, suggesting that a novel neuroprosthesis can be developed for humans to restore bladder function after SCI by stimulating and/or blocking the pudendal nerves.

Superficial peroneal neuromodulation of nonobstructive urinary retention in cats.

AIMS: To determine if superficial peroneal nerve stimulation (SPNS) can improve nonobstructive urinary retention (NOUR). METHODS: In α-chloralose anesthetized cats, NOUR was induced by repetitive application (4-16 times) of 30-minute tibial nerve stimulation (TNS: 5 Hz frequency, 0.2 ms pulse width) at 4 to 6 times threshold intensity (T) for inducing toe twitches. SPNS (1 Hz, 0.2 ms) at 2 to 4 times threshold intensity (T) for inducing posterior thigh muscle contractions was applied either continuously (SPNSc) during a cystometrogram (CMG) or during voiding (SPNSv) by a surgically implanted cuff electrode or by skin surface electrodes to determine if the stimulation reduced NOUR induced by prolonged TNS. RESULTS: During control CMGs, efficient (86.4% ± 5.5%) voiding occurred with a postvoid residual (PVR) volume equal to 14.9% ± 6.2% of control bladder capacity. NOUR elicited by prolonged TNS significantly (P < .05) increased bladder capacity to 168.6% ± 15.5% of control, reduced voiding efficiency to 30.4% ± 4.8%, and increased PVR to 109% ± 9.2% of control. Using the implanted cuff electrode, SPNSc and SPNSv significantly (P < .05) increased voiding efficiency to 66.7% ± 7.4% and 65.0% ± 5.9%, respectively, and reduced PVR to 52.2% ± 11.4% and 64.3% ± 11.6%, respectively. SPNSc but not SPNSv significantly (P < .05) reduced bladder capacity to 133.4% ± 15% of control. Transcutaneous SPNSv but not SPNSc also significantly (P < .05) reversed the TNS-induced NOUR responses. CONCLUSIONS: This study shows that SPNS is effective in reversing NOUR induced by prolonged TNS. Transcutaneous SPNS provides the opportunity to develop a noninvasive neuromodulation therapy for NOUR to treat more patients than current sacral neuromodulation therapy.

Microbe-Derived Butyrate and Its Receptor, Free Fatty Acid Receptor 3, But Not Free Fatty Acid Receptor 2, Mitigate Neointimal Hyperplasia Susceptibility After Arterial Injury.

Background Arterial restenosis after vascular surgery is a common cause of midterm restenosis and treatment failure. Herein, we aim to investigate the role of microbe-derived butyrate, FFAR2 (free fatty acid receptor 2), and FFAR3 (free fatty acid receptor 3) in mitigating neointimal hyperplasia development in remodeling murine arteries after injury. Methods and Results C57BL/6 mice treated with oral vancomycin before unilateral femoral wire injury to deplete gut microbiota had significantly diminished serum and stool butyrate and more neointimal hyperplasia development after arterial injury, which was reversed by concomitant butyrate supplementation. Deficiency of FFAR3 but not FFAR2, both receptors for butyrate, exacerbated neointimal hyperplasia development after injury. FFAR3 deficiency was also associated with delayed recovery of the endothelial layer in vivo. FFAR3 gene expression was observed in multiple peripheral arteries, and expression was increased after arterial injury. Treatment of endothelial but not vascular smooth muscle cells with the pharmacologic FFAR3 agonist 1-methylcyclopropane carboxylate stimulated cellular migration and proliferation in scratch assays. Conclusions Our results support a protective role for butyrate and FFAR3 in the development of neointimal hyperplasia after arterial injury and delineate activation of the butyrate-FFAR3 pathway as a valuable strategy for the prevention and treatment of neointimal hyperplasia.