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Background: Fecal incontinence, constipation, and pelvic pain are common pelvic floor symptoms (PFS), and frequently coexist with lower urinary tract symptoms (LUTS). However, their association with the longitudinal trajectory of LUTS have not been well described. Our objective was to investigate the association between PFS and the course of LUTS in community-dwelling men and women., Methods: Men and women aged ≥16 years were invited to participate in a prospective observational cohort study. At baseline, and after 12 and 24 months, participants filled in the International Consultation on Incontinence Modular Questionnaire (ICIQ-MLUTS and ICIQ-FLUTS) for men and women respectively, the Wexner incontinence and constipation scale, and a questionnaire on pelvic pain. Generalized estimating equations were used to examine the association between change scores in defecation problems and pelvic pain, and LUTS change scores., Results: A total of 694 men and 997 women gave informed consent, with 417 men and 566 women included in the analysis. The mean age was 63.2 ± 12.7 years for men and 58.6 ± 14.8 years for women. The study showed minor changes in LUTS scores over the 0-12 and 12-24-month periods. Generalized estimating equations revealed positive associations between changes in constipation and fecal incontinence and LUTS changes in both sexes. For instance, a one-point increase in Wexner constipation score was associated with 0.376 (0.165, 0.587) points higher LUTS change in men and 0.223 (0.109, 0.336) points in women during the 0-12-month follow-up. However, associations between changes in pain and LUTS scores varied across sexes and time periods., Conclusions: We observed minor changes in LUTS over time and weak associations between PFS and LUTS that sometimes differed between males and females, emphasizing the need for sex-specific considerations. These insights can provide valuable guidance for the development of targeted prevention trials, ultimately aiming to enhance overall pelvic health and patient well-being., (© 2024 The Author(s). Neurourology and Urodynamics published by Wiley Periodicals LLC.)

The closure of the urethra under the condition of stress is the result of a reflex contraction of the urethral rhabdosphincter and pelvic floor muscles. This is likely induced by activity of the abdominal muscles due to a sudden increase in abdominal pressure. This reflex contraction with an increase of urethral pressure occurs a few milliseconds before an increase in intraabdominal pressure. The urethral pressure increase during stress is only possible with fixation of the urethra by the pubourethral ligaments (PUL), facilitating urethral kinking. The highest and most important increase in pressure and resistance occurs in the distal urethra due to this kinking of the urethra., (© 2024 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background and Objective: The aim of the present report was to provide an overview of the use of the artificial urinary sphincter (AUS) in adult females with stress urinary incontinence (SUI) over the past 50 years., Methods: A literature search was conducted in December 2022 and January 2023 using the MEDLINE and Embase databases, screening for randomized controlled trials (RCTs), prospective and retrospective series and reviews on AUS. Only articles published in English or French were included. The search strategy involved a free text protocol and the narrative review reporting checklist was completed., Key Content and Findings: The AUS is a device used over the past 50 years for SUI caused by intrinsic sphincter deficiency (ISD). It has the theoretical ability to simulate the function of a biological urinary sphincter. Although the role of the AUS for females with ISD remains heterogeneous from one part of the world to the other, the existing literature demonstrates that AUS yields satisfactory functional outcomes in female SUI patients, comparable or better to what has been reported in male AUS series. Hence, the main barrier to its adoption has so far been the technical challenge of its implantation at the bladder neck. Regarding the results of AUS implantation in females, we included in this review 3 reviews, retrospective studies and 1 prospective study. In recent years, robotic techniques of female AUS implantation have spread significantly with promising outcomes including numerous reports suggesting that it may decrease its morbidity. In the near future, the development of electromechanical devices may further expand the role of AUS in the management of female SUI., Conclusions: While the use of AUS in female patients provides excellent functional outcomes, it has been limited to scarce centers. However, due to the rise of minimally invasive approaches, it has started spreading again over the past few years. The future of AUS is likely to be bright, fed by technological advances of the device and robotic surgical system, high level of evidence studies and joint efforts of the urological community to facilitate its diffusion across the world., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-23-58/coif). The series “50 Years Anniversary of the Modern Artificial Urinary Sphincter” was commissioned by the editorial office without any funding or sponsorship. E.C.K., T.G., R.K., G.A.V.K., F.V.D.A. and B.P. are consultants for Boston Scientific. BP is also a consultant for Intuitive Surgical, Medtronic, and IBSA and has received speakers’ fees from Pierre Fabre, Abbvie, and IPSEN. GAVK has received payment for expert testimony from Solace Therapeutics. The authors have no other conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

Objectives: Neuroimaging studies have advanced our understanding of the intricate central nervous system control network governing lower urinary tract (LUT) function, shedding light on mechanisms for urine storage and voiding. However, a lack of consensus in methodological approaches hinders the comparability of results among research groups and limits the translation of this knowledge to clinical applications, emphasizing the need for standardized methodologies and clinical utilization guidelines., Methods: This paper reports the discussions of a workshop at the 2023 meeting of the International Consultation on Incontinence Research Society, which reviewed uncertainties and research priorities to progress the field of neuroimaging in LUT control and dysfunction., Results: Neuroimaging holds great potential for improving our understanding of LUT control and pathophysiological conditions. To date, functional neuroimaging techniques have not yet achieved sufficient strength to make a direct clinical impact. Potential approaches that can improve the clinical utilization of neuroimaging were discussed and research questions proposed., Conclusions: Neuroimaging offers a valuable tool for investigating LUT control, but it's essential to acknowledge the potential for oversimplification when interpreting brain activity due to the complex neural processing and filtering of sensory information. Moreover, technical limitations pose challenges in assessing key brain stem and spinal cord centers, particularly in cases of neurological dysfunction, highlighting the need for more reliable imaging of these centers to advance our understanding of LUT function and dysfunction., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Objectives: Currently, sacral neuromodulation (SNM) outcomes are often suboptimal, and changing stimulation parameters might improve SNM efficacy. Burst stimulation mimics physiological burst firing of the nervous system and might therefore benefit patients treated with SNM. The purpose of the present pilot study was to evaluate the effect of various Burst SNM paradigms on bladder and urethral pressure in patients with overactive bladder (OAB) or nonobstructive urinary retention (NOUR)., Materials and Methods: The bladder was filled to 50% of its capacity under general anesthesia in six patients with an implanted sacral lead for SNM purposes. Bladder pressure, and mid- and proximal urethral pressure were measured using conventional (Con-) SNM and various Burst SNM paradigms (10-20-40 Hz interburst frequency) with increasing amplitudes up to 5 mA for Con-SNM and 4 mA for Burst SNM., Results: Burst SNM caused a substantial increase in both bladder and urethral pressure. In contrast, Con-SNM caused a milder increase in urethral pressure, and only one patient showed a modest increase in bladder pressure. Furthermore, the pressure increase was higher in the proximal urethra than in the midurethra using Burst-SNM, whereas Con-SNM caused comparable increases in proximal and midurethra pressure., Conclusions: Burst SNM induces bladder contraction compared with Con-SNM and induces higher pressure increases in bladder and proximal urethra than does Con-SNM in patients with OAB or NOUR, indicating a higher degree of autonomic nervous system stimulation. The observed responses could not be fully explained by the total charge of the Burst SNM paradigms, which suggests the importance of individual Burst SNM parameters, such as frequency and amplitude. Future studies should assess the feasibility and efficacy of Burst SNM in awake patients., Competing Interests: Conflict of Interest Stefan De Wachter is a consultant for Medtronic, receives a research grant from Medtronic, and is cofounder and shareholder in Amber Therapeutics. The remaining authors reported no conflict of interest., (Copyright © 2024 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Nocturia, the need to urinate at night, is a common symptom in patients with obstructive sleep apnoea (OSA). Continuous positive airway pressure treatment can reduce nocturia in some patients, but the underlying mechanisms are complex and not fully understood. OSA affects the autonomic nervous system, oxidative stress and endothelial damage. Furthermore, the commonly held theory attributing polyuria to a false signal of cardiac overload and response natriuresis has limitations. A comprehensive approach to the management of nocturia in OSA, considering factors such as comorbidities, medication use, alcohol consumption and lifestyle, is needed. Effective management of nocturia in OSA requires a multidisciplinary approach, and urologists should be aware of the potential effect of OSA on physiology and refer patients for further testing at a sleep centre. In addition to continuous positive airway pressure, other interventions such as oral appliances and surgical obstruction treatment could be beneficial for some patients. Overall, understanding the complex interplay between OSA and nocturia is crucial for optimizing patient outcomes., (© 2024. Springer Nature Limited.)

Background: Adverse childhood events (ACEs) are prevalent and lead to well-established adverse health sequelae in adulthood. Recent literature has claimed that exposure to trauma in early life may worsen lower urinary tract symptoms (LUTS) because emotion can alter the perception of bodily distress in the brain. Specifically, depressive symptoms might influence the association between ACEs and LUTS. We aimed to describe the associations between ACEs and LUTS among males and females and to determine whether depressive symptoms mediated these associations., Methods: This study was a secondary analysis of the Coevorden observational cohort study (n = 1691, age ≥16 years). For this observational study participants filled in the male or female modules of the International Consultation on Incontinence Questionnaire for LUTS (ICIQ-MLUTS and ICIQ-FLUTS, respectively), the NEMESIS Childhood Trauma Questionnaire (emotional neglect, psychological abuse, physical abuse, and sexual abuse within the family), and the Patient Health Questionnaire (PHQ-9) for depression., Results: Overall, 564 males and 811 females answered all required items related to LUTS and ACEs. A series of regression models were then estimated to test for mediation: LUTS on ACEs, depression on ACEs, and LUTS on both ACEs and depression. The models were also adjusted for the following covariates: age, body mass index, diabetes mellitus, current smokers, educational level, and vaginal delivery (if female). Depressive symptoms were shown to mediate the association between ACEs and LUTS in both males and females., Conclusion: Childhood adversity and depression are areas of interest during the clinical assessment of patients with LUTS. Early detection of these conditions might help to manage risk, aid in the prevention of LUTS, and facilitate trauma-informed care., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Purpose: The prevalence of lower urinary tract symptoms (LUTS), characterized by problems regarding storage and/or voiding of urine, is known to significantly increase with age. Effective communication between the lower urinary tract and the central nervous system (CNS) is essential for the optimal function of this system, and heavily relies on the efficient interaction between the bladder urothelium and the afferent nerve fibers situated in close proximity to the urothelium within the lamina propria., Methods: We aimed to quantify aging-related differences in the expression of calcitonin gene-related peptide (CGRP, an established marker for sensory nerve fibers) in the trigonal mucosal layers of young (3-4 months) and aged (25-30 months) rats. We evaluated trigonal tissue from 3 animals per age group. Tissue was serially sectioned at 10 μm and stained for CGRP. Images were taken along the full length of the tissue. For each image we computed the total CGRP-positive area (μm2) and the median value for each animal was used for further analysis., Results: Upon statistical analysis the aged rats show a significantly lower CGRP-positive area compared to young rats (P=0.0049). These results indicate that aging has a negative effect on the area of CGRP-positive signal in the trigone., Conclusion: The structural and functional integrity of the sensory web in the trigonum of rats is negatively affected by the aging process, potentially leading to impaired communication between the bladder urothelium the CNS. Consequently, these perturbations in the sensory system may contribute to the pathogenesis or exacerbation LUTS.

Objective: To review the effect of bladder outlet procedures on urodynamic outcomes and symptom scores in males with detrusor underactivity (DU) or acontractile detrusors (AD)., Materials and Methods: We performed a systematic review and meta-analysis of research publications derived from PubMed, Embase, Web of Science, and Ovid Medline to identify clinical studies of adult men with non-neurogenic DU or AD who underwent any bladder outlet procedure. Outcomes comprised the detrusor pressure at maximum flow (P det Q max ), maximum flow rate (Q max ), international prostate symptom score (IPSS), and quality of life (QoL). This study is registered under PROSPERO CRD42020215832., Results: We included 13 studies of bladder outlet procedures, of which 6 reported decreased and 7 reported improved P det Q max after the procedure. Meta-analysis revealed an increase in the pooled mean P det Q max of 5.99 cmH 2 0 after surgery (95% CI: 0.59-11.40; p = 0.03; I 2 95%). Notably, the P det Q max improved in all subgroups with a preoperative bladder contractility index (BCI) <50 and decreased in all subgroups with a BCI ≥50. All studies reported an improved Q max after surgery, with a pooled mean difference of 5.87 mL/s (95% CI: 4.25-7.49; I 2 93%). Only three studies reported QoL, but pooling suggested significant improvements after surgery (mean, -2.41 points; 95% CI: -2.81 to -2.01; p = 0.007). All seven studies reporting IPSS demonstrated improvement (mean, -12.82; 95% CI: -14.76 to -10.88; p < 0.001)., Conclusions: This review shows that P det Q max and Q max increases after surgical bladder outlet procedures in men with DU and AD. Bladder outlet procedures should be discussed as part of the shared decision-making process for this group. The evidence was of low to very low certainty., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Aims: Pelvic floor symptoms (PFS), including lower urinary tract symptoms, defecation problems, sexual dysfunction, and pelvic pain, are common in males and females. Comparing pelvic floor musculature (PFM) function between sexes may reveal important differences relevant to clinical care. This study aimed to compare male and female PFM function and to assess the function of both sexes with the number and type of PFS., Methods: We purposively enrolled males and females aged ≥ 21 years with 0-4 PFS based on questionnaire responses in an observational cohort study. Participants then underwent PFM assessment, and muscle function in the external anal sphincter (EAS) and puborectal muscle (PRM) were compared between sexes. The relationships between muscle function and the number and type of PFS were explored., Results: Of the invited 400 males and 608 females, 199 and 187 underwent PFM assessment, respectively. Compared with females, males more often showed increased EAS and PRM tone during assessments. Compared with males, females more often showed weaker maximum voluntary contraction (MVC) of the EAS and dysfunctional endurance of both muscles; additionally, those with zero or one PFS, sexual dysfunction, and pelvic pain more often showed a weak MVC of the PRM., Conclusions: Despite a few similarities between males and, females we found differences in muscle tone, MVC, and endurance between male and female PFM function. These findings provide useful insights into the differences in PFM function between males and females., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: We aimed to study the test-retest reliability of the Multiple Array Probe Leiden (MAPLe), a multiple electrode probe designed to acquire and discriminate electromyography signals in the pelvic floor muscles, in men with lower urinary tract symptoms (LUTS)., Methods: Adult male patients with LUTS with sufficient knowledge of Dutch language, but without complications (e.g., urinary tract infection), or previous urologic cancer and/or urologic surgery were enrolled. In the initial study, next to physical examination and uroflowmetry, all men underwent MAPLe assessment at baseline and after 6 weeks. Second, participants were reinvited for a new assessment using a stricter protocol. A time interval of 2 h (M2) and 1 week (M3) after baseline (M1) allowed the calculation of the intraday agreement (M1 vs. M2), and the interday agreement (M1 vs. M3) for all 13 MAPLe variables., Results: The outcomes of the initial study in 21 men suggested a poor test-retest reliability. The second study in 23 men showed a good test-retest reliability with intraclass correlations ranging from 0.61 (0.12-0.86) to 0.91 (0.81-0.96). The agreement was generally higher for the intraday determinations than for the interday determinations., Conclusions: This study revealed a good test-retest reliability of the MAPLe device in men with LUTS, when using a strict protocol. With a less strict protocol, the test-retest reliability of MAPLe was poor in this sample. To make valid interpretations of this device in a clinical or research setting, a strict protocol is needed., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

The aim of this opinion paper is to determine the entities that define the maximal urethral pressure (MUP) during rest and during bladder filling that is needed to guarantee continence in females. For the development of this opinion, the literature was searched for via the Pubmed database and historic sources. Animal studies indicate that the maximal urethral pressure is determined by the smooth muscle activity in the mid-urethra. Additionally, during increased smooth muscle tone development, the largest sympathetic responses are found in the middle part of the urethra. This could be confirmed in human studies that are unable to find striated EMG activity in this area. Moreover, the external urethral striated sphincter is situated at the distal urethra, which is not the area with the highest pressure. The external urethral sphincter only provides additional urethral pressure in situations of exertion and physical activity. From a physics point of view, the phasic pressure of the external striated sphincter at the distal urethra cannot be added to the tonic pressure generated by the smooth muscle in the mid-urethra. The assertion that mid-urethral pressure is the result of different pressure forces around the urethra, including that of the external striated sphincter, is not supported by basic research evidence combined with physical calculation and should therefore be considered a misconception in the field of functional urology.

The pathophysiological mechanisms of overactive bladder syndrome (OAB) remain largely unknown, with major involvement of the central nervous system (CNS). The periaqueductal gray (PAG) is a brainstem area which is indicated to play an essential role in bidirectional communication between the bladder and the CNS. We aimed to assess consistency of PAG functional organization across different bladder sensory states in OAB patients. We propose, that PAG functional organization patterns across sensory states will differ between controls and OAB patients. We analyzed fMRI scans at 7 Tesla from six controls and two OAB patients. The Louvain module detection algorithm was applied to parcellate the PAG in empty and full bladder states. We assessed within-subject consistency and investigated differences in this consistency between both groups. High within-subject agreement of PAG parcellations between empty and full bladder states was demonstrated in both groups. Additionally, we showed that the correlations between PAG clusters in both bladder states were significantly different in patients compared to controls ( p = 0.039). The methods introduced here offer a promising tool to assess functional organization of the PAG and understand the underlying pathology and the role of this region in OAB syndrome.

Aim: Due to the introduction of a new implantable pulse generator (IPG), the Interstim II, patients with either a dynamic graciloplasty or an abdominally placed IPG for sacral neuromodulation could not undergo surgery to replace their IPG in the case of end of battery life. For these patients, the Medtronic Replacement Adaptor 09106 was created. This retrospective case series aims to study safety and feasibility of the Medtronic Replacement Adaptor 09106 in patients with abdominally placed IPGs., Methods: Seventeen patients (11 women, six men) received a replacement adaptor with a follow-up of 6 months. Outcome measures consisted of a bowel habit diary. Adverse events were classified using the Clavien-Dindo classification., Results: Outcome measures in the bowel habit diaries after replacement (feasibility) did not differ significantly from outcome measures before replacement. Adverse events occurred in four out of 17 patients (24%): two patients initially showed pocket site pain (Clavien-Dindo Grade I), which resolved without intervention. One patient suffered from poor wound closure (Clavien-Dindo Grade II) and one patient had persisting pocket pain (Clavien-Dindo Grade IIIa) for which a pocket revision was performed. Statistical analyses were performed making paired comparisons using a Wilcoxon signed rank test., Conclusion: The Medtronic Replacement Adaptor 09106 is a valuable option for patients with dynamic graciloplasty or sacral neuromodulation and abdominal IPG and has complication rates similar to replacement of the Interstim without Replacement Adaptor 09106., (© 2022 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Purpose: Substantive evidence supports a role of chronic stress in the development, maintenance, and even enhancement of functional bladder disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Increased urinary frequency and bladder hyperalgesia have been reported in rodents exposed to a chronic stress paradigm. Here, we utilized a water avoidance stress (WAS) model in rodents to investigate the effect of chronic stress on vascular perfusion and angiogenesis., Methods: Female Wistar-Kyoto rats were exposed to WAS for 10 consecutive days. Bladder neck tissues were analyzed by western immunoblot for vascular endothelial growth factor (VEGF) and nerve growth factor precursor (proNGF). Vascular perfusion was assessed by fluorescent microangiography followed by Hypoxyprobe testing to identify regions of tissue hypoxia., Results: The expression of VEGF and proNGF in the bladder neck mucosa was significantly higher in the WAS rats than in the controls. There was a trend toward increased vascular perfusion, but without a statistically significant difference from the control group. The WAS rats displayed a 1.6-fold increase in perfusion. Additionally, a greater abundance of vessels was observed in the WAS rats, most notably in the microvasculature., Conclusion: These findings show that chronic psychological stress induces factors that can lead to increased microvasculature formation, especially around the bladder neck, the region that contains most nociceptive bladder afferents. These findings may indicate a link between angiogenesis and other inflammatory factors that contribute to structural changes and pain in IC/BPS.

Objectives: Researchers and clinicians tend to focus on one pelvic floor symptom (PFS) at the time. However, the pelvic floor acts as one functional unit, increasing the likelihood of concurrent PFS in patients with pelvic floor dysfunction. There is also a paucity of literature on the prevalence of concomitant PFS, especially in males. Therefore, we explored the occurrence of concomitant PFS in community-dwelling males and females., Materials and Methods: This prospective observational population-based cohort study included males and females aged ≥16 years from a single Dutch municipality. Participants completed validated questionnaires on lower urinary tract symptoms (LUTS), defecation problems, sexual dysfunction, pelvic pain, and pelvic organ prolapse. Medical general practitioner records were examined. Furthermore, a randomly selected group of non-responders aged &lt;80 years received a short questionnaire, to study response bias., Results: We invited 11 724 people, among which 839 females and 566 males completed the questionnaires. Of the female participants, 286 (34.1%) reported no PFS, and 251 (29.9%) reported two or more PFS. The most prevalent PFS clusters in females were sexual dysfunction and pelvic pain, sexual dysfunction and defecation problems, LUTS and defecation problems, and LUTS, defecation problems, and pelvic pain. Of the male participants, 212 (37.5%) reported no PFS, and 191 (33.7%) reported two or more PFS. The most prevalent clusters in males were sexual dysfunction and LUTS, defecation problems and LUTS, and sexual dysfunction, LUTS, and defecation problems., Conclusion: A considerable overlap existed between PFS, with differences in PFS clusters between females and males. Of note, females reported pelvic pain more than males. We conclude that healthcare providers should address all PFS in males and females., (© 2022 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: Pelvic floor symptoms (PFS), such as lower urinary tract symptoms, defecation disorders, sexual problems, and genital-pelvic pain, are prevalent in men. Thorough physical assessments of the external anal sphincter (EAS) and the puborectal muscle (PRM) are the keys to unraveling the role of muscle dysfunction., Objectives: To explore associations within and between the EAS and PRM and between muscle (dys-) function and the number of male PFS., Methods: This cross-sectional study purposively enrolled men aged ≥21 years with 0-4 symptoms from a larger study. After extensive external and internal digital pelvic floor assessment, we explored (1) agreement between muscle function of the EAS versus PRM (using cross tabulation), (2) associations within and between the EAS and PRM (using heatmaps), and (3) associations between muscle function and number of PFS (using a visual presentation [heatmaps] and χ 2  tests)., Results: Overall, 42 out of 199 men (21%) had completely normal muscle function. Sixty-six (33.2%) had no symptoms, of which 53 (80%) had some degree of muscle dysfunction. No clear dose-response relationship existed between muscle (dys-) function and the number of symptoms. The PRM showed both more dysfunction and severer dysfunction than the EAS., Conclusions: No clear association exists between muscle dysfunction and the number of symptoms, and the absence of PFS does not indicate normal muscle function for all men. Dysfunction levels are highest for the PRM. Further pelvic floor muscle research is warranted in men with PFS., (© 2022 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

The periaqueductal gray (PAG) is a brain stem area designated to play an essential role in lower urinary tract (LUT) control. Post-mortem human and animal studies have indicated that the PAG is symmetrically organized in functionally and anatomically distinct columns which are involved in sympathetic or parasympathetic autonomic control of the LUT. The current study aims to find consistency across subjects and identify homologous clusters between subjects. Here, we evaluated data from 10 female participants. During a bladder filling protocol, we ran a resting-state functional magnetic resonance imaging (fMRI) scan while participants experienced a strong desire to void. A voxel-by-voxel correlation matrix of the PAG was created and parcellated using the Louvain module detection algorithm. Resulting in a map of the PAG in which each voxel is assigned to a cluster as determined by the Louvain module detection algorithm. The spatial similarity of resulting clusters between participants was assessed by computing the Dice similarity coefficient for all cluster comparisons. Next, we designed a permutation test to create randomized parcellation maps which enabled us to statistically test the similarity values observed across participants. We observed several significantly similar clusters between subjects compared to permutations ( p ≤ 0.05). These results show that the PAG can be parcellated into distinct clusters which show a similar spatial distribution at the group level. This analysis is a crucial step to determine the agreement between in vivo PAG parcellations and the functional and anatomical columnar organization of the PAG which is known from previous research. These advancements may enable us to identify the relationship between LUT symptoms, such as urgency, and activity patterns in the PAG in normal and pathological states., Competing Interests: Author GK received consultancy fees and conducted trials for Astellas. These activities were unrelated to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Rijk, Janssen, Fernández Chadily, Birder, Rahnama’i, van Koeveringe and van den Hurk.)

Aim: The aim of this study is to evaluate safety and efficacy of ASP8302, a novel positive allosteric modulator for the muscarinic M3 receptor (M3-PAM), in patients with underactive bladder (UAB)., Methods: A randomized, double-blind, placebo-controlled multicenter study was performed in adult male/female subjects with UAB, defined as incomplete bladder emptying (postvoid residual volume [PVR] > 100 ml) without significant bladder outlet obstruction and/or overactive bladder. Subjects were randomized (1:1) to receive 4-week oral once-daily administration of 100 mg ASP8302 or matching placebo. Primary endpoint was a change from baseline in PVR measured by catheterization after standardized bladder filling (PVR C2 ). Other endpoints included PVR and bladder voiding efficiency (BVE) measured in various ways, uroflowmetry, bladder diary, and questionnaires. Pressure-flow studies were performed in a subgroup., Results: One hundred and thirty-five patients were randomized (ASP8302 group: 65 patients, placebo group: 70 patients). The median change in PVR C2 was -40.0 ml (ASP8302) versus -35.0 ml (placebo) and the difference between groups was -5.0 ml (p = 0.960). In males, functional and symptomatic outcomes improved, for example, maximum urine flow rate (Q max ) and detrusor pressure at Q max (P det.Qmax ) increased (mean difference in change ASP8302 vs. placebo: 3.8 ml/s, p = 0.031 and 12.7 cm H 2 O, p = 0.034, respectively). Urinary incontinence episodes/24 h decreased in males with preexisting incontinence (mean difference: -0.35; p = 0.028). The incidence of adverse events was similar between study groups (ASP8302: 33.3%, placebo: 31.4%). In the included subjects, both baseline urine flow and bladder voiding pressure was low. Compared with PVR, simultaneous BVE measurements were more consistent between various methods (spontaneous vs. standardized bladder filling, catheterization vs. ultrasound [US])., Conclusions: ASP8302 was safe and well tolerated in patients with UAB identified by nonurodynamic clinical criteria, but it did not show efficacy in the primary endpoint. However, in males it showed improvement of symptoms and functional parameters. BVE (using US) is a more optimal outcome measure than PVR in UAB., (© 2022 Wiley Periodicals LLC.)

Aims: Sacral neuromodulation (SNM) and Botulinum toxin A (BoNT-A) injections are well-known third-line treatment options in patients with refractory overactive bladder (OAB). Our aim is to evaluate the success rate of SNM in patients who received prior therapy with BoNT-A injections., Methods: All patients with OAB symptoms referred for SNM between 2006 and 2019 were included. History taking and 3-day voiding diaries assessed the complaints and suitability for SNM. The success rate of SNM in patients who received prior BoNT-A was compared with BoNT-A naive patients. Success was defined as an improvement of 50% or greater in voiding diary parameters. Satisfaction was registered at their most recent visit., Results: A total of 263 patients underwent SNM test stimulation, of which 75 (16 male/57 female) received prior BoNT-A and 188 (46 male/142 female) were BoNT-A naive. Success rate for SNM in BoNT-A naive patients was 72.9% and in BoNT-A patients 66.7% (p = 0.316). Success rate after ≤2 BoNT-A injections was 68.5%, compared to 61.1% after ≥3 injections (p >  0.05). Success rate in patients perceiving lack of efficacy of BoNT-A was 67.4% (p > 0.05), subjected to temporary CISC was 73.7% (p > 0.05) and with temporary effect of BoNT-A was 50% (p > 0.05). In 86% of BoNT-A patients the system was still activated and used to their satisfaction at their last follow-up visit (mean FU, 40.70 months)., Conclusion: SNM in patients with refractory OAB who failed prior BoNT-A is an excellent approach. The number of injections nor reason of BoNT-A discontinuation have predictive value for success with SNM., (© 2021 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Purpose: Until recently, the urine of healthy individuals was assumed to be sterile. However, improvement of bacterial detection methods has debunked this assumption. Recent studies have shown that the bladder contains microbiomes, which are not detectable under standard conditions. In this review, we aimed to present an overview of the published literature regarding the relationship between urinary microbiota and functional disorders of the genitourinary system., Methods: We searched Medline, PubMed, Embase, The Cochrane library and Scopus to identify RCTs published, with MeSH and free keywords including microbiota, bladder pain syndrome, prostatitis, kidney stone disease, and bladder cancer until September 2020. Randomized controlled trials investigating microbiome and lower urinary tract symptoms were included. Non-randomized trials, cross-over trials and pooled studies were excluded. The articles were critically appraised by two reviewers., Conclusion: The urine microbiome is a newly introduced concept, which has attracted the attention of medical researchers. Since its recent introduction, researchers have conducted many fruitful studies on this phenomenon, changing our perspective toward the role of bacteria in the urinary tract and our perception of the genitourinary system health., Result: A deeper understanding of the urinary microbiome can help us to develop more efficient methods for restoring the microbiota to a healthy composition and providing symptom relief. Modification of the urinary microbiome without antibiotic use can be a possible venue for future research.

Aims: The periaqueductal gray (PAG) is a brain stem area involved in processing signals related to urine storage and voiding. The PAG is proposed to be responsible for projecting afferent information from the bladder to cortical and subcortical brain areas and acts as a relay station projecting efferent information from cortical and subcortical areas to the pons and spinal cord. Here, we use 7-Tesla functional magnetic resonance imaging to parcellate the PAG into functionally distinct clusters during a bladder filling protocol., Methods: We assess the similarity between parcellation results in empty and full bladder states and show how these parcellations can be used to create dynamic response profiles of connectivity changes between clusters as a function of bladder sensations., Results: For each of our six healthy female participants, we found that the agreement between at least one of the clusters in both states resulting from the parcellation procedure was higher than could be expected based on chance (p ≤ .05), and observed that these clusters are significantly organized in a symmetrical lateralized fashion (p ≤ .05). Correlations between clusters change significantly as a function of experienced sensations during bladder filling (p ≤ .05)., Conclusions: This opens new possibilities to investigate the effects of treatments of lower urinary tract symptoms on signal processing in the PAG, as well as the investigation of disease-specific bladder filling related dynamic signal processing in this small brain structure., (© 2020 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Introduction and Hypothesis: Urethral instability (URI) has in the past been defined by the International Continence Society (ICS), but was excluded from ICS terminology and definitions shortly after because of a lack of consensus about the clinical importance of this phenomenon. Recently, interest in URI and its possible role in overactive bladder (OAB) increased again. In the last decade, a beta 3 adrenoreceptor agonist (mirabegron) was approved for the treatment of OAB. The effect of mirabegron on urethral pressure during filling cystometry is unknown. The aim of this study was to assess the influence of mirabegron on urethral pressure variations during urodynamic investigation and the association of symptoms and voiding diary data before and during treatment., Methods: This prospective study included 51 consecutive adult female patients, referred with OAB. Patients were evaluated using a voiding diary, two validated questionnaires and two urodynamic investigations, one before and one after 6 weeks of treatment with mirabegron. URI was defined as an urethral pressure drop exceeding 30 cmH 2 O during filling cystometry., Results: The prevalence of URI was 31% at initial urodynamic investigation, and 19% at second investigation. URI is more common than DO with 18% prevalence at initial evaluation. Treatment with mirabegron resulted in significant changes in symptoms and urodynamic sensory markers in patients with URI., Conclusion: Urethral pressure variations are significantly reduced by treatment with mirabegron in patients with URI. URI seems to have a predictive value in treatment choices for OAB. Future research should elucidate this.

Objective: Sacral neuromodulation (SNM) has been used to treat patients with lower urinary tract dysfunction and bowel dysfunction for many years. Success rates vary between 50% and 80%, indicating that there is much room for improvement. Altering stimulation parameters may result in improved outcome. This paper reports a systematic review of the clinical efficacy of nonconventional stimulation parameters on urinary tract and bowel dysfunction., Materials and Methods: Three databases were used for the literature search: Ovid (Medline, Embase) and PubMed. Papers were screened by two independent reviewers, who also extracted data from these papers. Clinical papers studying SNM stimulation parameters, that is, intermittent stimulation, frequency, pulse width, and amplitude, in urinary tract and bowel dysfunction were included. Quality of included papers was assessed using standardized guidelines., Results: Out of 5659 screened papers, 17 papers, studying various stimulation parameters, were included. Overall quality of these papers differed greatly, as some showed no risk of bias, whereas others showed high risk of bias. Stimulation parameters included intermittent stimulation, frequency, pulse width, amplitude, and unilateral vs. bilateral stimulation. Especially high frequency SNM and either a narrow or wide pulse width seem to improve efficacy in patients with bowel dysfunction. Additionally, implementation of short cycling intervals is promising to improve quality of life for patients with urinary tract or bowel dysfunction., Conclusion: The results of our systematic review indicate that stimulation parameters may improve efficacy of SNM in treatment of both urinary tract dysfunction and bowel dysfunction., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC. on behalf of International Neuromodulation Society.)

Objective: Conventional sacral neuromodulation (SNM) has shown to be an effective treatment for lower urinary tract and bowel dysfunction, but improvements of clinical outcome are still feasible. Currently, in preclinical research, new stimulation parameters are being investigated to achieve better and longer effects. This systematic review summarizes the status of SNM stimulation parameters and its effect on urinary tract and bowel dysfunction in preclinical research., Materials and Methods: The literature search was conducted using three databases: Ovid (Medline, Embase) and PubMed. Articles were included if they reported on stimulation parameters in animal studies for lower urinary tract or bowel dysfunction as a primary outcome. Methodological quality assessment was performed using the SYRCLE Risk of Bias (RoB) tool for animal studies., Results: Twenty-two articles were eligible for this systematic review and various aspects of stimulation parameters were included: frequency, intensity, pulse width, stimulation signal, timing of stimulation, and unilateral vs. bilateral stimulation. In general, all experimental studies reported an acute effect of SNM on urinary tract or bowel dysfunction, whereas at the same time, various stimulation settings were used., Conclusions: The results of this systematic review indicate that SNM has a positive therapeutic effect on lower urinary tract and bowel dysfunction. Using low-frequency-SNM, high-frequency-SNM, bilateral SNM, and higher pulse widths showed beneficial effects on storage and evacuation dysfunction in animal studies. An increased variability of stimulation parameters may serve as a basis for future improvement of the effect of SNM in patients suffering from urinary tract or bowel dysfunction., (© 2020 The Authors. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC. on behalf of International Neuromodulation Society.)

Purpose of Review: The aim of the present report was to review the recent evidences regarding the use of artificial urinary sphincter (AUS) in adult females., Recent Findings: While the excellent functional outcomes of AUS in female patients with stress urinary incontinence (SUI) due to intrinsic sphincter deficiency (ISD) have been reported for decades, its use has remained confidential in most countries likely due to its challenging implantation and inherent morbidity. Over the past few years, laparoscopic and, more recently, robotic techniques of AUS implantation in female patients have been described with promising perioperative outcomes. As a result, the use of AUS has increased in several countries. The indications are mostly recurrent or persistent SUI after previous anti-incontinence procedures and neurogenic SUI. Owing to its unique potential to restore continence while maintaining low outlet resistance during the voiding phase, AUS may be of special interest in female patients with detrusor underactivity. High level of evidence data from trials which are underway, along with developments in robotic surgery and technological refinements of the device, may well, almost 50 years after its introduction, give to the AUS its momentum as a major contributor in the female SUI armamentarium. While the use of AUS in female patients has been restricted to some countries and a few high-volume centers, it has started spreading again over the past few years, thanks to the rise of minimally invasive approaches which facilitate its implantation, and this is yielding promising outcomes.

Objective: The prevalence of nocturia in patients with obstructive sleep apnea syndrome (OSAS) who received continuous positive airways pressure (CPAP) treatment was studied as well as the effect of CPAP treatment on nocturia., Methods: All patients that were referred to the pulmonology department of a large teaching hospital in the Netherlands and received a CPAP mask for OSAS were interviewed and invited to take part in the study (N = 274). After informed consent, all patients were asked about the number of nocturia episodes before and after CPAP., Results: In this prospective analysis, 274 patients (190 male and 84 female) were included. The mean age was 60.3 years (SE = 0.7). Sixty-four patients (23.4%) reported no nocturia episodes before CPAP and 210 patients (76.4%) reported ≥1 nocturia episode(s). Treatment of OSAS with CPAP reduced nocturia with one or more episodes per night in 42.3% of the patients. Clinically relevant nocturia (≥2 voids per night) was reduced from 73.0% to 51.5%. There were no statistically significant gender differences., Conclusion: The prevalence of nocturia in patients diagnosed with OSAS is 75.8% in both sexes. After treatment with CPAP, almost half of patients experienced a decrease in the nocturia frequency of one or more voids. Clinically relevant nocturia was reduced with one-third after CPAP. CPAP not only reduced the number of voids during the night but also improved the associated quality of life., (© 2020 Wiley Periodicals, Inc.)

Aims: During filling cystometry, urethral pressure variations (UPV) can be observed. The clinical relevance and a clear definition of this phenomenon are still a matter of debate. For further research and definition of UPV, it is important to determine how this condition can best be demonstrated. The purpose of this study is to compare continuous urethral pressure measurements with a single urethral-sensor catheter and a triple urethral-sensor catheter in demonstrating UPV., Methods: Seventy-five adult female patients requiring urodynamic investigation enrolled in this prospective study. All patients underwent two series of filling and voiding cystometry. One series was performed with a dual-air balloon sensor urodynamic catheter, the other series with a triple urethral-sensor catheter. UPV were defined as urethral pressure drop exceeding 30 cmH2O., Results: The prevalence of UPV was 37.3% (28 out of 75 patients), more common than detrusor overactivity. The triple urethral-sensor catheter was more sensitive than the single urethral-sensor catheter: In eight patients UPV were demonstrated with both catheters and in 18 patients only in the measurement with the triple urethral-sensor catheter. This difference in detection was significant (P < .001)., Conclusion: There is an additional value in measurement with the triple urethral-sensor catheter for demonstration of UPV during filling cystometry. Currently, continuous measurement of urethral pressure during filling cystometry and UPV is not defined within International Continence Society terminology. The single urethral-sensor catheter is useful for a start, however, it demonstrates less than half of all UPV., (© 2019 Wiley Periodicals, Inc.)

Background and Objective: In addition to the evaluation of voiding symptoms, in the evaluation of patients with nocturia, one should also consider other related causes such as sleep disorders, obstructive sleep apnoea (OSAS), diabetes and heart failure. In this study, we have aimed to assess the current knowledge and implementation of the EAU guidelines regarding nocturia in common urological practice in the Netherlands., Setting and Participants: In a national cross-sectional survey distributed among 450 urologists and urology residents in the Netherlands, the implementation of the recommendations of the European Association of Urology (EAU) guidelines on nocturia evaluation and management was studied., Results and Limitations: This survey revealed that only some aspects of the EAU guidelines are applied in the daily clinical practice and that some important parts are not. For example, only a minority asks about alcohol consumption and symptoms suggestive for diabetes or OSAS. In addition, a majority reported to use a bladder diary for 1-3 days instead of for a minimum of 3 days as recommended by the EAU guidelines. In the management of nocturia, a trial of timed diuretic therapy is only reported by a minority, whereas the use of beta-3 antagonists, which is not mentioned in the guidelines, is applied by a large majority. Desmopressin recommended for nocturnal polyuria is prescribed by two-third of Dutch urologists., Conclusions: These observations mandate better education and campaigns to raise the awareness on the EAU-guideline recommendations for nocturia.

Introduction: This article reports the prevalence of self-reported voiding complaints and the relationship with other pelvic floor and bladder dysfunctions (PFD)., Materials and Methods: Women with a variety of PFDs were referred to the pelvic care center. A standardised questionnaire on 6 PFDs was used. Frequencies of patient characteristics, PFDs and voiding complaints were calculated. Cross tabulation was used to investigate correlations and Pearson correlation coefficients to reveal the strength of the association between PFDs and self-reported voiding complaints., Results: Data of 4470 women were included. Prevalence of (self-reported) voiding Lower urinary tract symptoms was 59.5%. Incomplete bladder emptying is the most prevalent voiding complaint. Self-reported voiding complaints are weakly correlated to age (r = 0.15, p < 0.01) and have moderate correlation with self-reported recurrent urinary tract infections (r = 0.34, p < 0.01), pelvic floor, bladder and bowel complaints. However, the correlation between the feeling of incomplete bladder emptying and the presence of recurrent urinary tract infections is weak (r = 0.06, p = 0.02)., Conclusion: Voiding complaints have a high prevalence and symptom bother in women visiting a pelvic care center., (Copyright © 2019 by S. Karger AG, Basel.)

Objectives: To investigate the differences in bladder sensations of overactive bladder (OAB) patients compared to healthy volunteers. In addition, to see if bladder sensations are different in men and women. Methods: In a prospective, longitudinal study (METC 09-2-095), 66 volunteers and 68 OAB patients were included. Anticholinergic medication was stopped. Subjects filled out a sensation-related bladder diary (SR-BD), for two periods of 3 days, including a 4-points urgency scale and visual analogue scale for perception of bladder fullness. Results: In total, 6160 voids were assessed. Patients voided more often with higher degrees of urge at a lower mean voided volume (193 vs 270 ml/void; p  < 0.001) than healthy volunteers. The mean urinary frequency per litre diuresis was also higher (5.8 vs 4.1/l; p  < 0.001) in patients. At the same voided volume: patients perceived a higher mean bladder fullness, independent of the degree of urge, and higher urgency (1.4 vs 0.5/100 ml; p  < 0.001) than healthy volunteers. There were no gender differences in the above-mentioned voiding parameters, except for the mean voided volume at urge 3 in volunteers (340 ml in men vs 362 ml in women; p  = 0.03) and urge 1 in patients (171 ml in men vs 135 ml in women; p  = 0.027). Conclusions: Bladder sensations were significantly increased in everyday life for both male and female OAB patients compared to healthy volunteers. OAB patients experienced a higher mean bladder fullness sensation, independent of the degree of urge, and higher mean urge/urgency at the same voided volume than volunteers. Bladder sensations are crucial in the assessment of treatment response.

Introduction: Commercially approved implantable systems for sacral neuromodulation require the implantation of a multipolar lead subcutaneously connected to an implantable pulse generator (IPG). Eliminating the need for an IPG would eliminate the need for tunneling of the lead, reduce procedure time, infection risk, and the need for IPG replacement. The objective was to demonstrate the feasibility of implanting the AHLeveeS System in the S3 Foramen to stimulate the S3 sacral nerve., Materials and Methods: A first-in-human, prospective, single center, nonrandomized, acute feasibility clinical investigation at the Maastricht University Medical Center+. Patients with refractory overactive bladder underwent acute implantation of the AHLeveeS neurostimulator before the InterStim procedure. Outcome measurements included motor responses, procedural time and a scoring of the difficulty of the implant and explant procedure. Retrospectively, qualitative responses to the stimulation protocol were assessed by video motion analyses. Only descriptive statistics were used., Results: During the stimulation a motor response to stimulation was seen in four of the five subjects. In all implantations the AHLeveeS was correctly placed. The median time for complete procedure was 24 minutes. The implant and explant procedures were successfully performed and no device or procedure related adverse events occurred., Conclusions: The results from this acute first-in-human study demonstrate the feasibility of implantation and acute stimulation of the sacral nerve with this mid-field powered system. Future clinical studies will focus on safety and efficacy of a chronically implanted device., (© 2019 Wiley Periodicals, Inc.)

Introduction: With increasing life expectancy, comorbidities become overt in Duchenne muscular dystrophy (DMD). Although micturition problems are common, bladder function is poorly understood in DMD. We studied dystrophin expression and multiple isoform involvement in the bladder during maturation to gain insights into their roles in micturition., Methods: Dystrophin distribution was evaluated in rat bladders by immunohistochemical colocalization with smooth muscle, interstitial, urothelial, and neuronal markers. Protein levels of Dp140, Dp71, and smooth muscle were quantitated by Western blotting of neonatal to adult rat bladders., Results: Dystrophin colocalized with smooth muscle cells and afferent nerve fibers. Dp71 was expressed two- to threefold higher compared with Dp140, independently of age. Age-related muscle mass changes did not influence isoform expression levels., Discussion: Dystrophin is expressed in smooth muscle cells and afferent nerve fibers in the urinary bladder, which underscores that micturition problems in DMD may have not solely a myogenic but also a neurogenic origin. Muscle Nerve 60: 202-210, 2019., (© 2019 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.)

The periaqueductal gray matter (PAG), as one of the mostly preserved evolutionary components of the brain, is an axial structure modulating various important functions of the organism, including autonomic, behavioral, pain, and micturition control. It has a critical role in urinary bladder physiology, with respect to storage and voiding of urine. The PAG has a columnar composition and has extensive connections with its cranially and caudally located components of the central nervous system (CNS). The PAG serves as the control tower of the detrusor and sphincter contractions. It serves as a bridge between the evolutionary higher decision-making brain centers and the lower centers responsible for reflexive micturition. Glutamatergic cells are the main operational neurons in the vlPAG, responsible for the reception and relay of the signals emerging from the bladder, to related brain centers. Functional imaging studies made it possible to clarify the activity of the PAG in voiding and filling phases of micturition, and its connections with various brain centers in living humans. The PAG may be affected in a wide spectrum of disorders, including multiple sclerosis (MS), migraine, stroke, Wernicke's encephalopathy, and idiopathic normal pressure hydrocephalus, all of which may have voiding dysfunction or incontinence, in certain stages of the disease. This emphasizes the importance of this structure for the basic understanding of voiding and storage disorders and makes it a potential candidate for diagnostic and therapeutic interventions.

Introduction: Many of the currently available therapies for urinary incontinence target the peripheral autonomic system, despite many etiologies residing in the central nervous system. Following previous experiments that determined the ventrolateral column of the periaqueductal gray matter (vlPAG), to be the main afferent station of bladder sensory signals, we aimed for electrophysiological characterization of vlPAG neurons using single unit recording., Methods: 15 rats were anesthetized and underwent implantation with electrodes at the dome and the neck of the bladder, to electrically stimulate the detrusor. After craniotomy, a glass micropipette was inserted in vlPAG to record neuronal action potentials. The detrusor was stimulated by a series of 20 Hz pulses, for a total duration of 50 s at an intensity of 2 mA, for each vlPAG neuron selected. Single unit recordings were performed on a total of 26 neurons. Confirmation of electrode position was made by iontophoretic ejection of Pontamine sky blue., Results: The firing rate of vlPAG neurons decreased significantly during the stimulation period. Peristimulus time histogram (PSTH) analysis showed 24 out of 26 neurons to be unresponsive to stimulation. All recorded vlPAG neurons showed irregular firing patterns., Conclusions: The change in firing rate may point to an overall inhibitory influence of bladder stimulation on vlPAG neurons. These data suggest an inhibitory relay station at the vlPAG, before sensory bladder signals would affect pontine micturition center. The lack of the inhibitory effect on PSTH may be due to a longer interval between neuronal response and the stimulation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The Think Tank aimed to discuss the pitfalls and advantages of current definitions in terms of research and management of underactive bladder (UAB). UAB broadly defines a symptom complex of bladder emptying problems and does not indicate a specific pathology. Detrusor underactivity (DU) is a urodynamic diagnosis from pressure-flow studies. The correlation of UAB with DU remains to be precisely determined., Methods: The presentations and subsequent discussion, leading to research recommendations during the Think Tank of the International Consultation on Incontinence Research Society in Bristol, 2017, are summarized., Results: To develop more specific individualized management strategies, the Think Tank panel proposed (i) that, since defining a single type of index patient to represent all UAB will not fulfill all clinical research needs, several index patients should be defined by phenotyping of patients with UAB, including, children, young men and women, elderly male and female patients with co-existing DU and detrusor overactivity, and neurological patients with UAB; (ii) prospective longitudinal studies to assess the natural history of UAB, in the different target populations, based on different UAB phenotypes, should be initiated; (iii) DU should be precisely defined by urodynamic parameters; and (iv) work to develop validated specific questionnaires combined with non-invasive tests for screening, diagnosis and follow up, needs to be continued., Conclusions: The precise relationship of UAB to DU remains to be defined. Phenotyping patients with UAB/DU, performing prospective trials of natural history, and developing symptom questionnaires and diagnostic investigations will improve our ability to identify and treat UAB/DU., (© 2018 Wiley Periodicals, Inc.)

Objectives: To determine the phenotype of the ventrolateral part of the periaqueductal gray matter neurons after bladder stimulation., Methods: In the experimental group, electrical stimulation of the bladder was carried out under freely moving condition by a bipolar stimulation electrode implanted in the bladder wall. Thereafter, the brain sections were processed for immunohistochemical analysis using antibodies against c-Fos (neuronal activation marker) together with one of the following: tyrosine hydroxylase (dopaminergic cell marker), vesicular glutamate transporter (glutamatergic cell marker), serotonin, glutamate decarboxylase (glutamate decarboxylase 67, gamma-aminobutyric acid cell marker) and neuronal nitric oxide synthase. We used design-based confocal stereological analysis to quantify the immunohistochemically stained sections., Results: A significant increase in the number of c-Fos-positive cells in the ventrolateral part of the periaqueductal gray matter after stimulation was found. Furthermore, the ratio of c-Fos cells double labeled with vesicular glutamate transporter was significantly higher in the ventrolateral part of the periaqueductal gray matter region in the stimulated compared with the sham group. Quantitative analysis of the other four cell types did not show any significant difference., Conclusion: These findings suggest that glutamatergic neurotransmission in the ventrolateral part of the periaqueductal gray matter is seemingly the main pathway to be activated after receiving sensory signals from the bladder., (© 2018 The Japanese Urological Association.)

Reflexes, that involve the spinobulbospinal pathway control both storage and voiding of urine. The periaqueductal gray matter (PAG), a pontine structure is part of the micturition pathway. Alteration in this pathway could lead to micturition disorders and urinary incontinence, such as the overactive bladder symptom complex (OABS). Although different therapeutic options exist for the management of OABS, these are either not effective in all patients. Part of the pathology of OABS is faulty sensory signaling about the filling status of the urinary bladder, which results in aberrant efferent signaling leading to overt detrusor contractions and the sensation of urgency and frequent voiding. In order to identify novel targets for therapy (i.e., structures in the central nervous system) and explore novel treatment modalities such as neuromodulation, we aimed at investigating which areas in the central nervous system are functionally activated upon sensory afferent stimulation of the bladder. Hence, we designed a robust protocol with multiple readout parameters including immunohistological and behavioral parameters during electrical stimulation of the rat urinary bladder. Bladder stimulation induced by electrical stimulation, below the voiding threshold, influences neural activity in: (1) the caudal ventrolateral PAG, close to the aqueduct; (2) the pontine micturition center and locus coeruleus; and (3) the superficial layers of the dorsal horn, sacral parasympathetic nucleus and central canal region of the spinal cord. In stimulated animals, a higher voiding frequency was observed but was not accompanied by increase in anxiety level and locomotor deficits. Taken together, this work establishes a critical role for the vlPAG in the processing of sensory information from the urinary bladder and urges future studies to investigate the potential of neuromodulatory approaches for urological diseases.

A strong association between functional bladder disorders and bladder sensation is well-known, with a relationship between malfunctioning detrusor muscle and abnormal sensation arising from the sub-urothelium and the lamina propria (LP), has been suggested. However, the exact underlying pathophysiology of these bladder disorders is not completely understood. Therefore, it is important to gain knowledge on sensory innervation of the urinary bladder in order to understand the neural network function in healthy and diseased bladder. In the present study we aim at the development of a computer-assisted method for 3D-tracking of sensory innervation in the murine bladder mucosa using two-photon laser scanning microscopy (TPLSM). TPLSM was performed on 10 fixed, stained (CGRP) bladder samples in both the trigone and dome. Nerve tracking was performed in subvolumes (6.3±2.910 6 μm 3 ; median±IQR) of 22 stacks with determining total nerve length, nerve segment lengths, curviness, straightness, and locations of branching and ending points in the lamina propria (LP). The results show that the highest concentration of afferent fibres was found at the urothelium-LP interface. Nerve curviness, a presumed indicator of nerve activity, showed an equal value throughout the complete LP. We found a significantly higher median nerve segment length in the LP of the trigone and significantly more curved nerves in the dome of the bladder. This indicates an adaptation to, or an involvement in the detection of, bladder volume changes. Conclusively, we successfully developed a computer-assisted method for 3D tracking of sensory nerve fibres in the LP of the murine bladder wall., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: To assess an association between affective symptoms and conventional urodynamic results in a pilot study., Methods: The study represents a retrospective analysis of prospectively obtained clinical data, voiding diaries, urodynamic parameters and Hospital Anxiety and Depression Scale (HADS)., Results: A total of 74 patients with urinary frequency attending a multidisciplinary pelvic care centre was included in this study. There was a significant association between the total HADS scores and presence of DO (P = 0.019). In addition, results showed an association between HADS anxiety scores (≥8) and Detrusor Overactivity (DO) (P = 0.018) and between HADS depression scores (≥8) and the feeling of urgency (P = 0.028). Comparative analysis showed differences in age, mean voiding volume, bladder capacity and strong desire between patients with DO and those without., Conclusion: This pilot study revealed an association between psychometric parameters and urodynamic results indicating a common pathway of bladder function and affective complaints. Further research is needed to elucidate which parts of the bladder-brain axis are involved and how these parts correspond by means of urodynamics., (© 2016 John Wiley & Sons Australia, Ltd.)

Background: Rapid development of novel treatment options demands valid preclinical screening models for urothelial carcinoma (UC). The translational value of high-throughput drug testing using 2-dimensional (2D) cultures is limited while for xenograft models handling efforts and costs often become prohibitive for larger-scale drug testing. Therefore, we investigated to which extent the chicken chorioallantoic membrane (CAM) assay might provide an alternative model to study antineoplastic treatment approaches for UC., Methods: The ability of 8 human UC cell lines (UCCs) to form tumors after implantation on CAMs was investigated. Epithelial-like RT-112 and mesenchymal-like T-24 UCCs in cell culture or as CAM tumors were treated with cisplatin alone or combined with histone deacetylase inhibitors (HDACi) romidepsin and suberanilohydroxamic acid. Tumor weight, size, and bioluminescence activity were monitored; tumor specimens were analyzed by histology and immunohistochemistry. Western blotting and quantitative real time polymerase chain reaction were used to measure protein and mRNA expression., Results: UCCs were reliably implantable on the CAM, but tumor development varied among cell lines. Expression of differentiation markers (E-cadherin, vimentin, CK5, CK18, and CK20) was similar in CAM tumors and 2D cultures. Cellular phenotypes also remained stable after recultivation of CAM tumors in 2D cultures. Bioluminescence images correlated with tumor weight. Cisplatin and HDACi decreased weight and growth of CAM tumors in a dose-dependent manner, but HDACi treatment acted less efficiently as in 2D cultures, especially on its typically associated molecular markers. Synergistic effects of HDACi and subsequent cisplatin treatment on UCCs were neither detected in 2D cultures nor detected in CAM tumors., Conclusion: Our results demonstrate that the CAM assay is a useful tool for studying tumor growth and response to conventional anticancer drugs under 3D conditions, especially cytotoxic drugs as cisplatin. With some limitations, it might serve as a cost- and time-effective preclinical screening assay for novel therapeutic approaches before further assessment in expensive and cumbersome animal models., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Encrustation of urinary biomaterials is common; however, the incidence of surface deposition on the Vesair ® intravesical pressure-attenuation balloon has not been previously reported. The purpose of this analysis is to determine the incidence and potential risk factors for encrustation of the Vesair intravesical balloon., Methods: The SOLECT trial is a prospective randomized controlled trial conducted at several European centers to evaluate the safety and efficacy of the Vesair balloon for the treatment of female stress urinary incontinence (SUI). Women included in the study demonstrated SUI symptoms for more than 12 months without complicating factors, such as history of recurrent urinary tract infections or nephrolithiasis. All balloons removed from women enrolled in the SOLECT trial were analyzed for surface characteristics and encrustation. Surface deposition severity was quantified and composition analyzed with infrared spectroscopy and scanning electron microscopy. Incidence of surface deposition was tabulated and risk factors analyzed., Results: One hundred and five balloons removed from 75 women were included in this analysis. Measurable stone deposition of less than 1.5 mm was found on four balloons (3.8%), surface granules were noted on 42 (40.0%), surface film on 11 (10.5%), and both granules and film on two (1.9%). Analysis identified calcium oxalate both in measurable encrustation deposits as well as those with surface granulation. Pooled analysis found that dwell time was a risk factor for calcium deposition., Conclusion: The rate of encrustation on the Vesair intravesical balloon is low and does not appear to increase the rate of adverse outcomes or reduce clinical efficacy., Funding: Solace Therapeutics, Inc.

Introduction: Detrusor underactivity (DU) is currently a topic that receives major attention within functional urology. Urologists are often confronted with men who present with voiding dysfunction without bladder outlet obstruction (BOO) or after desobstructive or neuromodulation treatment. Their impaired bladder emptying is suspected to be related to failure of detrusor contractile function. Earlier research indicated that patients with non-obstructive urinary retention (NOR), for example, detrusor underactivity (DU), have a lower success rate after sacral neuromodulation (SNM) compared to patients treated with SNM for storage dysfunction. However, predicting factors for treatment success in the NOR group have not yet been defined., Methods and Evidence: The aim of this study was to assess whether the use of the new BOO-contractility (Maastricht-Hannover) nomogram can identify and predict SNM non-responders. Our results in 18 men showed that only 20% of patients below the 10th percentile, but 86% of men between the 10 and 25th percentiles of the nomogram can be treated successfully with SNM. All successfully treated patients voided without needing self- catheterisation., Conclusions: This pilot study showed for the first time that SNM treatment response in male patients with impaired bladder emptying can be predicted with the BOO-contractility (Maastricht-Hannover) nomogram. Men below the 10th percentile are likely to be treatment non-responders, whereas the majority of men above the 10th percentile are responders. Neurourol. Urodynam. 36:808-810, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aim: Increased afferent fibre activity contributes to pathological conditions such as the overactive bladder syndrome. Nerve fibres running near the urothelium are considered to be afferent as no efferent system has yet been described. The aim of this study was to identify sub-types of afferent nerve fibres in the mouse bladder wall based on morphological criteria and analyse regional differences., Materials and Methods: 27 bladders of six month old C57BL/6 mice were removed and tissues were processed for immunohistochemistry. Cryostat sections were cut and stained for Protein Gene Product 9.5 (PGP), calcitonin gene related polypeptide (CGRP), neurofilament (NF), vesicular acetylcholine transporter (VAChT) and neuronal nitric oxide synthase (nNOS)., Results: In the sub-urothelium, different types of afferent nerve fibre were found, i.e. immunoreactive (IR) to; CGRP, NF, VAChT, and/or nNOS. At the bladder base, the sub-urothelium was more densely innervated by CGRP-IR and VAChT-IR nerve fibres, then at the lateral wall. NF- and nNOS nerves were sparsely distributed in the sub-urothelium throughout the bladder. At the lateral wall the inner muscle is densely innervated by CGRP-IR nerve fibres. NF, VAChT and nNOS nerves were evenly distributed in the different muscle layers throughout the bladder. Nerve fibre terminals expressing CGRP and NF were found within the extra-mural ganglia at the bladder base., Conclusions: Different types of afferent nerve fibres were identified in the sub-urothelium of the mouse bladder. At the bladder base the sub-urothelium is more densely innervated than the lateral wall by CGRP-IR and VAChT-IR afferent nerve fibres. CGRP and NF afferent nerve fibres in the muscle layer probably relay afferent input to external ganglia located near the bladder base. The identification of different afferent nerves in the sub-urothelium suggests a functional heterogeneity of the afferent nerve fibres in the urinary bladder., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: Detrusor underactivity (DU) has lately gained increasing interest because this bladder condition is an important cause of post-void residual urine and lower urinary tract symptoms (LUTS) in adult men. Until now, DU can only be diagnosed by pressure-flow measurement. Therefore, the aim of this study was to search for noninvasive tests which can safely predict DU in adult men., Methods: Unselected, treatment-naïve male patients aged ≥40 years with uncomplicated, non-neurogenic LUTS were prospectively evaluated. All men received-after standard assessment of male LUTS-ultrasound detrusor wall thickness (DWT) measurements at a bladder filling ≥250 ml and computer urodynamic investigation. DU was defined as incomplete bladder emptying (>30 ml) in the absence of bladder outlet obstruction or dysfunctional voiding. Classification and regression tree (CART) analysis was used to determine parameters and threshold values for DU., Results: The study population consisted of 143 consecutive men with medians of 62 years, IPSS 16, and prostate volume 35 ml. In total, 33 patients (23.1 %) had DU. CART analysis showed that all men with DWT ≤ 1.23 mm plus bladder capacity >445 ml had DU. This multivariate model has a sensitivity of 42 %, specificity of 100 %, positive predictive value of 100 %, and negative predictive value of 85 %., Conclusions: This study showed that all men with ultrasound DWT ≤ 1.23 mm + bladder capacity >445 ml have DU. Combination of these two tests could help physicians to diagnose DU noninvasively in clinical practice. A prospective independent study should confirm these results.

OnabotulinumtoxinA intradetrusor injections are considered a highly effective localized therapy for refractory detrusor overactivity. However, despite evidence for distant systemic effects of onabotulinumtoxinA, little is known on potential systemic side effects following intradetrusor injections. Given that onabotulinumtoxinA is a highly potent toxin this is an important safety issue specifically with regard to repeat injections and parallel treatments with botulinum toxin. Hence, it was the purpose of this prospective study to investigate, using heart rate variability (HRV) analysis, whether onabotulinumtoxinA causes systemic effects on cardiac function following intradetrusor injections. Patients with neurogenic detrusor overactivity (NDO) and age-matched healthy controls were recruited. Concomitant medication and diseases affecting the cardio-vascular system were exclusion criteria. A 3-channel resting electrocardiogram (ECG) was recorded in supine position for 15min during four consecutive visits: 1) 2weeks prior onabotulinumtoxinA intradetrusor injections, 2) 10min prior injections, 3) 30min after injections, and 4) 6weeks after injections. NDO patients received intradetrusor injections (300units Botox®) between visits 2 and 3. The control group had no intervention. Short-term (5min) HRV analysis included assessment of frequency and time domain parameters. Statistical analysis was performed using ANOVA with repeated measures and the t-test. Due to multiple comparisons, α was corrected to 0.0125 (Bonferroni method). Twelve healthy volunteers (5♀, 7♂; 46±12years old) and 12 NDO patients (5♀, 7♂; 46±13years old) completed all measurements. Comparing both groups, resting heart rate was significantly higher in the patients group at visit 4 only. No further significant differences in time and frequency domain parameters were discovered. Within the NDO group, standard deviation of the normal to normal intervals (SDNN) in the ECG demonstrated a significant decrease (1.70 to 1.53ms, p=0.003) from visit 3 to 4, whereas the total power (TP) significantly increased (3.05 to 3.29ms 2 , p=0.009) from visit 2 to 3. This increase subsided until visit 4., Study Limitations: single treatment investigation under resting conditions only. In conclusion, onabotulinumtoxinA intradetrusor injections do not seem to affect resting state cardiac function. Short-term changes such as total power might rather result from natural cardio-vascular responses to the procedure itself (e.g. discomfort, stress). Further detailed investigations also under physical stress and repeated injections are necessary to fully exclude systemic cardiac side effects of onabotulinumtoxinA intradetrusor injections., (Copyright © 2016. Published by Elsevier Inc.)

Aims: Voiding dysfunction in adult men may be caused by bladder outlet obstruction (BOO) and/or detrusor underactivity (DU). Until now, it is only possible to classify BOO and DU by pressure-flow analysis. Low values of the maximum Watts factor (W max ) indicate DU but thresholds for the diagnosis have not been established. Purpose of this study was to construct a nomogram using bladder outlet resistance and detrusor contractility in order to classify BOO and DU simultaneously., Methods: Treatment naïve men aged ≥40 years with uncomplicated lower urinary tract symptoms (LUTS) were prospectively evaluated. Patients were assessed with IPSS, prostate volume, uroflowmetry, post-void residual, and pressure-flow measurement. The bladder outlet obstruction index (BOOI) was used to determine BOO-grade and W max to calculate detrusor contractility. Individual BOOI-W max values were plotted in a graph. Linear interpolation was applied to determine the 10th, 25th, 50th, 75th, and 90th percentiles., Results: Retrospective analysis of 822 male patients with means of 64 years, IPSS 16, and prostate volume of 40 cc. Patient and clinical parameters of the <25th percentile groups were significantly different compared to the 25th-50th percentiles: age (66 vs. 63 years, P = 0.006), bladder capacity (503 vs. 442 ml, P = 0.009), post-void residual urine (167 vs. 116 ml, P = 0.001), and voiding efficiency (67% vs. 73%, P = 0.015)., Conclusions: The nomogram quantifies the relationship between detrusor contractility and BOO in men with LUTS. A measurement value <25th percentile correlates with clinical indicators of DU and is proposed as a cut-off value for DU-diagnosis. Higher age, bladder capacity, and PVR as well as lower voiding efficiency indicate DU. Neurourol. Urodynam. 35:980-986, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Our study aimed to examine and quantify age-related structural alterations in the healthy mouse bladder using ex vivo two-photon laser scanning microscopy (TPLSM). Freshly dissected bladders from 25-, 52-, and 85-week-old C57bl/6J mice were examined, and morphological analyses and quantification of cell layers and nerves were performed. The numbers of stretched, curled, branched, and total number of nerves in volume units of the stained muscle layer were quantified. We observed differences in the bladder wall architecture and innervation with age. Especially in 85-week-old mice, age-related changes were found, including detachment of urothelial cells and an increase in connective tissue, intermingled with the smooth muscle fibers in the muscle layer (collagen-smooth muscle ratio of 1.15 ± 0.29). In 25- and 52-week-old mice, the collagen-smooth muscle ratios were 0.20 ± 0.04 and 0.31 ± 0.11, respectively, and a clear separation of collagen and muscle was observed. The overall number of nerves and the number of curled nerves were significantly higher in the 85-week-old mice (74.0 ± 13.0 and 25.9 ± 4.8, respectively), when comparing to 25-week-old mice (26.0 ± 2.7 and 6.7 ± 1.2, respectively) and 52-week-old mice (43.8 ± 4.3 and 22.1 ± 3.3, respectively). Significant age-related alterations in bladder morphology and innervation were found, when comparing freshly dissected bladder tissue from 25-, 52-, and 85-week-old mice. The higher number of curled nerves might be an indication of an increased neurotransmitter release, resulting in a higher nerve activity, with a part of the nerves being possibly mechanically impaired. This study shows that two-photon laser scanning microscopy of healthy aging male mice is a useful method to investigate and quantify the age-related changes in the bladder wall., Competing Interests: Compliance with ethical standards Experimental protocols were approved by the animal ethics committee of Maastricht University, and were carried out according to institutional guidelines, and reported in accordance with the ARRIVE guidelines.