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.

Recurrent and complicated urinary tract infections in women: Utility of advanced testing to enhance care.

BACKGROUND: The United States currently faces a public health crisis with regarding to antibiotic-resistant bacteria, and new urinary tract infection (UTI) diagnostics are needed. Women with recurrent UTI (rUTI) and complicated UTI (cUTI) are at particular risk given their complexity and the paucity of adequate testing modalities. The standard urine culture (SUC) is the cornerstone for diagnosis, but it has many shortcomings. These pitfalls lead to dissatisfaction and frustration among women afflicted with rUTI and cUTI, as well as overuse of antibiotics. One innovation is PCR UTI testing, which has been shown to outperform SUC among symptomatic women. AIMS: This article discusses UTI PCR testing, as well as a possible role in clinical practice. MATERIALS AND METHODS: Published literature was reviewed and summarized. RESULTS: Management of rUTI and cUTI is complex, and providers should have all diagnostics available to facilitate providing optimal care. Urine PCR testing faces reimbursement issues despite fulfilling clinical indication parameters as described by insurance companies. DISCUSSION: The role of UTI PCR testing remains unclear. Reimbursement issues have led to underuse and limited real-world outcomes reinforcing benefit. CONCLUSION: This study proposes an algorithm for PCR testing among women with rUTI and cUTI.

What is the best first choice oral drug therapy for OAB?

AIMS: The management of overactive bladder (OAB) involves lifestyle changes and conservative measures in the first instance with the use of liquid/dietary advice, weight loss, and bladder training. Thereafter oral pharmacotherapy is instigated in symptomatic patients. Antimuscarinics and beta 3 agonists form the main classes of drug therapy in this field. Views on what is the best first line OAB treatment is changing based on recent evidence and adverse event profiles of these medications. METHODS: At the ICI-RS meeting 2023, Bristol, UK this topic was discussed and debated as a proposal. The following article summarizes the concepts presented that day as well as the interactive discussion that took place thereafter. RESULTS: OAB guidelines are moving in many circumstances to an either antimuscarinic or beta 3 agonist approach based on patient factors. Several studies have raised concerns on the long-term impact of antimuscarinics, in relation to cognition, dementia, cardiovascular events, and mortality all related to antimuscarinic load. Neither antimuscarinics nor beta 3 agonists have good persistence and adherence rates in the medium to long term. Several barriers also exist to prescribing including guidelines recommending utilizing drugs with the lowest acquisition cost and "step therapy." A newer approach to managing OAB is personalized therapy in view of the many possible etiological factors and phenotypes. These concepts are highlighted in this article. CONCLUSIONS: Current oral pharmacotherapy in managing OAB is limited by adverse events, adherence and persistence problems. Both antimuscarinics and beta 3 agonists are efficacious but most clinical trials demonstrate significant placebo effects in this field. Personalizing treatment to the individual seems a logical approach to OAB. There is a need for better treatments and further studies are required of existing treatments with high quality longer term outcomes.

A better understanding of basic science may help our management of LUTS/LUTD in older persons with nocturnal polyuria and nocturia: ICI-RS 2024.

AIMS: To discuss the role of autocrine/paracrine signaling of urothelial arginine vasopressin (AVP) on mammalian bladder capacities and micturition thresholds, impact of distension on water/urea reabsorption from the bladder, review of the literature to better characterize the central/peripheral effects of AVP, desmopressin (dAVP) toxicity, and urine biomarkers of nocturia. METHODS: This review summarizes discussions during an International Consultation on Incontinence-Research Society 2024 think tank with respect to the role of urothelial AVP in aged individuals with nocturnal polyuria, impact of solute and water reabsorption by the bladder on uninterrupted sleep, central effects of AVP, pharmacological basis of dAVP toxicity, and biomarkers in nocturia/lower urinary tract dysfunction (LUTD) with neurological diseases. RESULTS: Consensus recognized AVP function and pathways in the central nervous system (CNS), pre-proAVP localized using immunohistochemistry in bladder sections from adult/aged noncancerous human punch biopsies and rodent bladder sections is likely to accelerate the systemic uptake of water and urea from the bladder of anesthetized mice instilled with 3H-water and 14C-urea. Mechanisms for charged and uncharged solutes and water transport across the bladder, mechanism of dAVP toxicity, and utility of urine biomarkers in those with neurological diseases/nocturia were determined from literature reviews. CONCLUSION: Pre-proAVP is present in human/rodent bladders and may be involved in water reabsorption from bladder that prevents the sensation of fullness for uninterrupted sleep in healthy adults. The mechanism of action of AVP in the CNS was discussed, as was electrolyte/water transport across the bladder, the basis for dAVP toxicity, and feasibility of urine biomarkers to identify nocturia/LUTD with neurological diseases.

Exploring lifelong overactive bladder: Transitions, evidence, and clinical implications; A modified Delphi process.

INTRODUCTION: Overactive bladder (OAB) is a prevalent urological condition characterized by urinary urgency, with or without urgency urinary incontinence, accompanied by increased daytime frequency and nocturia. However, the current definition of OAB lacks a specified time frame, hindering our understanding of the temporal aspects and transitions that occur within the OAB spectrum. METHODS: A modified Delphi study was conducted in three rounds, involving a panel of international experts in functional urology, urogynaecology, geriatrics, transitional medicine, and pediatric urology. The study took place between February 2023 and June 2023 and employed two sequential rounds of online surveys, followed by a final hybrid group discussion session in June 2023. RESULTS: The Delphi process resulted in a consensus definition of lifelong OAB as a persistent and continuous condition that may manifest differently from birth and evolve over time, with varying levels of clinical perception. The course of its progression is influenced by transition periods and modifying factors, mainly anatomical, hormonal, and psychosocial/stressors. Three main transition periods were identified: achievement of daytime continence, adulthood to elderly, and transition to frail elderly. The panel also considered the therapeutic and diagnostic implications of lifelong OAB, as well as future research prospects in terms of importance and feasibility. CONCLUSIONS: Future longitudinal research is needed to develop this concept and further identify transitions and temporal dynamics.

Can we predict whether a man with acute or chronic urinary retention will void after bladder outflow resistance reduction surgery? ICI-RS 2023.

AIMS: To address the predictive factors of a successful voiding after bladder outflow resistance reduction surgery (BORRS) in men presenting with acute or chronic urinary retention (UR). METHODS: A think tank (TT) of ICI-RS was gathered in 2023, Bristol, UK, to discuss several aspects of the problem, such as the pathophysiology of UR, the clinical and urodynamic evaluation of men with UR and whether it is possible to predict which men will be able to successfully void after treatment with contemporary surgical options. RESULTS: The TT agreed that successful voiding after BORRS depends on several factors but that a strong recommendation cannot be made regarding preoperative evaluation and whether there are predictive factors of success because of the heterogeneity of patients and methodology in published trials. The diagnosis of obstruction in men with UR may be challenging when there is apparent reduced detrusor contraction during urodynamic studies. Even in the absence of bladder contractility there is documentation of such cases that have voided adequately after BORRS. Still, detrusor underactivity and inadequate relief of prostatic obstruction are the main causes of an unsuccessful voiding after BORRS. Conventional resection and enucleation methods remain the most successful surgeries in relieving UR in men, whereas the efficacy of minimally invasive surgical treatments needs to be assessed further. CONCLUSION: Research is needed to understand the pathophysiology of UR and the predictors of successful voiding after different types of BORRS in men with UR.

Can we predict and manage persistent storage and voiding LUTS following bladder outflow resistance reduction surgery in men? ICI-RS 2023.

AIMS: Lower urinary tract symptoms (LUTS) persist in up to 50% of patients after bladder outflow resistance reduction surgery (BORRS) in men. Our think tank aims to address the predictive factors for persistent LUTS after BORRS and to propose the recommendations for future research to enable improved better patient counseling and selection by more accurate prediction of treatment outcome. METHODS: A think tank of ICI-RS gathered in 2023, Bristol, UK, to discuss the pre and postsurgical clinical and urodynamic evaluation of men undergoing BORRS and whether it is possible to predict which men will have persistent LUTS after BORRS. RESULTS: Our think tank agrees that due to the multifactorial, and still not fully understood, etiology of male LUTS it is not possible to precisely predict in many men who will have persistent LUTS after BORRS. However, severe storage symptoms (overactive bladder, OAB) in association with low volume and high amplitude detrusor overactivity and low bladder capacity in preoperative urodynamics, increase the likelihood of persistent OAB/storage symptoms after BORRS. Furthermore, patients who are clearly obstructed and have good bladder contractility on preoperative pressure flow studies do better postoperatively compared to their counterparts. However, the benefit of pressure flow studies is decreased in patients who do not acceptably void during the study. Poor voiding after BORRS may occur due to persistent obstruction or detrusor underactivity. CONCLUSION: Future research is needed to increase our understanding of why male LUTS persist after surgery, and to enable better patient selection and more precise patient counseling before BORRS.

Is it Possible to Regenerate the Underactive Detrusor? Part 2 Electrical Stimulation Therapies, Treatment of Bladder Outlet Obstruction, Constipation, and Pelvic Floor Disorders ICI-RS 2024.

INTRODUCTION: Detrusor muscle weakness is commonly noted on urodynamics in patients with refractory voiding difficulty. No clinical therapy has been proven to augment the strength of a detrusor contraction. METHODS: This subject was discussed at a think-tank at the International Consultation on Incontinence-Research Society (ICI-RS) held in Bristol, June 2024. The discussions of the think-tank are being published in two parts. This second part discusses the role of electrical stimulation therapies, treatment of bladder outlet obstruction, constipation, and pelvic floor disorders, in the enhancement of strength of a detrusor contraction. RESULTS: Electrical stimulation therapies, specifically sacral neuromodulation, have long been used in the salvage of patients with refractory nonobstructive voiding dysfunction. Clinical improvements can be noted in men following bladder outlet resistance reduction surgery especially, though not limited to those with demonstrable obstruction. Some patients may also show improvement with pelvic floor relaxation therapies and constipation care. However, there is a lack of high-quality urodynamic data to demonstrate an improvement in the strength of a detrusor contraction with these therapies. The think-tank recommends standards for future clinical studies examining treatments aimed at improving an underactive detrusor. CONCLUSIONS: Studies need to examine whether clinical improvement following treatment of patients with an underactive detrusor is associated with improvement in strength of the detrusor contraction. New therapeutic options should apply specified standards for assessing and reporting the impact on detrusor contraction.

Is It Possible to Regenerate the Underactive Detrusor? Part 1 Molecular and Stem Cell Therapies Targeting the Urinary Bladder and Neural Axis ICI-RS 2024.

INTRODUCTION: Detrusor muscle weakness is commonly noted on urodynamics in patients with refractory voiding difficulty. No approved therapies have been proven to augment the strength of a detrusor voiding contraction. METHODS: This subject was discussed by a think-tank at the International Consultation on Incontinence- Research Society (ICI-RS) meeting held in Bristol, June 2024. The discussions of the think-tank are being published in two parts. This first part discusses molecular and stem cell therapies targeting the urinary bladder and the neural axis. RESULTS: Senescence of the urothelium and extracellular ATP acting through P2X3 receptors might be important in detrusor underactivity. Several molecules such as parasympathomimetics, acotiamide, ASP8302, neurokinin-2 agonists have been explored but none has shown unequivocal clinical benefit. Different stem cell therapy approaches have been used, chiefly in neurogenic dysfunction, with some studies showing benefit. Molecular targets for the neural axis have included TRPV-4, Bombesin, and serotoninergic receptors and TAC-302 which induces neurite growth. CONCLUSIONS: Several options are currently being pursued in the search for an elusive molecular or stem cell option for enhancing the power of the detrusor muscle. These encompass a wide range of approaches that target each aspect of the contraction mechanism including the urothelium of bladder and urethra, myocyte, and neural pathways. While none of these have shown unequivocal clinical utility, some appear promising. Lessons from other fields of medicine might prove instructive. CLINICAL TRIAL REGISTRATION: Not necessary. Not a clinical trial.

Prevalence of Sleep CALM nocturia factors in a male veteran population.

INTRODUCTION: Nocturia is a complex and multifactorial condition, associated with several genitourinary abnormalities as well as a host of conditions beyond the urinary tract, and thus often poses a significant diagnostic challenge in real-world practice. Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications, the so-called "Sleep C.A.L.M." factors, are five common causes of nocturia requiring judicious evaluation according to current consensus guidelines. This study aims to assess the prevalence of the Sleep C.A.L.M. factors in a nocturia clinical population. METHODS: Retrospective analysis of frequency-volume charts from men with ≥2 nocturnal voids as well as concurrent demographic, clinical, and medical history data to identify patients with each of the Sleep C.A.L.M. FACTORS: Comorbidities and medications were classified as a single group. RESULTS: A total of 213 subjects met the criteria for inclusion (median age 68.0 [63.5-75.5] years). The prevalence of 1) sleep disorders, 2) comorbidities and/or medication use, 3) actions (i.e., modifiable behaviors/lifestyle factors), and 4) lower urinary tract dysfunction was 31%, 31%, 19%, and 41%, respectively. Among included participants, 73% were found to have at least 1 Sleep C.A.L.M. factor, and 33% had multiple Sleep C.A.L.M. FACTORS: Results were similar upon stratification by age and nocturnal polyuria status. CONCLUSIONS: The Sleep C.A.L.M. factors are highly common among nocturia patients in the clinical urology setting. Although many of these factors are strongly associated with advanced age in community-based nocturia study samples, they appear common even among younger men in a nocturia patient population; the differential effect of age and individual Sleep C.A.L.M. factors on nocturia pathophysiology requires further investigation.

How do we make progress in phenotyping patients with LUT such as OAB and underactive detrusor, including using urine markers and microbiome data, in order to personalize therapy? ICI-RS 2023: Part 1.

INTRODUCTION: Overactive bladder (OAB) and Underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction. OBJECTIVES: The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment. METHODS: A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU investigating metabolic, neurogical, psychological and gastrointestinal aspects with the aim to personalize the treatment. RESULTS AND CONCLUSIONS: The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract symptoms, such as OAB and UAB. The intricate interplay between the lower urinary tract and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one-size-fits-all approach.

How do we make progress in phenotyping patients with lower urinary tract such as overactive bladder and underactive detrusor, including using urine markers and microbiome data, to personalize therapy? ICI-RS 2023-Part 2.

INTRODUCTION: Overactive bladder (OAB) and underactive bladder (UAB) could be associated with metabolic syndrome, affective disorders, sex hormone deficiency, changes in urinary microbiota, functional gastrointestinal disorders, or autonomic nervous system dysfunction. OBJECTIVES: The aim of this Think Tank was to provide a guide on how to investigate OAB and/or detrusor underactivity (DU) patients to better clarify the underlying pathophysiology and possibly personalize the treatment. METHODS: A compendium of discussion based on the current evidence related to phenotyping patients with OAB or DU using urodynamic tests, functional neuro-imaging, urinary markers, and microbiome. RESULTS AND CONCLUSIONS: The article emphasizes the critical significance of adopting a comprehensive yet tailored approach to phenotyping patients with lower urinary tract (LUT) symptoms, such as OAB and UAB. The intricate interplay between the LUT and various factors, metabolic, neurological, psychological, and gastrointestinal can define unique LUT profiles, enabling personalized therapies to replace the one-size-fits-all approach.

Evaluation of new treatments for benign prostatic obstruction: ICI-RS 2023.

AIMS: To address how invasive therapies for benign prostatic obstruction (BPO) have been evaluated, what their effect is on BPO, if they can prevent progression to BPO and how new therapies need to be evaluated before implementation into clinical practice. METHODS: The think tank conducted a literature review and looked at the previous and current American Urological Association, European Association of Urology and the International Consultation on Urological Diseases guidelines to see what procedures have been used to treat BPO. They then assessed whether trials have been conducted before implementation of the procedures and whether they have been compared to a "gold" standard treatment. The use of urodynamics has also been addressed in the think tank in relation the clinical trials as well as terminology. RESULTS: Guidelines vary in the use of terminology when it comes to BPO with some continuing to use the term benign prostatic hyperplasia (BPH). There are several procedures for example, TUNA, which have become obsolete although continues to be mentioned in the guidelines until recently. Majority of procedures have been introduced without comparing to "gold" standard treatment and without any long-term data. There continues to be many unknowns with regard to the success of some of the BPO procedures and why some of the adverse events develop. CONCLUSION: There needs to be more robust long-term clinical trials conducted of new BPO therapies, with men who have both lower urinary tract symptoms and urinary retention, before introduction into clinical practice.

New therapeutic targets to prevent benign prostatic enlargement and symptomatic progression to benign prostatic obstruction-ICI-RS 2023.

AIMS: Benign prostatic enlargement (BPE) can impact lower urinary tract function due to its potential progression to benign prostatic obstruction (BPO). Treatment options include removal of the obstruction by surgery or through use of therapeutics designed to slow growth or reduce tissue stress imposed by muscular stromal components. Inflammation and development of fibrosis can also raise intrinsic tissue stress within the gland, further impacting obstruction. Outflow tract obstruction can also impact emission and ejaculation if the obstruction persists. METHODS: This review summarizes an ICI-RS think tank considering novel drug treatments that might address BPO caused by progressive development of BPE, as well as manage decompensation changes to bladder function. RESULTS: Topics included recent advances in our understanding of pathological changes occurring to the prostate and other lower urinary tract tissues during progressive development of BPE, and how prevention or reversal might benefit from the identification of novel drug targets. These included contractile properties of prostatic tissues, the impact of BPE and its effects on bladder function, the deposition of intramural fibrotic tissue with protracted BPO, the role of inflammation in the development of BPE and its progression to BPO. In particular, we discussed current therapeutic options for treating BPE/BPO, and new therapeutic targets, what they treat and their advantage over current medications. CONCLUSION: Several new drug targets were identified, including soluble guanylate cyclase (sGC), the receptor for nitric oxide (NO•), and sGC activators that promotes sGC-mediated cGMP production when sGC is inactivated and unresponsive to NO•.

How does the lower urinary tract contribute to bladder sensation? ICI-RS 2023.

AIM: Bladder sensation is critical for coordinating voluntary micturition to maintain healthy bladder function. Sensations are initiated by the activation of sensory afferents that innervate throughout the bladder wall. However, the physiological complexity that underlies the initiation of bladder sensory signaling in health and disease remains poorly understood. This review summarises the latest knowledge of the mechanisms underlying the generation of bladder sensation and identifies key areas for future research. METHODS: Experts in bladder sensory signaling reviewed the literature on how the lower urinary tract contributes to bladder sensation and identified key research areas for discussion at the 10th International Consultation on Incontinence-Research Society. RESULTS: The importance of bladder sensory signals in maintaining healthy bladder function is well established. However, better therapeutic management of bladder disorders with exaggerated bladder sensation, including overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) is limited by a lack of knowledge in a number of key research areas including; the contribution of different nerves (pudendal, pelvic, hypogastric) to filling sensations in health and disease; the relative contribution of stretch sensitive (muscular) and stretch-insensitive (mucosal) afferents to bladder sensation in health and disease; the direct and indirect contributions of the muscularis mucosae to bladder contraction and sensation; and the impact of manipulating urothelial release factors on bladder sensation. CONCLUSION: Disturbances in bladder sensory signaling can have severe consequences for bladder sensation and function including the development of OAB and IC/BPS. Advancing therapeutic treatments for OAB and IC/BPS requires a deeper understanding of the mechanisms underlying the generation of bladder sensation, and key areas for future research have been identified.

Beyond the urothelium: Interplay between autonomic nervous system and bladder inflammation in urinary tract infection, bladder pain syndrome with interstitial cystitis and neurogenic lower urinary tract dysfunction in spinal cord injury-ICI-RS 2023.

INTRODUCTION: Inflammation and neuronal hypersensitivity are reactive protective mechanisms after urothelial injury. In lower urinary tract dysfunctions (LUTD), such as urinary tract infection (UTI), bladder pain syndrome with interstitial cystitis (BPS/IC) and neurogenic LUTD after spinal cord injury (SCI), chronic inflammation can develop. It is unclear how the protective reactionary inflammation escalates into chronic disease in some patients. METHODS: During its 2023 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the urothelial and inflammatory changes after UTI, BPS/IC and SCI. Potential factors contributing to the evolution into chronic disease were explored in a think-tank. RESULTS: Five topics were discussed. (1) Visceral fat metabolism participates in the systemic pro-inflammatory effect of noradrenalin in BPS/IC and SCI. Sympathetic nervous system-adipocyte-bladder crosstalk needs further investigation. (2) Sympathetic hyperactivity also potentiates immune depression in SCI and needs to be investigated in BPS/IC. Gabapentin and tumor necrosis factor-α are promising research targets. (3) The exact peripheral neurons involved in the integrative protective unit formed by nervous and immune systems need to be further identified. (4) Neurotransmitter changes in SCI and BPS/IC: Neurotransmitter crosstalk needs to be considered in identifying new therapeutic targets. (5) The change from eubiosis to dysbiosis in SCI can contribute to UTI susceptibility and needs to be unraveled. CONCLUSIONS: The think-tank discussed whether visceral fat metabolism, immune depression through sympathetic hyperactivity, peripheral nerves and neurotransmitter crosstalk, and the change in microbiome could provide explanations in the heterogenic development of chronic inflammation in LUTD. High-priority research questions were identified.

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.

Could a better understanding of the underlying pathophysiologies lead to more informed treatment choices in patients with lower urinary tract dysfunction due to an acontractile or underactive detrusor? ICI-RS 2023.

INTRODUCTION: The underlying pathophysiology behind a diagnosis of acontractile or underactive detrusor at invasive urodynamics is very heterogeneous. Lack of etiological classification currently limits the possibility of stratifying therapy. METHODS: This subject was discussed at a think-tank on the subject at the International Consultation on Incontinence-Research Society held in Bristol, June 2023. This manuscript is a result of those deliberations and the subsequent discussions of the think-tank. RESULTS: There are challenges in defining abnormalities of detrusor contraction with resultant implications for available evidence. Pathology at any level of the neuromuscular pathway can impair or prevent a detrusor voiding contraction. Attempts have been made to identify clinical markers that might predict an underactive detrusor but strong supporting evidence is lacking. Hence, a holistic approach to phenotyping requires specialized neuro-imaging as well as physiological investigations. Several general measures can help individuals with an abnormal detrusor contraction. The search for a molecule to enhance the detrusor voiding contraction remains elusive but there are promising new candidates. Neuromodulation can help select individuals but data is not well stratified by underlying etiology. Manipulation of central neurotransmitters might offer an alternate therapeutic option. CONCLUSIONS: A better understanding of the underlying pathophysiologies behind an abnormality of the detrusor voiding contraction is needed for improving management. Towards this goal, the think-tank proposes a classification of the underactive detrusor that might help in selecting and reporting more well-defined patient cohorts.

Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications ("Sleep C.A.L.M.") in the evaluation and management of nocturia: A simple approach to a complex diagnosis.

INTRODUCTION: Nocturia arises from a fundamental mismatch between nocturnal urine production, storage capacity, and sleep architecture, which may be driven by abnormalities of the genitourinary tract, but also by sleep disorders, medical diseases, patient actions/lifestyle factors, or medications. This article introduces a novel system for organizing the complex differential diagnosis for nocturia, as proposed by an international collective of practicing urologists, physician specialists, and sleep experts: "Sleep CALM"-Sleep Disorders, Comorbidities, Actions, Lower Urinary Tract Dysfunction, and Medications. METHODS: Narrative review of current evidence regarding the relevance of each "Sleep CALM" factor to nocturia pathogenesis, evaluation, and management. RESULTS: Nocturia and sleep disorders are highly intertwined and often bidirectional, such that nocturnal awakenings for reasons other than a sensation of bladder fullness should not be used as grounds for exclusion from nocturia treatment, but rather leveraged to broaden therapeutic options for nocturia. Nocturia is an important potential harbinger of several serious medical conditions beyond the genitourinary tract. Urologists should have a low threshold for primary care and medical specialty referral for medical optimization, which carries the potential to significantly improve nocturnal voiding frequency in addition to overall health status. Adverse patient actions/lifestyle factors, lower urinary tract dysfunction, and medication use commonly coexist with disordered sleep and comorbid medical conditions, and may be the primary mediators of nocturia severity and treatment response, or further exacerbate nocturia severity and complicate treatment. CONCLUSION: "Sleep CALM" provides a memorable and clinically relevant means by which to structure the initial patient history, physical exam, and clinical testing in accordance with current best-practice guidelines for nocturia. Although not intended as an all-encompassing diagnostic tool, the "Sleep CALM" schema may also be useful in guiding individualized ancillary testing, identifying the need for specialty referral and multidisciplinary care, and uncovering first-line treatment targets.

A uro-protective agent with restorative actions on urethral and striated muscle morphology.

PURPOSE: Aging increases oxidative stress, which can have delirious effects on smooth and striated muscle resulting in bladder dysfunction. Consequently, in women aged over 60 years, urinary incontinence (UI) is a prevalent health problem. Despite the prevalence and consequences, UI continues to be undertreated simply because there are few therapeutic options. METHODS: Here we investigated whether 8-aminoguanine (8-AG), a purine nucleoside phosphorylase (PNPase inhibitor), would restore urethra and external sphincter (EUS) muscle morphology in the aged rat. Aged (> 25 months) female Fischer 344 rats were randomized to oral treatment with 8-AG (6 weeks) or placebo, and the urethra and EUS were evaluated by electron microscopy and protein expression (western immunoblotting). RESULTS: Aging was associated with mitochondrial degeneration in smooth and striated muscle cells as compared to young rats. We also observed a significant increase in biomarkers such as PARP, a downstream activator of oxidative/nitrosative stress. Treatment of aged rats with 8-AG normalized all abnormalities to that of a younger state. CONCLUSIONS: 8-AG, a potent inhibitor of PNPase, reverses age-related lower urinary tract morphological and biochemical changes. Our observations support the concept that 8-AG will reverse age-induced lower urinary tract disorders such as UI. These initial findings could have therapeutic implications for the prevention and treatment of age-related UI.