A constrained mixture-micturition-growth (CMMG) model of the urinary bladder: Application to partial bladder outlet obstruction (BOO).

We present a constrained mixture-micturition-growth (CMMG) model for the bladder. It simulates bladder mechanics, voiding function (micturition) and tissue adaptations in response to altered biomechanical conditions. The CMMG model is calibrated with both in vivo and in vitro data from healthy male rat urinary bladders (cystometry, bioimaging of wall structure, mechanical testing) and applied to simulate the growth and remodeling (G&R) response to partial bladder outlet obstruction (BOO). The bladder wall is represented as a multi-layered, anisotropic, nonlinear constrained mixture. A short time scale micturition component of the CMMG model accounts for the active and passive mechanics of voiding. Over a second, longer time scale, G&R algorithms for the evolution of both cellular and extracellular constituents act to maintain/restore bladder (homeostatic) functionality. The CMMG model is applied to a spherical membrane model of the BOO bladder utilizing temporal data from an experimental male rodent model to parameterize and then verify the model. Consistent with the experimental studies of BOO, the model predicts: an initial loss of voiding capacity followed by hypertrophy of SMC to restore voiding function; bladder enlargement; collagen remodeling to maintain its role as a protective sheath; and increased voiding duration with lower average flow rate. This CMMG model enables a mechanistic approach for investigating the bladder's structure-function relationship and its adaption in pathological conditions. While the approach is illustrated with a conceptual spherical bladder model, it provides the basis for application of the CMMG model to anatomical geometries. Such a mechanistic approach has promise as an in silico tool for the rational development of new surgical and pharmacological treatments for bladder diseases such as BOO.

Efficacy and Tolerability of Mirabegron Compared with Antimuscarinic Monotherapy or Combination Therapies for Overactive Bladder: A Systematic Review and Network Meta-analysis.

BACKGROUND: Mirabegron is an established treatment alternative to antimuscarinic therapy for patients with overactive bladder (OAB), as shown by efficacy and tolerability data from phase III trials. OBJECTIVE: To assess efficacy and tolerability of mirabegron 50mg versus antimuscarinic monotherapies and combination therapies. DESIGN, SETTING, AND PARTICIPANTS: Systematic literature review and network meta-analysis of randomised controlled trials (2000-2017) assessing eligible treatments for OAB. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy assessments included micturition frequency, urgency urinary incontinence, dry rate, and 50% reduction in incontinence. Tolerability assessments included dry mouth, constipation, blurred vision, and hypertension. RESULTS AND LIMITATIONS: A total of 64 studies (n=46 666) were included in the network meta-analysis. Mirabegron 50mg was significantly more efficacious than placebo for all efficacy endpoints. Comparable overall efficacy was observed for mirabegron 50mg versus most active treatments, but solifenacin 10mg monotherapy and solifenacin 5mg plus mirabegron 25 or 50mg in combination were more efficacious for some/all outcomes. Mirabegron 50mg was significantly better tolerated regarding dry mouth, constipation, and urinary retention than 21/22, 9/20, and 7/10 active comparators, respectively; similar overall tolerability was observed between mirabegron 50mg and all treatments (including placebo) for the remaining endpoints. Limitations of the study included between-trial variations in the definition of certain endpoints and heterogeneity of the available data (eg, number of studies and patients assessed) for comparator treatments across different endpoints. CONCLUSIONS: The relief of key OAB symptoms produced by mirabegron 50mg is significantly better than placebo, and similar to a range of common antimuscarinics, with the benefit of significantly fewer bothersome anticholinergic side effects such as dry mouth. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg appears to provide an efficacy benefit compared with mirabegron 50mg, with the expected side effects of individual antimuscarinics. PATIENT SUMMARY: This study assessed the efficacy and tolerability of different drug treatments for OAB. Mirabegron 50mg was as effective as antimuscarinic therapy, with fewer common, bothersome side effects such as dry mouth, constipation, and urinary retention. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg was more effective than mirabegron 50mg alone, but with more anticholinergic side effects.

Medical Expulsive Therapy for Ureterolithiasis: The EAU Recommendations in 2016.

Medical expulsive therapy (MET), in particular α-blockers, have been recommended as supportive medication if observational treatment of a ureteral stone was an option. Over the years, a considerable number of randomized controlled trials (RCT) as well as several meta-analyses have been published on MET, supporting the use of α-blockers. However, several recently published high quality, large, placebo-controlled randomized trials raised serious doubts about the effectiveness of α-blockers. The contradictory results of meta-analyses of small RCTs versus the findings of large, well conducted multicenter trials show the methodological vulnerability of meta-analyses, in particular if small single center, lower quality, papers have been included. Small single center trials, for instance, tend to show larger treatment effects compared to multicenter RCTs. It also shows the responsibility of careful planning when conducting a RCT. Trial registration as a prerequisite for approval by ethics committees could in addition minimize publication bias. Weighting the current evidence on whether to use MET, or not, it seems that in distal ureteral stones larger than 5mm, there may be a potential therapeutic benefit for the use of α-blockers. Patients should be informed about the possible, but as yet unproven benefit of using α-blockers in this situation, as well as their off-label use and potential side effects.

Detrusor underactivity and the underactive bladder: Symptoms, function, cause-what do we mean? ICI-RS think tank 2014.

Impaired bladder emptying is a well-recognized cause of lower urinary tract symptoms. However, the symptoms produced do not always relate to voiding, and may include frequency, urgency and incontinence. Conversely, the etiology of symptoms of disturbed voiding is not necessarily dependent upon objectively impaired voiding. Terms including underactive bladder, detrusor underactivity, and impaired contractility describe aspects of these problems, and have been used somewhat interchangeably. It is possible that the present lack of effective therapy in many cases relates to both etiologic and diagnostic uncertainty stemming from terminologic imprecision. Detrusor underactivity has a standardized definition, unlike underactive bladder and impaired contractility. The relationships of symptoms, function, and cause were the focus of a 2014 ICI-RS Think Tank entitled Does Detrusor Underactivity Exist, and if so it is neurogenic, myogenic, or both? This review presents a summary of the problem and the Think Tank conclusions. A terminologic hierarchy and specific research goals are presented.

Biomaterials for pelvic floor reconstructive surgery: how can we do better?

Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are major health issues that detrimentally impact the quality of life of millions of women worldwide. Surgical repair is an effective and durable treatment for both conditions. Over the past two decades there has been a trend to enforce or reinforce repairs with synthetic and biological materials. The determinants of surgical outcome are many, encompassing the physical and mechanical properties of the material used, and individual immune responses, as well surgical and constitutional factors. Of the current biomaterials in use none represents an ideal. Biomaterials that induce limited inflammatory response followed by constructive remodelling appear to have more long term success than biomaterials that induce chronic inflammation, fibrosis and encapsulation. In this review we draw upon published animal and human studies to characterize the changes biomaterials undergo after implantation and the typical host responses, placing these in the context of clinical outcomes.

Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women.

OBJECTIVE: Family studies and twin studies demonstrate that lower urinary tract symptoms and pelvic organ prolapse are heritable. This review aimed to identify genetic polymorphisms tested for an association with lower urinary tract symptoms or prolapse, and to assess the strength, consistency, and risk of bias among reported associations. STUDY DESIGN: PubMed and HuGE Navigator were searched up to May 1, 2014, using a combination of genetic and phenotype key words, including "nocturia," "incontinence," "overactive bladder," "prolapse," and "enuresis." Major genetics, urology, and gynecology conference abstracts were searched from 2005 through 2013. We screened 889 abstracts, and retrieved 78 full texts. In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes. Fixed and random effects metaanalyses were conducted using codominant models of inheritance. We assessed the credibility of pooled associations using the interim Venice criteria. RESULTS: In pooled analysis, the rs4994 polymorphism of the ADRB3 gene was associated with overactive bladder (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.7-3.6; n = 419). The rs1800012 polymorphism of the COL1A1 gene was associated with prolapse (OR, 1.3; 95% CI, 1.0-1.7; n = 838) and stress urinary incontinence (OR, 2.1; 95% CI, 1.4-3.2; n = 190). Other metaanalyses, including those for polymorphisms of COL3A1,LAMC1,MMP1,MMP3, and MMP9 did not show significant effects. Many studies were at high risk of bias from genotyping error or population stratification. CONCLUSION: These metaanalyses provide moderate epidemiological credibility for associations of variation in ADRB3 with overactive bladder, and variation of COL1A1 with prolapse. Clinical testing for any of these polymorphisms cannot be recommended based on current evidence.

Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men.

CONTEXT: Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS. OBJECTIVE: To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations. EVIDENCE ACQUISITION: A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies. EVIDENCE SYNTHESIS: We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I(2)=27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes. CONCLUSIONS: Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses. PATIENT SUMMARY: Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.

Moving towards a comprehensive assessment of lower urinary tract symptoms (LUTS).

AIMS: To evaluate the utility of the International Prostate Symptom Score (IPSS) and the LUTS Tool when assessing lower urinary tract symptoms (LUTS). Secondary objectives were to examine associations of LUTS and treatment seeking. METHODS: Analyses were performed using EpiLUTS data, a population-based, cross-sectional, Internet survey of men and women (aged ≥40) in Sweden, UK, and US with a sample of 30,000 participants. Participants completed the IPSS and the LUTS Tool. Prevalence rates of symptoms captured by the LUTS Tool were compared using IPSS summary scores: 0, 1-7, 8-19, and ≥20. LUTS Tool subscale scores were calculated. Pearson correlations between the LUTS Tool symptoms and subscales and IPSS symptoms were performed. Logistic regressions evaluated the associations of IPSS scores and LUTS Tool subscales with treatment seeking for LUTS. RESULTS: The IPSS did not assess some symptoms (i.e., incontinence) for which there was a high prevalence among participants. Correlations between the 7 symptoms assessed by the IPSS and LUTS Tool were moderate to high ranging between 0.37 (nocturia women) and 0.77 (weak stream men), indicating concordance. While the LUTS Tool subscales and the total IPSS score were all significantly associated with treatment seeking, the LUTS Tool OAB subscale in men and Voiding subscale in women most strongly predicted treatment seeking. CONCLUSION: LUTS that are excluded from the IPSS, most notably incontinence, were prevalent even among mildly symptomatic participants. Since storage symptoms appear to drive treatment seeking, identifying, and treating these symptoms is essential when caring for patients with LUTS.

Urinary incontinence and its relationship to mental health and health-related quality of life in men and women in Sweden, the United Kingdom, and the United States.

BACKGROUND: Differences in health burden associated with urinary incontinence (UI) subtypes have been previously described, but the majority of studies are in women. Additional research is needed to examine the prevalence and burden of UI subtype including postmicturition incontinence, nocturnal enuresis, coital incontinence, and incontinence for unspecified reasons. OBJECTIVE: Examine the burden of UI in men and women in Sweden, the United Kingdom, and the United States. DESIGN, SETTING, AND PARTICIPANTS: Secondary analyses of the Epidemiology of Lower Urinary Tract Symptoms (EpiLUTS), a cross-sectional Internet survey, were performed. Participants who reported UI were categorized as (1) urgency urinary incontinence (UUI) only, (2) stress urinary incontinence (SUI) only, (3) mixed urinary incontinence (MUI), (4) UUI plus other incontinence (OI), (5) SUI plus OI, or (6) OI. Differences in health outcomes across UI groups were explored by gender using descriptive statistics and general linear models. MEASUREMENTS: Outcomes included treatment seeking for urinary symptoms, perception of bladder condition, depression, anxiety, and health-related quality of life (HRQL). RESULTS AND LIMITATIONS: Of 14 140 men and 15 860 women, 6479 men (45.8%) and 10 717 women (67.6%) reported UI. The most prevalent UI subgroups were OI in men and SUI in women. MUI and SUI plus OI had the greatest treatment seeking among men, whereas MUI and UUI plus OI had the greatest treatment seeking among women. Men with MUI had the highest rates of anxiety, followed by those with UUI plus OI and SUI plus OI, and OI with a similar trend observed for depression. Anxiety and depression were highest in SUI plus OI and MUI women. MUI and UUI plus OI men and women had significantly lower HRQL compared with other UI groups. CONCLUSIONS: UI is common in men and women aged >40. Individuals with UUI combined with SUI or OI bear a greater mental health burden and report poorer HRQL.

Contemporary management of lower urinary tract disease with botulinum toxin A: a systematic review of botox (onabotulinumtoxinA) and dysport (abobotulinumtoxinA).

CONTEXT: The use of botulinum toxin A (BoNTA) in the treatment of lower urinary tract dysfunction has expanded in recent years and the off-licence usage list includes neurogenic detrusor overactivity (NDO), idiopathic detrusor overactivity (IDO), painful bladder syndrome (PBS), and lower urinary tract symptoms resulting from bladder outflow obstruction (BOO) or detrusor sphincter dyssynergia (DSD). There are two commonly used preparations of BoNTA: Botox (onabotulinumtoxinA) and Dysport (abobotulinumtoxinA). OBJECTIVE: To compare the reported outcomes of onabotulinumtoxinA and abobotulinumtoxinA in the treatment of NDO, IDO, PBS, DSD, and BOO for adults and children. EVIDENCE ACQUISITION: We performed a systematic review of the published literature on PubMed, Scopus, and Embase in the English language reporting on outcomes of both BoNTA preparations. Review articles and series with <10 cases were excluded. The articles were graded for level of evidence and conclusions drawn separately for data with higher-level evidence. EVIDENCE SYNTHESIS: There is high-level evidence for the use of onabotulinumtoxinA and abobotulinumtoxinA in adults with NDO but only for abobotulinumtoxinA in children with NDO. Only onabotulinumtoxinA has level 1 evidence supporting its use in IDO, BOO, DSD, and PBS/interstitial cystitis. CONCLUSIONS: We identified good-quality studies that evaluated onabotulinumtoxinA for all the indications described above in adults; such was not the case with abobotulinumtoxinA. Although this does not imply that onabotulinumtoxinA is more effective than abobotulinumtoxinA, it should be a consideration when counselling patients on the use of botulinum toxin in urologic applications. The two preparations should not be used interchangeably, either in terms of predicting outcome or in determining doses to be used.

The impact of overactive bladder on mental health, work productivity and health-related quality of life in the UK and Sweden: results from EpiLUTS.

OBJECTIVE: • To examine the prevalence and burden of overactive bladder (OAB) with bother in the UK and Sweden compared to OAB without bother and no/minimal OAB/lower urinary tract (LUTS) symptoms, respectively. PATIENTS AND METHODS: • A cross-sectional population-representative survey was conducted via the Internet in the UK, Sweden and USA. • Participants rated the frequency and bother of OAB and LUTS. Patient outcomes included the Overactive Bladder Questionnaire Short Form, Patient Perception of Bladder Condition, Short Form-12, Hospital Anxiety and Depression Scale-Anxiety and Hospital Anxiety and Depression Scale-Depression, as well as questions about treatment seeking and work productivity. • OAB was defined as urgency at least sometimes or the presence of urinary urgency incontinence. Three subgroups were compared: no/minimal symptoms, OAB without bother and OAB with bother. • Analyses were conducted by gender and country using general linear and logistic regression models to examine bothersome OAB and treatment seeking. RESULTS: • Survey response was 59.2%; 10,000 people (4724 men and 5276 women) participated. • The prevalence of OAB with bother at least 'somewhat' was 10.9% and 14.6% for men in the UK and Sweden, and 22.5% and 33.7% for women in the UK and Sweden, respectively. • Men and women with bothersome OAB were significantly more likely to seek treatment, report the lowest levels of health-related quality of life and work productivity and the highest levels of anxiety and depression compared to those with no/minimal symptoms and OAB without bother. • Greater symptom severity of urgency, urgency urinary incontinence, frequency, nocturia, and increasing levels of anxiety were strongly predictive of OAB bother in both men and women. • Predictors of treatment seeking included frequency, bother as a result of urgency, and lower levels of depressive symptoms in men, and frequency, nocturia and urgency in women. CONCLUSIONS: • OAB is common in the UK and Sweden, and women are more likely to be affected then men. • The impact of OAB is evident across generic and condition-specific domains of health-related quality of life.