The use of animal models in preclinical investigations for the development of a surgical mesh for pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: Polypropylene (PP) mesh for the treatment of pelvic organ prolapse (POP) has raised substantial concerns over long-term complications, leading to its ban in multiple countries. In response, emerging materials are being explored as alternatives for prolapse surgery. Preclinical animal models have historically played a pivotal role in validating medical devices, prior to clinical trials. Successful translation of these materials necessitates the identification of suitable animal models that replicate the female human pelvis and its biomechanical properties. Preclinical in vivo testing assesses the safety of surgical mesh and treatment efficacy in preventing POP recurrence. METHODS: The research critically reviews animal models used for preclinical pelvic mesh testing over the last decade and proposes a promising model for future preclinical studies. RESULTS: Rats were the most common mammal used for toxicity and biocompatibility investigations through abdominal implantation. Although non-human primates serve as a gold standard for efficacy testing, ethical considerations limit their use owing to their close biological and cognitive resemblance to humans. Consequently, sheep were the most preferred large animal model owing to their reproductive system similarities and propensity for spontaneous POP following parity. CONCLUSION: The study contributes valuable insights into the selection of appropriate animal models for preclinical pelvic mesh testing, offering guidance that is crucial for enhancing the safety and efficacy of novel surgical interventions in the treatment of POP.

Cytokines in Bladder Pain Syndrome: A Review of the Literature.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is poorly understood with both the aetiology and pathophysiology being unknown. Symptoms overlap with other disorders, such as overactive bladder (OAB) and chronic pelvic pain disorders such as endometriosis, making a consensus on how to diagnosis and manage patients challenging. The development of biomarkers for BPS may be the key to understanding more about its pathophysiology, as well as aiding diagnosis, subclassification, and discovering new drug targets for its management. As inflammation is widely understood to hold a central role in BPS, the evaluation of cytokines has gained interest. This article summarises the current literature and understanding of urinary, serum, and bladder tissue cytokines found elevated in patients with bladder pain syndrome. METHODS: literature search using Pub Med with the keywords "bladder pain syndrome", "painful bladder syndrome", "bladder pain", "Interstitial cystitis" AND "cytokines" or "inflammation". This study was except from institutional approval. RESULTS: Thirty-six cytokines have been identified as being statistically significantly elevated in either the serum, urine, or bladder tissue of patients with bladder pain syndrome in the 22 studies identified in this review of the literature. These cytokines include those from the interleukin group (n = 14), the CXC chemokine group (n = 5), and the C-C chemokine group (n = 7). CONCLUSIONS: CXCL-1, CXCL-8, CXCL-9, CXCL-10, CXCL-11 from the CXC chemokine group, and CCL2, CCL4, CCL5, CCL7, and CCL11 from the C-C chemokine group have been found to be significantly elevated in patients with bladder pain in the literature. Many of these analytes also have supporting evidence for their roles in bladder pain from animal models and studies in other chronic inflammatory conditions. It is likely that a single cytokine will not serve as an adequate biomarker of disease in bladder pain syndrome for either diagnosis or disease severity. Instead, panels of inflammatory mediators may reveal more about the different pathways of inflammation leading to similar presentations of bladder pain in patients.

The location of pain and urgency sensations during cystometry.

AIMS: The relationship between bladder pain and urinary urgency sensations is poorly understood. We analyzed the relationship between locations and intensities of urgency and pain sensations felt during filling cystometry. METHODS: Participants completed the King's Health Questionnaire (KHQ) to indicate presence of bladder pain or urgency. During cystometry, participants scored the intensity of urgency and pain, both in the suprapubic and the urethral region, on a VAS scale of 0-10 at a baseline, at first desire, normal desire, strong desire to void, and at maximum cystometric capacity during filling. We allocated the participants to six groups; those reporting urgency or not, pain or not, both symptoms and neither. Friedman's Test was used to ascertain if all scores increased significantly, the Wilcoxon Signed Rank Test was used to demonstrate the difference between scores, and agreement for findings during cystometry was tested with Mann-Whitney U. RESULTS: A total of 68 women participated; 38 participants reported pain, 57 reported urgency, and 33 reported both symptoms. Pain and urgency scores significantly increased during cystometry (P < 0.0001). For participants reporting pain, suprapubic pain was rated significantly higher than urethral pain. Participants reporting both symptoms, felt more urgency than pain, and again pain more suprapubically than urethrally. Participants reporting only urgency scored suprapubic and urethral urgency similarly at all desires. CONCLUSIONS: Pain and urgency are well differentiated sensations and are felt at different locations although pain is seemingly easier localized. Neurourol. Urodynam. 36:620-625, 2017. © 2016 Wiley Periodicals, Inc.

Association between joint hypermobility and pelvic organ prolapse in women: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Abnormalities of common collagen proteins have been noted in individuals affected by POP and JHM, suggesting a common aetiology. We assessed strength, consistency and potential for bias in pooled associations of the relationship between JHM and POP. METHODS: We searched MEDLINE, EMBASE and CINAHL, as well as International Continence Society (ICS) and International Urogynaecologic Association (IUGA) annual meeting abstracts, including reference lists, without language restrictions. We included case-control and cohort studies and applied strict criteria for choosing eligible studies. Methodologically trained reviewers independently screened abstracts and full texts to confirm eligibility. We extracted data on study and patient characteristics, clinical assessment tools, and methodology. We assessed comparability and representativeness of source populations, confidence in the assessment of JHM and POP and adjustment for confounding and missing data. Meta-analysis was performed using a random effects model. RESULTS: We retrieved 39 full texts, of which 14 were used in the meta-analysis. Overall pooled odds ratio (OR) was 2.37 [95 % confidence interval (CI) 1.54-3.64, I(2) = 77.0 %]. We identified no significant factors in meta-regression, and there was no evidence of publication bias; six studies were at high risk of bias with frequent differences in sampling frames, limited validity for clinical assessments and failure to match for important prognostic variables. CONCLUSIONS: We found a strong association between POP and JHM, with an effect size that is clinically relevant. Our findings are limited by high heterogeneity and the potential for residual confounding factors. JHM is an important early indicator for POP risk, and future longitudinal studies should explore the shared aetiology.

Polypropylene Pelvic Mesh: What Went Wrong and What Will Be of the Future?

BACKGROUND: Polypropylene (PP) pelvic mesh is a synthetic mesh made of PP polymer used to treat pelvic organ prolapse (POP). Its use has become highly controversial due to reports of serious complications. This research critically reviews the current management options for POP and PP mesh as a viable clinical application for the treatment of POP. The safety and suitability of PP material were rigorously studied and critically evaluated, with consideration to the mechanical and chemical properties of PP. We proposed the ideal properties of the 'perfect' synthetic pelvic mesh with emerging advanced materials. METHODS: We performed a literature review using PubMed/Medline, Embase, Cochrane Library (Wiley) databases, and ClinicalTrials.gov databases, including the relevant keywords: pelvic organ prolapse (POP), polypropylene mesh, synthetic mesh, and mesh complications. RESULTS: The results of this review found that although PP is nontoxic, its physical properties demonstrate a significant mismatch between its viscoelastic properties compared to the surrounding tissue, which is a likely cause of complications. In addition, a lack of integration of PP mesh into surrounding tissue over longer periods of follow up is another risk factor for irreversible complications. CONCLUSIONS: PP mesh has caused a rise in reports of complications involving chronic pain and mesh exposure. This is due to the mechanical and physicochemical properties of PP mesh. As a result, PP mesh for the treatment of POP has been banned in multiple countries, currently with no alternative available. We propose the development of a pelvic mesh using advanced materials including emerging graphene-based nanocomposite materials.

Women's perspective of botulinum toxin treatment for overactive bladder symptoms.

INTRODUCTION AND HYPOTHESIS: This study aimed to evaluate the women's' views and expectations about outcomes and complications of botulinum toxin treatment for overactive bladder (OAB) symptoms. METHODS: Consecutive women with OAB symptoms and detrusor overactivity were requested to fill out a multiple choice questionnaire to assess whether they would consider botulinum and what outcomes as well as complications they would find acceptable to undergo this treatment. RESULTS: Two hundred sixty-one women, mean age of 58 (range, 38-78) years, were studied. Two hundred twenty-four were treatment-naive women (group A), while 37 were no responders to anticholinergics (group B). Only 49.6% of women in group A and 54% in group B would accept botulinum toxin. No significant differences were found between treatment-naive women and non-responders to anticholinergics (p > 0.05). CONCLUSIONS: Acceptance of botulinum toxin treatment involves a complex interaction of efficacy and possible complications. The balance of these factors changes the acceptability of the treatment.

Transvaginal ultrasound measurement of bladder wall thickness: a more reliable approach than transperineal and transabdominal approaches.

OBJECTIVES To validate transperineal, transabdominal and transvaginal ultrasound (US) techniques to measure bladder wall thickness (BWT). SUBJECTS AND METHODS Women underwent US measurement of BWT at three different anatomical sites: anterior wall, dome and trigone of the bladder by two 'blinded' operators using transabdominal, transperineal and transvaginal approaches at separate visits and by a single operator using transabdominal and transperineal techniques. Bland-Altman analysis was used to determine interobserver reliability for all three techniques and intraobserver reliability for transabdominal and transperineal methods. RESULTS In all, 25 women were scanned. The transperineal US had a high interobserver mean difference when measuring the anterior BWT (-0.34) and a high intraobserver mean difference when measuring the anterior (0.54) and dome BWT (0.33). Transabdominal US had a high interobserver mean difference for all measurements of BWT, and a high intraobserver mean difference when measuring the trigonal thickness (0.56). Transvaginal US had a consistent interobserver mean difference for all three measurements. The transperineal and transabominal approaches had the widest intraobserver and interobserver 95% confidence intervals of the mean difference when compared with the transvaginal approach. CONCLUSIONS Transabdominal and transperineal US for measuring BWT did not have good intraobserver and interobserver reliability for measurement of the three anatomical sites to determine mean BWT. Transvaginal US had good interobserver reliability, thus mean BWT is best measured using the transvaginal approach.

Is the beneficial effect of antimuscarinics related to motor or sensory changes in the bladder?

INTRODUCTION AND HYPOTHESIS: The aim of the study was to assess the sensory and motor effects of antimuscarinic treatment on the bladder in women with overactive bladder, detrusor overactivity demonstrated on urodynamics and a mean bladder wall thickness (BWT) greater than 5 mm. METHODS: Fifty-eight women underwent treatment with antimuscarinics in 12 weeks. Before treatment and at 1, 2, 6 and 12 weeks of treatment, women completed the patient perception of bladder condition (PPBC) single-item global questionnaire, indicated the severity of their urgency on a visual analogue scale (VAS) and underwent transvaginal ultrasound to determine mean bladder wall thickness (BWT). RESULTS: PPBC and VAS scores for urgency declined throughout the treatment course whereas mean BWT declined during the first 6 weeks of treatment and then reached a plateau after falling to below 5 mm. CONCLUSION: The mechanism of action of antimuscarinics appears to be a complex interaction of sensory and motor components.

Ultrasound measurement of vaginal wall thickness: a novel and reliable technique.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to validate a technique to measure the vaginal wall thickness (VWT) using two-dimensional ultrasound. METHODS: Women were scanned by two independent operators and by the same operator at two separate visits at the level of the bladder neck, the apex of the bladder, the anterior fornix, the anorectal junction, rectum and posterior fornix. Fresh female cadavers were scanned and ultrasound thickness of the vagina was compared to histological thickness. RESULTS: Bland Altman analysis revealed a low mean difference between operators and between visits by the same operator. The 95% confidence intervals as a percentage of the mean vaginal wall thickness ranged between 2.8% and 7.4%. There was a low percentage difference between ultrasound and histological vaginal wall thickness. CONCLUSION: Ultrasound vaginal wall thickness demonstrated good intra- and interoperator reliability, as well as consistency with histological measurement. It is a valid technique.

Urogynaecological problems in pregnancy and postpartum sequelae.

PURPOSE OF REVIEW: Women in pregnancy can experience lower urinary tract symptoms which are related to the pregnancy and delivery and iatrogenic, and related to use of epidural anaesthesia and urethral catheters. This article assesses the controversial relationship between pregnancy and delivery and the development of urinary incontinence and pelvic organ prolapse. RECENT FINDINGS: Lower urinary tract symptoms are common in pregnancy and they peak in the third trimester. If women have lower urinary tract symptoms prior to pregnancy, they are more likely to persist after delivery. Vaginal delivery is the factor most strongly associated with stress urinary incontinence after delivery and elective caesarean section may be protective. Vaginal childbirth causes levator ani injury and increase in levator hiatus size, and these persist following vaginal delivery. Women with levator ani injuries may be twice as likely to develop uterovaginal prolapse. Voiding difficulties are more likely to occur after a traditional epidural than a low dose or combined spinal epidural. SUMMARY: There is radiological evidence supporting pelvic floor injury following vaginal childbirth and epidemiological evidence for the relationship between vaginal delivery and urinary incontinence and pelvic organ prolapse. Rigorous long-term studies are needed to identify the direct relationship between these two phenomena.

Long-term prospective randomized study comparing two different regimens of oxybutynin as a treatment for detrusor overactivity.

OBJECTIVE: Prospective randomized trial to compare two low starting doses of oxybutynin, using an incremental regimen to assess patient compliance and treatment efficacy in the long-term. STUDY DESIGN: Women with detrusor overactivity were included. Oxybutynin was randomly prescribed with a starting dose of either 2.5 mg bd or 5 mg nocte. Instructions were given to increase oxybutynin up to 5 mg tds over a period of 6 weeks fortnightly. After two years we re-contacted all the women, using a specific questionnaire to assess the efficacy, acceptability and compliance with these two different regimens. Twenty-two women in each group were calculated to show a 5% difference with a significance of 0.05 and a power of 0.9. The chi2-test was used to compare the two groups and a P-value < 0.05 was considered significant. RESULTS: Ninety-six women were included; 66 (68.75%) (mean age 57.5 years) responded to our questionnaire. Twenty-seven had a starting dose of 2.5 mg oxybutynin twice a day and 39 of 5 mg nocte. 34.8% complained of side effects. Only 19 (43.2%) out of the 44, not on medication anymore abandoned oxybutynin for adverse reactions. Most of the patients stopped oxybutynin within 4 months. 53.0% reported improvement or cure. 39.4% denied any benefit and 7.6% (none still on oxybutynin) did not answer. The two groups did not differ for duration of treatment, improvement with oxybutynin, maximum dose they reached, the present dose, and the present urinary symptoms. CONCLUSION: This study did not show any advantage in efficacy or compliance with oxybutynin when two different regimens of low starting were used. Two-thirds of patients discontinued the therapy within 4-6 months. Therefore, patients on anticholinergics should be reassessed after 6 months in clinical practice.

Is ultrasound estimation of bladder weight a useful tool in the assessment of patients with lower urinary tract symptoms?

INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the relationship between ultrasound estimation of bladder weight (UEBW), symptoms and urodynamic diagnosis. METHODS: Women with lower urinary tract symptoms underwent urodynamics studies and measurement of UEBW at a fixed bladder volume. RESULTS: Women with overactive bladder symptoms had a median UEBW of 48.3 g (95% CI 44-52), with stress urinary incontinence a median UEBW of 35.1 g (95% CI 30-41) and with mixed urinary incontinence a median UEBW of 40.0 g (95% CI 37-43) (p<0.001). Women with detrusor overactivity had a median UEBW of 48.0 g (95% CI 46-51), with urodynamic stress incontinence a median UEBW of 30 g (95% CI 29-31) and detrusor overactivity and urodynamic stress incontinence a median UEBW of 37.3 g (95% CI 33-41) (p<0.001). CONCLUSIONS: UEBW is higher in women with overactive bladder and detrusor overactivity. UEBW may be a useful tool in women with lower urinary tract symptoms.

Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations.

PURPOSE: We studied the cellular localization of muscarinic receptor subtypes 2 and 3 in the human bladder and related any changes in overactive and painful bladder syndromes to measures of clinical dysfunction. MATERIALS AND METHODS: Bladder specimens obtained from patients with painful bladder syndrome (11), idiopathic detrusor overactivity (12) and from controls with asymptomatic microscopic hematuria (16) were immunostained using specific antibodies to muscarinic receptor subtypes 2 and 3, and to vimentin, which is a marker for myofibroblasts. Immunostaining results were quantified with computerized image analysis and correlated with clinical dysfunction using frequency and urgency scores. RESULTS: Muscarinic receptor subtype 2 and 3 immunoreactivity was observed in the urothelium, nerve fibers and detrusor layers. In addition, strong myofibroblast-like cell staining, similar to vimentin, was present in the suburothelial region and detrusor muscle. A significant increase in suburothelial myofibroblast-like muscarinic receptor subtype 2 immunoreactivity was seen in patients with painful bladder syndrome (p = 0.0062) and idiopathic detrusor overactivity (p = 0.0002), and in muscarinic receptor subtype 3 immunoreactivity in those with idiopathic detrusor overactivity (p = 0.0122) with a trend in painful bladder syndrome. Muscarinic receptor subtype 2 and 3 immunoreactivity significantly correlated with the urgency score (p = 0.0002 and 0.0206, respectively) and muscarinic receptor subtype 2 immunoreactivity correlated with the frequency score (p = 0.0029). No significant difference was seen in urothelial and detrusor muscarinic receptor subtypes 2 and 3 or vimentin immunostaining. CONCLUSIONS: To our knowledge this is the first study to show the cellular localization of muscarinic receptor subtypes 2 and 3 in the human bladder. The increase in muscarinic receptor subtypes 2 and 3 immunostaining in myofibroblast-like cells in clinical bladder syndromes and its correlation with clinical scores suggests a potential role in pathophysiological mechanisms and the therapeutic effect of anti-muscarinic agents.

Determining the importance of change in the overactive bladder questionnaire.

PURPOSE: The overactive bladder questionnaire assesses symptom bother and health related quality of life in patients with overactive bladder. It has been shown to be reliable, valid and responsive. We established the minimally important difference of the overactive bladder questionnaire. MATERIALS AND METHODS: Post hoc analyses from 2 clinical trials were performed. Distribution based, eg effect size, and anchor based analyses using perception of treatment benefit and clinical variables were used. RESULTS: The mean age of the 2 study populations was 58.8 and 58.7 years, respectively. Patients were predominantly female (51.8% and 75.1%) and white (83.9% and 87%, respectively). Half SD of the overactive bladder questionnaire symptom bother subscale was 9.1 to 9.3, and half SD of the overactive bladder questionnaire health related quality of life subscales (coping, concern, sleep and social interaction) was 9.8 to 13.2. Questionnaire subscales had moderate to large effect sizes with the largest effect sizes for symptom bother (-0.85 to -1.09). Anchor based analyses showed that significantly greater change scores were associated with greater patient perceived treatment benefit and satisfaction. The difference between change scores in patients perceiving no and little benefit was 7.4 to 16.5 for all questionnaire scales except social interaction with the majority greater than 10 points. Greater change scores were consistently associated with greater improvements in micturition diary variables. CONCLUSIONS: Multiple methodologies provide strong justification for the recommendation of a 10-point minimally important difference for all overactive bladder questionnaire subscales. This minimally important difference may be conservative for some subscales, although a uniform minimally important difference is recommended to facilitate interpretation of the overactive bladder questionnaire.

Comparison of the efficacy, safety, and tolerability of propiverine and oxybutynin for the treatment of overactive bladder syndrome.

AIM: To compare the effects of propiverine and oxybutynin on ambulatory urodynamic monitoring (AUM) parameters, safety, and tolerability in patients with overactive bladder. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre, crossover study. Patients (n = 77) received two of the following treatments during two 2-week periods: propiverine 20 mg once daily, propiverine 15 mg three times daily, oxybutynin 5 mg three times daily, and placebo. AUM parameters, salivary flow, visual near point, and heart rate were assessed. RESULTS: A consistent order in the efficacy between active treatment groups was observed for the reduction in mean involuntary detrusor contractions (IDCs; oxybutynin 15 mg

The relationship between urinary symptom questionnaires and urodynamic diagnoses: an analysis of two methods of questionnaire administration.

OBJECTIVE: To assess whether method of administration of a standard urinary symptom questionnaire alters the relationship of symptoms with urodynamic diagnoses. DESIGN: Randomised crossover study. SETTING: Tertiary Urogynaecology Unit, London, UK. PARTICIPANTS: One hundred and fourteen women attending a tertiary urogynaecology clinic. METHODS: Women were randomised to either an initial interview-assisted questionnaire in the clinic with a follow up postal questionnaire or an initial pre-outpatient questionnaire followed by an interview-assisted questionnaire at the clinic visit. Video cystourethrography or saline cystometry was performed at the clinic visit. MAIN OUTCOME MEASURES: Question responses were compared with urodynamic diagnoses. RESULTS: With an interview method, only severity of incontinence was significantly associated with detrusor overactivity (U= 593.5, P= 0.012). With self-completion, severity of nocturia (U= 477, P < 0.05), urgency (U= 395, P= 0.003), urge urinary incontinence (U= 392, P= 0.003), leakage without warning (U= 443, P= 0.035) and incomplete voiding (U= 413, P= 0.01) were significantly associated with detrusor activity. On interview the symptom of stress urinary incontinence (U= 523, P= 0.002) and use of pads (U= 564.5, P= 0.011) were significantly associated with a diagnosis of urodynamic stress incontinence. Severity of stress urinary incontinence (U= 276, P < 0.001), frequency of leakage (U= 348.5, P= 0.004), use of protection (U= 432.5, P < 0.018), nocturnal incontinence (U= 393.5, P= 0.002) and quantity of leakage (U= 441.5, P < 0.05) on self-completion were strongly associated with diagnosed urodynamic stress incontinence. There was no association between the symptoms of urgency or urge incontinence and the urodynamic stress incontinence. CONCLUSIONS: Postal questionnaire responses have a better relationship with urodynamics, both for urodynamic stress incontinence and detrusor over activity, than interview-assisted questionnaire responses. However, no symptom has a high enough specificity and sensitivity to replace urodynamic testing.

Can ultrasound replace ambulatory urodynamics when investigating women with irritative urinary symptoms?

OBJECTIVE: To determine whether transvaginal ultrasound measurement of bladder wall thickness could replace ambulatory urodynamics when investigating women with lower urinary tract dysfunction not explained by conventional laboratory urodynamic studies. DESIGN: A blinded prospective study. SETTING: Tertiary referral unit in a London teaching hospital. POPULATION: One hundred and twenty-eight women referred for ambulatory urodynamics with equivocal laboratory urodynamic findings or whose symptoms were not explained by the laboratory urodynamic findings. METHODS: Transvaginal ultrasound assessment of bladder wall thickness was performed in three planes with an empty bladder prior to ambulatory urodynamics. Mean bladder wall thickness was calculated and the results analysed with respect to the ambulatory urodynamic diagnosis. MAIN OUTCOME METHODS: Mean bladder wall thickness in women with a normal ambulatory study or a diagnosis of detrusor instability, genuine stress incontinence (GSI) or mixed incontinence. RESULTS: Using a one way analysis of variance (ANOVA) bladder wall thickness was found to be significantly different in all diagnostic groups and this reached significance (P = 0.0001). There was no overlap in the 95% confidence intervals representing a diagnosis of detrusor instability or genuine stress incontinence. CONCLUSIONS: Transvaginal ultrasound assessment of mean bladder wall thickness is a sensitive screening tool, which can detect detrusor instability in those women with equivocal laboratory urodynamics. In women who have no evidence of GSI on laboratory studies, a cutoff of 6.0mm is highly suggestive of detrusor instability. However, in those women with GSI then ambulatory studies probably remain the investigation of choice.