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Background Recommendations against prostate-specific antigen (PSA) testing in 2012 have increased advanced-stage diagnosis and prostate cancer–specific mortality rates. Objective To present the position of the European Association of Urology (EAU) in 2021 and provide recommendations for the use of PSA testing as part of a risk-adapted strategy for the early detection of prostate cancer. Evidence acquisition The authors combined their review of relevant literature, including the EAU prostate cancer guidelines 2021 update, with their own knowledge to provide an expert opinion, representing the EAU’s position in 2021. Evidence synthesis The EAU has developed a risk-adapted early prostate cancer detection strategy for well-informed men based on PSA testing, risk calculators, and multiparametric magnetic resonance imaging, which can differentiate significant from insignificant prostate cancer. This approach largely avoids the overdiagnosis/overtreatment of men unlikely to experience disease-related symptoms during their lifetime and facilitates an early diagnosis of men with significant cancer to receive active treatment. It also reduces advanced-stage diagnosis, thereby potentially reducing prostate cancer–specific mortality and improving quality of life. Education is required among urologists, general practitioners, radiologists, policy makers, and healthy men, including endorsement by the European Commission to adapt the European Council’s screening recommendations in its 2022 plan and requests to individual countries for its incorporation into national cancer plans. Conclusions This risk-adapted approach for the early detection of prostate cancer will reverse current unfavourable trends and ultimately save lives. Patient summary The European Association of Urology has developed a patient information leaflet and algorithm for the early diagnosis of prostate cancer. It can identify men who do not need magnetic resonance imaging or a biopsy and those who would not show any symptoms versus those with more aggressive disease who require further tests/treatment. We need to raise awareness of this algorithm to ensure that all well-informed men at risk of significant prostate cancer are offered a prostate-specific antigen test. Take Home Message A risk-adapted early prostate cancer detection strategy, incorporating prostate-specific antigen testing, multiparametric magnetic resonance imaging, risk calculators, and biomarkers, will avoid overdiagnosis/overtreatment of insignificant cancers and ensure early detection and treatment of significant cancers, thereby improving quality of life and reducing prostate cancer–related deaths.

Background Female urethral diverticula (UD) are an uncommon and often overlooked aetiology in women presenting with lower urinary tract symptoms, urethral pain, and recurrent urinary tract infection. With increasing awareness, appropriate imaging is more commonly undertaken with consideration given to surgical management. Objective The video presented demonstrates the technique for excising large and/or complex UD using a modified prone jack-knife position—a position that offers excellent surgical access and allows the surgeon to operate in a more ergonomic position. Design, setting, and participants A retrospective review of the data on patients undergoing excision of UD at a tertiary referral unit was performed. Surgical procedure Urethral and suprapubic catheters (±insertion of ureteric stents) were placed in supine position. UD excised in the modified prone jack-knife position (±placement of a Martius flap). Measurements Subjective cure rate, recurrence rate, rates of postoperative urinary incontinence, need for secondary incontinence procedure, and postoperative complications were measured. Results and limitations A total of 121 patients were operated on in the study period. The mean follow-up time was 10 mo (range 3–40). The most frequent presenting symptoms included a vaginal mass (n = 76, 63%), followed by dysuria (n = 72, 60%) and pelvic pain (n = 71, 59%). An identifiable aetiological factor was present in 45 patients, including traumatic vaginal delivery (18, 15%), prior periurethral surgery (17, 14%), and urethral dilatation (10, 8%). All patients underwent postvoiding magnetic resonance imaging (MRI) to confirm the diagnosis and plan surgery. UD ranged in maximum diameter from 8 to 48 mm, with a mean of 43 mm (standard deviation 9.24). The most common anatomical location was midurethral (55, 46%), followed by distal (36, 30%), proximal (25, 21%), and full length (5, 4%). Most UDs were single in configuration (74%), followed by multiloculated (15%), saddle shaped (7%), and circumferential (5%). On preoperative videourodynamics, 17 (14%) had stress urinary incontinence. UD excision was undertaken in the modified prone jack-knife position in all cases. A Martius flap was utilised in 36 (30%). The median postoperative postvoiding residual was 26 ml (interquartile range 0–40). In total, 88 (73%) patients were continent postoperatively and 16 (13%) experienced de novo stress urinary incontinence. Of the 37 with pre-existing stress incontinence symptoms, 20 (54%) were continent after operation. A total of 14 patients had subsequent autologous fascial sling at 6 mo. In total, five symptomatic recurrences occurred (4%); of these patients, three elected to undergo surgical excision, all of whom had symptom resolution and were continent after operation. A total of 11 patients (9%) experienced a Clavien-Dindo grade I–II complication within 90 d after operation. Five patients complained of dyspareunia, which resolved by 6 mo. Conclusions The modified prone jack-knife position facilitates excellent access for excision of both simple and complex UDs. This positioning of the patient is not widely recognised amongst urologists. Using this approach, there were low rates of symptomatic recurrence and de novo stress incontinence at medium-term follow-up. Associated urinary incontinence resolves in over half of patients following UD excision; hence, we advocate deferring any incontinence procedure until after the results of surgery are established. Patient summary Surgical removal of urethral outpouching (diverticula) in women is challenging due to its potential to damage the nearby sphincter muscle, which controls continence, or the urethra tube. Placement of patients on their front, rather than on their back, provides excellent access for the surgical removal of urethral diverticula. With this approach, we achieved excellent rates of cure and low rates of urinary incontinence at an average follow-up of 10 mo.

Purpose of review Urethrotomy remains the first-line therapy in the treatment of a urethral stricture despite data showing no real chance of a cure after repeated urethrotomies. An anastomotic or an augmentation urethroplasty using oral mucosa can be offered to patients following failed urethrotomy. The potential for a tissue engineered solution as an alternative to native tissue has been explored in recent years and is reviewed in this article. Recent findings More than 80 preclinical studies have investigated a tissue-engineered approach for urethral reconstruction mostly using decellularized natural scaffolds derived from natural extracellular matrix with or without cell seeding. The animal models used in preclinical testing are not representative of disease processes seen with strictures in man. The available clinical studies are based on small noncontrolled series. Summary There is a potential role for tissue engineering to provide a material for substitution urethroplasty and work has demonstrated this. Further work will require a rigorous basic science programme and adequate evaluation of the material prior to its introduction into clinical practice. The research with tissue engineering applied to the urethra has not yet been resulted in a widely available material for clinical use that approaches the efficacy seen with the use of autologous grafts.

Prostate cancer (PCa) is one of the first three causes of cancer mortality in Europe. Screening in asymptomatic men (aged 55–69 yr) using prostate-specific antigen (PSA) is associated with a migration toward lower staged disease and a reduction in cancer-specific mortality. By 20 yr after testing, around 100 men need to be screened to prevent one PCa death. While this ratio is smaller than for breast and colon cancer, the long natural history of PCa means many men die from other causes. As such, the nonselective use of PSA testing and radical treatments can lead to overdiagnosis and overtreatment. The European Association of Urology (EAU) supports measures to encourage appropriate PCa detection through PSA testing, while reducing overdiagnosis and overtreatment. These goals may be achieved using personalized risk-stratified approaches. For diagnosis, the greatest benefit from early detection is likely to come in men assessed using baseline PSA levels at the age of 45 yr to individualize screening intervals. Multiparametric magnetic resonance imaging as well as risk calculators based on family history, ethnicity, digital rectal examination, and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis. For treatment, the EAU advocates balancing patient's life expectancy and cancer's mortality risk when deciding an approach. Active surveillance is encouraged in well-informed patients with low-risk and some intermediate-risk cancers, as it decreases the risks of overtreatment without compromising oncological outcomes. Conversely, the EAU advocates radical treatment in suitable men with more aggressive PCa. Multimodal treatment should be considered in locally advanced or high-grade cancers. Patient summary: Implementation of prostate-specific antigen (PSA)-based screening should be considered at a population level. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45 yr). The level of this test, combined with family history, ethnicity, and other factors, can be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated. The European Association of Urology supports the implementation of prostate-specific antigen (PSA)-based screening at a population level in Europe. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45 yr). This, together with family history, ethnicity, and other factors, should be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated.

Urethrotomy remains the first-line therapy in the treatment of a urethral stricture despite data showing no real chance of a cure after repeated urethroplasties. An anastomotic or an augmentation urethroplasty with oral mucosa should be offered to patients with a failed urethrotomy. The availability of grafts can be a concern for both patients and surgeons. The potential for a tissue-engineered solution has been explored in recent years and is explored in this article.More than 80 preclinical studies have investigated a tissue-engineered approach for urethral reconstruction mostly using decellularized natural scaffolds with or without cell seeding. The animal models used in preclinical testing are not representative of disease processes seen with strictures in man. The available clinical studies were of small sample size and lacked control groups. The choice of biomaterial were mostly acellular matrices derived from natural extracellular matrix. The reported success rates in the pilot clinical studies were highly variable.The research with tissue engineering of the urethra has not yet been translated into a clinically available material. This is an area where much more research is needed and we would conclude that it is an area of unmet clinical need where users of tissue-engineered urethra in the future need to carry out a rigorous basic science programme and need to be cautious in drawing conclusions based on initial experience and report on long-term clinical results.

PURPOSE OF REVIEW To review the current clinical management of stress urinary incontinence and pelvic organ prolapse following the adverse complications seen in the use of polypropylene mesh to treat both. RECENT FINDINGS Materials developed for use in abdominal hernia repair have not proven risk-free when used to support pelvic organs particularly when inserted via the vagina. Following unacceptably high levels of severe complications when high-density polypropylene mesh is inserted via the vagina to treat pelvic organ prolapse, reported over the last decade, there is now an agreed consensus between surgeons about surgical approaches and materials, which should be recommended for use in stress urinary incontinence and pelvic organ prolapse. SUMMARY There is a need for new biomaterials and tissue engineered/regenerative medicine approaches to treat stress urinary incontinence and pelvic organ prolapse. New materials need to be evaluated critically in both preclinical and clinical studies before being adopted into routine clinical use.

Context In recent years, there has been a rapid uptake in the use of laparoscopic and robotic surgery within urological oncological surgery. There is now growing interest in applying these surgical techniques to functional and reconstructive urology (FRU). Objective To provide an overview of the use of robotic surgery within the sphere of functional and reconstructive urology and discuss the research needs and the likely role of robotic technology in future. Evidence acquisition A PubMed-based literature review performed in March 2019 identified all articles published regarding the use of robotic surgery within FRU for the reconstruction of the upper tracts, bladder, bladder neck, pelvic floor, and urinary sphincter; creation of urinary diversion; and repair of genitourinary fistulae. Evidence synthesis There is a need to study the robotic approach in carefully designed prospective studies to better establish safety and clinical efficacy as well as the economic viability as compared with laparoscopic and open approaches. Conclusions The use of the robotic minimally invasive approach has many potential advantages; however, there is a need for a high level of technical expertise and experience, especially in some of the complex and technically challenging scenarios often seen within FRU. Surgeons should ensure that they have received sufficient training in not only the surgical principles of FRU, but also the assessment, management, and follow-up of patients. Moreover, it is imperative not to compromise important surgical steps. Patient summary In this report, we looked into the use of robotic technologies in the treatment of functional and reconstructive problems of the urinary tract. We found that the robotic approach has not yet been evaluated in prospective clinical studies in this field. There is a need for carefully designed prospective studies to establish the safety and efficacy of robotic surgeries.

INTRODUCTION AND OBJECTIVES Soft tissue interposition (STI) using local and/or regional flaps is often necessary in urogenital reconstruction to stimulate wound healing and prevent recurrence. Harvesting STI flaps can cause donor site morbidity and may not be available in some patients. In this study, we designed estradiol (E2) releasing hydrogel that could be used as an alternative to a STI flap and to investigate its ability to stimulate tissue production and angiogenesis. MATERIALS AND METHODS A hydrogel was constructed by crosslinking a solution of estradiol, methacrylated gelatin (15%, w/v), and methacrylated hyaluronic acid (1%, w/v). The release of estradiol was measured using a UV-spectrophotometer (λmax = 220 nm). Angiogenesis was evaluated by an ex ovo chicken embryo chorioallantoic membrane (CAM) assay. RESULTS Estradiol was gradually released from the hydrogel over 21 days. The hydrogels could be easily manipulated with surgical forceps without any deformation. The hydrogels significantly increased collagen production of human dermal fibroblasts (HDFs). Scanning electron microscopic examination demonstrated that HDFs produced significantly more extracellular matrix (ECM) on estradiol releasing hydrogels compared with the controls. Estradiol releasing hydrogels doubled the number of blood vessels growing toward the hydrogel compared with the controls (vasculogenic index, 59.6 [±6.4] and 25.6 [±4.0], respectively; [P

Background Polypropylene meshes cause severe complications in some patients. Materials that are biomechanically compatible and can better integrate into host tissues are urgently needed. Objective To design an oestradiol-releasing electrospun poly- l -lactic acid (PLA) mesh and evaluate its ability to stimulate new extracellular matrix and new blood vessel formation. Design, setting, and participants Human adipose derived mesenchymal cells (ADMSC) were isolated from fat. PLA meshes with micro- to nano-sized fibres containing 1%, 5%, and 10% oestradiol were constructed and used for in vitro and in vivo experiments. Intervention The angiogenic potential of the fibrous meshes was evaluated using an in vivo chorioallantoic membrane and an in vitro chick aortic arch assays. Outcome measurements and statistical analysis Oestradiol release was measured fluorometrically. The effect of fibrous meshes on proliferation and extracellular matrix (ECM) production of ADMSC was assessed using immunohistology. Mechanical properties were tested using a tensiometer. Results and limitations The ultrastructure of the mesh was not affected by the inclusion of oestradiol and mechanical properties were only slightly modified. Oestradiol was released from PLA meshes over a 5-mo period. ADMSCs cultured on oestradiol-releasing PLA meshes produced more ECM involving collagen I, collagen III, and elastin. Oestradiol-releasing meshes doubled new blood vessel formation in the chorioallantoic membrane assay ( p = 0.001) and outgrowth of pro-angiogenic cells in the aortic arch assay ( p = 0.001). Further studies in longer-term animal models are required to confirm these results. Conclusions Oestradiol-releasing PLA meshes increase ECM production and stimulate angiogenesis. As such, they are promising candidate materials to be used in pelvic floor repair and to improve the initial healing phase of a repair material following implantation. Patient summary In this study, we designed a tissue engineered material to be used to support weakened pelvic floor tissues in women to avoid the complications associated with current surgical mesh. Our results showed that this material can stimulate new blood vessel formation in simple chick assays and tissue production in vitro. Both properties should help with the integration of this material into patients’ tissues and merit further study in physiologically relevant animal models.

Background In the most of previous experiments, intrathecal administration of stem cells (SCs) was seen in the management of neurogenic bladder (NGB) following contusion or complete transaction in the rodent model of spinal cord injury (SCI). Here, we aimed to investigate whether intra bladder wall autologous bone marrow mesenchymal SC (BM-MSCs) transplantation, as a minimally invasive method, could improve bladder dysfunctions after a chronic phase of hemi- and complete-transection SCI in a female rat model. Material and methods A total of forty-two female Wistar rats were randomly divided into 6 groups (each in 7) and subjected to complete and incomplete spinal cord transection by a laminectomy at the T9 vertebral level. Four weeks after SCI operation, BM-MSCs (1 × 106/120 μl) were transplanted in six areas of the bladder muscle in rats with complete SCI (cSCI) and hemi SCI (hSCI) groups. In the rats from sham, cSCI and hSCI negative control groups, normal saline was injected instead of BM-MSCs. Four weeks post-cell transplantation, rats were subjected to conscious urodynamic for voiding function assessment. Results All bladders in cSCI and hSCI groups were the hyperreflexic type. The amplitude of uninhibited contraction in cSCI + BM-MSC group was decreased (p = 0.046). we noted that compliance was recovered in the hSCI + BM-MSCs group (p = 0.041). Residual volume was increased significantly after SCI while cell transplantation decreased this index in both hSCI and cSCI +BM-MSCs groups. The statistically significant result was only seen in the hSCI group (p = 0.046). Data showed that collagen deposition was markedly increased in the SCI group compared to the control or sham groups. These changes were decreased post-treatment in the hSCI group (p = 0.042). Conclusion Our study added a notion that urinary dysfunction associated with SCI, was improved following direct injection of autologous BM-MSC transplantation to bladder wall in the chronic phase of SCI injury.

Urethral stricture disease (USD) is initially managed with minimally invasive techniques such as urethrotomy and urethral dilatation. Minimally invasive techniques are associated with a high recurrence rate, especially in recurrent USD. Adjunctive measures, such as local drug injection, have been used in an attempt to reduce recurrence rates.To systematically review evidence for the efficacy and safety of adjuncts used alongside minimally invasive treatment of USD.A systematic review of the literature published between 1990 and 2020 was conducted in accordance with the PRISMA checklist.A total of 26 studies were included in the systematic review, from which 13 different adjuncts were identified, including intralesional injection (triamcinolone, n = 135; prednisolone, n = 58; mitomycin C, n = 142; steroid-mitomycin C-hyaluronidase, n = 103, triamcinolone-mitomycin C-N-acetyl cysteine, n = 50; platelet-rich plasma, n = 44), intraluminal instillation (mitomycin C, n = 20; hyaluronic acid and carboxymethylcellulose, n = 70; captopril, n = 37; 192-iridium brachytherapy, n = 10), application via a lubricated catheter (triamcinolone, n = 124), application via a coated balloon (paclitaxel, n = 106), and enteral application (tamoxifen, n = 30; deflazacort, n = 36). Overall, 13 randomised controlled trials were included in the meta-analysis. Use of any adjunct was associated with a lower rate of USD recurrence (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.27-0.50; p 0.001) compared to no adjunct use. Of all the adjuncts, mitomycin C was associated with the lowest rate of USD recurrence (intralesional injection: OR 0.23, 95% CI 0.11-0.48; p 0.001; intraluminal injection: OR 0.11, 95% CI 0.02-0.61; p = 0.01). Urinary tract infection (2.9-14%), bleeding (8.8%), and extravasation (5.8%) were associated with steroid injection; pruritis of the urethra (61%) occurred after instillation of captopril; mild gynaecomastia (6.7%) and gastrointestinal side effects (6.7%) were associated with oral tamoxifen.Adjuncts to minimally invasive treatment of USD appear to lower the recurrence rate and are associated with a low adjunct-specific complication rate. However, the studies included were at high risk of bias. Mitomycin C is the adjunct supported by the highest level of evidence.We reviewed studies on additional therapies (called adjuncts) to minimally invasive treatments for narrowing of the urethra in men. Adjuncts such as mitomycin C injection result in a lower recurrence rate compared to no adjunct use. The use of adjuncts appeared to be safe and complications are uncommon; however, the studies were small and of low quality.

Study Objectives We examined associations between self-reports about typical sleep patterns and sleep data derived from a wearable device worn on a nightly basis for a prolonged period (mean = 214 nights). We hypothesized that sleep characteristics would correlate better across different methods of assessment (self-report versus wearable) than they would correlate within the same method, a classic psychometric approach (multitrait, multimethod matrix). Methods A cross-national sample of 6,230 adult wearable users completed a brief sleep questionnaire collecting data on sleep duration and number of awakenings (NAW) and provided informed consent to link their responses to data from their wearable watches. The data collection for the wearable occurred over 12 months and the sleep questionnaire was completed subsequent to that. Results Results indicated a large (r = .615) correlation between sleep duration as assessed with the wearable and by self-report. A medium-to-large correlation (r = .406) was also seen for NAW. The multitrait, multimethod matrix suggested minimal method variance, i.e. similar “traits” (sleep duration and NAW) correlated across methods but within a given method, and such “traits” were generally unrelated. Conclusions The results suggest that the longer period of data collection with the wearable generates more stable estimates of sleep than have been reported in most studies of actigraphy. Alternatively, the data might imply that individuals modify their self-reports about sleep via daily feedback to align their perceptions to the output of the wearable.

Contains fulltext : 220648.pdf (Publisher’s version ) (Closed access) The coronavirus disease 2019 (COVID-19) pandemic is unlike anything seen before by modern science-based medicine. Health systems across the world are struggling to manage it. Added to this struggle are the effects of social confinement and isolation. This brings into question whether the latest guidelines are relevant in this crisis. We aim to support urologists in this difficult situation by providing tools that can facilitate decision making, and to minimise the impact and risks for both patients and health professionals delivering urological care, whenever possible. We hope that the revised recommendations will assist urologist surgeons across the globe to guide the management of urological conditions during the current COVID-19 pandemic.

Background There is an urgent need to develop better materials to provide anatomical support to the pelvic floor without compromising its function. Objective Our aim was to assess outcomes after simulated vaginal prolapse repair in a sheep model using three different materials: (1) ultra-lightweight polypropylene (PP) non-degradable textile (Restorelle) mesh, (2) electrospun biodegradable ureidopyrimidinone-polycarbonate (UPy-PC), and (3) electrospun non-degradable polyurethane (PU) mesh in comparison with simulated native tissue repair (NTR). These implants may reduce implant-related complications and avoid vaginal function loss. Design, setting, and participants A controlled trial was performed involving 48 ewes that underwent NTR or mesh repair with PP, UPy-PC, or PU meshes (n = 12/group). Explants were examined 60 and 180 d (six per group) post-implantation. Intervention Posterior rectovaginal dissection, NTR, or mesh repair. Outcome measurements and statistical analysis Implant-related complications, vaginal contractility, compliance, and host response were assessed. Power calculation and analysis of variance testing were used to enable comparison between the four groups. Results There were no visible implant-related complications. None of the implants compromised vaginal wall contractility, and passive biomechanical properties were similar to those after NTR. Shrinkage over the surgery area was around 35% for NTR and all mesh-augmented repairs. All materials were integrated well with similar connective tissue composition, vascularization, and innervation. The inflammatory response was mild with electrospun implants, inducing both more macrophages yet with relatively more type 2 macrophages present at an early stage than the PP mesh. Conclusions Three very different materials were all well tolerated in the sheep vagina. Biomechanical findings were similar for all mesh-augmented repair and NTR. Constructs induced slightly different mid-term inflammatory profiles. Patient summary Product innovation is needed to reduce implant-related complications. We tested two novel implants, electrospun and an ultra-lightweight polypropylene textile mesh, in a physiologically relevant model for vaginal surgery. All gave encouraging outcomes., European Urology Focus, 6 (1), ISSN:2405-4569

PLUS investigated the efficacy and safety of mirabegron add-on therapy in men with overactive bladder symptoms receiving tamsulosin for underlying lower urinary tract symptoms attributable to benign prostatic hyperplasia.In this phase 4 study a 4-week 0.4 mg tamsulosin run-in period was followed by a 12-week, randomized, double-blind, treatment period in which patients initially received 25 mg mirabegron or placebo add-on therapy. At 4 weeks doses were titrated to 50 mg mirabegron or placebo equivalent. Efficacy end points were changes from baseline to end of treatment in mean number of micturitions per day (primary), mean volume voided per micturition, number of urgency episodes per day, total urgency and frequency score, and total International Prostate Symptom Score (secondary). Safety assessments included treatment emergent adverse events, and post-void residual volume, and maximum urinary flow measurements.Of the 676 men most were 65 years old or older (380, 56.2%). Tamsulosin plus mirabegron was statistically superior to tamsulosin plus placebo in reducing the mean number of micturitions per day (-2.00 vs -1.62; adjusted difference -0.39; 95% CI -0.76, -0.02). Statistically superior results were noted for tamsulosin plus mirabegron in mean volume voided per micturition, urgency episodes per day, and total urgency and frequency score (not International Prostate Symptom Score). Higher overall treatment emergent adverse event rates were observed with tamsulosin plus placebo, although higher rates of drug related treatment emergent adverse events were noted with tamsulosin plus mirabegron. Urinary retention rates were higher in the tamsulosin plus mirabegron group. Post-void residual volume and maximum urinary flow results were not clinically meaningful.The results of PLUS underscore the utility of mirabegron add-on therapy to treat men with overactive bladder symptoms receiving tamsulosin for benign prostatic hyperplasia.

α1-adrenoceptor antagonists can impact upon sexual function and have potential in the treatment of erectile dysfunction. Human erectile tissue contains predominantly α1A-adrenoceptors, and here we examined whether contractions of this tissue are mediated by the functional phenotype, the α1L-adrenoceptor. Functional experiments using subtype selective agonists and antagonists, along with radioligand ([3H]tamsulosin) binding assays, were used to determine the α1-adrenoceptor population. A61603, a α1A-adrenoceptor agonist, was a full agonist with a potency 21-fold greater than that of noradrenaline. The α1A- and α1D-adrenoceptor antagonist tamsulosin antagonized noradrenaline responses with high affinity (pKD = 9.7 ± 0.3), whilst BMY7378 (100 nM) (α1D-adrenoceptor antagonist) failed to antagonize responses. In contrast, relatively low affinity estimates were obtained for both prazosin (pKD = 8.2 ± 0.1) and RS17053 (pKD = 6.9 ± 0.2), antagonists which discriminate between the α1A- and α1L-adrenoceptors. [3H]Tamsulosin bound with high affinity to the receptors of human erectile tissue (pKD = 10.3 ± 0.1) with a receptor density of 28.1 ± 1.4 fmol mg−1 protein. Prazosin displacement of [3H]tamsulosin binding revealed a single homogenous population of binding sites with a relatively low affinity for prazosin (pKi = 8.9). Taken together these data confirm that the receptor mediating contraction in human erectile tissue has the pharmacological properties of the α1L-adrenoceptor. Keywords: Erectile tissue, α1-adrenoceptor subtypes, α1L-adrenoceptor, Tamsulosin, Prazosin

Aims To develop a comprehensive patient-reported bladder assessment tool (BAT) for assessing overactive bladder (OAB) symptoms, bother, impacts, and satisfaction with treatment. Methods Subjects were consented and eligibility was confirmed by a recruiting physician; subjects were then scheduled for in-person interviews. For concept elicitation and cognitive interviews, 30 and 20 subjects, respectively, were targeted for recruitment from US sites. All interviews were conducted face-to-face, audio-recorded, transcribed verbatim, anonymized, and analyzed using a qualitative data analysis software program. A draft BAT was created based on the results of the concept elicitation interviews and further revised based on cognitive interviews as well as feedback from an advisory board of clinical and patient-reported outcome (PRO) experts. Results Nocturia, daytime frequency, and urgency were reported by all subjects (n = 30, 100.0%), and incontinence was reported by most subjects (n = 25, 83.3%). The most frequently reported impacts were waking up to urinate (n = 30, 100.0%), embarrassment/shame (n = 24, 80.0%), stress/anxiety (n = 23, 76.7%), and lack of control (n = 23, 76.7%). Following analysis, item generation, cognitive interviews, and advisory board feedback, the resulting BAT contains four hypothesized domains (symptom frequency, symptom bother, impacts, and satisfaction with treatment) and 17 items with a 7-day recall period. Conclusions The BAT has been developed in multiple stages with input from both OAB patients and clinical experts following the recommended processes included in the FDA PRO Guidance for Industry. Once fully validated, we believe it will offer a superior alternative to use of the bladder diary and other PROs for monitoring OAB patients in clinical trials and clinical practice.

Both TRPV1 and P2X receptors present on bladder sensory nerve fibres have been implicated in mechanosensation during bladder filling. The aim of this study was to determine possible interactions between these receptors in modulating afferent nerve activity. In wildtype (TRPV1+/+) and TRPV1 knockout (TRPV1−/−) mice, bladder afferent nerve activity, intravesical pressure, and luminal ATP and acetylcholine levels were determined and also intracellular calcium responses of dissociated pelvic DRG neurones and primary mouse urothelial cells (PMUCs). Bladder afferent nerve responses to the purinergic agonist αβMethylene-ATP were depressed in TRPV1−/− mice (p ≤ 0.001) and also in TRPV1+/+ mice treated with the TRPV1-antagonist capsazepine (10 µM; p ≤ 0.001). These effects were independent of changes in bladder compliance or contractility. Responses of DRG neuron to αβMethylene-ATP (30 µM) were unchanged in the TRPV1−/− mice, but the proportion of responsive neurones was reduced (p ≤ 0.01). Although the TRPV1 agonist capsaicin (1 µM) did not evoke intracellular responses in PMUCs from TRPV1+/+ mice, luminal ATP levels were reduced in the TRPV1−/− mice (p ≤ 0.001) compared to wildtype. TRPV1 modulates P2X mediated afferent responses and provides a mechanistic basis for the decrease in sensory symptoms observed following resiniferatoxin and capsaicin treatment for lower urinary tract symptoms.

Context\ud Retropubic (RP-TVT) and transobturator miurethral (TO-TVT) midurethral sling (MUS) are popular surgical treatments for female stress urinary incontinence. The long-term efficacy and safety of the procedures is still a topic of intense clinical research and several randomised controlled trials (RCTs) have been published in the last years\ud \ud Objective\ud To evaluate the efficacy and safety of MUS compared with other surgical treatments for female stress urinary incontinence.\ud \ud Evidence acquisition\ud A systematic review and meta-analysis of the literature was performed using the Medline, Scopus, and Web of Science databases to update our previously published analyses.\ud \ud Evidence synthesis\ud Twenty-eight RCTs were identified. In total, the meta-analyses included 15 855 patients. Patients receiving MUS had significantly higher overall (odds ratio [OR]: 0.59, p = 0.0003) and objective (OR: 0.51, p = 0.001) cure rates than those receiving Burch colposuspension. Patients undergoing MUS and pubovaginal slings had similar cure rates. Patients treated with RT-TVT had higher subjective (OR: 0.83, p = 0.03) and objective (OR: 0.82, p = 0.01) cure rates than those receiving TO-TVT. However, the latter had a lower risk of intraoperative bladder or vaginal perforation (OR: 2.4, p = 0.0002), pelvic haematoma (OR: 2.61, p = 0.002), urinary tract infections (OR: 1.31, p = 0.04) and voiding lower urinary tract symptoms (OR: 1.66, p = 0.002). Sensitivity analyses limited to RCTs with follow-up durations >60 mo demonstrated similar outcomes for RP-TVT and TO-TVT. No significant differences in efficacy were identified comparing inside-to-out and outside-to-in TO-TVT but vaginal perforations were less common with the former (OR: 0.21, p = 0.0002).\ud \ud Conclusions\ud The present analysis confirms the superiority of MUS over Burch colposuspension. The studies comparing insertion of RT-TVT and TO-TVT showed higher subjective and objective cure rates for the RP-TVT but at the cost of higher risks of some complications and voiding lower urinary tract symptoms. Efficacy of inside-out and outside-in techniques of TO-TVT insertion was similar, although the risk of vaginal perforation was lower in the inside-to-out TO-TVT.\ud \ud Patient summary\ud Retropubic and transobturator midurethral slings are a popular treatment for female stress urinary incontinence. The available literature suggest that those slings are either more effective or safer than other older surgical procedures. Retropubic tapes are followed with slightly higher continence rates as compared with the transobturator tapes but are associated with higher risk of intra- and postoperative complications.

Objectives To compare the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (OAB) using network meta-analysis (NMA). Subjects and Methods Information sources were searched for randomized blinded controlled trials, of at least 2 weeks duration, comparing any dose of onabotulinumtoxinA, eligible oral/transdermal anticholinergics, or mirabegron, with each other or placebo, in adults with OAB. Bayesian random-effects models were used to synthesize the results at week 12: NMA for responder analyses and network meta-regression (NMR) for change from baseline analyses. The NMR was used to adjust for differences in baseline severity between studies. Sensitivity analysis, excluding studies considered to be at a high risk of methodological bias, was conducted. Results 56 randomized trials were included in the networks. For each outcome, results are reported for all licensed treatment doses. For each NMR, results are based on patients with an average number of episodes of the outcome at baseline. After 12 weeks, all treatments are more efficacious than placebo. Patients who received onabotulinumtoxinA (100U) had, on average, the greatest reductions in urinary incontinence episodes (UIE), urgency, and micturition frequency, and the highest odds of achieving decreases of 100% and ≥50% in the daily number of UIE. When comparing onabotulinumtoxinA with other pharmacotherapies, mean differences favoured onabotulinumtoxinA 100U over all comparators for UIE and urgency (credible intervals excluded zero) and all but two of the comparators for micturition frequency. OnabotulinumtoxinA 100U was also associated with higher odds of achieving a 100% and ≥50% decrease in daily UIE than most other licensed treatments in the network. The exclusion of studies with a high risk of bias had little impact on the conclusions. Conclusion The results indicate that, after 12 weeks, onabotulinumtoxinA 100U provides greater relief of OAB symptoms compared with most other licensed doses of other pharmacotherapies in the network. This article is protected by copyright. All rights reserved.

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Vaginal meshes used in the treatment of stress urinary incontinence (SUI) and pelvic organ prolapse (POP) have produced highly variable outcomes, causing life-changing complications in some patients while providing others with effective, minimally invasive treatments. The risk:benefit ratio when using vaginal meshes is a complex issue in which a combination of several factors, including the inherent incompatibility of the mesh material with some applications in pelvic reconstructive surgeries and the lack of appropriate regulatory approval processes at the time of the premarket clearance of these products, have contributed to the occurrence of complications caused by vaginal mesh. Surgical mesh used in hernia repair has evolved over many years, from metal implants to knitted polymer meshes that were adopted for use in the pelvic floor for treatment of POP and SUI. The evolution of the material and textile properties of the surgical mesh was guided by clinical feedback from hernia repair procedures, which were also being modified to obtain the best outcomes with use of the mesh. Current evidence shows how surgical mesh fails biomechanically when used in the pelvic floor and materials with improved performance can be developed using modern material processing and tissue engineering techniques.

Context Current literature suggests that several pathophysiological factors and mechanisms might be responsible for the nonspecific symptom complex of overactive bladder (OAB). Objective To provide a comprehensive analysis of the potential pathophysiology underlying detrusor overactivity (DO) and OAB. Evidence acquisition A PubMed-based literature search was conducted in April 2018, to identify randomised controlled trials, prospective and retrospective series, animal model studies, and reviews. Evidence synthesis OAB is a nonspecific storage symptom complex with poorly defined pathophysiology. OAB was historically thought to be caused by DO, which was either "myogenic" (urgency initiated from autonomous contraction of the detrusor muscle) or "neurogenic" (urgency signalled from the central nervous system, which initiates a detrusor contraction). Patients with OAB are often found to not have objective evidence of DO on urodynamic studies; therefore, alternative mechanisms for the development of OAB have been postulated. Increasing evidence on the role of urothelium/suburothelium and bladder afferent signalling arose in the early 2000s, emphasising an afferent "urotheliogenic" hypothesis, namely, that urgency is initiated from the urothelium/suburothelium. The urethra has also recently been regarded as a possible afferent origin of OAB—the "urethrogenic" hypothesis. Several other pathophysiological factors have been implicated, including metabolic syndrome, affective disorders, sex hormone deficiency, urinary microbiota, gastrointestinal functional disorders, and subclinical autonomic nervous system dysfunctions. These various possible mechanisms should be considered as contributing to diagnostic and treatment algorithms. Conclusions There is a temptation to label OAB as "idiopathic" without obvious causation, given the poorly understood nature of its pathophysiology. OAB should be seen as a complex, multifactorial symptom syndrome, resulting from multiple potential pathophysiological mechanisms. Identification of the underlying causes on an individual basis may lead to the definition of OAB phenotypes, paving the way for personalised medical care. Patient summary Overactive bladder (OAB) is a storage symptom syndrome with multiple possible causes. Identification of the mechanisms causing a patient to experience OAB symptoms may help tailor treatment to individual patients and improve outcomes.

Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are conditions which result in significant physical, mental and social consequences for women worldwide. The high rates of recurrence reported with primary repair for POP led to the use of synthetic mesh to augment repairs in both primary and secondary cases following failed previous POP repair. The widely reported, unacceptably high rates of complications associated with the use of synthetic, transvaginal mesh in pelvic floor repair have severely limited the treatment options that surgeons can offer. This article summarises the recent advances in pelvic floor repair, such as improved quantification and modelling of the biomechanics of the pelvic floor and the developing technology within the field of tissue engineering for treatment of SUI/POP, including biomaterials and cell-based therapies. Finally, we will discuss the issues surrounding the commercial introduction of synthetic mesh for use within the pelvic floor and what lessons can be learned for the future as well as the current guidance surrounding treatment for SUI/POP.

Introduction In the last decade therapeutic options for patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE) have constantly increased. Although transurethral resection of the prostate (TURP) is still considered the surgical gold standard, different lasers and advanced techniques have been introduced as alternatives to TURP. Evidence acquisition A non-systematic Medline/Pubmed literature search was performed with different combination of terms including: "BPH," "M-TURP," "B-TURP" "bladder outlet obstruction," "YAG laser," "Diode laser," "Potassium titanyl phosphate," "KTP," "bladder outlet obstruction" (BOO), "BOO in small prostate". Only studies reporting prostate volume ≤40 cc were considered for this review. Evidence syntesis Current evidence on the use of laser as a therapeutic modality as compared to TURP reported similar functional results of bipolar-TURP, Thulium laser and Greenlight. For prostate gland ≤40 cc, HoLEP can be technically more difficult while Holmium-TUIP seems to be a valid option but with a higher rate of retrograde ejaculation which is considerably higher than the rate in electrocautery series. The diode laser showed excellent intra-operatively haemostasis with clear endoscopic vision and durable improvements in functional results, but may produce greater passive thermal energy conduction that can cause scrotal edema and anal pain. However, conclusions need to be drawn after median to long term evaluation of patients and consideration of the economic implications, coupled with the potential for reducing morbidity. Conclusions Evidence acquisition from the literature showed that mini-invasive surgeries, including Greenlight laser and Holmium laser incision represent valid alternatives to TURP in prostate ≤40 g. We reported effective results of laser therapy as therapeutic modalities as compared to TURP for the small prostate ≤40 mL, both for enucleation and excision or cauterization, however cost effective of laser in the current literature are still scarce and it should be implemented.

Serious complications can develop with the mesh implants used for stress urinary incontinence and pelvic organ prolapse surgery. We evaluated 2 materials currently in clinical use and 2 alternative materials using a rabbit abdominal model to assess host response and biomechanical properties of the materials before and after implantation.Poly-L-lactic acid and polyurethane meshes were electrospun to be compared to commercially available polypropylene and polyvinylidene fluoride meshes. A total of 40 immunocompetent full-thickness abdominal wall defect rabbit models were used, including 8 in each of the poly-L-lactic acid, polyurethane, polyvinylidene fluoride and polypropylene experimental groups, and sham controls. Two 20 mm defects were created per animal and primarily repaired. The experimental groups then underwent onlay of each repair material while sham controls did not. Four rabbits per group were sacrificed at days 30 and 90. Abdominal wall specimens containing the defect with or without repair material were explanted to be assessed by histology (hematoxylin and eosin staining, and immunohistochemistry) and biomechanical testing at 30 and 90 days.At 90 days of implantation tissues repaired with all 4 materials showed biomechanical properties without significant differences. However, polypropylene and polyvinylidene fluoride meshes demonstrated a sustained chronic inflammatory response profile by 90 days. In contrast, poly-L-lactic acid and polyurethane meshes integrated well into host tissues with a decreased inflammatory response, indicative of constructive remodeling.Poly-L-lactic acid and polyurethane alternative materials achieved better host integration in rabbit models than current synthetic repair materials.

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.

Botulinum toxin and nerve stimulation are viable options for overactive bladder refractory to pharmacotherapy. Treatment choice depends on multiple factors including associated symptoms, bladder function, and health economics. Decision-making should be individualised to the particular situation taking into account patient preference.

Anterior urethral strictures are a common urological problem and urethrotomy has limited efficacy if repeated treatment is needed. An increasing number of studies have shown that mitomycin C has potential as an adjunct to urethrotomy for improving its success rate.

AIMS: Stress urinary incontinence and pelvic organ prolapse are very common conditions with a proportion of patients requiring implantation of synthetic materials for a durable repair. However increasing numbers of post-surgical complications have been reported related to the use of polypropylene meshes. One hypothesis for the adverse response is poor mechanical matching of the relatively stiff polypropylene mesh particularly as materials in the pelvic floor will need to cope with decades of distension as occurs with increase of intraabdominal pressure on coughing, laughing, or sneezing. METHODS: In this study we have undertaken a very simple fatigue testing regime to compare the mechanical abilities of six materials. Four commercial meshes in clinical use and two novel electrospun materials not yet evaluated in the clinic were assessed using a uniaxial tensile test. This was performed on six samples of each dry material and on another six samples of each material after just 3 days of fatigue conditions using a dynamic bioreactor. RESULTS: The four commercial materials showed permanent mechanical deformation after just 3 days of stretching these materials by 25% elongation on a regular dynamic cycle, whereas the two new materials presented more elastic properties without deformation. CONCLUSIONS: We suggest that a test as simple as this 3-day fatigue testing is sufficient to distinguish between materials which have already been found to cause complications clinically and newer materials yet to be tested clinically which will hopefully prove more mechanically appropriate for implantation in the pelvic floor. ispartof: NEUROUROLOGY AND URODYNAMICS vol:38 issue:1 pages:107-115 ispartof: location:United States status: published

Urethral stricture disease is increasingly common occurring in about 1% of males over the age of 55. The stricture tissue is rich in myofibroblasts and multi-nucleated giant cells which are thought to be related to stricture formation and collagen synthesis. An increase in collagen is associated with the loss of the normal vasculature of the normal urethra. The actual incidence differs based on worldwide populations, geography, and income. The stricture aetiology, location, length and patient's age and comorbidity are important in deciding the course of treatment. In this review we aim to summarise the existing knowledge of the aetiology of urethral strictures, review current treatment regimens, and present the challenges of using tissue-engineered buccal mucosa (TEBM) to repair scarring of the urethra. In asking this question we are also mindful that recurrent fibrosis occurs in other tissues—how can we learn from these other pathologies? Keywords: Urethral strictures, Fibrosis, Tissue-engineered buccal mucosa, Augmentation urethroplasty

Stress urinary incontinence (SUI) is a largely ousted but significant medical, social, and economic problem. Surveys suggest that nowadays approximately 10% of the male and 15% of the female population suffer from urinary incontinence at some stage in their lifetime. In women, two major etiologies contribute to SUI: degeneration of the urethral sphincter muscle controlling the closing mechanism of the bladder outflow and changes in lower pelvic organ position associated with degeneration of connective tissue or with mechanical stress, including obesity and load and tissue injury during pregnancy and delivery. In males, the reduction of the sphincter muscle function is sometimes due to surgical interventions as a consequence of prostate cancer treatment, benign prostate hyperplasia, or of neuropathical origin. Accordingly, for women and men different therapies were developed. In some cases, SUI can be treated by physical exercise, electrophysiological stimulation, and pharmacological interventions. If this fails to improve the situation, surgical interventions are required. In standard procedures, endoprostheses for mechanical support of the weakened tissue or mechanical valves for a bladder outflow control are implanted. In 20% of cases treated, repeat procedures are required as implants yield all sorts of side effects in time. Based on preclinical studies, the application of an advanced therapy medicinal product (ATMP) such as implantation of autologous cells may be a curative and long-lasting therapy for SUI. Cellular therapy could also be an option for men suffering from incontinence caused by injury of the nerves controlling the muscular sphincter system. Here we briefly report on human progenitor cells, especially on mesenchymal stromal cells (MSCs), their expansion and differentiation to smooth muscle or striated muscle cells in vitro, labeling of cells for in vivo imaging, concepts of improved, precise, yet gentle application of cells in muscle tissue, and monitoring of injected cells in situ.

Background Urethral strictures can be difficult to diagnose at an early stage because the urinary flow rate does not diminish until the urethral calibre is ≤3mm. In the past, posturethral surgery follow-up has relied upon flow rates and contrast imaging. Objective To evaluate the role of flexible urethroscopy in the follow-up of patients undergoing urethroplasty. Design, setting, and participants Prospective flexible urethroscopy follow-up of 144 male patients who underwent urethroplasty by a single surgeon over a 10-yr period at a tertiary referral centre. Intervention Flexible urethroscopy at 3, 6, and 12 mo postoperatively, and annually thereafter. Outcome measurements and statistical analysis Type of recurrence, based on urethroscopy findings, and further interventions were measured. Actuarial analysis was performed using Kaplan-Meier curves and a log-rank test. Results and limitations All 144 patients underwent flexible urethroscopy follow-up over a median postoperative follow-up of 22 mo (range: 1–96 mo). No further intervention was required for 117 patients (81.25%); 27 (18.75%) developed recurrences that required further treatment. Recurrences included diaphragms (13 patients) or significant restenosis (14 patients). Diaphragms were treated by urethrotomy, gentle dilatation, or a short course of intermittent self-dilatation. Restenosis required repeated simple procedures or surgical revision. Most recurrences (26 of 27, 96%) were detected within the first year. Urinary peak flow-rate data were available for 11 of 27 of these recurrences; 7 patients had flow rates >15ml/s. Anastomotic procedures had greater success than augmentation urethroplasty ( p =0.0136); there was no significant difference in outcomes between redo and non-redo surgery ( p =0.2093) Conclusions Endoscopic follow-up of patients after urethroplasty enables earlier identification and treatment of recurrences compared to the use of urinary flow rates alone. It also enables the identification of two different morphologic recurrence patterns that require different types of intervention. Patient summary Endoscopy detects most stricture recurrences within 1 yr after urethroplasty and is more sensitive than using urinary flow rates alone.

Pelvic fracture urethral injuries comprise one of the most challenging reconstructive procedures in urology. The obliterated or stenosed urethra can usually be effectively repaired by an end-to-end anastomosis (bulbomembranous anastomosis). To achieve this, a progression of surgical steps can be used to make a tension-free anastomosis. Before undertaking surgery it is important to comprehensively assess the patient to define their anatomical defects, in particular the site of the stenosis, the length of the distraction injury and the integrity of the bladder neck, and thus guide preoperative decision-making. Contemporary reports suggest that most pelvic fracture urethral distraction defects (PFUDD) can be adequately managed by a perineal approach. Nevertheless it is essential that all surgeons treating these injuries are familiar with the whole spectrum of operative steps that are necessary to repair PFUDD.

Purpose of review Pelvic floor disorders can present with lower urinary tract symptoms, bowel, sexual dysfunction, and/or pain. Symptoms of pelvic muscle spasm (nonrelaxing pelvic floor or hypertonicity) vary and can be difficult to recognize. This makes diagnosis and management of these disorders challenging. In this article, we review the current evidence on pelvic floor spasm and its association with voiding dysfunction. Recent findings To distinguish between the different causes of voiding dysfunction, a video urodynamics study and/or electromyography is often required. Conservative measures include patient education, behavioral modifications, lifestyle changes, and pelvic floor rehabilitation/physical therapy. Disease-specific pelvic pain and pain from pelvic floor spasm needs to be differentiated and treated specifically. Trigger point massage and injections relieves pain in some patients. Botulinum toxin A, sacral neuromodulation, and acupuncture has been reported in the management of patients with refractory symptoms. Summary Pelvic floor spasm and associated voiding problems are heterogeneous in their pathogenesis and are therefore often underrecognized and undertreated; it is therefore essential that a therapeutic strategy needs to be personalized to the individual patient's requirements. Therefore, careful evaluation and assessment of individuals using a multidisciplinary team approach including a trained physical therapist/nurse clinician is essential in the management of these patients.

The recent International Consultation on Urological Disease (ICUD) panel 2010 confirmed that a urethral stricture is defined as a narrowing of the urethra consequent upon ischaemic spongiofibrosis, as distinct from sphincter stenoses and a urethral disruption injury. Whenever possible, an anastomotic urethroplasty should be performed because of the higher success rate as compared to augmentation urethroplasty. There is some debate currently regarding the critical stricture length at which an anastomotic procedure can be used, but clearly the extent of the spongiofibrosis and individual anatomical factors (the length of the penis and urethra) are important, the limitation for this being extension of dissection beyond the peno-scrotal junction and the subsequent production of chordee. More recently, there has been interest in whether to excise and anastomose or to carry out a stricturotomy and reanastomosis using a Heineke-Miculicz technique. Augmentation urethroplasty has evolved towards the more extensive use of oral mucosa grafts as compared to penile skin flaps, as both flaps and grafts have similar efficacy and certainly the use of either dorsal or ventral positioning seems to provide comparable results. It is important that the reconstructive surgeon is well versed in the full range of available repair techniques, as no single method is suitable for all cases and will enable the management of any unexpected anatomical findings discovered intra-operatively.

Alpha1 -adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α1A -adrenoceptors, and this study investigated whether the low affinity state of this receptor (α1L -adrenoceptor) is involved in mediating contractions of this tissue. The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [(3) H]tamsulosin binding experiments to identify the α1 -adrenoceptor subtype population present in the human vas deferens. The α1A -adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α1D -adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (α1A - and α1D -adrenoceptor selective) had a high affinity (pKd = 9.9). [(3) H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [(3) H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively). These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α1 -adrenoceptors which have the pharmacological properties of the putative α1L -adrenoceptor, the same functional receptor previously identified in the human prostate.

Purpose Autologous buccal mucosa is commonly utilized in the surgical treatment of urethral strictures. Extensive strictures require a larger quantity of tissue, which may lead to donor site morbidity. This review assesses progress in producing tissue engineered buccal mucosa as an alternative graft material. Results Few clinical studies have introduced cells onto biological or synthetic scaffolds and implanted resulting constructs in patients. The available studies show that buccal mucosa cells on acellular human dermis or on collagen matrix lead to good acute stage tissue integration. Urothelial cells on a synthetic substrate also perform well. However while some patients do well many years post-grafting, others develop stricture recurrence. Acellular biomaterials used to treat long urethral defects in animals commonly lead to fibrosis. Conclusions Tissue engineered buccal mucosa shows promise as a substitute for native tissue. The fibrosis which occurs months post-implantation may reflect the underlying disease process recurring in these patients.

Background Surgery for stress urinary incontinence (SUI) has been dominated recently by synthetic midurethral tapes. Increasing recognition of serious complications associated with nonabsorbable polypropylene mesh has led to resurgence in interest in alternative approaches, such as the autologous fascial sling (AFS). Despite being an efficacious and durable option in women with recurrent and complex SUI, there has been a reluctance to consider AFS in women with primary SUI due to a perception that it is only appropriate for treating patients with intrinsic sphincter deficiency (ISD) and is associated with high rates of urinary retention and de novo storage symptoms. Objective The video presented demonstrates the technique for a loosely applied midurethral AFS. In contrast to AFS applied at the bladder neck, this technical modification in patients who demonstrate primary SUI without ISD avoids high rates of de novo storage symptoms and urinary retention. Design, setting, and participants A retrospective review of data on patients undergoing AFS at a tertiary referral unit. Surgical procedure AFS placement in a "loose" fashion using a short length of fascia suspended on a suture bilaterally at the midurethral level rather than at the bladder neck and only using more tension in patients with ISD. Measurements Subjective cure rate, rates of postoperative storage symptoms, and urinary retention necessitating intermittent self-catheterisation (ISC). Results and limitations A total of 106 patients underwent AFS; the mean follow-up period was 9 mo. The mean age was 52.6 (range 24–83) yr. In total, 46.2% had primary SUI, whilst all of the remaining 53.8% had undergone prior surgical intervention. Overall subjective cure occurred in 79.2% of patients; a further 15.1% described significant subjective improvement in symptoms, whilst 5.7% reported no change in symptoms. In those with primary SUI, rates of subjective cure, improvement, and nonresolution of symptoms were 87.8%, 12.2%, and 0%, respectively. In individuals with prior surgical intervention, rates of subjective cure, improvement, and nonresolution of symptoms were 72.0%, 17.5%, and 10.5%, respectively. De novo storage symptoms occurred in 8.2% of those with primary SUI compared with 14.0% of those with prior surgical intervention. Only 2.0% patients with primary SUI needed to perform ISC beyond 2 wk compared with 10.5% of those after prior surgery. Conclusions A midurethral AFS appears to be effective and safe both in women with primary SUI who want to avoid the placement of permanent material and its attendant risks, and in more complex cases where this is less appropriate. Patient summary A graft taken from the covering of the abdominal muscle or the outer aspect of the thigh is an alternative to a synthetic vaginal mesh in women who have stress urinary incontinence requiring surgical treatment. Placing the graft loosely at the midpoint of the urethral tube, rather than at the bladder neck, reduces the risk of postoperative voiding difficulty and overactive bladder symptoms. Long-term data have suggested an outcome at least as good as a synthetic nonabsorbable tape without the potential for sling erosion into adjacent structures, as it avoids the use of nonabsorbable material.

Objective To evaluate the potential of solifenacin 5 mg combined with mirabegron 25 or 50 mg to deliver superior efficacy compared with monotherapy, with acceptable tolerability, in the general overactive bladder (OAB) population with urinary incontinence (UI). Patients and Methods After a 4-week placebo run-in, patients aged 18 years with wet OAB (urgency, urinary frequency and UI) for 3 months who recorded on average 8 micturitions/24 h, 1 urgency episode/24 h, and 3 UI episodes over the 7-day micturition diary, were eligible for randomisation to double-blind treatment [2:2:1:1:1:1 ratio, solifenacin 5 mg + mirabegron 25 mg (combined S5 + M25 group); solifenacin 5 mg + mirabegron 50 mg (combined S5 + M50 group); solifenacin 5 mg; mirabegron 25 mg; mirabegron 50 mg; or placebo for 12 weeks], and 2-weeks' single-blind, placebo run-out. Co-primary efficacy variables were change from baseline to end of treatment (EoT) in the mean number of UI episodes/24 h and micturitions/24 h, assessed using a 7-day electronic micturition diary. Secondary efficacy variables included change from baseline to EoT in the mean volume voided/micturition, change from baseline at weeks 4, 8, 12 and EoT in mean number of UI episodes/24 h, micturitions/24 h, urgency episodes/24 h, urgency UI (UUI) episodes/24 h and nocturia episodes/24 h; the percentage of patients (responders) achieving zero UI episodes/24 h at EoT in the last 7 days prior to each visit, micturition frequency normalisation (

Context: Surgical nonautologous meshes have been used for several decades to repair abdominal wall herniae. Implantable materials have been adopted for the treatment of female and male stress urinary incontinence (SUI) and female pelvic organ prolapse (POP). Objective: A consensus review of existing data based on published meta-analyses and reviews. Evidence acquisition: This document summarises the deliberations of a consensus group meeting convened by the European Association of Urology (EAU) and the European Urogynecological Association, to explore the current evidence relating to the use of polypropylene (PP) materials used for the treatment of SUI and POP, with reference to the 2016 EAU guidelines (European Association of Urology 2016), the European Commission's SCENIHR report on the use of surgical meshes (SCENIHR 2015), other available high-quality evidence, guidelines, and national recommendations. Evidence synthesis: Current data suggest that the use of nonautologous durable materials in surgery has well-established benefits but significant risks, which are specific to the condition and location they are used for. Various graft-related complications have been described-such as infection, chronic pain including dyspareunia, exposure in the vagina, shrinkage, erosion into other organs of xenografts, synthetic PP tapes (used in SUI), and meshes (used in POP)-which differ from the complications seen with abdominal herniae. Conclusions: When considering surgery for SUI, it is essential to evaluate the available options, which may include synthetic midurethral slings (MUSs) using PP tapes, bulking agents, colposuspension, and autologous sling surgery. The use of synthetic MUSs for surgical treatment of SUI in both male and female patients has good efficacy and acceptable morbidity. Synthetic mesh for POP should be used only in complex cases with recurrent prolapse in the same compartment and restricted to those surgeons with appropriate training who are working in multidisciplinary referral centres. Patient summary: Synthetic slings can be safely used in the surgical treatment of stress incontinence in both male and female patients. Patients need to be aware of the alternative therapy and potential risks and complications of this therapy. Synthetic mesh for treating prolapse should be used only in complex cases with recurrent prolapse in specialist referral centres. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved

Detrusor underactivity (DUA) is a poorly understood, yet common, bladder dysfunction, referred to as underactive bladder, which is observed in both men and women undergoing urodynamic studies. Despite its prevalence, no effective therapeutic approaches exist for DUA. Exactly how the contractile function of the detrusor muscle changes with ageing is unclear. Data from physiological studies in animal and human bladders are contradictory, as are the results of the limited number of clinical studies assessing changes in urodynamic parameters with ageing. The prevalence of DUA in different patient groups suggests that multiple aetiologies are involved in DUA pathogenesis. Traditional concepts focused on either efferent innervation or myogenic dysfunction. By contrast, contemporary views emphasize the importance of the neural control mechanisms, particularly the afferent system, which can fail to potentiate detrusor contraction, leading to premature termination of the voiding reflex. In conclusion, the contemporary understanding of the aetiology and pathophysiology of DUA is limited. Further elucidation of the underlying mechanisms is needed to enable the development of new and effective treatment approaches.

Synthetic non-degradable meshes used in pelvic floor surgery can cause serious complications such as tissue erosion. A repair material composed of an autologous oral fibroblast seeded degradable polylactic acid scaffold may be a viable alternative. The aims of this study were to investigate the effects of media supplementation with additives (ascorbic acid-2-phosphate, glycolic acid and 17-β-oestradiol) on the mechanical properties of these scaffolds. Oral fibroblasts were isolated from buccal mucosa. The effects of the three additives were initially compared in two-dimensional culture to select the most promising collagen stimulating additive. Sterile electrospun scaffolds were seeded with 500,000 oral fibroblasts and fixed in 6-well plates and subjected to ascorbic acid-2-phosphate (the best performing additive) and/or mechanical stimulation. Mechanical stimulation by fluid shear stress was induced by rocking scaffolds on a platform shaker for 1 h/day for 10 of 14 days of culture. In two-dimensional culture, ascorbic acid-2-phosphate (concentrations from 0.02 mM to 0.04 M) and glycolic acid (10 µM) led to significantly greater total collagen production, but ascorbic acid-2-phosphate at 0.03 mM produced the greatest stimulation (of the order of >100%). In three-dimensional culture, mechanical stimulation alone gave non-significant increases in stiffness and strength. Ascorbic acid-2-phosphate (0.03 mM) significantly increased collagen production in the order 280% in both static and mechanically stimulated scaffolds (p

It is now clearly recognized that the function of the lower urinary tract represents a complex interaction between the bladder and its outlet, acting under the control of the central nervous system. While in the past attention has principally focused on the motor (efferent) control of the bladder, sensory (afferent) innervation is now known to be an important therapeutic target. This change in emphasis is strongly supported by both basic science and clinical evidence demonstrating the efficacy of therapy directed at the afferent system. This chapter summarizes the neurophysiological control mechanism that underpins normal lower urinary tract function, emphasizing the importance of the afferent system as a potential therapeutic target. Neurourol. Urodynam. 33:S6–S13, 2014. © 2014 Wiley Periodicals, Inc.

In this systematic review of the literature, a search of the PubMed database was conducted to identify articles dealing with augmentation/substitution urethral reconstruction of the anterior urethral stricture. The evidence was categorized by stricture site, surgical technique, and the type of tissue used. The committee appointed by the International Consultation on Urological Disease reviewed this data and produced a consensus statement relating to the augmentation and substitution of the anterior urethra. In this review article, the background pathophysiology is discussed. Most cases of urethral stricture disease in the anterior urethra are consequent on an ischemic spongiofibrosis. The choice of technique and the surgical approach are discussed along with the potential pros and cons of the use of a graft vs a flap. There is research potential for tissue engineering. The efficacy of the surgical approach to the urethra is reviewed. Whenever possible, a 1-stage approach is preferable from the patient's perspective. In some cases, with complex penile urethral strictures, a 2-stage procedure might be appropriate, and there is an important potential role for the use of a perineal urethrostomy in cases where there is an extensive anterior urethral stricture or where the patient does not wish to undergo complex surgery, or medical contraindications make this hazardous. It is important to have accurate outcome measures for the follow-up of patients, and in this context, a full account needs to be taken of patients' perspectives by the use of appropriate patient-reported outcome measures. The use of symptoms and a flow rate can be misleading. It is well established that with a normally functioning bladder, the flow rate does not diminish until the caliber of the urethra falls below 10F. The most accurate means of following up patients after stricture surgery are by the use of endoscopy or visualization by urethrography. Careful consideration needs to be made of the outcomes reported in the world literature, bearing in mind these aforementioned points. The article concludes with an overview of the key recommendations provided by the committee.

AIM: To report the effects of radical hysterectomy and nerve-sparing techniques on lower urinary tract function in women. METHODS: A literature search was performed in Pubmed and Medline using the keywords bladder after radical hysterectomy, nerve sparing radical hysterectomy, and urinary dysfunction following radical hysterectomy. Significant results and citations were reviewed manually by the authors. RESULTS: The sympathetic and parasympathetic systems innervating the lower urinary tract may be disrupted due to resection of uterosacral and rectovaginal ligaments, the dorsal and lateral paracervix, the caudal part of the vesico-uterine ligaments, and the vagina. This supports the neurogenic etiology of early and late bladder dysfunction after radical surgery. Bladder disorders are also related to the extent of radical surgery. The neuropathopysiology of lower urinary tract symptoms after radical hysterectomy is not fully understood. Recent data have highlighted the role of urethral sphincter pressure in the etiology of postoperative incontinence. Various surgical approaches have been developed to preserve autonomic pelvic innervation. CONCLUSIONS: Nerve-sparing techniques appear to improve bladder function without compromising overall survival. Studies comparing the effects of nerve-sparing radical hysterectomy with standard surgery yielded encouraging results in respect of postoperative lower urinary tract function. Clinical trials with a long period of follow-up are required for better comprehension of the complex pathophysiology of bladder dysfunction after radical hysterectomy.

We evaluated the efficacy, safety and tolerability of the EP1 receptor antagonist ONO-8539 in patients with overactive bladder syndrome.This was a 12-week, randomized, double-blind, placebo controlled, parallel group, multicenter study with a 2-week single blind placebo run-in phase. The 435 patients were randomized to receive twice daily ONO-8539 (30, 100 or 300 mg), placebo or once daily tolterodine (4 mg).At the end of the 12-week treatment no statistically significant difference was found between ONO-8539 and placebo in the change from baseline in the number of micturitions per 24 hours. The primary end points for 30, 100 and 300 mg ONO-8539, and placebo were -1.02, -1.53, -1.31 and -1.40, respectively. There was no statistically significant difference between any ONO-8539 group and placebo in the change from baseline in the number of urgency or urinary urgency incontinence episodes per 24 hours, or the mean volume voided per micturition, which were secondary end points. Statistically significant differences for tolterodine vs placebo were observed in the change from baseline in the number of micturitions (p = 0.045), urgency episodes (p = 0.04) and mean volume voided per micturition (p0.001). The incidence of adverse events was 54.1% in the placebo group, 43.0% to 54.0% in the ONO-8539 groups and 46.6% in the tolterodine group. The intensity of adverse events was similar among the treatment groups. Similar to other treatments, the most frequently reported adverse events after ONO-8539 were nasopharyngitis and diarrhea.The results of this study, which to our knowledge represents the first evaluation of ONO-8539 in patients with overactive bladder, suggest a minimal role for EP1 receptor antagonism in the management of overactive bladder syndrome.