Design, implementation and assessment of a novel, introductory curriculum into female, neurological and urodynamic urology: a 7-year experience of urology simulation bootcamp course.

PURPOSE: To present the seven-year experience of a multi-component and interactive module on female, neurological and urodynamic urology (FNUU) training at the UK National Urology Simulation Bootcamp Course (USBC) and demonstrate trainee satisfaction and competency progression. METHODS: During the week-long USBC, a four-hour module on FNUU was designed which consisted of short interactive presentations with an emphasis on practical stations in urodynamics, intravesical botulinum toxin injection, urethral bulking injection, female pelvic examination and, initially, mid-urethral tapes (subsequently replaced with percutaneous sacral nerve evaluation). The trainee's level of knowledge, operative experience and confidence were assessed pre- and post-course. The practical assessment consisted of preparation and intravesical administration of botulinum toxin, female pelvic examination, urodynamic trace interpretation or mid-urethral tape simulation. Trainee feedback was also collected. RESULTS: Two-hundred sixty-one newly appointed urology trainees participated in the USBC during this period. A high level of satisfaction was constantly reported. The highest rated session was urethral bulking with 72% being very satisfied, followed by Botox and urodynamics. The final assessment showed 70% had achieved level 4 competency in cystoscopy and Botox. Qualitative feedback was also obtained. CONCLUSION: To our knowledge, this is the first module of its kind, and it shows that it is feasible to develop, implement and evaluate an introductory curriculum into FNUU that is reproducible over a 7-year period with very positive feedback.

Use of donor bladder tissues for in vitro research.

OBJECTIVES: To evaluate deceased non-heart beating (DNHB) donors and deceased heart beating (DHB) brain-stem dead donors, as sources of viable urological tissue for use in biomedical research. To identify sources of viable human bladder tissue as an essential resource for cell biological research aimed at understanding human diseases of the bladder and for developing new tissue engineering and regenerative medicine strategies for bladder reconstruction. Typically, normal human urinary tract tissue is obtained from adult or paediatric surgical patients with benign urological conditions, but few surgical procedures yield useful quantities of healthy bladder tissue for research. PATIENTS AND METHODS: Research ethics committee approval was obtained for collection of donor bladder tissue. Consent for DHB donors was undertaken by the Donor Transplant Coordinators. Tissue Donor Coordinators were responsible for consent for DNHB donors and the retrieval of bladders was coordinated through the National Blood Service Tissue Banking Service. All retrievals were performed by practicing urologists and care was taken to maintain sterility and to minimise bacterial contamination. Two bladders were retrieved from DNHB donors and four were retrieved from DHB donors. RESULTS: By histology, DNHB donor bladder tissue exhibited marked urothelial tissue damage and necrosis, with major loss or absence of urothelium. No cell cultures could be established from these specimens, as the urothelial cells were not viable in primary culture. Bladder urothelium from DHB donors was intact, but showed some damage, including loss of superficial cells and variable separation from the basement membrane. All four DHB bladder specimens yielded viable urothelial cells that attached in primary culture, but cell growth was slow to establish and cultures showed a limited capacity to form a functional barrier epithelium and a propensity to senesce early. CONCLUSIONS: We have shown that normal human bladder urothelial cell cultures can be established and serially propagated from DHB donor bladders. However, our study suggests that rapid post-mortem changes to the bladder affect the quality and viability of the urothelium, rendering tissue from DNHB donors an inadequate source for urothelial cell culture. Our experience is that whereas patients are willing to donate surgical tissue for research, there is a barrier to obtaining consent from next of kin for retrieved tissues to be used for research purposes.

Clinical and Patient-reported Outcome Measures in Men Referred for Consideration of Surgery to Treat Lower Urinary Tract Symptoms: Baseline Results and Diagnostic Findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM).

BACKGROUND: Clinical evaluation of male lower urinary tract symptoms (MLUTS) in secondary care uses a range of assessments. It is unknown how MLUTS evaluation influences outcome of therapy recommendations and choice, notably urodynamics (UDS; filling cystometry and pressure flow studies). OBJECTIVE: To report participants' sociodemographic and clinical characteristics, and initial diagnostic findings of the Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM). UPSTREAM is a randomised controlled trial evaluating whether symptoms are noninferior and surgery rates are lower if UDS is included. DESIGN, SETTING, AND PARTICIPANTS: A total of 820 men (≥18 yr of age) seeking treatment for bothersome LUTS were recruited from 26 National Health Service hospital urology departments. INTERVENTION: Care pathway based on routine, noninvasive tests (control) or routine care plus UDS (intervention arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome is International Prostate Symptom Score (IPSS) and the key secondary outcome is surgery rates 18 mo after randomisation. International Consultation on Incontinence Questionnaires were captured for MLUTS, sexual function, and UDS satisfaction. Baseline clinical and patient-reported outcome measures (PROMs), and UDS findings were informally compared between arms. Trends across age groups for urinary and sexual PROMs were evaluated with a Cuzick's test, and questionnaire items were compared using Pearson's correlation coefficient. RESULTS AND LIMITATIONS: Storage LUTS, notably nocturia, and impaired sexual function are prominent in men being assessed for surgery. Sociodemographic and clinical evaluations were similar between arms. Overall mean IPSS and quality of life scores were 18.94 and 4.13, respectively. Trends were found across age groups, with older men suffering from higher rates of incontinence, nocturia, and erectile dysfunction, and younger men suffering from increased daytime frequency and voiding symptoms. Men undergoing UDS testing expressed high satisfaction with the procedure. CONCLUSIONS: Men being considered for surgery have additional clinical features that may affect treatment decision making and outcomes, notably storage LUTS and impaired sexual function. PATIENT SUMMARY: We describe initial assessment findings from a large clinical study of the treatment pathway for men suffering with bothersome urinary symptoms who were referred to hospital for further treatment, potentially including surgery. We report the patient characteristics and diagnostic test results, including symptom questionnaires, bladder diaries, flow rate tests, and urodynamics.

A Rare Urachal Cyst in a Case of Ketamine-induced Cystitis Provides Mechanistic Insights.

OBJECTIVE: To establish whether the urothelial ulceration observed in ketamine-induced cystitis is triggered by urinary or systemic factors. This was achieved with a rare case where an urachal cyst was found near the bladder dome in a patient undergoing cystectomy for unremitting pain following ketamine abuse. METHODS: Clinical investigations included cystoscopy, video urodynamic investigation, and computed tomography of the kidneys, ureters, and bladder. Histological staining was combined with immunoperoxidase labeling for markers of transitional epithelial differentiation. RESULTS: The urachus found near the dome of the bladder was observed to be a separate cyst, with no evidence of patency found during surgery or video urodynamic investigation. The urachus was lined by a mildly reactive metaplastic epithelium of mixed transitional and columnar morphologies. Evidence of widespread cytokeratin 13, basal p75(NTR), and sparse superficial uroplakin 3a immunoreactivity suggested the urachal epithelium was fundamentally transitional in nature. Near total loss of bladder urothelium was observed from regions in contact with urine, whereas the urachal epithelium (not exposed to urine) remained healthy. CONCLUSION: This study supports the hypothesis that urinary (and not systemic) factors are the main driver of urothelial ulceration in ketamine-induced cystitis. The most likely excreted factors responsible are ketamine and potentially its metabolites. This study reinforces the importance of complete cessation of ketamine use in patients with ketamine-induced cystitis.

Vesicovaginal fistulae.

Vesicovaginal fistula (VVF) formation represents a condition with devastating consequences for the patient and continues to pose a significant challenge to the surgeon. Quick and accurate diagnosis, followed by timely repair is essential to the successful management of these cases. A thorough understanding of the pathophysiology and anatomy of the fistula, potential factors that may compromise healing and experience in the fundamental principles of fistula repair are the vital tools of the fistula surgeon. This review was undertaken to provide an overview of the key areas in VVF investigation and management.

Assessing UK specialists' knowledge of the diagnostic criteria for painful bladder syndrome/interstitial cystitis.

The aim of this study was to assess UK clinicians' knowledge of the National Institute of Diabetes, Digestive and Kidney diseases (NIDDK) criteria for painful bladder syndrome (PBS)/interstitial cystitis (IC). A questionnaire survey was distributed nationally to 100 gynaecologists and urologists. The main outcome measure was to determine whether respondents knew the NIDDK diagnostic criteria for PBS/IC. All respondents cared for women with lower urinary tract dysfunction in their daily practice; 40% had a special interest in urogynaecology. Most (83%) knew that urgency, frequency and pain are required to diagnose PBS/IC; however, few were aware of exclusion/inclusion criteria. The minority perform double fill at cystoscopy, and only 56% were aware that glomerulations and/or Hunner's ulcers are required to diagnose IC. Urologists with a special interest in female urology answered nearly 75% of the questionnaire correctly in contrast to less than 40% of general gynaecologists. The findings suggest misdiagnosis of PBS/IC may be widespread in the UK. The NIDDK criteria are complex and appear to be of little relevance in clinical practice highlighting the need for more clearly defined diagnostic criteria.

The implementation of European Association of Urology guidelines in the management of acute epididymo-orchitis.

INTRODUCTION: Acute epididymo-orchitis is a common and increasing problem. This retrospective study reviewed whether the European Association of Urology guidelines for the management of acute epididymo-orchitis, which form the basis of this Trust's present inter-departmental guidelines, are being effectively implemented. PATIENTS AND METHODS: Case notes of 53 patients attending the emergency department with acute epididymo-orchitis over a 6-month period were reviewed retrospectively. The hospital results' database was used to confirm the diagnostic tests requested on patients at the time of their initial presentation. RESULTS: Of the study cohort, 26 patients were aged 35 years. The results demonstrated that a sexual history was documented in only 43.4% of cases. A mid-stream urine sample was sent for routine culture in 54.7% of cases whilst urine for the Chlamydia polymerase chain reaction (PCR) test was obtained in 17% and a urethral swab performed in 5.6%. Antibiotics were prescribed in 81% of cases. Of these patients, 46.5% received ciprofloxacin alone (mean age, 52 years; range, 18-87 years), 25.5% received doxycycline alone (mean age, 30 years; range, 18-45 years) and 21% received both ciprofloxacin and doxycycline (mean age, 33 years; range 18-49 years). In 26.4% of cases, verbal advice to attend a genito-urinary medicine clinic was given, whilst a formal telephone referral was made in only one case. Formal urological follow-up was arranged for only three out of 11 patients aged > 50 years. CONCLUSIONS: Although a joint emergency department/urology clinical protocol for the investigation and treatment of acute epididymo-orchitis already exists within the Trust, our current management conforms to this in only a minority of cases. Many different strategies can be employed in the implementation of clinical practice guidelines and all are associated with variable degrees of success. The regular movement of junior staff through each department necessitates that the distribution of management protocols and guidelines occurs at frequent intervals throughout the year and that their implementation is continuously monitored so that, if necessary, further implementation strategies can be employed.

Differentiation potential of urothelium from patients with benign bladder dysfunction.

OBJECTIVE: To develop a novel in vitro approach to test the hypothesis that failure of urothelial differentiation underlies the aetiopathology of interstitial cystitis (IC), where there is evidence of compromised urinary barrier function, as benign dysfunctional bladder disease encompass several poorly understood clinically defined conditions, including IC, idiopathic detrusor overactivity (IDO) and stress urinary incontinence (SUI). MATERIALS AND METHODS: Biopsy-derived urothelial cells from dysfunctional bladder biopsies were propagated as finite cell lines and examined for their capacity to differentiate in vitro, as assessed by the acquisition of a transitional cell morphology, a switch from a cytokeratin (CK)13(lo)/CK14(hi) to a CK13(hi)/CK14(lo) phenotype, expression of claudin 3, 4 and 5 proteins, and induction of uroplakin gene transcription. RESULTS: Two of 12 SUI cell lines showed early senescent changes in culture and were not characterized further; one of seven IC, one of five IDO and a further three SUI cell lines had some evidence of senescence at passage 3. Of the seven IC-derived cell lines, four showed a near normal range of differentiation-associated responses, but the remainder showed little or no response. Most IDO cell lines (four of five) showed a normal differentiation response, but at least three of the 10 SUI cell lines showed some compromise of differentiation potential. CONCLUSION: This study supports the existence of a subset of patients with IC in whom a failure of urothelial cytodifferentiation might contribute to the disease, and provides a novel platform for investigating the cell biology of urothelium from SUI and other benign dysfunctional conditions.

Urothelial differentiation in vesicoureteric reflux and other urological disorders of childhood: a comparative study.

OBJECTIVE: The strong familial basis of vesicoureteric reflux (VUR) is well recognised, however little progress has been made in identifying the causative genes. In this study we have investigated whether human vesicoureteric reflux (VUR) is associated with the aberrant expression of urothelial differentiation-associated antigens in view of the VUR phenotype of the Uroplakin IIIa (UPIIIa) "knockout" mouse. METHODS: Samples of urothelium were collected from 13 children with primary VUR, four children with secondary VUR and from seven children with non-refluxing disorders of the urinary tract. Immunohistochemistry was used to assess the expression of five uroplakin (UP) and cytokeratin (CK) differentiation-restricted antigens, UPIa, UPIb, UPIIIa, CK13 and CK20. Samples were ranked blind according to immunohistochemical patterns relating to the differentiation-associated distributions of the five antigens and the results were analysed statistically using the Kruskal-Wallis test. RESULTS: No objective differences in urothelial morphology or the expression of the five differentiation antigens were discernable in the urothelium of children with primary VUR, when compared with urothelium of children with a range of other pathology including VUR associated with duplication or pelvic renal ectopia, VUR secondary to outflow obstruction and non-refluxing upper tract obstruction. The p-values ranged from 0.168-0.651 and were not considered statistically significant. CONCLUSION: The results indicate that primary VUR is not associated with any major, collective abnormality of urothelial differentiation in man. In particular our findings provide no support for the suggestion that abnormalities of UPIIIa expression are implicated in the aetiology of human primary VUR.

PPARgamma-regulated tight junction development during human urothelial cytodifferentiation.

Urothelial barrier function is maintained by apical membrane plaques and intercellular tight junctions (TJ). Little is known about the composition and regulation of TJ expression in human urothelium. In this study, we have characterised the expression of TJ components in situ and their regulation in an in vitro model of differentiating normal human urothelial (NHU) cells. In normal ureteric urothelium in situ, there was a differentiation-associated profile of claudins 3, 4, 5, 7, ZO1 and occludin proteins. Proliferating NHU cells in vitro expressed predominantly claudin 1 protein and transcripts for claudins 1-5 and 7. Following induction of differentiation by pharmacological activation of PPARgamma and blockade of EGFR, there was de novo expression of claudin 3 mRNA and protein and downregulation of claudin 2 transcription. There was also a massive increase in expression of claudin 4 and 5 proteins which was due to inhibition of proteasomal degradation of claudin 4 and consequential stabilisation of the claudin 5 heterodimerisation partner. NHU cell differentiation was accompanied by relocalisation of TJ proteins to intercellular junctions. The differentiation-associated development of TJ formation in vitro reflected the stage-related TJ expression seen in situ. This was distinct from changes in TJ composition of NHU cells mediated by increasing the calcium concentration of the medium. Our results imply a role for PPARgamma and EGFR signalling pathways in regulating TJ formation in NHU cells and support the hypothesis that TJ development is an integral part of the urothelial differentiation programme.