Do we understand voiding dysfunction in women? Current understanding and future perspectives: ICI-RS 2017.

AIMS: Urinary retention in women is poorly understood, compared to the equivalent condition in men, and was the subject of a dedicated session organized at the International Consultation on Incontinence Research Society (ICI-RS) in Bristol, United Kingdom, 2017. METHODS: The current understanding of the pathophysiological correlates of idiopathic voiding dysfunction in women, the role of urodynamics, neurophysiology, and non-invasive tests in characterizing functional bladder outlet obstruction due to a non-relaxing urethral sphincter, and poorly defined diagnosis of detrusor underactivity were reviewed. RESULTS: Putative factors underlying the pathogenesis of urinary retention following urinary tract infections were discussed. Further research is required to explore the association between bladder wall inflammation and alterations in detrusor contractile functions. The complex interrelationship between urinary retention and psychological co-morbidities and sexual trauma were explored, and the overlap between these and psychological co-morbidities and functional neurological problems with functional urological problems were recognized. Understanding the mechanism of action of sacral neuromodulation, often a successful treatment for urinary retention, would provide insight into the underlying factors that may be responsible for urinary retention. Specifically, there is a need to understand the role of the endogenous enkephalinergic system in the pathogenesis of urinary retention and to identify predictors of successful treatment with sacral neuromodulation. Based on current understanding and potential directions of research in the future, an algorithm for the evaluation of women with voiding dysfunction was proposed. CONCLUSIONS: In the future, recommendations for research should lead to a better understanding of urinary retention in women and its treatment.

What are the additional signs and symptoms in patients with detrusor underactivity and coexisting detrusor overactivity?

AIMS: This study aimed to determine what difference the inclusion of patients with coexisting detrusor overactivity (DO) makes to the signs and symptoms of patients with detrusor underactivity (DU). METHODS: A total of 250 male and 435 female urodynamic tests were analyzed retrospectively. Signs and symptoms which showed a statistically significant difference between DU without DO and DU with DO were identified. RESULTS: Males with DO in addition to DU had higher age and number of daily micturitions, and were more likely to report urgency with or without urgency incontinence than males with DU without DO. They also had lower volumes for first desire to void, volume voided, and post void residual urine, lower abdominal pressure at Qmax and were less likely to report a history of retention or reduced bladder filling sensation than males with DU without DO. Females with DO in addition to DU had higher age and BMI, and were more likely to report urgency incontinence, higher day and night pad usage, constipation and have reduced anal tone than females with DU without DO. They also had lower volumes for first desire to void, volume voided, and post void residual urine, and lower abdominal pressure at Qmax than females who had DU without DO. CONCLUSIONS: There are differences in signs and symptoms between patients who have DU without DO, compared to patients having DU with DO. This understanding will help future studies investigating treatment options for DU patients.

Signs and symptoms that distinguish detrusor underactivity from mixed detrusor underactivity and bladder outlet obstruction in male patients.

AIMS: This study aimed to identify signs and symptoms which show differences between men with detrusor underactivity (DU) compared to those with both DU and bladder outlet obstruction (BOO). METHODS: One thousand six hundred and twelve urodynamic tests on male patients were analyzed retrospectively. Signs and symptoms which showed a statistically significant difference between patients with DU alone and patients with both DU+BOO were identified. RESULTS: In the DU only group, considering only patients without a history of bladder outlet surgery, the number of daytime micturitions was lower, maximum voided volume on the bladder diary was higher, and slow stream was reported less often, whereas urinary tract infections were reported more often than for DU+BOO males. The average urine flow rate and abdominal pressure at maximum flow were greater in the DU males, compared to the DU+BOO males. CONCLUSIONS: These data suggest that by combining symptoms, medical history and signs, that could be measured without the need for invasive urodynamics, it may be possible to identify men with DU in a non-invasive way. By doing so, men with DU could be separated from men with both DU+BOO, with sufficient specificity to allow the use of any new non-surgical treatment modalities, such as new and effective medical therapy.

Signs and Symptoms of Detrusor Underactivity: An Analysis of Clinical Presentation and Urodynamic Tests From a Large Group of Patients Undergoing Pressure Flow Studies.

BACKGROUND: The clinical diagnosis of detrusor underactivity (DU) is hampered by the need for invasive pressure flow studies (PFS) in combination with a lack of knowledge of the associated signs and symptoms. This has contributed to a lack of awareness of DU and underactive bladder, and to the assumption that symptoms are always due to bladder outlet obstruction (BOO). OBJECTIVE: To investigate the signs and symptoms recorded in a large urodynamic database of patients who met the diagnoses of DU, BOO, and normal, to identify the clinical features associated with DU. DESIGN, SETTING, AND PARTICIPANTS: From the database of 28282 adult PFS records, 1788 patients were classified into: (1) those with DU without BOO; (2) those with BOO without DU; and (3) those with normal PFS. RESULTS: Patients with DU reported a statistically significantly higher occurrence of decreased and/or interrupted urinary stream, hesitancy, feeling of incomplete bladder emptying, palpable bladder, and absent and/or decreased sensation compared with patients with normal PFS. Other differences were found between men with DU and BOO, and between women with DU and normal PFS. CONCLUSIONS: There are signs and symptoms that can distinguish DU patients from patients with normal PFS and further distinguish between DU and BOO, which is traditionally invasively diagnosed. This is a first step to better understand the clinical presentation of DU patients, is consistent with the recent underactive bladder working definition, and justifies further exploration of the signs and symptoms of DU. PATIENT SUMMARY: The clinical diagnosis of detrusor underactivity is hampered by the need for invasive urodynamics in combination with a lack of knowledge of the associated signs and symptoms. This study has shown that there are signs and symptoms that can distinguish men and women patients with DU from patients with either normal urodynamic studies or with BOO.

Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men.

OBJECTIVE: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated. MATERIALS AND METHODS: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years. In arm 1, subjects received single-dose tamsulosin hydrochloride modified release capsules (0.4 mg) alone and with steady-state mirabegron oral controlled absorption system tablets (100 mg once daily) in random sequence. In arm 2, subjects received single-dose mirabegron alone and with steady-state tamsulosin. Samples for mirabegron and tamsulosin plasma concentrations were collected. Blood pressure (BP) and pulse rate (PR) were measured and orthostatic stress tests were performed. RESULTS: Mirabegron increased tamsulosin C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(∞) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) to 85% (90% CI 71 - 103%) and AUC(∞) to 84% (90% CI 74 - 95%) without effect on t1/2. Mirabegron and tamsulosin co-treatment caused no statistically significant changes (p > 0.05) in PR or systolic BP versus mono-treatment up to 12 hours post-dose. Mean diastolic BP decreases of -2.1 (95% CI -4.1, -0.1) to -4.2 (-7.5, -0.9) mmHg in arm 1 and -3.0 (-5.7, -0.3) to -4.2 (-7.4, -1.0) mmHg in arm 2 were observed, statistically significant (p < 0.05) at several time points, not accompanied by orthostatic symptoms or increases in positive orthostatic stress tests. Adverse and orthostatic events were balanced across treatments. CONCLUSIONS: The observed pharmacokinetic interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety or safety profiles.

Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial.

BACKGROUND: Antimuscarinic agents are currently the predominant treatment option for the clinical management of the symptoms of overactive bladder (OAB). However, low rates of persistence with these agents highlight the need for novel, effective and better-tolerated oral pharmacological agents. Mirabegron is a ß3-adrenoceptor agonist developed for the treatment of OAB, with a mechanism of action distinct from that of antimuscarinics. In a randomized, double-blind, placebo- and active-controlled Phase 3 trial conducted in Europe and Australia (NCT00689104), mirabegron 50 mg and 100 mg resulted in statistically significant reductions from baseline to final visit, compared with placebo, in the co-primary end points - mean number of incontinence episodes/24 h and mean number of micturitions/24 h. We conducted a post hoc, subgroup analysis of this study in order to evaluate the efficacy of mirabegron in treatment-naïve patients and patients who had discontinued prior antimuscarinic therapy because of insufficient efficacy or poor tolerability. METHODS: Patients were randomized to placebo, mirabegron 50 or 100 mg, or tolterodine extended release (ER) 4 mg orally, once-daily, for 12 weeks. For the post hoc analysis, the primary patient population was divided into the following subgroups: (1) patients who had not received any prior antimuscarinic OAB medication (treatment-naïve) and (2) patients who had received prior antimuscarinic OAB medication. The latter subgroup was further subdivided into patients who discontinued due to: (3) insufficient efficacy or (4) poor tolerability. Analysis of the co-primary efficacy endpoints by subgroup was performed using analysis of covariance with treatment group, subgroup, sex, geographical region, and subgroup-by-treatment interaction as fixed factors; and baseline value as a covariate. RESULTS: Mirabegron, 50 mg and 100 mg once-daily, demonstrated similar improvements in the frequency of incontinence episodes and micturitions in OAB patients who were antimuscarinic-naïve and who had discontinued prior antimuscarinic therapy. While mirabegron demonstrated improvements in incontinence and micturition frequency in patients who had discontinued prior antimuscarinic therapy due to insufficient efficacy, the response to tolterodine was similar to that of placebo. CONCLUSION: In this post hoc subgroup analysis, mirabegron provided treatment benefits in OAB patients who were antimuscarinic treatment-naïve and in patients who had received prior antimuscarinic treatment.

Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a ß(3)-adrenoceptor agonist, in overactive bladder.

BACKGROUND: Despite several antimuscarinic treatment options for overactive bladder (OAB), there is still a need for distinct treatment approaches to manage this condition. Mirabegron, a ß(3)-adrenoceptor agonist, has demonstrated efficacy and tolerability for up to 12 wk in phase 3 trials. OBJECTIVE: To assess the 12-mo safety and efficacy of mirabegron. DESIGN, SETTING, AND PARTICIPANTS: Patients ≥ 18 yr of age with OAB symptoms for ≥ 3 mo. INTERVENTIONS: After a 2-wk single-blind placebo run-in, patients with eight or more micturitions per 24h and three or more urgency episodes in a 3-d micturition diary were randomized 1:1:1 to once-daily mirabegron 50mg, mirabegron 100mg, or tolterodine extended release (ER) 4 mg for 12 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary variable: incidence and severity of treatment-emergent AEs (TEAEs). Secondary variables: change from baseline at months 1, 3, 6, 9, and 12 in key OAB symptoms. RESULTS AND LIMITATIONS: A total of 812, 820, and 812 patients received mirabegron 50mg, mirabegron 100mg, and tolterodine ER 4 mg, respectively. Baseline demographic and OAB characteristics were similar across groups. TEAEs were reported in 59.7%, 61.3%, and 62.6% of patients, respectively; most were mild or moderate. Serious TEAEs were reported in 5.2%, 6.2%, and 5.4% of patients, respectively. The most common TEAEs were similar across groups. Dry mouth was reported by 2.8%, 2.3%, and 8.6% of patients, respectively. Adjusted mean changes from baseline to final visit in morning systolic blood pressure were 0.2, 0.4, and -0.5mm Hg for mirabegron 50mg, 100mg, and tolterodine ER 4 mg, respectively. Mirabegron and the active control, tolterodine, improved key OAB symptoms from the first measured time point of 4 wk, and efficacy was maintained throughout the 12-mo treatment period. The study was not placebo controlled, which was a limitation. CONCLUSIONS: The safety and tolerability of mirabegron was established over 1 yr, with sustained efficacy observed over this treatment period. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00688688.

Factors involved in the occurrence of bleeding complications after enucleation for cornea donation.

PURPOSE: To identify risk factors for the occurrence of bleeding complications after enucleation for cornea donation, in order to develop preventive activities to reduce the occurrence of bleeding complications and especially the development of ocular hematomas. METHODS: From all Dutch cornea donors deceased in the year 2006, donor characteristics, retrieval characteristics, and bleeding complication data were collected. First, univariate relations between donor and retrieval factors and bleeding complications were determined. Then, multivariate logistic regression analysis was used to identify factors significantly associated with bleeding complications. RESULTS: In 114 of the 1173 cornea donors (9.7%), bleeding complications occurred, with ocular hematomas developing in 39 (3.3% of all cornea donors). Donor factors significantly associated with bleeding complications were age [odds ratio (OR) 0.96 (95% CI 0.94-0.97)], weight [OR 1.03 (1.02-1.04)], heart failure [OR 2.10 (1.12-3.94)], thrombocyte aggregation inhibitor use [OR 1.64 (1.02-2.64)], and chronic alcoholic liver disease [OR 2.85 (1.11-7.31)]. The most significant factor associated with bleeding complications was the retrieval sequence. If cornea donation was followed by any other tissue retrieval, the risk of bleeding complications was strongly increased. CONCLUSIONS: : This study shows that the tissue retrieval sequence in multitissue donors is the most important factor associated with the occurrence of bleeding complications. The risk of bleeding and ocular hematoma is lower if cornea donation is performed after all other retrievals. However, if the tissue retrieval sequence is altered, the effect of prolonged postmortem time on corneal quality must be taken into account.

Allocation of corneas in europe.

BACKGROUND: To safeguard a fair distribution of available corneas, (inter)national and regional allocation principles have to be developed and implemented. METHODS: To obtain information about allocation principles over the world, a literature search was done. Allocation in Europe was investigated by international data of Bio Implant Services Foundation (BIS) over the period 2002-2007. RESULTS: For 4 different types of corneal grafts, e.g. random, HLA-typed, lamellar and emergency corneas, different allocation principles are described. Applying allocation criteria leads to dynamics in the donor and patient pool, which could be monitored by establishing the mean waiting time for each kind of corneal graft. Specific attention should be given to the division of corneas over the pools of different graft types, to ensure equal access to a transplant for all cornea patients. CONCLUSIONS: Due to new surgical techniques and seasonal changes in the supply of corneal grafts, allocation is a dynamic process, which has to be closely monitored.

Social lifestyle, risk-taking behavior, and psychopathology in young adults born very preterm or with a very low birthweight.

OBJECTIVE: To assess social lifestyle, risk-taking behavior, and psychopathology in young adults born very preterm or with a very low birthweight. STUDY DESIGN: This study was part of the 19-year follow-up in a large ongoing collaborative study in The Netherlands (the POPS study) on the long-term outcome of prematurity and dysmaturity. 656 adolescents from the POPS study without serious handicap were compared with peers in the general population in lifestyle, risk-taking behavior, psychopathology, and social participation. RESULTS: Adolescents from the POPS study smoked significantly less than their peers. Compared with their peers, boys from the POPS study consumed alcohol less often, and girls from the POPS study consumed alcohol approximately as often. Lifetime drug-use was significantly lower than in the reference group. With the exception of fare-dodging, criminal behavior in POPS adolescents was significantly lower than in control subjects. Boys had more trouble in establishing a relationship. The clinical psychopathology reported by POPS subjects was not significantly higher than in control subjects. CONCLUSION: Adolescents born very preterm or with a very low birthweight without serious disabilities engaged less in risk-taking behavior, did not show more psychopathology, but had more difficulties in establishing social contacts. The latter might be attributable to a more prominent internalizing behavior.