β3-Adrenoceptor agonist mirabegron is effective for overactive bladder that is unresponsive to antimuscarinic treatment or is related to benign prostatic hyperplasia in men

Purpose

To investigate the safety and efficacy of mirabegron for patients with overactive bladder (OAB) that is unresponsive to antimuscarinic agents or is related to benign prostatic hyperplasia (BPH).

Methods

Fifty-two newly diagnosed OAB patients (M group) and 45 patients with OAB that was unresponsive to antimuscarinics (S group) received mirabegron 50 mg once daily and were evaluated by OAB symptom score (OABSS), IPSS-QOL index, and IPSS at the time of baseline, 4 and 8 weeks. Newly diagnosed OAB patients treated with antimuscarinic agents were compared as controls.

Results

Mirabegron was effective for 85.2 % in M group. Significant improvements were seen in each domain of OABSS, and there was no significant difference with antimuscarinic therapy. Mirabegron was efficacious for 61.6 % of S group, and significant decreases of OABSS and IPSS-QOL index were observed. Significant improvements were also seen in voiding symptoms in men. Post-void residual urine volumes before and after treatment were 32.1 and 34.8 ml, and 26.2 and 31.3 ml in M and S group, respectively, and there was no significant difference. The incidence of adverse events was 8.4 %, although none were serious, and the patients recovered spontaneously after mirabegron was discontinued.

Conclusion

The present study suggests mirabegron is as effective as antimuscarinics for OAB. It improves OAB symptoms in patients with OAB for which antimuscarinic agents are insufficient. This study revealed that mirabegron improves not only OAB symptoms related to BPH, but also voiding symptoms in men. Low and mild incidences of side effects support the safe utility of mirabegron.     

Treatment status and risk factors for incidence and persistence of urinary incontinence in women

Introduction and hypothesis

The objective of this analysis was to describe urinary incontinence (UI) incidence and persistence over 5 years in association with treatment status, sociodemographic, medical, and lifestyle factors, in a racially/ethnically diverse population-based female sample.

Methods

The Boston Area Community Health Survey enrolled 3,201 women aged 30-79 years of black, Hispanic, and white race/ethnicity. Five-year follow-up was completed by 2,534 women (conditional response rate 83.4 %), allowing population-weighted estimates of UI incidence and persistence rates. Predictors of UI were determined using multivariate logistic regression models.

Results

Incidence of UI at least monthly was 14.1 % and weekly 8.9 %. Waist circumference at baseline and increasing waist circumference over 5-year follow-up were the most robust predictors of UI incidence in multivariate models (P?≤?0.01). Among 475 women with UI at baseline, persistence was associated with depression symptoms [monthly UI, odds ratio (OR)?=?2.39, 95 % confidence interval (CI) 1.14–5.02] and alcohol consumption (weekly UI, OR?=?3.51, 95 % CI 1.11–11.1). Among women with weekly UI at baseline, 41.7 % continued to report weekly UI at follow-up, 14.1 % reported monthly UI, and 44.2 % had complete remission. Persistence of UI was not significantly higher (58.2 % vs. 48.0 %, chi-square P?=?0.3) among untreated women. Surgical or drug treatment for UI had little impact on estimates for other risk factors or for overall population rates of persistence or remission.

Conclusions

Women with higher gains in waist circumference over time were more likely to develop UI, but waist circumference was not predictive of UI persistence. UI treatments did not affect associations for other risk factors. Additional research on the role of alcohol intake in UI persistence is warranted.     

An exploratory, placebo-controlled, dose–response study of the efficacy and safety of onabotulinumtoxinA in spinal cord injury patients with urinary incontinence due to neurogenic detrusor overactivity

Purpose

To explore the dose response to onabotulinumtoxinA 50, 100, and 200 U in patients with spinal cord injury (SCI) with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO).

Methods

Patients (N = 73) with SCI (level T1 or lower) with NDO and UI (≥14 UI episodes/week) received 30 intradetrusor injections of onabotulinumtoxinA (50 U [n = 19], 100 U [n = 21], or 200 U [n = 17]) or placebo (n = 16) via cystoscopy, avoiding the trigone. Changes from baseline in UI episodes/week, volume voided/micturition, maximum cystometric capacity, and maximum detrusor pressure (MDP) during first involuntary detrusor contraction (IDC) were evaluated. Adverse events (AEs) were assessed.

Results

A significant linear dose response for UI episodes/week was identified at weeks 18, 30, 36, 42, and 54 (P < 0.05) with a similar trend (P = 0.092) at week 6 (primary time point). A significant linear dose response was observed in volume/void at all post-treatment time points up to week 54 (P < 0.05) and in MDP during first IDC at week 6 (P = 0.034). The proportion of patients who achieved continence at week 6 was highest in the 200 U group. Duration of effect was longest with the 200 U dose, compared with other treatment groups. The AEs were comparable across groups; urinary tract infection was the most common AE across all treatment groups.

Conclusions

In this exploratory dose–response study of SCI patients with UI due to NDO, onabotulinumtoxinA 200 U was the most effective dose. The AE profile was comparable across all groups.     

Predictors of postoperative antimuscarinics in women with mixed urinary incontinence after transobturator surgery

Introduction and hypothesis

The study sought to identify the risk factors of postoperative use of antimuscarinics after transobturator surgery in women with mixed urinary incontinence (MUI) displaying both urodynamic stress urinary incontinence (SUI) and involuntary detrusor contraction (IDC) with leakage in urodynamic study.

Methods

The clinical data of 103 patients with MUI who underwent transobturator tape (TOT) sling surgery were retrospectively reviewed. The patients were followed at least a year. To determine risk factors for postoperative use of antimuscarinics, variables of only those with P values?<?0.05 on univariate analysis were included in the multivariate logistic regression analysis with forward stepwise building.

Results

Eight-four (81.6 %) of 103 patients were included in this study. The cure rate of urge urinary incontinence (UUI) was 69.0 % (58/84). Antimuscarinics were prescribed postoperatively in 22 (26.2 %) of 84 patients. Variables affecting postoperative use of antimuscarinics were age, parity, episode of any UUI, preoperative use of antimuscarinics, predominant urgency incontinence type, detrusor pressure at maximum flow, and Urogenital Distress Inventory 6. Increasing age and preoperative use of antimuscarinics increased the odds of postoperative use of antimuscarinics following TOT surgery.

Conclusion

Patients who were older and had taken antimuscarinics preoperatively were significantly associated with postoperative use of antimuscarinics.     

CORR® ORS Richard A. Brand Award for Outstanding Orthopaedic Research: Engineering Flexor Tendon Repair With Lubricant,Cells, and Cytokines in a Canine Model

Background

Adhesions and poor healing are complications of flexor tendon repair.

Questions/purposes

The purpose of this study was to investigate a tissue engineering approach to improve functional outcomes after flexor tendon repair in a canine model.

Methods

Flexor digitorum profundus tendons were lacerated and repaired in 60 dogs that were followed for 10, 21, or 42 days. One randomly selected repair from either the second or fifth digit in one paw in each dog was treated with carbodiimide-derivatized hyaluronic acid, gelatin, and lubricin plus autologous bone marrow stromal cells stimulated with growth and differentiation factor 5; control repair tendons were not treated. Digits were analyzed by adhesion score, work of flexion, tendon-pulley friction, failure force, and histology.

Results

In the control group, 35 of 52 control tendons had adhesions, whereas 19 of 49 treated tendons had adhesions. The number of repaired tendons with adhesions in the control group was greater than the number in the treated group at all three times (p = 0.005). The normalized work of flexion in treated tendons was 0.28 (± 0.08), 0.29 (± 0.19), and 0.32 (± 0.22) N/mm/° at Day 10, Day 21, and Day 42 respectively, compared with the untreated tendons of 0.46 (± 0.19) at Day 10 (effect size, 1.5; p = 0.01), 0.77 (± 0.49) at Day 21 (effect size, 1.4; p < 0.001), and 1.17 (± 0.82) N/mm/° at Day 42 (effect size, 1.6; p < 0.001). The friction data were comparable to the work of flexion data at all times. The repaired tendon failure force in the untreated group at 42 days was 70.2 N (± 8.77), which was greater than the treated tendons 44.7 N (± 8.53) (effect size, 1.9; p < 0.001). Histologically, treated repairs had a smooth surface with intrinsic healing, whereas control repairs had surface adhesions and extrinsic healing.

Conclusions

Our study provides evidence that tissue engineering coupled with restoration of tendon gliding can improve the quality of tendon healing in a large animal in vivo model.

Clinical Relevance

Tissue engineering may enhance intrinsic tendon healing and thus improve the functional outcomes of flexor tendon repair.     

Validation of the Imperial College Surgical Assessment Device (ICSAD) for labour epidural placement

Purpose

Technical proficiency in anesthesia has historically been determined subjectively. The purpose of this study was to establish the construct validity for the Imperial College Surgical Assessment Device (ICSAD), a measure of hand motion efficiency, as an objective assessment tool for technical skill performance, by examining its ability to distinguish between operators of different levels of experience performing a labour epidural. Concurrent validity for the ICSAD was investigated by comparison to a validated task specific checklist (CL) and global rating scale (GRS).

Methods

A single blinded, prospective, controlled study design compared three groups of subjects: novice residents (<30 epidurals), experienced residents (>100 epidurals), and staff anesthesiologists (>500 epidurals). Performance was measured using the ICSAD (number of movements, path length, time) and scores from a CL and GRS graded by examiners blinded to the level of training. Data were analyzed by multivariate analysis of variance (MANOVA).

Results

Twenty-nine subjects were recruited. Novice residents had longer path lengths compared to experienced residents (P = 0.031) and staff anesthesiologists (P = 0.0004), made more movements (P = 0.012) and took more time than staff (P = 0.009). Novice residents scored significantly worse on the GRS compared to experienced residents (P = 0.029) and staff (P = 0.01) and had significantly lower CL scores compared to staff (P = 0.003).

Conclusions

Construct and concurrent validity for the ICSAD was established for a regional anesthesia technique by demonstrating that it can distinguish between operators of different levels of experience and by comparing it to the current standards of technical skill assessment.     

Hysterectomy and urinary incontinence in postmenopausal women

Introduction and hypothesis

To evaluate an association between hysterectomy and urinary incontinence (UI) in postmenopausal women.

Methods

Women (aged 50–79) with uteri (N?=?53,569) and without uteri (N?=?38,524) who enrolled in the Women’s Health Initiative (WHI) Observational Study between 1993 and 1996 were included in this secondary analysis. Baseline (BL) and 3-year demographic, health/physical forms and personal habit questionnaires were used. Statistical analyses included univariate and logistic regression methods.

Results

The baseline UI rate was 66.5 %, with 27.3 % of participants having stress urinary incontinence (SUI), 23 % having urge UI (UUI), and 12.4 % having mixed UI (MUI). 41.8 % of women had undergone hysterectomy, with 88.1 % having had the procedure before age 54. Controlling for health/physical variables, hysterectomy was associated with UI at BL (OR 1.25, 95 % CI 1.19, 1.32) and over the 3-year study period (OR 1.23, 95 % CI 1.11, 1.36). Excluding women with UI at BL, a higher incidence of UUI and SUI episodes was found in hysterectomy at year 3. Among women who had undergone hysterectomy, those with bilateral oophorectomy (BSO) did not have increased odds of developing UI at BL or over the 3-year study period. Hormone use was not associated with a change in UI incidence (estrogen + progesterone, p?=?0.17; unopposed estrogen, p?=?0.41).

Conclusions

Risk of UI is increased in postmenopausal women who had undergone hysterectomy compared with women with uteri.     

Caffeine and urinary incontinence in US women

Introduction and hypothesis

The goal of this study was to characterize associations between caffeine consumption and severity of urinary incontinence (UI) in US women. We hypothesized that moderate and high caffeine intake would be associated with UI in US women when controlling for other factors associated with UI.

Methods

US women participated in the 2005–2006 and 2007–2008 National Health and Nutrition Examination Survey (NHANES), a cross-sectional, nationally representative survey. Using the Incontinence Severity Index, UI was categorized as “any” and “moderate/severe”. Types of UI included stress, urge, mixed, and other. Food diaries were completed, and average water (grams/day), total dietary moisture (grams/day), and caffeine (milligrams/day) intake were calculated into quartiles. Stepwise logistic regression models were constructed adjusting for sociodemographics, chronic diseases, body mass index, self-rated health, depression, physical activity, alcohol use, dietary water and moisture intake, and reproductive factors.

Results

From the 4,309 nonpregnant women (aged ≥20 years) who had complete UI and dietary data, UI prevalence for any UI was 41.0 % and 16.5 % for moderate/severe UI, with stress UI the most common type (36.6 %). Women consumed a mean caffeine intake of 126.7 mg/day. After adjusting for multiple factors, caffeine intake in the highest quartile (≥204 mg/day) was associated with any UI [prevalence odds ratio (POR) 1.47, 95 % confidence interval (CI) 1.07–2.01], but not moderate/severe UI (POR 1.42, 95 % CI 0.98–2.07). Type of UI (stress, urgency, mixed) was not associated with caffeine intake.

Conclusions

Caffeine intake ≥204 mg/day was associated with any UI but not with moderate/severe UI in US women.     

Clinical impact of and contributing factors to urinary incontinence in women 5 years after first delivery

Introduction and hypothesis

This study was conducted to investigate the prevalence of and contributing factors to urinary incontinence (UI) in women 5 years after their first birth and to evaluate the associations of UI with delivery mode and quality of life.

Methods

Between 2005 July and 2006 March, primiparous women who delivered at term in a tertiary hospital were recruited into this cohort study. Immediately postpartum, the women completed a structured urogynecological questionnaire regarding lower urinary tract symptoms. Then the same urogynecological questionnaire, the Incontinence Impact Questionnaire (IIQ-7), and the Urinary Distress Inventory (UDI-6) were mailed to them 5 years later to follow up on UI. Three hundred and twelve women responding to the mailed questionnaires were included in the analyses.

Results

The prevalence 5 years after first delivery of stress (SUI) and urge (UUI) UI were 43.6 % and 19.2 %, respectively. Women with UI during their first pregnancy were more likely to develop UI 5 years postpartum than those without it; women who delivered their first child vaginally had a greater incidence of UI than those having cesarean birth; UUI in women following cesarean delivery more negatively impacted emotional health than it did following vaginal birth, whereas the impact of SUI did not significantly differ between delivery groups.

Conclusions

UI during the first pregnancy and vaginal delivery in primiparous women may predict an increased risk of having UI 5 years after delivery. UUI adversely affected women’s emotional health, especially in those undergoing cesarean section.     

Does urinary incontinence have fetal origins? Results from a nationwide twin study

Introduction and hypothesis

The aim of this study is to evaluate the effect of birth weight and being born small for gestational age (SGA) on urinary incontinence (UI) among premenopausal women.

Methods

In 2005, a total of 14,094 female twins born 1959–1985 who had been included in the Swedish Twin Registry participated in a survey on common exposures and complex diseases, including urinary incontinence. Information regarding birth weight and gestational age was obtained from the Medical Birth Register (for twins born 1973–1985) and from the medical archives (for twins born 1959–1972). A logistic regression model based on generalized estimating equations was used to estimate odds ratios (ORs) with 95 % confidence intervals (CIs).

Results

In both crude and adjusted analysis, birth weight and SGA had no effect on UI. An interaction between low birth weight (<2,500 g) and body mass index (BMI) later in life was found for overall and stress UI. Compared with women who were not overweight and had a birth weight above 2,500 g, overweight women (BMI?≥?25) who had a normal birth weight had a 35 % higher odds of incontinence , while overweight women who had a low birth weight had an approximately 85 % higher odds of UI (OR?=?1.84, 95 % CI 1.39–2.45 for overall UI; OR?=?1.83, 95 % CI 1.35–2.48 for stress UI).

Conclusions

Birth weight and SGA had no direct effect on urinary incontinence; however, low birth weight in combination with an elevated adult BMI may contribute to the risk of urinary incontinence later in life.     

Written versus oral disclosure of fecal and urinary incontinence in women with dual incontinence

Introduction and hypothesis

To compare fecal incontinence (FI) and urinary incontinence (UI) disclosure in women with dual incontinence (DI), and to assess UI disclosure in DI subjects compared with women with UI alone. We hypothesized that women with DI would be less likely to disclose FI in comparison to UI and as likely to disclose UI as women with UI alone.

Methods

We performed a retrospective chart review of new patient visits to an academic urogynecology clinic from 2007 to 2011. Clinical records were reviewed; demographic data and responses to the Incontinence Severity Index (ISI) and Wexner scales were recorded. Patients’ written responses to the ISI and Wexner were compared with the diagnoses obtained from the oral history by the physician.

Results

Of 1,899 women in the database, 557 women were diagnosed with DI and 447 women were diagnosed with UI alone. Women with DI were less likely to orally disclose FI than UI (135 out of 557 [23 %], vs 485 out of 557 [87 %], p?p?=?0.66). In the multivariate analysis, DI subjects had greater odds of disclosing FI to their physicians if they had private insurance (OR 1.9, 95 %CI 1.2, 3.0) or Wexner score >7 (OR 9.0, 95 % CI 5.4,14.8) and lower ISI score (OR 1.5, CI 1.4, 1.6).

Conclusions

Women with DI were less likely to report FI in comparison to UI. Patients were more likely to orally report FI when the symptoms were severe.     

Comparison of erythropoietin and sildenafil protective role against ischemia/reperfusion injury of the testis in adult rats

Purpose

Tissue damage in testicular torsion/detorsion is caused not only by the ischemia, but also by the ischemia/reperfusion injury after detorsion. Erythropoietin and sildenafil are considered to protect against ischemia/reperfusion injury. Here, we studied and compared their actions in testicular torsion/detorsion in adult rats.

Methods

Twenty-two adult male Wistar Albino rats were divided into four groups. Rats in group A (n = 5) were sham operated. Rats in group B (n = 5), group C (n = 6) and group D (n = 6) underwent torsion of the right testis and detorsion after 90 min. No pharmaceutical intervention was performed in group B. Erythropoietin (1,000 IU/kg) and sildenafil (0.7 mg/kg) were injected intraperitoneally in groups C and D, respectively, after 60 min of torsion. All animals were killed 24 h after detorsion, and their right testis was extracted, placed into 10 % formalin solution and sent for histopathological examination. The histological changes in the testes were scored according to the four-point grading system proposed by Cosentino et al.

Results

All rats in group A had normal testicular architecture (grade 1). The untreated group B had a mean grade of 3.81 (range 3.65–4). The treated groups C (mean grade 3.24; range 3.05–3.45) and D (2.69, range 2.4–2.9) presented statistically significant better results (lower grades) compared with the untreated group B. Group D had significantly better results (lower grades) than group C.

Conclusions

The intraperitoneal injection of erythropoietin and sildenafil protects against ischemia/reperfusion injury after testicular torsion and detorsion. Sildenafil may have a stronger action than erythropoietin at the doses used in this study.     

Family history and its association to curve size and treatment in 1,463 patients with idiopathic scoliosis

Purpose

To study family history in relation to curve severity, gender, age at diagnosis and treatment in idiopathic scoliosis.

Methods

A self-assessment questionnaire on family history of scoliosis was administered to 1,463 untreated, brace or surgically treated idiopathic scoliosis patients.

Results

Out of the 1,463 patients, 51 % had one or more relatives with scoliosis. There was no significant difference between females and males, nor between juvenile and adolescent study participants in this respect (p = 0.939 and 0.110, respectively). There was a significant difference in maximum curve size between patients with one or more relatives with scoliosis (median 35°, interquartile range 25) and patients without any relative with scoliosis (median 32°, interquartile range 23) (p = 0.022). When stratifying patients according to treatment (observation, brace treatment or surgery), we found that it was more common to have a relative with scoliosis among the treated patients (p = 0.011). The OR for being treated was 1.32 (95 % CI 1.06–1.64) when the patient had a relative with scoliosis, compared to not having.

Conclusions

Larger curve sizes were found in patients with a family history of scoliosis than in the ones without. No relation between family history and gender or between family history and age at onset of idiopathic scoliosis was found. Although the presence of a family history of scoliosis may not be a strong prognostic risk factor, it indicates that these patients are at higher risk of developing a more severe curve.     

Assessment of urinary incontinence in the women in Eastern Turkey

Introduction and hypothesis

The aims of the present study were to determine the types of UI among women visiting the urology department, to identify the potential risk factors associated with each type of UI, and to identify healthcare-seeking behaviors of affected women in our region.

Methods

The data of 617 community-dwelling women, who were at least 18 years of age or older and who presented with a complaint of UI ongoing over a year, and those without UI, who were admitted for any other reason, from June 2010 to April 2012, were evaluated.

Results

Mean age was 51.29 years (range 18–110 years); median parity was 3.54 (range 0–11) and 88.2 % of the women were married. Mean BMI was 28.01 kg/m². Very few women (18.5 %) accepted UI as a disease and searched for medical help by themselves; however, the remaining women (81.5 %) were brought or directed for evaluation by someone else. Stress UI was reported by 43 women (10.5 %), urge UI and mixed UI were noted by 153 (37.5 %) and 212 (52 %) women respectively.

Conclusions

The most frequent type of UI was mixed UI in our region. Age, BMI, multiparity, and hypertension were identified to have a different importance for each type of UI, but diabetes mellitus, birth trauma, gynecological surgery, lumbar disc hernia (LDH), and multiple sclerosis (MS) were the other important related factors. However, a small number of patients accepted UI as a disease and searched for therapy. This reveals that the public should be informed in detail about female UI in developing countries.     

Urinary incontinence among Muslim women in Israel: risk factors and help-seeking behavior

Introduction and hypothesis

The prevalence of urinary incontinence (UI) varies among women in different cultures. Muslim women with UI have complex issues related to the need for cleaning (ablution) before prayer. The aim was to assess the prevalence of UI, factors associated with it, its effect on quality of life, and help-seeking behavior among Muslim women.

Methods

This was a cross-sectional study. Self-administered questionnaires completed by women 18–75 years of age who visited the primary care clinic between 21 June 2015 and 9 October 2015 and additional data collected from their medical records.

Results

A total of 492 women (mean age 31.8 ± 9.5 years) participated in the study. Of these, 43% suffered from UI and 19% from severe to very severe UI. The mean score for interference in daily life (0–10) was 6.3 ± 3.7. Sixty percent of women with UI had stress incontinence, 23% urge incontinence, and 9% mixed incontinence. Only 10% had consulted previously with their physician regarding UI. Increased BMI (OR = 1.048, 95% CI 1.009–1.089) and polygamy (OR = 1.943, 95% CI 1.007–3.749) were associated with severe to very severe UI. Age, parity, and more severe degrees of UI were associated with help-seeking behavior (OR = 1.065 95% CI 1.008–1.125, OR = 0.763 95% CI 0.624–0.934, OR = 4.073 95% CI 1.410–11.765 respectively).

Conclusions

Urinary incontinence is very common among Muslim women in primary care in southern Israel and significantly impairs their quality of life. Only a small percentage consults with their physician.

     

Evaluation of Guanylyl Cyclase C Lymph Node Status for Colon Cancer Staging and Prognosis

Purpose

The prognostic significance of guanylyl cyclase C (GCC) gene expression in lymph nodes (LNs) was evaluated in patients with stage II colon cancer who were not treated with adjuvant chemotherapy. We report a planned analysis performed on 241 patients.

Methods

GCC mRNA was quantified by RT-qPCR using formalin-fixed LN tissues from patients with untreated stage II colon cancer who were diagnosed from 1999–2006 with at least ten LNs examined and blinded to clinical outcomes. Lymph node ratio (LNR) is the number of GCC-positive nodes divided by total number of informative LNs. Risk categories of low (0–0.1) and high (> 0.1) for LNR were chosen by significance using Cox regression models. The data were tested for association with time to recurrence.

Results

Twenty-nine patients (12%) had a disease recurrence or cancer death. The LNR significantly predicted higher recurrence risk for 84 patients (34.9%) classified as high risk (hazard ratio (HR), 2.38; P = 0.02). The estimated 5-year recurrence rates were 10% and 27% for the low- and high-risk groups, respectively. After adjusting for age, T stage, number of nodes assessed, and MMR status, a significant association remained (HR, 2.61; P = 0.02). In a subset of patients (n = 181) with T3 tumor, ≥ 12 nodes examined and negative margins, a significant association between the GCC LNR and recurrence risk also was observed (HR, 5.06; P = 0.003).

Conclusions

Our preliminary results suggest that detection of GCC mRNA in LNs is associated with risk of disease recurrence in patients with untreated stage II colon cancer. A larger validation study is ongoing.