The effect of 12 weeks of estriol cream on stress urinary incontinence post-menopause: A prospective multinational observational study.

OBJECTIVE: To quantitate the changes in stress urinary incontinence (SUI) outcome measures after 12 weeks of vaginal estriol cream in women with stress incontinence. METHODS: A prospective multicentre observational study conducted in tertiary urogynaecology centers. Postmenopausal women with pure SUI or stress predominant mixed urinary incontinence (MUI), not receiving any other treatment for their incontinence were given written instructions regarding digital application of a standard dose of vaginal estriol cream. Outcomes were measured at baseline and 12 weeks. The primary objective outcome was vaginal pH. The primary subjective outcome was the stress domain of the Urogenital Distress Inventory-6 (UDI-6). The secondary objective outcome used was the erect cough stress test. Two quality of life questionnaires and two patient reported outcomes were also included. RESULTS: The 46 postmenopausal recruits had a median age of 62.1 interquartile range (IQR 56.2-65.4). At follow up, the primary subjective outcome SUI domain [UDI-6] significantly improved from 83.3 (IQR 50-100) to 33.3 (33.3-66.7, p ≤ 0.001) as did vaginal pH [from 5.1 (4.9-5.9) to 4.9 (4.6-5.0] p ≤ 0.001; 18/43 patients (42%) were dry on cough stress test. CONCLUSIONS: Twelve weeks of vaginal estriol cream significantly reduced symptoms of stress urinary incontinence in this sample of postmenopausal women.

Efficacy and patient acceptability of the continence dish.

INTRODUCTION AND HYPOTHESIS: The continence dish has been a treatment option since 2002 for women with stress urinary incontinence (SUI) who decline surgery, but few quantitative objective efficacy data are published. We aimed to determine the efficacy and acceptability of this device for pure SUI or mixed incontinence (MUI). METHODS: Prospective interventional cohort study of 100 women with SUI or stress-predominant MUI who were interested to use the device; International Consultation on Incontinence Questionnaire (ICIQ) was primary outcome measure; 24-h pad test and Incontinence Impact Questionnaire (IIQ) were secondary outcomes. Acceptability was determined by device retention for 4 weeks, adverse events and ability to self-insert the device. RESULTS: Of 100 suitable women, 9 were not actually fitted, and 27 did not complete (acceptability: 64/100). The rate of adverse events was 7.7%, with 62.5% of users able to self-insert the device: 22 (34%) had pure SUI; 66% had MUI. In SUI, 68% were 'dry' on ICIQ median value 4.0 (IQR 2.5-8.5); 88% were dry on 24-h pad test (median 0.0, IQR 0.0-8.5). The "dry rate" was lower in MUI: 36% for ICIQ (median 9.0, IQR 5.0-15.0) and 62% for 24-h pad test (median 6.2, IQR 0.95-19.7). A "good" response on IIQ occurred in 88% of SUI and 69% of MUI. CONCLUSION: These new data showing strong objective benefits of the continence dish should be further validated by randomized trials, but this information should be made available to women seeking treatment options for SUI/MUI (particularly in view of concerns regarding mesh mid-urethral slings).

Effect of antibiotics on urine leakage in women with refractory detrusor overactivity: A phase IIb randomized trial.

AIM: Because bacterial cystitis is common in women with refractory detrusor overactivity, the aim was to compare the efficacy of 6 weeks of rotating antibiotics versus placebo, in conjunction with an anticholinergic, in controlling the symptoms of urge incontinence. METHODS: In a multicenter phase IIb double-blinded randomized placebo-controlled trial, women with urodynamically proven refractory detrusor overactivity were randomized in a 2:1 ratio of antibiotics versus placebo for 6 weeks, in addition to darifenacin for 6 months. Any woman with disabling cystitis symptoms was given appropriate antibiotics ("clinical override"). The primary outcome was the degree of urge incontinence change at 6 weeks and 6 months on 24-h pad test. Secondary outcomes were changes in leaks and voids per day measured on 3-day bladder diary and quality of life measures. Microbiological data were collected at all visits. RESULTS: Although 278 women were screened, only 36 were randomized and 33 (91.7%) completed the trial. Leakage on 24-h pad test decreased at 6 months by 75 g in patients receiving antibiotics versus 35 g in placebo. Cure of urge incontinence occurred at 6 months in 10/21 (48%) of antibiotics versus 2/12 (17%) of placebo. Clinical override, necessitating treatment of cystitis, occurred in 41.6% of placebo versus 16.7% of the antibiotic group by 6 months. CONCLUSION: Despite the small sample size, the study showed a significant reduction in pad leakage and leaks per day over 24 h in the active treatment group over a 6-month period. Nearly half of patients on placebo had disabling urinary tract infection symptoms that required clinical override treatment.

Estriol serum levels in new and chronic users of vaginal estriol cream: A prospective observational study.

AIMS: To quantify estriol serum concentrations in "new" and "chronic users" of topical estriol cream using quantitative liquid chromatography tandem mass spectrometry. METHODS: In this singlecentre prospective observational study, postmenopausal women with urogynaecological complaints were enrolled: 40 had not used topical estriol previously ("new users") and 50 had been applying estriol cream for more than 12 weeks ("chronic users"). In "new users," serum estriol levels were measured at baseline and after 12 weeks use. Estriol cream 1 mg/g was used daily for 3 weeks, then twice weekly with applicator (group 1A) or digitally (group 1B) or three times per week digitally (group 1C). "Chronic users" applied the cream twice (n = 7) or three (n = 43) times per week. Serum samples were taken in the morning after using cream the previous night. The main outcome measures were estriol serum concentrations in "new" and "chronic users" of estriol cream. RESULTS: Baseline serum estriol concentrations were less than 5 pmol/L in all 40 "new users." At 12 weeks, the 12-hour serum estriol levels ranged from less than 5 to 494 pmol/L (median 22.8; Interquartile range [IQR] 9.2-108.5). Seven "new users" had levels more than 100 pmol/L. Most of the 50 "chronic users" also had 12-hour levels less than 100 pmol/L (median 15.1 pmol/L [IQR 2.7-33.9]: three had levels more than 100 pmol/L. CONCLUSIONS: This study reports serum estriol concentrations in a large number of "new" and "chronic users" of vaginal estriol cream, employing a novel highly sensitive and specific technique. Overall, the results are reassuring: 87% had 12-hour estriol levels less than 100 pmol/L.

Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells.

Integrins are transmembrane adhesion receptors that play an important role in hematopoiesis by facilitating interactions between hematopoietic cells and extracellular matrix components of the bone marrow and hematopoietic tissues. These interactions are important in regulating the function, proliferation, and differentiation of hematopoietic cells, as well as their homing and mobilization in the bone marrow. Not surprisingly altered expression and function of integrins plays a key role in the development and progression of cancer including leukemias. However, the regulation of integrin gene expression is not well characterized and the mechanisms by which integrin genes are disrupted in cancer remain unclear. Here we demonstrate for the first time that a key regulator of hematopoiesis, RUNX1, binds to and regulates the promoters of both the ITGA6 and ITGB4 genes in myeloid cells. The ITGA6 and ITGB4 integrin genes form the α6ß4 integrin receptor. However, our data indicate that RUNX1 functions differently at these two promoters. RUNX1 regulates ITGA6 through a consensus RUNX1 binding motif in its promoter. In contrast, although the ITGB4 promoter is also activated by RUNX1, it does so in the absence of a recognized consensus RUNX1 binding motif. Furthermore, our data suggest that regulation of ITGB4 may involve interactions between the promoter and upstream regulatory elements.

NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation.

Tachykinins are expressed within bladder-innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium or sensory afferents directly. Here, we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signaling from the bladder during distension, urothelial transmitter release ex vivo, and direct responses to neurokinin A (NKA) on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder-afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100 nM). Intravesical NKA significantly decreased bladder compliance but had no direct effect on mechanosensitivity to bladder distension (30 µl/min). GR159897 alone enhanced bladder compliance but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, whereas acetylcholine levels were reduced. NKA-mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.

A prospective "bottom up" study of the costs of faecal incontinence in ambulatory patients.

BACKGROUND AND AIM: The few studies that have examined direct costs of faecal incontinence are limited in that they employed retrospective databases, postal surveys, and focused upon institutionalised patients or post partum women. The aim of the current study was to identify the direct pre-treatment costs of faecal incontinence expended by a range of home dwelling patients and identify relationships between costs and severity of incontinence. METHODS: Consecutive patients attending an outpatient clinic for treatment of faecal incontinence were interviewed using a questionnaire, modeled on the Dowel Bryant Incontinence Cost Index. The information collected included costs of: (i) basic personal hygiene: pads, laundry, wipes, cleansers; (ii) medication: loperamide, creams and stool bulking agents; and (iii) diagnostic: medical attendance, anorectal physiology, colonoscopy. Costs were broken down into personal expenses, government costs, and costs to health funds. A St Mark's Faecal Incontinence Severity Score was recorded. RESULTS: A total of 100 consecutive patients consented (15 males, 85 females) mean age 70.8 (SD12) years. Mean St Mark's score was 12 (SD4.5). The median total patient cost was $437.72 AUD (range 0-2807) per annum. Government costs were $537AUD (range 135-1657), and health fund median $0 AUD (0-1628). Incontinence severity correlated with personal expense only median $283.75AUD (range 0-2350). The aged were more incontinent but costs did not increase in relation to age. CONCLUSION: Faecal incontinence results in a substantial financial burden for both patients and Government. Effective treatments which relieve the financial burden of faecal incontinence, are likely to be economically advantageous into the future for both patients and Government.

Vascular measures of atherosclerosis in detrusor overactivity and controls.

AIM: The mechanisms leading to the development of detrusor overactivity (DO) are still relatively poorly understood, however, animal studies suggest that atherosclerosis and reduced blood flow to the bladder may be one etiological pathway. Thus, the aim of this study was to evaluate signs of atherosclerosis in a large cohort of women with detrusor overactivity, using two precise measures of atherosclerotic vascular impairment, Ankle Brachial Index (ABI), and Brachial-ankle Pulse Wave Velocity (baPWV). METHODS: A prospective cohort study measuring ABI and baPWV of women with DO and controls was conducted. The ABI and baPWV were measured using an automated oscillometric blood pressure machine, to evaluate the degree of atherosclerosis in patients with DO and controls. Associations between ABI and baPWV and important confounding variables were assessed by a linear regression model. RESULTS: Ninety-eight women with DO, and 98 controls without any symptoms of DO were studied. Multivariate analysis showed an increase in left baPWV of approximately 96 cm/s units of velocity (95%CI 20.65-172.05, P = 0.01) is predicted significantly by the presence or absence of detrusor overactivity (as well by independent factors of age, diastolic blood pressure and body mass index). A similar effect was seen for right baPWV. CONCLUSIONS: On linear regression modeling, the presence of DO was a strong predictor for an increased PWV when controlling for age, BMI and diastolic blood pressure (DBP), thus supporting the hypothesis that atherosclerosis may contribute to the etiology of DO.

The urinary microbiome in patients with refractory urge incontinence and recurrent urinary tract infection.

INTRODUCTION AND HYPOTHESIS: Urinary urge incontinence is a chronic, debilitating condition that is difficult to treat. Patients refractory to standard antimuscarinic therapy often experience recurrent urinary tract infections (rUTIs). The microbiota of these refractory patients with rUTI remains unexplored. METHODS: A midstream urine (MSU) sample was collected from patients with refractory urge incontinence and coexistent rUTI during acute symptomatic episodes. Culture-based diagnosis was performed using routine microbiological methods. Culture-independent profiling was performed using bacterial 16S RNA profiling. E. coli strain typing was performed by amplicon pyrosequencing of the fimH gene. RESULTS: Over 2 years, 39 patients with refractory urge incontinence and coexistent rUTI were studied, yielding 9 severely affected cases. These 9 patients were carefully monitored for a further 2 years, resulting in the collection of 102 MSU samples, 70 of which were diagnosed as UTI (median of 8 UTIs/woman). Culture-independent analysis of 38 of these samples revealed the existence of a diverse urinary microbiota. Strain typing of E. coli identified instances of rUTI caused by the same persisting strain and by new infecting strains. CONCLUSIONS: Patients with refractory urge incontinence and coexistent rUTI possess a diverse urinary microbiota, suggesting that persistent bladder colonisation might augment the pathology of their chronic condition.

Does motivation predict outcome of pelvic floor muscle retraining?

AIMS: Although pelvic floor muscle training (PFMT) is effective for stress urinary incontinence (SUI), patients need to be motivated to obtain cure. An instrument to assess motivation in such patients was published in 2009: the Incontinence Treatment Motivation Questionnaire (ITMQ). The ITMQ consists of five domains: (i) positive attitudes toward PFMT; (ii) reasons for not doing PFMT; (iii) difficulties living with incontinence; (iv) desire for treatment; and (v) incontinence severity influencing motivation. The aim of the present study was to examine the relationship between ITMQ scores and treatment success. METHODS: After referral for PFMT, women with SUI completed the ITMQ. Pre- and post-treatment outcomes were the International Consultation on Incontinence Questionnaire (ICIQ) score and a 24-hr pad test. Correlations between ITMQ scores and baseline, as well as post-treatment change in ICIQ scores and pad test results were examined. Additionally, the demographics of non-participants, participants, and patients lost to follow-up were compared. RESULTS: Of 85 recruits, 18 did not complete the ITMQ, 14 were lost to follow-up, thus 53 completed the PFMT programme and undertook either one or both outcomes. Pre-treatment, severity on ICIQ correlated with total ITMQ (ρ = 0.33, P = 0.01). Post-treatment change in pad test was inversely correlated with Domain 2 (ρ = -0.33, P = 0.03). CONCLUSIONS: The pre-treatment severity of incontinence was significantly associated with motivation for treatment. Unfortunately, post-treatment change correlated with only one domain of the questionnaire. Further modification of the ITMQ is envisaged. Neurourol. Urodynam. 36:316-321, 2017. © 2015 Wiley Periodicals, Inc.

The Effect of Vaginal Oestriol Cream on Subjective and Objective Symptoms of Stress Urinary Incontinence and Vaginal Atrophy: An International Multi-Centre Pilot Study.

AIM: Subjectively and objectively assess stress urinary incontinence (SUI) symptoms before and after topical oestrogen therapy. METHODS: A prospective study was performed in 3 centres in South-Africa, Australia and the Netherlands. Postmenopausal women with SUI were treated with topical oestriol cream for 6 weeks. The primary subjective outcome was the Patient's Global Impression of Improvement (PGI-I) scale. The primary objective outcome was vaginal pH. Secondary subjective outcomes were: the International Consultation on Incontinence Questionnaire-Urinary Incontinence-Short Form, the Incontinence Impact Questionnaire, the Urogenital Distress Inventory (UDI-6) and the most bothersome symptom approach. Secondary objective outcome was the erect cough pad test. Compliance was scored. RESULTS: A total of 68 women were enrolled. Half of the participants reported improvement on the PGI-I scale after treatment. Vaginal pH was significantly lower after treatment (median 5.3 (interquartile range (IQR) 4.5-6.0) vs. 5.0 (4.4-5.4), p = 0.002). Improvement on the UDI stress domain was observed (p = 0.01). No statistically significant differences were found in the other subjective outcomes. Baseline and repeat cough pad tests demonstrated a wide variation with no significant difference. Compliance was high (median 100 (IQR 83-100%)). CONCLUSION: Topical oestriol cream during 6 weeks improved quality of life and vaginal pH but no other objective measures of incontinence.

The Leukemia Inhibitory Factor Receptor Gene Is a Direct Target of RUNX1.

Activation of cytokine signaling via the leukemia inhibitory factor receptor (LIFR) plays an integral role in hematopoiesis, osteogenesis, and placental development, along with mediating neurotrophic mechanisms. However, the regulatory control of the LIFR gene has remained largely unexplored. Here, we characterize the LIFR gene as a novel target of the RUNX1 transcription factor. The RUNX1 transcription factor is an essential regulator of hematopoiesis and is a frequent target of point mutations and chromosomal alterations in leukemia. RUNX1 regulates hematopoiesis through its control of genes important for hematopoietic cell growth, proliferation, and differentiation, including a number of cytokines and cytokine receptors. LIFR is regulated by two alternate promoters: a placental-specific and a ubiquitously active general promoter. We show that both of these promoters are regulated by RUNX1. However, in myeloid cells LIFR expression is driven solely by the general LIFR promoter with our data indicating that the placental promoter is epigenetically silenced in these cells. While RUNX1 activates the LIFR general promoter, the oncogenic RUNX1-ETO fusion protein generated by the t(8;21) translocation commonly associated with acute myeloid leukemia represses promoter activity. The data presented here establish LIFR as a transcriptional target of RUNX1 and suggest that disruption of RUNX1 activity in myeloid cells may result in altered LIFR signaling in these cells.

Pelvic floor dysfunction in female Sjögren's syndrome: an 8-year audit.

INTRODUCTION AND HYPOTHESIS: The classic triad of dry eyes, mouth and vagina is known to most gynaecologists as pathognomonic of Sjögren's syndrome, but rheumatologists seldom consider vaginal symptoms. Our hypothesis was that women with Sjögren's syndrome would have an increased likelihood of postoperative voiding dysfunction, severe vaginal stenosis or poor response to anticholinergics compared with the general urogynaecology patient. METHODS: All patients with Sjögren's syndrome were prospectively recorded from July 2007 to June 2015. Presenting complaint, pelvic examination findings, previous/subsequent pelvic surgery, voiding dysfunction and response to anticholinergics were noted. The denominator, all new urogynaecology patients, was prospectively recorded. RESULTS: Fifteen patients were identified over 8 years (0.5 % of 2794 new presentations). Of the seven patients who had previously undergone surgery elsewhere, all had demonstrable pelvic tissue fibrosis; five had such severe fibrosis that no speculum could be passed. Anticholinergic medications were completely intolerable in 10/11 (91 %) women, and severe postoperative voiding dysfunction occurred in 6/9 (67 %) women. Only 2/15 (13 %) women were unaffected by fibrosis, postoperative voiding dysfunction or intolerance to anticholinergics. CONCLUSIONS: This audit demonstrates a substantial risk of vaginal stenosis, postoperative voiding dysfunction or severe intolerance to anticholinergics in women with Sjögren's syndrome.

Objective efficacy of the tension-free vaginal tape in obese/morbidly obese women versus non-obese women, at median five year follow up.

BACKGROUND: One subjective long-term evaluation of the tension-free vaginal tape (TVT) success rate in obese women showed a worse prognosis in the obese, but objective studies have been limited to short-term follow-up (less than two years). AIM: To determine whether the long-term objective cure rate in obese/morbidly obese women who underwent TVT was reduced, compared to non-obese women (at five or more years). MATERIALS AND METHODS: Body mass index (BMI) was collected on patients undergoing TVT procedure. Recruited patients were asked to perform a 24 h pad test and complete an International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF) at five years postoperatively. Data was analyzed according to pre-operative urodynamic diagnoses and BMI, using 'routine' and 'strict' objective definitions of objective cure. RESULTS: At median follow-up of 64 months (interquartile range 58-80 months), 136 patients returned a pad test and ICIQ-SF. Using a routine definition of cure (pad test of ≤10 g in a 24 h period), 96% of patients were cured overall. The BMI results (n = 119 patients) were stratified into ≤25, 25.1-35 and ≥35.1 kg/m2 , which represented 41, 53 and 6% of patients, respectively. The routine cure rates for these three groups were 98, 97 and 71%, respectively (P = 0.004). CONCLUSION: Long-term objective outcomes of the TVT in morbidly obese women are significantly poorer than in women with a normal BMI.

Individualised pelvic floor muscle training in women with pelvic organ prolapse (POPPY): a multicentre randomised controlled trial.

BACKGROUND: Pelvic organ prolapse is common and is strongly associated with childbirth and increasing age. Women with prolapse are often advised to do pelvic floor muscle exercises, but evidence supporting the benefits of such exercises is scarce. We aimed to establish the effectiveness of one-to-one individualised pelvic floor muscle training for reducing prolapse symptoms. METHODS: We did a parallel-group, multicentre, randomised controlled trial at 23 centres in the UK, one in New Zealand, and one in Australia, between June 22, 2007, and April 9, 2010. Female outpatients with newly-diagnosed, symptomatic stage I, II, or III prolapse were randomly assigned (1:1), by remote computer allocation with minimsation, to receive an individualised programme of pelvic floor muscle training or a prolapse lifestyle advice leaflet and no muscle training (control group). Outcome assessors, and investigators who were gynaecologists at trial sites, were masked to group allocation; the statistician was masked until after data analysis. Our primary endpoint was participants' self-report of prolapse symptoms at 12 months. Analysis was by intention-to-treat analysis. This trial is registered, number ISRCTN35911035. FINDINGS: 447 eligible patients were randomised to the intervention group (n=225) or the control group (n=222). 377 (84%) participants completed follow-up for questionnaires at 6 months and 295 (66%) for questionnaires at 12 months. Women in the intervention group reported fewer prolapse symptoms (ie, a significantly greater reduction in the pelvic organ prolapse symptom score [POP-SS]) at 12 months than those in the control group (mean reduction in POP-SS from baseline 3.77 [SD 5.62] vs 2.09 [5.39]; adjusted difference 1.52, 95% CI 0.46-2.59; p=0.0053). Findings were robust to missing data. Eight adverse events (six vaginal symptoms, one case of back pain, and one case of abdominal pain) and one unexpected serious adverse event, all in women from the intervention group, were regarded as unrelated to the intervention or to participation in the study. INTERPRETATION: One-to-one pelvic floor muscle training for prolapse is effective for improvement of prolapse symptoms. Long-term benefits should be investigated, as should the effects in specific subgroups. FUNDING: Chief Scientist Office of the Scottish Government Health and Social Care Directorates, New Zealand Lottery Board, and National Health and Medical Research Council (Australia).

RNA-seq profiling of a radiation resistant and radiation sensitive prostate cancer cell line highlights opposing regulation of DNA repair and targets for radiosensitization.

BACKGROUND: Radiotherapy is a chosen treatment option for prostate cancer patients and while some tumours respond well, up to 50% of patients may experience tumour recurrence. Identification of functionally relevant predictive biomarkers for radioresponse in prostate cancer would enable radioresistant patients to be directed to more appropriate treatment options, avoiding the side-effects of radiotherapy. METHODS: Using an in vitro model to screen for novel biomarkers of radioresistance, transcriptome analysis of a radioresistant (PC-3) and radiosensitive (LNCaP) prostate cancer cell line was performed. Following pathway analysis candidate genes were validated using qRT-PCR. The DNA repair pathway in radioresistant PC-3 cells was then targeted for radiation sensitization using the PARP inhibitor, niacinimide. RESULTS: Opposing regulation of a DNA repair and replication pathway was observed between PC-3 and LNCaP cells from RNA-seq analysis. Candidate genes BRCA1, RAD51, FANCG, MCM7, CDC6 and ORC1 were identified as being significantly differentially regulated post-irradiation. qRT-PCR validation confirmed BRCA1, RAD51 and FANCG as being significantly differentially regulated at 24 hours post radiotherapy (p-value =0.003, 0.045 and 0.003 respectively). While the radiosensitive LNCaP cells down-regulated BRCA1, FANCG and RAD51, the radioresistant PC-3 cell line up-regulated these candidates to promote cell survival post-radiotherapy and a similar trend was observed for MCM7, CDC6 and ORC1. Inhibition of DNA repair using niacinamide sensitised the radioresistant cells to irradiation, reducing cell survival at 2 Gy from 66% to 44.3% (p-value =0.02). CONCLUSIONS: These findings suggest that the DNA repair candidates identified via RNA-seq hold potential as both targets for radiation sensitization and predictive biomarkers in prostate cancer.

What is the role of covert infection in detrusor overactivity, and other LUTD? ICI-RS 2013.

A think tank was convened at the fourth ICI-RS meeting, which took place June 5-7, 2013 in Bristol UK, to consider current evidence and controversies surrounding the possible role of 'covert infection' in the pathophysiology of refractory detrusor overactivity (DO) and other lower urinary tract disorders (LUTD). The topic was chosen because several authors from different centers worldwide have recently published evidence which supports this concept. However, to date there is inconsistency regarding terminology and microbiological definitions, which were discussed by the participants. The mechanisms whereby infection/inflammation could actually promote aberrant detrusor contractions in the human remain controversial, and are more fully described in this report. Future requirements for research into this topic were outlined.

Nine-year objective and subjective follow-up of the ultra-lateral anterior repair for cystocele.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to determine the long-term objective and subjective outcomes of the native tissue ultra-lateral anterior repair for cystocele. METHODS: An observational study of patients from a single tertiary centre was carried out from January 1994 to December 2006. Patients who underwent an ultra-lateral anterior repair during this period were sent the Pelvic Floor Distress Inventory (PFDI) questionnaire and invited to return for a POP-Q examination. Symptoms of prolapse, stage of cystocele recurrence and reoperation rate were assessed at follow-up. RESULTS: Of the 135 patients recruited, 53 also had a POP-Q examination. Mean follow-up was 9.25 years (SD 3.2). The anatomical recurrence rate was 45 % at 9.25 years, but only 26 % of patients had recurrent prolapse symptoms. Most recurrences (43 %) occurred at between 1 and 5 years. The reoperation rate for cystocele was 7.4 %. CONCLUSION: Despite these rates of anatomical and symptomatic recurrence, only 7.4 % of patients underwent repeat cystocele surgery. Thus, symptomatic/anatomical recurrence of prolapse often does not mandate surgical correction. Considering that mesh complications require surgical management in approximately 10­15 %, this study supports the notion that the use of mesh in anterior vaginal repairs to reduce the risk of "recurrence" needs careful discussion with each patient.

Recent studies of genetic dysfunction in pelvic organ prolapse: the role of collagen defects.

Gynaecologists are becoming increasingly aware that women with a family history of prolapse are at an increased risk of prolapse refractory to treatment. In the past five years, several genetic mutations have been shown to correlate with increased prolapse susceptibility. These mutations can result in disordered collagen metabolism, which weaken the fascial support of the pelvic organs. This review examines the contemporary evidence regarding the role of collagen in prolapse.

Change in microbiota profile after vaginal estriol cream in postmenopausal women with stress incontinence.

Introduction: Vaginal estrogen is a treatment for genitourinary symptoms of menopause (GSM), which comprises vaginal atrophy and urinary dysfunction, including incontinence. Previous studies show that estrogen therapy promotes lactobacilli abundance and is associated with reduced GSM symptoms, including reduction of stress incontinence. However, detailed longitudinal studies that characterize how the microbiome changes in response to estrogen are scarce. We aimed to compare the vaginal microbiota of postmenopausal women, before and 12 weeks after vaginal estrogen cream. Methods: A total of 44 paired samples from 22 postmenopausal women with vaginal atrophy and stress incontinence were collected pre-vaginal estrogens and were compared to 12 weeks post-vaginal estrogen. Microbiota was characterized by 16S rRNA amplicon sequencing and biodiversity was investigated by comparing the alpha- and beta-diversity and potential markers were identified using differential abundance analysis. Results: Vaginal estrogen treatment was associated with a reduction in vaginal pH and corresponded with a significant reduction in alpha diversity of the microbiota. Healthy vaginal community state type was associated with lower mean pH 4.89 (SD = 0.6), in contrast to dysbiotic state which had a higher mean pH 6.4 (SD = 0.74). Women with lactobacilli dominant community pre-treatment, showed stable microbiota and minimal change in their pH. Women with lactobacilli deficient microbiome pre-treatment improved markedly (p = 0.004) with decrease in pH -1.31 and change to heathier community state types. Conclusion: In postmenopausal women with stress incontinence, vaginal estrogen promotes Lactobacillus and Bifidobacterium growth and lowers vaginal pH. Maximum response is seen in those with a dysbiotic vaginal microbiota pre-treatment.