Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion.

We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of N-myristoyl transferase (NMT), led to a significant blockade in parasite egress from the infected erythrocyte. Two rhoptry proteins were mislocalized in the cell, suggesting that rhoptry function is disrupted. We identified 16 NMT substrates for which myristoylation was significantly reduced by NMT inhibitor (NMTi) treatment, and, of these, 6 proteins were substantially reduced in abundance. In a viability screen, we showed that for 4 of these proteins replacement of the N-terminal glycine with alanine to prevent myristoylation had a substantial effect on parasite fitness. In detailed studies of one NMT substrate, glideosome-associated protein 45 (GAP45), loss of myristoylation had no impact on protein location or glideosome assembly, in contrast to the disruption caused by GAP45 gene deletion, but GAP45 myristoylation was essential for erythrocyte invasion. Therefore, there are at least 3 mechanisms by which inhibition of NMT can disrupt parasite development and growth: early in parasite development, leading to the inhibition of schizogony and formation of "pseudoschizonts," which has been described previously; at the end of schizogony, with disruption of rhoptry formation, merozoite development and egress from the infected erythrocyte; and at invasion, when impairment of motor complex function prevents invasion of new erythrocytes. These results underline the importance of P. falciparum NMT as a drug target because of the pleiotropic effect of its inhibition.

A prospective study to assess the effectiveness and safety of the BlueWind System in the treatment of patients diagnosed with urgency urinary incontinence.

BACKGROUND: Overactive bladder (OAB) affects one in six adults in Europe and the United States and impairs the quality of life of millions of individuals worldwide. When conservative management fails, third-line treatments including tibial neuromodulation (TNM) is often pursued. TNM has traditionally been accomplished percutaneously in clinic. OBJECTIVE: A minimally invasive implantable device activated by a battery-operated external wearable unit has been developed for the treatment of urgency urinary incontinence (UUI), mitigating the burden of frequent clinic visits and more invasive therapies that are currently commercially available. METHODS: A prospective, multicenter, single-arm, open-label, pivotal study evaluated the safety and effectiveness of the device in adult females with UUI (i.e., wet OAB) (BlueWind Implantable Tibial Neuromodulation [iTNM] system; IDE number #G200013; NCT03596671). Results with the device were previously published under the name RENOVA iStim, which has been since renamed as the Revi™ System. Approximately 1-month post-implantation of the device, participants delivered therapy at their convenience and completed a 7-day voiding diary before visits 6- and 12-months post-treatment initiation. The primary efficacy and safety endpoints were the proportion of responders to therapy ( ≥ 50% improvement on average number of urgency-related incontinence episodes) and incidence of adverse events from implantation to 12-month post-activation. RESULTS: A total of 151 participants, mean age 58.8 (SD: 12.5), were implanted; 144 and 140 completed the 6- and 12-month visits, respectively. The participants demonstrated mean baseline of 4.8 UUI/day (SD 2.9) and 10 voids/day (SD 3.3). Six and 12-months post-activation, 76.4% and 78.4% of participants, respectively, were responders to therapy in an intent-to-treat analysis. Of the 139 participants with completed 12-month diaries, 82% were responders, 50% were classified as "dry" (on at least 3 consecutive diary days), and 93.5% of participants reported that their symptoms improved. No implanted participant experienced an SAE related to the procedure or device. CONCLUSIONS: iTNM, delivered and powered by a patient-controlled external wearable communicating with an implant, demonstrated clinically meaningful and statistically significant improvement in UUI symptoms and a high safety profile. This therapy highlights the value of patient-centric therapy for the treatment of UUI.

Monofilament suture versus braided suture thread to improve pregnancy outcomes after vaginal cervical cerclage (C-STICH): a pragmatic randomised, controlled, phase 3, superiority trial.

BACKGROUND: Miscarriage in the second trimester and preterm birth are significant global problems. Vaginal cervical cerclage is performed to prevent pregnancy loss and preterm birth. We aimed to determine the effectiveness of a monofilament suture thread compared with braided suture thread on pregnancy loss rates in women undergoing a cervical cerclage. METHODS: C-STICH was a pragmatic, randomised, controlled, superiority trial done at 75 obstetric units in the UK. Women with a singleton pregnancy who received a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were centrally randomised (1:1) using minimisation to receive a monofilament suture or braided suture thread for their cervical cerclage. Women and outcome assessors were masked to allocation as far as possible. The primary outcome was pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life, analysed in the intention-to-treat population (ie, all women who were randomly assigned). Safety was also assessed in the intention-to-treat population. The trial was registered with ISRCTN, ISRCTN15373349. FINDINGS: Between Aug 21, 2015, and Jan 28, 2021, 2049 women were randomly assigned to receive a monofilament suture (n=1025) or braided suture (n=1024). The primary outcome was ascertained in 1003 women in the monofilament suture group and 993 women in the braided suture group. Pregnancy loss occurred in 80 (8·0%) of 1003 women in the monofilament suture group and 75 (7·6%) of 993 women in the braided suture group (adjusted risk ratio 1·05 [95% CI 0·79 to 1·40]; adjusted risk difference 0·002 [95% CI -0·02 to 0·03]). INTERPRETATION: Monofilament suture did not reduce rate of pregnancy loss when compared with a braided suture. Clinicians should use the results of this trial to facilitate discussions around the choice of suture thread to optimise outcomes. FUNDING: National Institute of Health Research Health Technology Assessment Programme.

Anal incontinence following obstetric anal sphincter injury: Is there a difference between subtypes? A systematic review.

AIMS: Obstetric anal sphincter injury (OASI) is associated with long-term anal incontinence (AI). We aimed to address the following questions: (a) are women with major OASI (grade 3c and 4) at higher risk of developing AI when compared to women with minor OASI (grade 3a and 3b)? (b) is a fourth-degree tear more likely to cause AI over a third-degree tear? METHODS: A systematic literature search from inception until September 2022. We considered prospective and retrospective cohort studies, cross-sectional and case-control studies without language restrictions. The quality was assessed by the Newcastle-Ottawa Scale and the Joanna Briggs Institute critical appraisal checklist. Risk ratios (RRs) were calculated to measure the effect of different grades of OASI. RESULTS: Out of 22 studies, 8 were prospective cohort, 8 were retrospective cohort, and 6 were cross-sectional studies. Length of follow-up ranged from 1 month to 23 years, with the majority of the reports (n = 16) analysing data within 12-months postpartum. Third-degree tears evaluated were 6454 versus 764 fourth-degree tears. The risk of bias was low in 3, medium in 14 and high in 5 studies, respectively. Prospective studies showed that major tears are associated with a twofold risk of AI for major tears versus minor tears, while retrospective studies consistently showed a risk of fecal incontinence (FI) which was two- to fourfold higher. Prospective studies showed a trend toward worsening AI symptoms for fourth-degree tears, but this failed to reach statistical significance. Cross-sectional studies with long-term (≥5 years) follow-up showed that women with fourth-degree tear were more likely to develop AI, with an RR ranging from 1.4 to 2.2. Out of 3, 2 retrospective studies showed similar findings, but the follow-up was significantly shorter (≤1 year). Contrasting results were noted for FI rates, as only 5 out of 10 studies supported an association between fourth-degree tear and FI. CONCLUSIONS: Most studies investigate bowel symptoms within few months from delivery. Data heterogeneity hindered a meaningful synthesis. Prospective cohort studies with adequate power and long-term follow-up should be performed to evaluate the risk of AI for each OASI subtype.

Can we increase the value of data from bladder diaries? International Consultation on Incontinence-Research Society 2023.

BACKGROUND: Bladder diaries represent a fundamental component in the assessment of patients presenting with lower urinary tract symptoms. Nevertheless, their importance often remains underappreciated and undervalued within clinical practice. This paper aims to conduct a comprehensive review of the existing literature concerning the utility of bladder diaries, underscore the criticality of their precision, elucidate the factors contributing to noncompliance with bladder diary completion, and investigate potential strategies for enhancing patient compliance. MATERIALS AND METHODS: A review of the English-language scientific literature available in the domains of Medline, Embase, Emcare, Midirs, and Cinahl was conducted. This was supplemented by discussion at the International Consultation on Incontinence Research Society Proposal session to define knowledge and identify gaps in knowledge surrounding the utility of bladder diaries. The existing evidence and outcome of the relevant discussion held in the meeting are presented. RESULTS: Bladder diaries (BD) serve to characterize the nature and severity of storage lower urinary tract symptoms (LUTS) and provide an objective record of an individual's urination patterns. They aid in the refinement and customization of treatment strategies based on the clinical responses documented in the diary, optimizing treatment outcomes. Notably, both BD and urodynamic studies (UDS) play complementary yet distinct roles in LUTS evaluation. BD offers a more comprehensive and accessible approach to assessing specific storage LUTS, particularly due to their affordability and widespread availability, especially in resource-limited settings. Nevertheless, the absence of a standardized BD format across global healthcare systems presents a significant challenge. Despite being recognized as reliable, noninvasive, validated, and cost-effective tools for evaluating patients with LUTS, the implementation and completion of BD have proven to be complex. The introduction of automated bladder diaries heralds an era of precise, real-time data collection, potentially enhancing the patient-clinician relationship. Completion of bladder diaries depends on an array of individual, social, and healthcare-specific factors. Compliance with bladder diary completion could be enhanced with clear instructions, patient education, regular follow-ups and positive re-enforcement. This study has identified four critical areas for future research: Addressing healthcare disparities between affluent and developing nations, enhancing the current functionality and effectiveness of bladder diaries, exploring the feasibility of incorporating bladder diaries into the treatment and education process and improving the quality and functionality of existing bladder diaries. CONCLUSION: Bladder diaries play a pivotal role in the evaluation and management of patients with LUTS, providing a holistic perspective. When their complete potential is harnessed, they have the capacity to revolutionize the paradigm of LUTS management, ushering in a patient-centered era of care.

International urogynecological consultation chapter 4.1: definition of outcomes for pelvic organ prolapse surgery.

INTRODUCTION AND HYPOTHESIS: This manuscript of Chapter 4 of the International Urogynecological Consultation (IUC) on Pelvic Organ Prolapse (POP) reviews the literature and makes recommendations on the definition of success in the surgical treatment of pelvic organ prolapse. METHODS: An international group containing seven urogynecologists performed an exhaustive search of the literature using two PubMed searches and using PICO methodology. The first search was from 01/01/2012-06/12/2022. A second search from inception to 7/24/2022 was done to access older references. Publications were eliminated if not relevant to the clinical definition of surgical success for the treatment of POP. All abstracts were reviewed for inclusion and any disagreements were adjudicated by majority consensus of the writing group. The resulting list of articles were used to inform a comprehensive review and creation of the definition of success in the surgical treatment of POP. OUTCOMES: The original search yielded 12,161 references of which 45 were used by the writing group. Ultimately, 68 references are included in the manuscript. For research purposes, surgical success should be primarily defined by the absence of bothersome patient bulge symptoms or retreatment for POP and a time frame of at least 12 months follow-up should be used. Secondary outcomes, including anatomic measures of POP and related pelvic floor symptoms, should not contribute to a definition of success or failure. For clinical practice, surgical success should primarily be defined as the absence of bothersome patient bulge symptoms. Surgeons may consider using PASS (patient acceptable symptom state) or patient goal attainment assessments, and patients should be followed for a minimum of at least one encounter at 6-12 weeks post-operatively. For surgeries involving mesh longer-term follow-up is recommended.

Laser treatment for genitourinary syndrome of menopause: Scientific Impact Paper No. 72 (July 2022): Scientific Impact Paper No. 72 (July 2022).

Genitourinary syndrome of menopause (GSM) is the term used to describe the group of symptoms including vaginal pain, vaginal dryness, itching, pain during sexual intercourse and fragile vaginal tissues as well as urinary symptoms including urinary frequency, urgency, incontinence, blood in the urine (haematuria) and recurrent urinary tract infections that occur due to a lack of the hormone estrogen. These symptoms can have a significant negative impact on psychosexual issues, sexual function and quality of life in postmenopausal women. Traditionally women have been treated with vaginal lubricants, vaginal moisturisers or low-dose vaginal estrogens. Lasers have been used in the cosmetic industry for collagen remodelling and repair of the skin. Therefore, it has been suggested that laser therapy may be used on the vagina as an alternative treatment for GSM. A review of all the published studies assessing the safety and efficacy of laser therapy for GSM have shown promising beneficial results. The majority of studies to date have been small, short-term, observational studies. However, there are randomised controlled trials underway. Laser treatment may be beneficial for the symptoms of GSM but until more robust evidence is available it should not be adopted into widespread practice, and should be used as part of a research study only.

Adapting to the Coronavirus Pandemic: Building and Incorporating a Diagnostic Pipeline in a Shared Resource Laboratory.

In March 2020, with lockdown due to the coronavirus pandemic underway, the Francis Crick Institute (the Crick) regeared its research laboratories into clinical testing facilities. Two pipelines were established, one for polymerase chain reaction and the other for Serology. This article discusses the Cricks Flow Cytometry Science Technology Platform (Flow STP) role in setting up the Serology pipeline. Pipeline here referring to the overarching processes in place to facilitate the receipt of human sera through to a SARs-CoV-2 enzyme-linked immunosorbent assay result. We examine the challenges that had to be overcome by a research laboratory to incorporate clinical diagnostics and the processes by which this was achieved. It describes the governance required to run the service, the design of the standard operating procedures (SOPs) and pipeline, the setting up of the assay, the validation required to show the robustness of the pipeline and reporting the results of the assay. Finally, as the lockdown started to ease in June 2020, it examines how this new service affects the daily running of the Flow STP. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.

Defining nocturnal polyuria in women.

AIMS: Nocturnal polyuria (NP) is defined by the International Continence Society (ICS) as "excessive production of urine during the main sleep period" and is one of the main causes of nocturia. The ICS recognized that "excessive" is not clearly defined and that this needs to be highlighted in both clinical and research settings. The aim of this study was to identify different definitions of NP and apply them to a population of women attending the Urogynaecology clinic. METHODS: This was a retrospective study of complete bladder diaries collected from women attending a tertiary Urogynaecology Unit. Six different definitions were identified and were divided into "absolute," "relative," and "functional definitions." Prevalence data were calculated and values generated for sensitivity, specificity, positive and negative predictive values when related to women voiding ≥ 2 times per night. RESULTS: Complete bladder diaries were obtained from 1398 women, over 6 years, with a mean age of 57 years. Prevalence varied across the definitions from 21.5% (absolute definition) to 77% (relative definition). Sensitivity ranged from 43% (absolute) to 87% (relative). The definitions that showed the highest combined sensitivity and specificity were the functional definitions. CONCLUSION: From this study it is clear that more work needs to be done to arrive at a consensus for defining NP to enable accurate diagnosis and development of treatment pathways. We propose that a relative definition may provide a more clinically relevant method of defining NP.

Making a decision about surgery for female urinary incontinence: a qualitative study of women's views.

INTRODUCTION AND HYPOTHESIS: This qualitative interview study explores aspects women with urinary incontinence(UI) reflect upon when considering whether or not to have surgery. Conducted prior to the recent mesh pause in the UK, the article provides insights for current and future approaches to shared decision-making. METHODS: Qualitative in-depth interviews of 28 patients referred to secondary care for stress and mixed UI who were considering UI surgery. Participants were recruited from four urogynaecology clinics in the Midlands and South England, UK. Interviews were conducted in clinics, in patient homes, and by telephone. Data analysis was based on the constant comparative method. RESULTS: Participants' accounts comprised three key concerns: their experience of symptoms, the extent to which these impacted a variety of social roles and demands, and overcoming embarrassment. Accounts drew on individual circumstances, values, and concerns rather than objective or measurable criteria. In combination, these dimensions constituted a personal assessment of the severity of their UI and hence framed the extent to which women prioritized addressing their condition. CONCLUSIONS: Acknowledging women's personal accounts of UI shifts the concept of 'severity' beyond a medical definition to include what is important to patients themselves. Decision-making around elective surgery must endeavour to link medical information with women's own experiences and personal criteria, which often change in priority over time. We propose that this research provides insight into how the controversy around the use of mesh in the UK emerged. This study also suggests ways in which facilitating shared decision-making should be conducted in future.

Minimum standards for reporting outcomes of surgery in urogynaecology.

INTRODUCTION AND HYPOTHESIS: The IUGA special interest group (SIG) identified a need for a minimum data set (MDS) to inform outcome measurements to be included and simplify data capture and standardise reporting for data collection systems. To define a minimum data set for urogynaecological surgical registries. METHODS: Existing registries provide an inventory of items. A modified Delphi approach was used to identify a MDS. At each stage reviewers ranked data points and used free text to comment. The rating used a scale of 0-10 at each review and a traffic light system rated the scores as desirable, highly desirable and mandatory. The scores were collated and reported back to clinicians prior to the further rounds. Outliers were highlighted and reviewers re-assessed prior to repeating the process. A comparison of the MDS was made with published outcomes. RESULTS: Reviewers were from the outcome SIG with emphasis on widespread representation. Fifteen clinicians from eight countries were involved. Four reviewers dissected the existing databases. Eighty data points were considered in four categories, background, preoperative, intraoperative and postoperative. Consensus was reached by the third round. Two points were added on review (date of surgery and urodynamics). Three background points, five preoperative points, seven intraoperative points and nine postoperative points were identified giving 24 minimum data points in the final recommendation. CONCLUSIONS: An MDS has been developed for urogynaecological surgical registries. These should be mandatory points which then allow larger varying points to be assessed. These points correspond well to data points used in published papers from established databases.

Botulinum injections for myofascial pelvic pain.

INTRODUCTION AND HYPOTHESIS: The aim of this study was to assess the impact of botulinum toxin injection in women with myofascial pelvic pain (MFPP) syndrome of the pelvic floor who had failed conservative treatment. METHODS: This was a retrospective descriptive observational study of 48 consecutive patients receiving botulinum toxin to the pelvic floor for MFPP syndrome in a tertiary teaching hospital over an 8-year period. Trigger points were identified, and botulinum toxin was injected into the pelvic floor at the trigger points in doses ranging from 50 to 200 units. The patient-reported global impression of improvement scale was used to evaluate the success at follow-up, and adverse effects were recorded. RESULTS: Forty-six women attended for follow-up at 3-6 months. Of these, 34 (74%) reported an improvement in their symptoms (slightly better, much better, very much better), 12 (26%) had no change, and no patients reported worsening of symptoms. One patient (2%) reported transient postoperative faecal incontinence, which resolved after 2 weeks. There appeared to be no difference in outcome between the doses. CONCLUSIONS: Botulinum toxin injection into the pelvic floor of women with MFPP appears to be beneficial in those who have failed conservative treatment. Prospective studies, including dose-finding studies, are now required.

Variation in surgical treatment advice for women with stress urinary incontinence: a study using clinical case vignettes.

INTRODUCTION: The aim of this study was to determine how recommendations of gynaecologists on surgical treatment for stress urinary incontinence (SUI) were influenced by patient characteristics. METHODS: Two hundred forty-five gynaecologists in the UK fully responded to an online questionnaire including 18 vignettes describing 7 clinical characteristics of women with SUI (age, body mass index, SUI type, previous SUI surgery, frequency of leakage, bother, physical status). The gynaecologists scored recommendations for surgery ranging from 1 'certainly not' to 5 'certainly yes'. Mean scores were used to calculate the relative impact ('weight') of each clinical characteristic. Latent class analysis was used to distinguish groups of gynaecologists with a particular practice style because they responded to the patient characteristics captured in the case vignettes in a similar way. RESULTS: The gynaecologists' overall average recommendation score was 2.9 (interquartile range 2 to 4). All patient characteristics significantly influenced the recommendation scores (p always < 0.001) but their impact was relatively small. SUI type was most important (weight 23%), followed by previous SUI surgery (weight 21%). Latent class analysis identified five groups of gynaecologists with practice styles that differed mainly with respect to their mean recommendation score, ranging from 1.3 to 4.0. CONCLUSIONS: Surgical treatment advice in response to case vignettes was only minimally influenced by patient characteristics. There were five groups of gynaecologists whose inclination to recommend surgical treatment varied. This suggests that there is lack of consensus on the role of surgery as a treatment for SUI. A considerable number of gynaecologists were reluctant to recommend surgery.

The effect of body mass index on retropubic midurethral slings.

BACKGROUND: Analyzing surgical databases uses "real-life" outcomes rather than highly selected cases from randomized controlled trials. Retropubic midurethral slings are a highly effective surgical treatment for stress urinary incontinence; however, if modifiable patient characteristics alter outcomes, thereby rendering treatments less effective, patients should be informed and given the opportunity to change that characteristic. OBJECTIVE: The aim of this study was to evaluate the effect of body mass index on patient-reported outcome measures by analyzing midurethral slings from the British Society of Urogynaecology database. MATERIALS AND METHODS: The British Society of Urogynaecology approved analysis of 11,859 anonymized midurethral slings from 2007 to 2016. The primary outcome of this retrospective cohort study was to assess how body mass index affects patient-reported outcome measures. Outcomes were assessed at 6 weeks, 3 months, 6 months, or 12 months after surgery, depending on local arrangements. Outcomes were compared by body mass index groups using χ2 tests. RESULTS: As BMI increased, Patient Global Impression of Improvement (PGI-I) scores declined. Women with a normal body mass index (18 to <25) reported feeling better in 91.6% of cases compared to lower rates in BMI groups >30 (87.7-72%) (P < .001). Patient-reported outcome measures for stress urinary incontinence inversely correlated with body mass index, with 97% of women with normal body mass index stating that they were cured/improved compared to women in higher body mass index groups (84-94%) reporting lower rates (P < .005). Patient-reported outcome measures for overactive bladder show that as body mass index increases, patients reported higher rates of worsening symptoms (P < .05). There were higher rates of perforation at the low and high extremes of body mass index. CONCLUSION: Our results suggest increased body mass index is associated with poorer outcomes after midurethral sling surgery, and that patients should be given the opportunity to change their body mass index. These data could help to develop a model to predict personalized success and complication rates, which may improve shared decision making and give an impetus to modify characteristics to improve outcomes.

International Consultation on Incontinence 2016; Executive summary: Urodynamic testing.

AIMS: The International Consultation on Incontinence has published an update of the recommendations for the diagnosis and management of urine incontinence (ICI2016). This manuscript summarizes the consultations committee-recommendations with regard to urodynamic assessment. METHODS: Expert consensus on the basis of structured evidence assessment has been the basis of the consultations publication and has been summarized by the committee for this manuscript. RESULTS: Patients that are not satisfied with their initial management on the basis of their reported signs and symptoms of urinary incontinence, as well as all patients with neurological abnormalities that are potentially relevant for the function of the lower urinary tract, may very likely profit from objective diagnosis and staging and grading of their dysfunction, with urodynamic testing, regardless their age, vulnerability and/or comorbidities. The principles and technical innovations as well as the principal recommendations for the utilization of (invasive) urodynamic assessment for women, men, children, and vulnerable elderly, with or without neurogenic lower urinary tract dysfunction with urinary incontinence are provided in this abbreviated ICI recommendations-document. CONCLUSIONS: The ICI2016 committee on urodynamics presents an executive summary of the most important reasons and recommendations for the use of urodynamic investigations for patients with urinary incontinence.

Pelvic floor muscle training for secondary prevention of pelvic organ prolapse (PREVPROL): a multicentre randomised controlled trial.

BACKGROUND: Pelvic floor muscle training can reduce prolapse severity and symptoms in women seeking treatment. We aimed to assess whether this intervention could also be effective in secondary prevention of prolapse and the need for future treatment. METHODS: We did this multicentre, parallel-group, randomised controlled trial at three centres in New Zealand and the UK. Women from a longitudinal study of pelvic floor function after childbirth were potentially eligible for inclusion. Women of any age who had stage 1-3 prolapse, but had not sought treatment, were randomly assigned (1:1), via remote computer allocation, to receive either one-to-one pelvic floor muscle training (five physiotherapy appointments over 16 weeks, and annual review) plus Pilates-based pelvic floor muscle training classes and a DVD for home use (intervention group), or a prolapse lifestyle advice leaflet (control group). Randomisation was minimised by centre, parity (three or less vs more than three deliveries), prolapse stage (above the hymen vs at or beyond the hymen), and delivery method (any vaginal vs all caesarean sections). Women and intervention physiotherapists could not be masked to group allocation, but allocation was masked from data entry researchers and from the trial statistician until after database lock. The primary outcome was self-reported prolapse symptoms (Pelvic Organ Prolapse Symptom Score [POP-SS]) at 2 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01171846. FINDINGS: Between Dec 21, 2008, and Feb 24, 2010, in New Zealand, and Oct 27, 2010, and Sept 5, 2011, in the UK, we randomly assigned 414 women to the intervention group (n=207) or the control group (n=207). One participant in each group was excluded after randomisation, leaving 412 women for analysis. At baseline, 399 (97%) women had prolapse above or at the level of the hymen. The mean POP-SS score at 2 years was 3·2 (SD 3·4) in the intervention group versus 4·2 (SD 4·4) in the control group (adjusted mean difference -1·01, 95% CI -1·70 to -0·33; p=0·004). The mean symptom score stayed similar across time points in the control group, but decreased in the intervention group. Three adverse events were reported, all of which were in the intervention group (one women had a fall, one woman had a pain in her tail bone, and one woman had chest pain and shortness of breath). INTERPRETATION: Our study shows that pelvic floor muscle training leads to a small, but probably important, reduction in prolapse symptoms. This finding will be important for women and caregivers considering preventive strategies. FUNDING: Wellbeing of Women charity, the New Zealand Continence Association, and the Dean's Bequest Fund of Dunedin School of Medicine.

Indirect treatment comparison (ITC) of medical therapies for an overactive bladder.

BACKGROUND: Overactive bladder syndrome (OAB) is a chronic and prevalent condition which has a negative impact on Quality of Life. The National Institute of Clinical Excellence issued two documents which give slightly varying algorithms of pharmacotherapy for OAB, offering mirabegron as a possible treatment in certain circumstances. In the absence of trials involving a direct comparison of therapies, an indirect comparison can provide useful information on the difference in treatment effects between competing interventions. OBJECTIVE: To compare effectiveness of available medical therapies for OAB using Bucher indirect treatment comparison (ITC) model. METHODS: A systematic literature search identified randomised controlled trials (RCT) assessing effectiveness of drugs for OAB versus placebo. Then indirect comparisons of the treatments effects were made, preserving the randomisation of the originally assigned patient groups, using Bucher method. MAIN RESULTS: 25 RCTs met inclusion criteria. In keeping with ITC method validity, four assessments were undertaken of mirabegron against anticholinergics, which were number of incontinence episodes, micturition episodes, urgency episodes in 24 h and volume of micturition. This indirect treatment analysis suggests that mirabegron is as effective as anticholinergics in managing of OAB, except for solifenacin which appears to be superior. CONCLUSIONS: These findings suggest that work looking into treatment choice should be individualized to patient characteristics rather than fitting patients to a treatment. Further work is required to identify what patient characteristics may be crucial and indicate that studies exploring the most effective sequence of managing treatment naïve patients and those with refractory disease.