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Objective: To investigate pelvic floor dysfunction (PFD; urinary incontinence (UI), faecal incontinence (FI) and prolapse) ≥20 years after childbirth and their association with delivery mode history and demographic characteristics. Design: Cohort study with long‐term follow‐up. Setting: Maternity units in Aberdeen and Birmingham (UK) and Dunedin (NZ). Population: Women giving birth in 1993/1994. Methods: Postal questionnaires at 20 (New Zealand) or 26 (United Kingdom) years after index birth (n = 6195). Regression analyses investigated associations between risk factors and UI, FI and prolapse symptoms. Main Outcome Measures: Prevalence of self‐reported UI, FI, 'something coming down' from or in the vagina (SCD), and the Pelvic Organ Prolapse‐Symptom Score, and relationships with delivery method. Results: Thirty‐seven per cent (n = 2270) responded at 20/26 years, of whom 61% reported UI (59% of whom reported more severe UI), 22% FI and 17% prolapse symptoms. Having only caesarean section (CS) was associated with a significantly lower risk of UI (OR 0.63, 95% CI 0.46–0.85), FI (OR 0.63, 95% CI 0.42–0.96) and SCD (OR 0.44, 95% CI 0.27–0.74) compared to only spontaneous vaginal deliveries (SVDs). Having any forceps delivery was associated with reporting FI compared to only SVDs (OR 1.29, 95% CI 1.00–1.66), but there was no association for UI (OR 0.95, 95% CI 0.76–1.19) or SCD (OR 1.05, 95% CI 0.80–1.38). Higher current BMI was associated with all PFD outcomes. Conclusions: Prevalence of PFD continues to increase up to 26 years following index birth, and differences were observed according to delivery mode history. Exclusive CS was associated with less risk of UI, FI and any prolapse symptoms. [ABSTRACT FROM AUTHOR]

Objective: To compare standard (native tissue) repair with synthetic mesh inlays or mesh kits.Design: Randomised controlled trial.Setting: Thirty-three UK hospitals.Population: Women having surgery for recurrent prolapse.Methods: Women recruited using remote randomisation.Main Outcome Measures: Prolapse symptoms, condition-specific quality-of-life and serious adverse effects.Results: A Mean Pelvic Organ Prolapse Symptom Score at 1 year was similar for each comparison (standard 6.6 versus mesh inlay 6.1, mean difference [MD] -0.41, 95% CI -2.92 to 2.11: standard 6.6 versus mesh kit 5.9, MD -1.21 , 95% CI -4.13 to 1.72) but the confidence intervals did not exclude a minimally important clinical difference. There was no evidence of difference in any other outcome measure at 1 or 2 years. Serious adverse events, excluding mesh exposure, were similar at 1 year (standard 7/55 [13%] versus mesh inlay 5/52 [10%], risk ratio [RR] 1.05 [0.66-1.68]: standard 3/25 [12%] versus mesh kit 3/46 [7%], RR 0.49 [0.11-2.16]). Cumulative mesh exposure rates over 2 years were 7/52 (13%) in the mesh inlay arm, of whom four women required surgical revision; and 4/46 in the mesh kit arm (9%), of whom two required surgical revision.Conclusions: We did not find evidence of a difference in terms of prolapse symptoms from the use of mesh inlays or mesh kits in women undergoing repeat prolapse surgery. Although the sample size was too small to be conclusive, the results provide a substantive contribution to future meta-analysis.Tweetable Abstract: There is not enough evidence to support use of synthetic mesh inlay or mesh kits for repeat prolapse surgery. [ABSTRACT FROM AUTHOR]

Bridge phases associated with a phase transition between two liquid phases occur when a two-component liquid mixture is confined between chemically patterned walls. In the bulk the liquid mixture with components A, B undergoes phase separation into an A-rich phase and a B-rich phase. The walls bear stripes attractive to A. In the bridge phase A-rich and B-rich regions alternate. Grand canonical Monte Carlo studies are performed with the alignment between stripes on opposite walls varied. Misalignment of the stripes places the nanoscopic liquid bridges under shear strain. The bridges exert a Hookean restoring force on the walls for small displacements from equilibrium. As the strain increases there are deviations from Hooke's law. Eventually there is an abrupt yielding of the bridges. Molecular dynamics simulations show the bridges form or disintegrate on time scales which are fast compared to wall motion and transport of molecules into or from the confined space. Some interesting possible applications of the phenomena are discussed. [ABSTRACT FROM AUTHOR]

Development of the Soil Pattern As an outcome of an ecological reconnaissance this account provides a record of the occurrences of two major regional types, a system of consolidated sand dunes and derived sands, referred to here as the Chestnut Sands, and a wide assortment of stony truncated 'desert pavement' soils or soil remnants described as Stone Mantles. The latter involve areas both of basement complex and of lava origin. Briefer observations are also given on other soils of lesser extent, including flash-flood, alluvial and lacustrine deposits. Although a present-day desert or semi-desert, the south Turkana region bears the stamp of successive erosion cycles, which have largely influenced its soil pattern. Modified remnants of the original end-Tertiary surface are probably discernible in the higher-lying stone mantles about the central hill ranges (Section 2, Introd.). Residual stone mantles of this class appear to be the last truncated remnants of an ancient soil cover. Ancient alluvial and lacustrine deposits, the former of conjectured and the latter of established Pleistocene age, have provided the material for other stone mantle areas (Section 2 ( b)). The present surface of all these has been affected by more recent erosion and deflation. On top of these several types of stone mantle, or the stony soils from which they originated, seems to have been deposited the deep mantle of the Chestnut Sands, blanketing at one time the greater part of the Turkana plain. These dune sands are regarded as a mainly aeolian drift, deposited during a period of active arid erosion, though their materials may have been derived from older surfaces (Section I, Introd.). They must be subsequent to the deposits which they overlie, and may possibly be compared with the Goz or Kordofan Sands of the Sudan, which have been very tentatively referred to the late Pleistocene (Andrew, 1948). As with the Goz Sands, the dunes of the Chestnut Sands presumably became fixed under less arid conditions. Finally, in common with the rest of the Turkanalandscape, they have been subjected to the present régime of brief seasonal flash-flood erosion and intervening wind action. Their formerly extensive dune structure has been greatly modified and from many areas they appear to have been removed wholesale. The redeposited Chestnut Sands, the flash-flood deposits and sandy riverine alluvia are the outcome of this latest phase of erosion. At the same time tracts of comparatively recent lacustrine sands and possible deltaic silts (Section 4 ( b) have been left in the east of the region as a result of the progressive retreat of Lake Rudolf. The influence of the resulting soil pattern on the vegetation of the region is very briefly indicated, with reference more particularly to the principal shrub components. [ABSTRACT FROM AUTHOR]

Objective: To investigate pelvic floor dysfunction (PFD; urinary incontinence (UI), faecal incontinence (FI) and prolapse) ≥20 years after childbirth and their association with delivery mode history and demographic characteristics., Design: Cohort study with long-term follow-up., Setting: Maternity units in Aberdeen and Birmingham (UK) and Dunedin (NZ)., Population: Women giving birth in 1993/1994., Methods: Postal questionnaires at 20 (New Zealand) or 26 (United Kingdom) years after index birth (n = 6195). Regression analyses investigated associations between risk factors and UI, FI and prolapse symptoms., Main Outcome Measures: Prevalence of self-reported UI, FI, 'something coming down' from or in the vagina (SCD), and the Pelvic Organ Prolapse-Symptom Score, and relationships with delivery method., Results: Thirty-seven per cent (n = 2270) responded at 20/26 years, of whom 61% reported UI (59% of whom reported more severe UI), 22% FI and 17% prolapse symptoms. Having only caesarean section (CS) was associated with a significantly lower risk of UI (OR 0.63, 95% CI 0.46-0.85), FI (OR 0.63, 95% CI 0.42-0.96) and SCD (OR 0.44, 95% CI 0.27-0.74) compared to only spontaneous vaginal deliveries (SVDs). Having any forceps delivery was associated with reporting FI compared to only SVDs (OR 1.29, 95% CI 1.00-1.66), but there was no association for UI (OR 0.95, 95% CI 0.76-1.19) or SCD (OR 1.05, 95% CI 0.80-1.38). Higher current BMI was associated with all PFD outcomes., Conclusions: Prevalence of PFD continues to increase up to 26 years following index birth, and differences were observed according to delivery mode history. Exclusive CS was associated with less risk of UI, FI and any prolapse symptoms., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Pelvic organ prolapse is common, causes unpleasant symptoms and negatively affects women's quality of life. In the UK, most women with pelvic organ prolapse attend clinics for pessary care., Objectives: To determine the clinical effectiveness and cost-effectiveness of vaginal pessary self-management on prolapse-specific quality of life for women with prolapse compared with clinic-based care; and to assess intervention acceptability and contextual influences on effectiveness, adherence and fidelity., Design: A multicentre, parallel-group, superiority randomised controlled trial with a mixed-methods process evaluation., Participants: Women attending UK NHS outpatient pessary services, aged ≥ 18 years, using a pessary of any type/material (except shelf, Gellhorn or Cube) for at least 2 weeks. Exclusions: women with limited manual dexterity, with cognitive deficit (prohibiting consent or self-management), pregnant or non-English-speaking., Intervention: The self-management intervention involved a 30-minute teaching appointment, an information leaflet, a 2-week follow-up telephone call and a local clinic telephone helpline number. Clinic-based care involved routine appointments determined by centres' usual practice., Allocation: Remote web-based application; minimisation was by age, pessary user type and centre., Blinding: Participants, those delivering the intervention and researchers were not blinded to group allocation., Outcomes: The patient-reported primary outcome (measured using the Pelvic Floor Impact Questionnaire-7) was prolapse-specific quality of life, and the cost-effectiveness outcome was incremental cost per quality-adjusted life-year (a specifically developed health Resource Use Questionnaire was used) at 18 months post randomisation. Secondary outcome measures included self-efficacy and complications. Process evaluation data were collected by interview, audio-recording and checklist. Analysis was by intention to treat., Results: Three hundred and forty women were randomised (self-management, n = 169; clinic-based care, n = 171). At 18 months post randomisation, 291 questionnaires with valid primary outcome data were available (self-management, n = 139; clinic-based care, n = 152). Baseline economic analysis was based on 264 participants (self-management, n = 125; clinic-based care, n = 139) with valid quality of life and resource use data. Self-management was an acceptable intervention. There was no group difference in prolapse-specific quality of life at 18 months (adjusted mean difference -0.03, 95% confidence interval -9.32 to 9.25). There was fidelity to intervention delivery. Self-management was cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained, with an estimated incremental net benefit of £564.32 and an 80.81% probability of cost-effectiveness. At 18 months, more pessary complications were reported in the clinic-based care group (adjusted mean difference 3.83, 95% confidence interval 0.81 to 6.86). There was no group difference in general self-efficacy, but self-managing women were more confident in pessary self-management activities. In both groups, contextual factors impacted on adherence and effectiveness. There were no reported serious unexpected serious adverse reactions. There were 32 serious adverse events (self-management, n = 17; clinic-based care, n = 14), all unrelated to the intervention. Skew in the baseline data for the Pelvic Floor Impact Questionnaire-7, the influence of the global COVID-19 pandemic, the potential effects of crossover and the lack of ethnic diversity in the recruited sample were possible limitations., Conclusions: Self-management was acceptable and cost-effective, led to fewer complications and did not improve or worsen quality of life for women with prolapse compared with clinic-based care. Future research is needed to develop a quality-of-life measure that is sensitive to the changes women desire from treatment., Study Registration: This study is registered as ISRCTN62510577., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/82/01) and is published in full in Health Technology Assessment ; Vol. 28, No. 23. See the NIHR Funding and Awards website for further award information.

Background: Prolapse affects 30-40% of women. Those using a pessary for prolapse usually receive care as an outpatient. This trial determined effectiveness and cost-effectiveness of pessary self-management (SM) vs clinic-based care (CBC) in relation to condition-specific quality of life (QoL)., Methods: Parallel-group, superiority randomised controlled trial, recruiting from 16 May 2018 to 7 February 2020, with follow-up to 17 September 2021. Women attending pessary clinics, ≥18 years, using a pessary (except Shelf, Gellhorn or Cube), with pessary retained ≥2 weeks were eligible. Limited manual dexterity; cognitive deficit; pregnancy; or requirement for non-English teaching were exclusions. SM group received a 30-min teaching session; information leaflet; 2-week follow-up call; and telephone support. CBC group received usual routine appointments. The primary clinical outcome was pelvic floor-specific QoL (PFIQ-7), and incremental net monetary benefit for cost-effectiveness, 18 months post-randomisation. Group allocation was by remote web-based application, minimised on age, user type (new/existing) and centre. Participants, intervention deliverers, researchers and the statistician were not blinded. The primary analysis was intention-to-treat based. Trial registration: https://doi.org/10.1186/ISRCTN62510577., Findings: The requisite 340 women were randomised (169 SM, 171 CBC) across 21 centres. There was not a statistically significant difference between groups in PFIQ-7 at 18 months (mean SM 32.3 vs CBC 32.5, adjusted mean difference SM-CBC -0.03, 95% CI -9.32 to 9.25). SM was less costly than CBC. The incremental net benefit of SM was £564 (SE £581, 95% CI -£576 to £1704). A lower percentage of pessary complications was reported in the SM group (mean SM 16.7% vs CBC 22.0%, adjusted mean difference -3.83%, 95% CI -6.86% to -0.81%). There was no meaningful difference in general self-efficacy. Self-managing women were more confident in self-management activities. There were no reported suspected unexpected serious adverse reactions, and 31 unrelated serious adverse events (17 SM, 14 CBC)., Interpretation: Pessary self-management is cost-effective, does not improve or worsen QoL compared to CBC, and has a lower complication rate., Funding: National Institute for Health and Care Research, Health Technology Assessment Programme (16/82/01)., Competing Interests: All authors declare a grant from National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme relating to the research described in the manuscript. In addition Lucy Dwyer reports being a member of the NICE guideline committee for non-surgical management and prevention of pelvic floor dysfunction and a member of the UK Clinical Guideline for best practice in the use of vaginal pessaries for pelvic organ prolapse committee; Aethele Khunda reports receiving an educational grant from Olympus Medical Systems to cover travel and accommodation costs to attend a laparoscopic urogynaecology workshop; Wael Agur reports grants from NIHR, consulting fees and payment for testimony from Oaklaw Consultancy Ltd., for Medico-legal Consultancy and financial/non-financial interest associated with Medical Innovation Systems; Karen Guerrero reports payment for expert testimony for the Medical Advisor NHS Scotland Central Legal Office and for NHS-funded study leave; Christine Hemming reports grants from NIHR HTA for two RCTs (11/129/183 and 07/60/18); John Norrie reports being a member of the following committees: NIHR CTU Standing Advisory Committee (2018-23), NIHR HTA & EME Editorial Board (2015–2019), EME Funding Committee Member (2019–2022), HTA General Committee (2016–2019), HTA Post-Funding Committee (2016–2019), HTA Funding Committee Policy Group (2016–2019), COVID-19 Reviewing (2020); Ranee Thakar reports a voluntary role at Royal College of Obstetricians and Gynaecologists; Rohna Kearney reports being topic lead for prolapse on NICE guideline NG123 published 2019; Angela Forrest reports payment for attending project meetings relating to the research; Suzanne Breeman reports grants from NIHR HTA for the VUE trial (11/129/183) and the PROSPECT trial (07/60/18 and NIHR133665). Suzanne Hagen, Carol Bugge, Andrew Elders, Helen Mason, Kirsteen Goodman, Doreen McClurg, Melanie Dembinsky, Lynn Melone, Catherine Best, Sarkis Manoukian, Margaret Graham, Jane Culverhouse and Mark Forrest have no additional disclosures to report relating to the manuscript., (© 2023 The Authors.)

Introduction and Hypothesis: Our aim was to compare the mid-term results of native tissue, biological xenograft and polypropylene mesh surgery for women with vaginal wall prolapse., Methods: A total of 1348 women undergoing primary transvaginal repair of an anterior and/or posterior prolapse were recruited between January 2010 and August 2013 from 35 UK centres. They were randomised by remote allocation to native tissue surgery, biological xenograft or polypropylene mesh. We performed both 4- and 6-year follow-up using validated patient-reported outcome measures., Results: At 4 and 6 years post-operation, there was no clinically important difference in Pelvic Organ Prolapse Symptom Score for any of the treatments. Using a strict composite outcome to assess functional cure at 6 years, we found no difference in cure among the three types of surgery. Half the women were cured at 6 years but only 10.3 to 12% of women had undergone further surgery for prolapse. However, 8.4% of women in the mesh group had undergone further surgery for mesh complications. There was no difference in the incidence of chronic pain or dyspareunia between groups., Conclusions: At the mid-term outcome of 6 years, there is no benefit from augmenting primary prolapse repairs with polypropylene mesh inlays or biological xenografts. There was no evidence that polypropylene mesh inlays caused greater pain or dyspareunia than native tissue repairs., (© 2022. The Author(s).)

Background: Pelvic organ prolapse (POP) is a common condition in women, where the downward descent of pelvic organs into the vagina causes symptoms which impacts quality of life. Vaginal pessaries offer an effective alternative to surgery for the management of POP. However, the need for regular follow-up can be burdensome for women and requires significant healthcare resources. The TOPSY study is a randomised controlled trial which aims to determine the clinical and cost-effectiveness of self-management of vaginal pessaries. This paper describes the theoretical and practical development of the self-management intervention., Methods: The intervention was developed using the MRC complex intervention framework, normalisation process theory (NPT) and self-management theory. The intervention aims to boost perceived self-efficacy in accordance with Bandura's social cognitive theory and is guided by the tasks and skills Lorig and Hollman describe as necessary to self-manage a health condition., Results: The TOPSY intervention was designed to support women to undertake the medical management, role management and emotional management of their pessary. The six self-management skills described by Lorig and Hollman: problem-solving, decision-making, resource utilisation, formation of a patient-provider partnership role, action planning and self-tailoring, are discussed in detail, including how women were supported to achieve each task within the context of pessary self-management. The TOPSY intervention includes a self-management support session with a pessary practitioner trained in intervention delivery, a follow-up phone call 2 weeks later and ongoing telephone or face-to-face support as required by the woman initiated by contacting a member of the research team., Conclusions: The TOPSY study intervention was developed utilising the findings from a prior service development project, intervention development and self-efficacy theory, relevant literature, clinician experience and feedback from pessary using women and members of the public. In 2022, the findings of the TOPSY study will provide further evidence to inform this important aspect of pessary management., Trial Registration: ISRCTN Registry ISRCTN62510577 . Registered on June 10, 2017., (© 2022. The Author(s).)

Background: Process evaluations have become a valued component, alongside clinical trials, of the wider evaluation of complex health interventions. They support understanding of implementation, and fidelity, related to the intervention and provide valuable insights into what is effective in a practical setting by examining the context in which interventions are implemented. The TOPSY study consists of a large multi-centre randomised controlled trial comparing the effectiveness of pessary self-management with clinic-based care in improving women's condition-specific quality of life, and a nested process evaluation. The process evaluation aims to examine and maximise recruitment to the trial, describe intervention fidelity and explore participants' and healthcare professionals' experiences., Methods: The trial will recruit 330 women from approximately 17 UK centres. The process evaluation uses a mixed-methods approach. Semi-structured interviews will be conducted with randomised women (18 per randomised group/n = 36), women who declined trial participation but agreed to interview (non-randomised women) (n = 20) and healthcare professionals recruiting to the trial (n ~ 17) and delivering self-management and clinic-based care (n ~ 17). The six internal pilot centres will be asked to record two to three recruitment discussions each (total n = 12-18). All participating centres will be asked to record one or two self-management teaching appointments (n = 30) and self-management 2-week follow-up telephone calls (n = 30). Process data (quantitative and qualitative) will be gathered in participant completed trial questionnaires. Interviews will be analysed thematically and recordings using an analytic grid to identify fidelity to the intervention. Quantitative analysis will be predefined within the process evaluation analysis plan., Discussion: The wide variety of pessary care delivered across the UK for women with pelvic organ prolapse presents specific localised contexts in which the TOPSY interventions will be implemented. Understanding this contextual variance is central to understanding how and in what circumstances pessary self-management can be implemented (should it be effective). The inclusion of non-randomised women provides an innovative way of collecting indispensable information about eligible women who decline trial participation, allowing broader contextualisation and considerations of generalisability of trial findings. Methodological insights from examination of recruitment processes and mechanisms have the potential to inform recruitment mechanisms and future recruitment strategies and study designs., Trial Registration: ISRCTN62510577 . Registered on 6 October 2017.

Background: Pelvic organ prolapse (or prolapse) is a common condition in women where the pelvic organs (bladder, bowel or womb) descend into the vagina and cause distressing symptoms that adversely affect quality of life. Many women will use a vaginal pessary to treat their prolapse symptoms. Clinic-based care usually consists of having a pessary fitted in a primary or secondary care setting, and returning approximately every 6 months for healthcare professional review and pessary change. However, it is possible that women could remove, clean and re-insert their pessary themselves; this is called self-management. This trial aims to assess if self-management of a vaginal pessary is associated with better quality of life for women with prolapse when compared to clinic-based care., Methods: This is a multicentre randomised controlled trial in at least 17 UK centres. The intervention group will receive pessary self-management teaching, a self-management information leaflet, a follow-up phone call and access to a local telephone number for clinical support. The control group will receive the clinic-based pessary care which is standard at their centre. Demographic and medical history data will be collected from both groups at baseline. The primary outcome is condition-specific quality of life at 18 months' post-randomisation. Several secondary outcomes will also be assessed using participant-completed questionnaires. Questionnaires will be administered at baseline, 6, 12 and 18 months' post-randomisation. An economic evaluation will be carried out alongside the trial to evaluate cost-effectiveness. A process evaluation will run parallel to the trial, the protocol for which is reported in a companion paper., Discussion: The results of the trial will provide robust evidence of the effectiveness of pessary self-management compared to clinic-based care in terms of improving women's quality of life, and of its cost-effectiveness., Trial Registration: ISRCTN Registry ISRCTN62510577 . Registered on June 10, 2017.

Objective: To compare standard (native tissue) repair with synthetic mesh inlays or mesh kits., Design: Randomised controlled trial., Setting: Thirty-three UK hospitals., Population: Women having surgery for recurrent prolapse., Methods: Women recruited using remote randomisation., Main Outcome Measures: Prolapse symptoms, condition-specific quality-of-life and serious adverse effects., Results: A Mean Pelvic Organ Prolapse Symptom Score at 1 year was similar for each comparison (standard 6.6 versus mesh inlay 6.1, mean difference [MD] -0.41, 95% CI -2.92 to 2.11: standard 6.6 versus mesh kit 5.9, MD -1.21 , 95% CI -4.13 to 1.72) but the confidence intervals did not exclude a minimally important clinical difference. There was no evidence of difference in any other outcome measure at 1 or 2 years. Serious adverse events, excluding mesh exposure, were similar at 1 year (standard 7/55 [13%] versus mesh inlay 5/52 [10%], risk ratio [RR] 1.05 [0.66-1.68]: standard 3/25 [12%] versus mesh kit 3/46 [7%], RR 0.49 [0.11-2.16]). Cumulative mesh exposure rates over 2 years were 7/52 (13%) in the mesh inlay arm, of whom four women required surgical revision; and 4/46 in the mesh kit arm (9%), of whom two required surgical revision., Conclusions: We did not find evidence of a difference in terms of prolapse symptoms from the use of mesh inlays or mesh kits in women undergoing repeat prolapse surgery. Although the sample size was too small to be conclusive, the results provide a substantive contribution to future meta-analysis., Tweetable Abstract: There is not enough evidence to support use of synthetic mesh inlay or mesh kits for repeat prolapse surgery., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Background: New surgical approaches for apical prolapse have gradually been introduced, with few prospective randomised controlled trial data to evaluate their safety and efficacy compared with traditional methods., Objective: To compare surgical uterine preservation with vaginal hysterectomy in women with uterine prolapse and abdominal procedures with vaginal procedures in women with vault prolapse in terms of clinical effectiveness, adverse events, quality of life and cost-effectiveness., Design: Two parallel randomised controlled trials (i.e. Uterine and Vault). Allocation was by remote web-based randomisation (1 : 1 ratio), minimised on the need for concomitant anterior and/or posterior procedure, concomitant incontinence procedure, age and surgeon., Setting: UK hospitals., Participants: Uterine trial - 563 out of 565 randomised women had uterine prolapse surgery. Vault trial - 208 out of 209 randomised women had vault prolapse surgery., Interventions: Uterine trial - uterine preservation or vaginal hysterectomy. Vault trial - abdominal or vaginal vault suspension., Main Outcome Measures: The primary outcome measures were women's prolapse symptoms (as measured using the Pelvic Organ Prolapse Symptom Score), prolapse-specific quality of life and cost-effectiveness (as assessed by incremental cost per quality-adjusted life-year)., Results: Uterine trial - adjusting for baseline and minimisation covariates, the mean Pelvic Organ Prolapse Symptom Score at 12 months for uterine preservation was 4.2 (standard deviation 4.9) versus vaginal hysterectomy with a Pelvic Organ Prolapse Symptom Score of 4.2 (standard deviation 5.3) (mean difference -0.05, 95% confidence interval -0.91 to 0.81). Serious adverse event rates were similar between the groups (uterine preservation 5.4% vs. vaginal hysterectomy 5.9%; risk ratio 0.82, 95% confidence interval 0.38 to 1.75). There was no difference in overall prolapse stage. Significantly more women would recommend vaginal hysterectomy to a friend (odds ratio 0.39, 95% confidence interval 0.18 to 0.83). Uterine preservation was £235 (95% confidence interval £6 to £464) more expensive than vaginal hysterectomy and generated non-significantly fewer quality-adjusted life-years (mean difference -0.004, 95% confidence interval -0.026 to 0.019). Vault trial - adjusting for baseline and minimisation covariates, the mean Pelvic Organ Prolapse Symptom Score at 12 months for an abdominal procedure was 5.6 (standard deviation 5.4) versus vaginal procedure with a Pelvic Organ Prolapse Symptom Score of 5.9 (standard deviation 5.4) (mean difference -0.61, 95% confidence interval -2.08 to 0.86). The serious adverse event rates were similar between the groups (abdominal 5.9% vs. vaginal 6.0%; risk ratio 0.97, 95% confidence interval 0.27 to 3.44). The objective anterior prolapse stage 2b or more was higher in the vaginal group than in the abdominal group (odds ratio 0.38, 95% confidence interval 0.18 to 0.79). There was no difference in the overall prolapse stage. An abdominal procedure was £570 (95% confidence interval £459 to £682) more expensive than a vaginal procedure and generated non-significantly more quality-adjusted life-years (mean difference 0.004, 95% confidence interval -0.031 to 0.041)., Conclusions: Uterine trial - in terms of efficacy, quality of life or adverse events in the short term, no difference was identified between uterine preservation and vaginal hysterectomy. Vault trial - in terms of efficacy, quality of life or adverse events in the short term, no difference was identified between an abdominal and a vaginal approach., Future Work: Long-term follow-up for at least 6 years is ongoing to identify recurrence rates, need for further prolapse surgery, adverse events and cost-effectiveness., Trial Registration: Current Controlled Trials ISRCTN86784244., Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 13. See the National Institute for Health Research Journals Library website for further project information., Competing Interests: Robert Freeman reports speaker fees [from Bard Medical (Covington, GA, USA), Astellas Pharma Inc. (Tokyo, Japan) and Pfizer Inc. (New York City, NY, USA)] and grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme. John Norrie reports membership of the following NIHR boards: the Cardiopulmonary Resuscitation Decision-making Committee, HTA Commissioning Board, HTA Commissioning Sub-Board (Expression of Interest), HTA Funding Boards Policy Group, HTA General Board and HTA Post-board Funding Teleconference; the NIHR Clinical Trials Unit Standing Advisory Committee; the NIHR HTA and Efficacy and Mechanism Evaluation Editorial Board; and the Pre-exposure Prophylaxis Impact Review Panel.

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The use of transvaginal mesh and biological graft material in prolapse surgery is controversial and has led to a number of enquiries into their safety and efficacy. Existing trials of these augmentations are individually too small to be conclusive. We aimed to compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against standard repair in women., Methods: We did two pragmatic, parallel-group, multicentre, randomised controlled trials for our study (PROSPECT [PROlapse Surgery: Pragmatic Evaluation and randomised Controlled Trials]) in 35 centres (a mix of secondary and tertiary referral hospitals) in the UK. We recruited women undergoing primary transvaginal anterior or posterior compartment prolapse surgery by 65 gynaecological surgeons in these centres. We randomly assigned participants by a remote web-based randomisation system to one of the two trials: comparing standard (native tissue) repair alone with standard repair augmented with either synthetic mesh (the mesh trial) or biological graft (the graft trial). We assigned women (1:1:1 or 1:1) within three strata: assigned to one of the three treatment options, comparison of standard repair with mesh, and comparison of standard repair with graft. Participants, ward staff, and outcome assessors were masked to randomisation where possible; masking was obviously not possible for the surgeon. Follow-up was for 2 years after the surgery; the primary outcomes, measured at 1 year and 2 years, were participant-reported prolapse symptoms (i.e. the Pelvic Organ Prolapse Symptom Score [POP-SS]) and condition-specific (ie, prolapse-related) quality-of-life scores, analysed in the modified intention-to-treat population. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN60695184., Findings: Between Jan 8, 2010, and Aug 30, 2013, we randomly allocated 1352 women to treatment, of whom 1348 were included in the analysis. 865 women were included in the mesh trial (430 to standard repair alone, 435 to mesh augmentation) and 735 were included in the graft trial (367 to standard repair alone, 368 to graft augmentation). Because the analyses were carried out separately for each trial (mesh trial and graft trial) some women in the standard repair arm assigned to all treatment options were included in the standard repair group of both trials. 23 of these women did not receive any surgery (15 in the mesh trial, 13 in the graft trial; five were included in both trials) and were included in the baseline analyses only. Mean POP-SS at 1 year did not differ substantially between comparisons (standard 5·4 [SD 5·5] vs mesh 5·5 [5·1], mean difference 0·00, 95% CI -0·70 to 0·71; p=0·99; standard 5·5 [SD 5·6] vs graft 5·6 [5·6]; mean difference -0·15, -0·93 to 0·63; p=0·71). Mean prolapse-related quality-of-life scores also did not differ between groups at 1 year (standard 2·0 [SD 2·7] vs mesh 2·2 [2·7], mean difference 0·13, 95% CI -0·25 to 0·51; p=0·50; standard 2·2 [SD 2·8] vs graft 2·4 [2·9]; mean difference 0·13, -0·30 to 0·56; p=0·54). Mean POP-SS at 2 years were: standard 4·9 (SD 5·1) versus mesh 5·3 (5·1), mean difference 0·32, 95% CI -0·39 to 1·03; p=0·37; standard 4·9 (SD 5·1) versus graft 5·5 (5·7); mean difference 0·32, -0·48 to 1·12; p=0·43. Prolapse-related quality-of-life scores at 2 years were: standard 1·9 (SD 2·5) versus mesh 2·2 (2·6), mean difference 0·15, 95% CI -0·23 to 0·54; p=0·44; standard 2·0 (2·5) versus graft 2·2 (2·8); mean difference 0·10, -0·33 to 0·52; p=0·66. Serious adverse events such as infection, urinary retention, or dyspareunia or other pain, excluding mesh complications, occurred with similar frequency in the groups over 1 year (mesh trial: 31/430 [7%] with standard repair vs 34/435 [8%] with mesh, risk ratio [RR] 1·08, 95% CI 0·68 to 1·72; p=0·73; graft trial: 23/367 [6%] with standard repair vs 36/368 [10%] with graft, RR 1·57, 0·95 to 2·59; p=0·08). The cumulative number of women with a mesh complication over 2 years in women actually exposed to synthetic mesh was 51 (12%) of 434., Interpretation: Augmentation of a vaginal repair with mesh or graft material did not improve women's outcomes in terms of effectiveness, quality of life, adverse effects, or any other outcome in the short term, but more than one in ten women had a mesh complication. Therefore, follow-up is vital to identify any longer-term potential benefits and serious adverse effects of mesh or graft reinforcement in vaginal prolapse surgery., Funding: UK National Institute of Health Research., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Background: The use of mesh in prolapse surgery is controversial, leading to a number of enquiries into its safety and efficacy., Objective: To compare synthetic non-absorbable mesh inlay, biological graft and mesh kit with a standard repair in terms of clinical effectiveness, adverse effects, quality of life (QoL), costs and cost-effectiveness., Design: Two randomised controlled trials within a comprehensive cohort (CC) study. Allocation was by a remote web-based randomisation system in a 1 :1 : 1 ratio (Primary trial) or 1 : 1 : 2 ratio (Secondary trial), and was minimised on age, type of prolapse repair planned, need for a concomitant continence procedure, need for a concomitant upper vaginal prolapse procedure and surgeon. Participants and outcome assessors were blinded to randomisation; participants were unblinded if they requested the information. Surgeons were not blinded to allocated procedure., Setting: Thirty-five UK hospitals., Participants: Primary study : 2474 women in the analysis (including 1348 randomised) having primary anterior or posterior prolapse surgery. Secondary study : 398 in the analysis (including 154 randomised) having repeat anterior or posterior prolapse surgery. CC3 : 215 women having either uterine or vault prolapse repair., Interventions: Anterior or posterior repair alone, or with mesh inlay, biological graft or mesh kit., Main Outcome Measures: Prolapse symptoms [Pelvic Organ Prolapse Symptom Score (POP-SS)]; prolapse-specific QoL; cost-effectiveness [incremental cost per quality-adjusted life-year (QALY)]., Results: Primary trials : adjusting for baseline and minimisation covariates, mean POP-SS was similar for each comparison {standard 5.4 [standard deviation (SD) 5.5] vs. mesh 5.5 (SD 5.1), mean difference (MD) 0.00, 95% confidence interval (CI) -0.70 to 0.71; standard 5.5 (SD 5.6) vs. graft 5.6 (SD 5.6), MD -0.15, 95% CI -0.93 to 0.63}. Serious non-mesh adverse effects rates were similar between the groups in year 1 [standard 7.2% vs. mesh 7.8%, risk ratio (RR) 1.08, 95% CI 0.68 to 1.72; standard 6.3% vs. graft 9.8%, RR 1.57, 95% CI 0.95 to 2.59]. There were no statistically significant differences between groups in any other outcome measure. The cumulative mesh complication rates over 2 years were 2 of 430 (0.5%) for standard repair (trial 1), 46 of 435 (10.6%) for mesh inlay and 2 of 368 (0.5%) for biological graft. The CC findings were comparable. Incremental costs were £363 (95% CI -£32 to £758) and £565 (95% CI £180 to £950) for mesh and graft vs. standard, respectively. Incremental QALYs were 0.071 (95% CI -0.004 to 0.145) and 0.039 (95% CI -0.041 to 0.120) for mesh and graft vs. standard, respectively. A Markov decision model extrapolating trial results over 5 years showed standard repair had the highest probability of cost-effectiveness, but results were surrounded by considerable uncertainty. Secondary trials : there were no statistically significant differences between the randomised groups in any outcome measure, but the sample size was too small to be conclusive. The cumulative mesh complication rates over 2 years were 7 of 52 (13.5%) for mesh inlay and 4 of 46 (8.7%) for mesh kit, with no mesh exposures for standard repair., Conclusions: In women who were having primary repairs, there was evidence of no benefit from the use of mesh inlay or biological graft compared with standard repair in terms of efficacy, QoL or adverse effects (other than mesh complications) in the short term. The Secondary trials were too small to provide conclusive results., Limitations: Women in the Primary trials included some with a previous repair in another compartment. Follow-up is vital to identify any long-term potential benefits and serious adverse effects., Future Work: Long-term follow-up to at least 6 years after surgery is ongoing to identify recurrence rates, need for further prolapse surgery, adverse effects and cost-effectiveness., Triai Registration: Current Controlled Trials ISRCTN60695184., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 20, No. 95. See the NIHR Journals Library website for further project information.

Background: One in three women who have a prolapse operation will go on to have another operation, though not necessarily in the same compartment. Surgery can result in greater impairment of quality of life than the original prolapse itself (such as the development of new-onset urinary incontinence, or prolapse at a different site). Anterior and posterior prolapse surgery is most common (90 % of operations), but around 43 % of women also have a uterine (34 %) or vault (9 %) procedure at the same time. There is not enough evidence from randomised controlled trials (RCTs) to guide management of vault or uterine prolapse. The Vault or Uterine prolapse surgery Evaluation (VUE) study aims to assess the surgical management of upper compartment pelvic organ prolapse (POP) in terms of clinical effectiveness, cost-effectiveness and adverse events., Methods/design: VUE is two parallel, pragmatic, UK multicentre, RCTs (Uterine Trial and Vault Trial). Eligible for inclusion are women with vault or uterine prolapse: requiring a surgical procedure, suitable for randomisation and willing to be randomised. Randomisation will be computer-allocated separately for each trial, minimised on: requiring concomitant anterior and/or posterior POP surgery or not, concomitant incontinence surgery or not, age (under 60 years or 60 years and older) and surgeon. Participants will be randomly assigned, with equal probability to intervention or control arms in either the Uterine Trial or the Vault Trial. Uterine Trial participants will receive either a vaginal hysterectomy or a uterine preservation procedure. Vault Trial participants will receive either a vaginal sacrospinous fixation or an abdominal sacrocolpopexy. Participants will be followed up by postal questionnaires (6 months post surgery and 12 months post randomisation) and also reviewed in clinic 12 months post surgery. The primary outcome is the participant-reported Pelvic Organ Prolapse Symptom Score (POP-SS) at 12 months post randomisation., Discussion: Demonstrating the efficacy of vault and uterine prolapse surgeries is relevant not only to patients and clinicians but also to health care providers, both in the UK and globally., Trial Registration: Current controlled trials ISRCTN86784244 (assigned 19 October 2012), and the first subject was randomly assigned on 1 May 2013.

Vitamin E is an essential nutrient for humans and is obtained primarily from food, especially oil, derived from the seed of plants. Genes encoding the committed steps in vitamin E synthesis in plants (VTE, loci 1-5) have been isolated and used for tocopherol pathway engineering with various degrees of success. As a complement to such approaches we have used quantitative trait loci analysis with two sets of Arabidopsis thaliana recombinant inbred lines and have identified 14 QVE (quantitative vitamin E) loci affecting tocopherol content and composition in seeds. Five QVE intervals contain VTE loci that are likely QVE gene candidates. Nine QVE intervals do not contain VTE loci and therefore identify novel loci affecting seed tocopherol content and composition. Several near-isogenic lines containing introgressions of the accession with increased vitamin E levels were shown to confer significantly elevated tocopherol levels compared with the recurrent parent. Fine-mapping has narrowed QVE7 (a gamma-tocopherol quantitative trait loci) to an 8.5-kb interval encompassing two genes. Understanding the basis of the QVE loci in Arabidopsis promises to provide insight into the regulation and/or metabolism of vitamin E in plants and has clear ramifications for improving the nutritional content of crops through marker-assisted selection and metabolic engineering.