A survey of prolapse practice in UK women's health physiotherapists: what has changed in the last decade?

INTRODUCTION AND HYPOTHESIS: Prolapse is a common female problem, and conservative treatments such as pelvic floor muscle training (PFMT) are important options for women. Evidence supporting the effectiveness of PFMT for prolapse has grown over the last decade, and it was hypothesised that practice and practice guidelines would have developed in line with the evidence. To assess this, up-to-date information about the practice of physiotherapists working in women's health regarding their treatment of prolapse was required. METHODS: An online survey sent to members of the Association of Chartered Physiotherapists in Women's Health and the Chartered Physiotherapists Promoting Continence. Results were compared with those of an earlier survey undertaken in 2002. RESULTS: A 49 % response rate was achieved. The majority of respondents were senior physiotherapists (55 %) and had worked in women's health for more than 10 years. Respondents were treating significantly more women with prolapse than a decade before: 36 % vs 14 % treated more than 50 women per year in 2002 and 2013 respectively (p < 0.001). Individualised PFMT (93 %), lifestyle advice (92 %) and biofeedback-assisted PFMT (83 %) were the most common treatment elements, with four being the average number of appointments. Forty-eight percent had changed their practice as a result of recent research; however, scepticism amongst medics, the referral of women directly for surgery, and constraints on resources were thought to be barriers to wider implementation of the evidence of PFMT for prolapse. CONCLUSIONS: There has been uptake of evidence-based prolapse practice by UK specialist physiotherapists in the last decade. Further research targeting the implementation of this evidence would be valuable in addressing potential barriers, and in supporting the need for physiotherapy in the treatment of prolapse.

Defecating disorders: a common cause of constipation in women.

Defecating disorders are a common and complex problem. There are a range of anatomical and functional bowel abnormalities that can lead to this condition. Treatment is difficult and needs a multidisciplinary approach. First line treatment for defecating disorders is conservative. For those that fail conservative treatment, some may respond to surgical therapy but with variable results. The aim of this review is to offer an overview of defecating disorders as well as provide an algorithm on how to diagnose and treat them with the help of a multidisciplinary and multimodal approach.

Pelvic-Floor-Muscle Training Adherence: Tools, Measurements and Strategies-2011 ICS State-of-the-Science Seminar Research Paper II of IV.

AIMS: This paper on pelvic-floor-muscle training (PFMT) adherence, the second of four from the International Continence Society's 2011 State-of-the-Science Conference, aims to (1) identify and collate current adherence outcome measures, (2) report the determinants of adherence, (3) report on PFMT adherence strategies, and (4) make actionable clinical and research recommendations. METHOD: Data were amassed from a literature review and an expert panel (2011 conference), following consensus statement methodology. Experts in pelvic floor dysfunction collated and synthesized the evidence and expert opinions on PFMT adherence for urinary incontinence (UI) and lower bowel dysfunction in men and women and pelvic organ prolapse in women. RESULTS: The literature was scarce for most of the studied populations except for limited research on women with UI. OUTCOME MEASURES: Exercise diaries were the most widely-used adherence outcome measure, PFMT adherence was inconsistently monitored and inadequately reported. Determinants: Research, mostly secondary analyses of RCTs, suggested that intention to adhere, self-efficacy expectations, attitudes towards the exercises, perceived benefits and a high social pressure to engage in PFMT impacted adherence. STRATEGIES: Few trials studied and compared adherence strategies. A structured PFMT programme, an enthusiastic physiotherapist, audio prompts, use of established theories of behavior change, and user-consultations seem to increase adherence. CONCLUSION: The literature on adherence outcome measures, determinants and strategies remains scarce for the studied populations with PFM dysfunction, except in women with UI. Although some current adherence findings can be applied to clinical practice, more effective and standardized research is urgently needed across all the sub-populations.

2014 consensus statement on improving pelvic floor muscle training adherence: International Continence Society 2011 State-of-the-Science Seminar.

AIMS: To summarize the findings and "expert-panel" consensus of the State-of-the-Science Seminar on pelvic floor muscle training (PFMT) adherence held prior to the 41st International Continence Society scientific meeting, Glasgow, 2011. METHODS: Summaries of research and theory about PFMT adherence (based on a comprehensive literature search) were presented by subject experts at the 2011 Seminar to generate discussion and guidance for clinical practice and future research. Supplemental research, post-seminar, resulted in, three review papers summarizing: (1) relevant behavioral theories, (2) adherence measurement, determinants and effectiveness of PFMT adherence interventions, and (3) patients' PFMT experiences. A fourth, reported findings from an online survey of health professionals and the public. RESULTS: Few high-quality studies were found. Paper I summarizes 12 behavioral frameworks relevant to theoretical development of PFMT adherence interventions and strategies. Findings in Paper II suggest both PFMT self-efficacy and intention-to-adhere predict PFMT adherence. Paper III identified six potential adherence modifiers worthy of further investigation. Paper IV found patient-related factors were the biggest adherence barrier to PFMT adherence. CONCLUSION: Given the lack of high-quality studies, the conclusions were informed by expert opinion. Adherence is central to short- and longer-term PFMT effect. More attention and explicit reporting is needed regarding: (1) applying health behavior theory in PFMT program planning; (2) identifying adherence determinants; (3) developing and implementing interventions targeting known adherence determinants; (4) using patient-centred approaches to evaluating adherence barriers and facilitators; (5) measuring adherence, including refining and testing instruments; and (6) testing the association between adherence and PFMT outcome.

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).

Reflecting on the methodological challenges of recruiting to a United Kingdom-wide, multi-centre, randomised controlled trial in gynaecology outpatient settings.

BACKGROUND: Successful recruitment of participants to any trial is central to its success. Trial results are routinely published, and recruitment is often cited to be slower and more difficult than anticipated. This article reflects on the methodological challenges of recruiting women with prolapse attending United Kingdom (UK) gynaecology outpatient clinics to a multi-centre randomised controlled trial (RCT) of physiotherapy, and the systems put in place in an attempt to address them. METHODS: Gynaecology outpatients with symptomatic prolapse were to be recruited over a 16-month period from 14 UK hospitals and one New Zealand hospital. Eligible women were informed about the trial by their gynaecologist and informed consent was obtained by the central trial office. Recruitment difficulties were encountered early on, and a number of strategies were employed to try to improve recruitment. RESULTS: Some strategies were more successful than others and they differed in the resources required. Actions that facilitated recruitment included increasing recruiting centres to 23 UK and two international hospitals, good centre support, using processes embedded in clinical practice, and good communication between the trial office, collaborators and participants. Collaborator incentives, whereby staff involved received the benefit immediately, were more successful than a nominal monetary payment per woman randomised. Barriers to recruitment included fewer eligible women than anticipated, patient's preference to receive active treatment rather than allocation to the control group, lack of support staff and high staff turnover. Geographical variations in Primary Care Trust Research Management and Governance approval systems and general practitioner (GP) referral procedures also impacted negatively on recruitment. CONCLUSIONS: Our article reflects on the methodological challenges of recruiting to a multi-centre RCT in a UK gynaecology setting. Effective interventions included increasing the number of recruiting centres and providing collaborator incentives. Barriers to recruitment included fewer eligible women than anticipated, patient's preference to be allocated to the treatment group, lack of support staff, and variations in approval systems and GP referral procedures. To improve the evidence base on clinical trial recruitment, trialists need to publish their experiences and lessons learned. Future RCTs should evaluate, where possible, the effect of strategies designed to improve recruitment and retention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN35911035.

Conservative prevention and management of pelvic organ prolapse in women.

BACKGROUND: Pelvic organ prolapse is common, and some degree of prolapse is seen in 50% of parous women. Women with prolapse can experience a variety of pelvic floor symptoms. Treatments include surgery, mechanical devices and conservative management. Conservative management approaches, such as giving lifestyle advice and delivering pelvic floor muscle training (PFMT), are often used in cases of mild to moderate prolapse. This is an update of a Cochrane review first published in 2004, and previously updated in 2006. OBJECTIVES: To determine the effects of conservative management (physical and lifestyle interventions) for the prevention or treatment of pelvic organ prolapse in comparison with no treatment or other treatment options (such as mechanical devices or surgery). SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 6 May 2010), EMBASE (1 January 1996 to 6 May 2010), CINAHL (1 January 1982 to 10 May 2010), PEDro (January 2009), the UK National Research Register (January 2009), ClinicalTrials.gov (April 2009), Current Controlled Trials register (April 2009), CENTRAL (Issue 1, 2009) and ZETOC (January 2009) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised trials in women with pelvic organ prolapse that included a physical or lifestyle intervention in at least one arm of the trial. DATA COLLECTION AND ANALYSIS: Two reviewers assessed all trials for inclusion/exclusion and methodological quality. Data were extracted by the lead reviewer onto a standard form and cross checked by another. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Six trials were included; three of these trials are new to this update. Four trials were small (less than 25 women per arm) and two had moderate to high risk of bias. Four trials compared PFMT as a treatment for prolapse against a control group (n = 857 women); two trials included women having surgery for prolapse and compared PFMT as an adjunct to surgery versus surgery alone (n = 118 women).PFMT versus controlThere was a significant risk of bias in two out four trials in this comparison. Prolapse symptoms and women's reports of treatment outcomes (primary outcomes) were measured differently in the three trials where this was reported: all three indicated greater improvement in symptoms in the PFMT group compared to the control group. Pooling data on severity of prolapse from two trials indicated that PFMT increases the chance of an improvement in prolapse stage by 17% compared to no PFMT. The two trials which measured pelvic floor muscle function found better function (or improvement in function) in the PFMT group compared to the control group; measurements were not known to be blinded. Two out of three trials which measured urinary outcomes (urodynamics, frequency and bother of symptoms, or symptom score) reported differences between groups in favour of the PFMT group. One trial reported bowel outcomes, showing less frequency and bother with symptoms in the PFMT group compared to the control group.PFMT supplementing surgery versus surgery aloneBoth trials were small and neither measured prolapse-specific outcomes. Pelvic floor muscle function findings differed between the trials: one found no difference between trial groups in muscle strength, whilst the other found a benefit for the PFMT group in terms of stronger muscles. Similarly findings relating to urinary outcomes were contradictory: one trial found no difference in symptom score change between groups, whilst the other found more improvement in urinary symptoms and a reduction in diurnal frequency in the PFMT group compared to the control group. AUTHORS' CONCLUSIONS: There is now some evidence available indicating a positive effect of PFMT for prolapse symptoms and severity. The largest most rigorous trial to date suggests that six months of supervised PFMT has benefits in terms of anatomical and symptom improvement (if symptomatic) immediately post-intervention. Further evidence relating to effectiveness and cost-effectiveness of PFMT, of different intensities, for symptomatic prolapse in the medium and long term is needed. A large trial of PFMT supplementing surgery is needed to give clear evidence about the usefulness of combining these treatments. Other comparisons which have not been addressed in trials to date and warrant consideration include those involving lifestyle change interventions, and trials aimed at prolapse prevention.

Feasibility, inter- and intra-rater reliability of physiotherapists measuring prolapse using the pelvic organ prolapse quantification system.

INTRODUCTION AND HYPOTHESIS: There is no agreed assessment tool for physiotherapists treating pelvic organ prolapse. This study hypothesised that pelvic organ prolapse quantification (POP-Q) assessment was a feasible measure for use by physiotherapists and tested inter- and intra-rater agreement. METHODS: Six physiotherapists and two gynaecologists participated. Women were recruited from uro/gynaecology clinics. Two POP-Q examinations were performed at the first clinic (gynaecologist, physiotherapist 1) and 1 week later (physiotherapist 1, physiotherapist 2). The examination was timed and women completed a short questionnaire. Using weighted kappa, agreement of POP-Q stage was assessed. RESULTS: Forty-five women were recruited (median age 59, range 32-87 years). Agreement between gynaecologist and physiotherapist was substantial (weighted kappa = 0.63). Weighted kappa was 0.67 for inter-rater agreement between two different physiotherapists and 0.71 for intra-rater reliability for the same physiotherapist. Examination time was significantly shorter (difference 53 +/- 73 s, p < 0.001) for gynaecologists. Participants found the examination acceptable. CONCLUSIONS: POP-Q is a feasible and reliable outcome measure for physiotherapists to use.

A randomized controlled trial of pelvic floor muscle training for stages I and II pelvic organ prolapse.

Forty-seven women participated in a pilot study for a multi-centre randomized controlled trial of the effectiveness of pelvic floor muscle training (PFMT) for women with prolapse. Women with symptomatic stage I or II prolapse [measured by Pelvic Organ Prolapse Quantification (POP-Q)] were randomized to a 16-week physiotherapy intervention (PFMT and lifestyle advice; n = 23) or a control group receiving a lifestyle advice sheet (n = 24). Symptom severity and quality of life were measured via postal questionnaires. Blinded POP-Q was performed at baseline and follow-up. Intervention women had significantly greater improvement than controls in prolapse symptoms (mean score decrease 3.5 versus 0.1, p = 0.021), were significantly more likely to have an improved prolapse stage (45% versus 0%, p = 0.038) and were significantly more likely to say their prolapse was better (63% versus 24%, p = 0.012). The data support the feasibility of a substantive trial of PFMT for prolapse. A multi-centre trial is underway.

Directed evolution of gene-shuffled IFN-alpha molecules with activity profiles tailored for treatment of chronic viral diseases.

Type I IFNs are unusually pleiotropic cytokines that bind to a single heterodimeric receptor and have potent antiviral, antiproliferative, and immune modulatory activities. The diverse effects of the type I IFNs are of differential therapeutic importance; in cancer therapy, an enhanced antiproliferative effect may be beneficial, whereas in the therapy of viral infections (such as hepatitis B and hepatitis C), the antiproliferative effects lead to dose limiting bone marrow suppression. Studies have shown that various members of the natural IFN-alpha family and engineered variants, such as IFN-con1, vary in the ratios between various IFN-mediated cellular activities. We used DNA shuffling to explore and confirm the hypothesis that one could simultaneously increase the antiviral and Th1-inducing activity and decrease the antiproliferative activity. We report IFN-alpha hybrids wherein the ratio of antiviral:antiproliferative and Th1-inducing: antiproliferative potencies are markedly increased with respsect to IFN-con1 (75- and 80-fold, respectively). A four-residue motif that overlaps with the IFNAR1 binding site and is derived by cross breeding with a pseudogene contributes significantly to this phenotype. These IFN-alphas have an activity profile that may result in an improved therapeutic index and, consequently, better clinical efficacy for the treatment of chronic viral diseases such as hepatitis B virus, human papilloma virus, HIV, or chronic hepatitis C.

Behavioral effects of chronic exposure to low levels of lead in Drosophila melanogaster.

Through human activity lead has become a serious environmental neurotoxin, known to affect activity levels, attention and both sensory and cognitive function in children. Study of lead would be facilitated by having a model system that could be manipulated easily and quickly. We find Drosophila melanogaster ideal as such, and we have been studying effects of lead on courtship, fecundity and locomotor activity. We raised Canton-S flies from eggs to adult day 6-7 on medium made with lead acetate solution (2-100 microgram/g), or with distilled water, and we measured adult body lead burdens by means of Inductively Coupled Plasma Mass Spectrometry (ICP-MS). To measure courtship effectiveness, five virgin females and five virgin males were transferred into an empty vial and the number of females that mated within 20min was recorded. To measure fecundity, all adult offspring from eggs produced by one female within 12 days of mating were counted. To measure locomotor activity, individual flies were transferred to a grid-labeled petri dish and the number of lines crossed in 30s was counted. The number of females mating within 20min was increased significantly by exposure to 2 or 8 microgram/g lead, and was decreased significantly by exposure to 20 or 50 microgram/g lead. Fecundity was increased significantly by exposure to 2 microgram/g lead, but was unaffected by exposure to 20 microgram/g lead. Locomotor activity was consistently higher for males than for females, and was significantly reduced only by exposure to 50 microgram/g lead, and then only for males. We thus defined for Drosophila a lowest observable effect level (LOEL) of 2 microgram/g lead, which is considerably lower than the doses shown previously to affect this animal. The dose-response curve was biphasic for the number of females mating within 20min, an example of hormesis, a non-linear response that has been reported for low levels of stressors as diverse as pollutants and radiation. We hope from further studies with Drosophila to understand better how lead affects the developing nervous system, and thus ultimately its effects on children.

Computational stabilization of human growth hormone.

Recombinant human growth hormone (hGH) is used worldwide for the treatment of pediatric hypopituitary dwarfism and in children suffering from low levels of hGH. It has limited stability in solution, and because of poor oral absorption, is administered by injection, typically several times a week. Development has therefore focused on more stable or sustained-release formulations and alternatives to injectable delivery that would increase bioavailability and make it easier for patients to use. We redesigned hGH computationally to improve its thermostability. A more stable variant of hGH could have improved pharmacokinetics or enhanced shelf-life, or be more amenable to use in alternate delivery systems and formulations. The computational design was performed using a previously developed combinatorial optimization algorithm based on the dead-end elimination theorem. The algorithm uses an empirical free energy function for scoring designed sequences. This function was augmented with a term that accounts for the loss of backbone and side-chain conformational entropy. The weighting factors for this term, the electrostatic interaction term, and the polar hydrogen burial term were optimized by minimizing the number of mutations designed by the algorithm relative to wild-type. Forty-five residues in the core of the protein were selected for optimization with the modified potential function. The proteins designed using the developed scoring function contained six to 10 mutations, showed enhancement in the melting temperature of up to 16 degrees C, and were biologically active in cell proliferation studies. These results show the utility of our free energy function in automated protein design.

Development of a cytokine analog with enhanced stability using computational ultrahigh throughput screening.

Granulocyte-colony stimulating factor (G-CSF) is used worldwide to prevent neutropenia caused by high-dose chemotherapy. It has limited stability, strict formulation and storage requirements, and because of poor oral absorption must be administered by injection (typically daily). Thus, there is significant interest in developing analogs with improved pharmacological properties. We used our ultrahigh throughput computational screening method to improve the physicochemical characteristics of G-CSF. Improving these properties can make a molecule more robust, enhance its shelf life, or make it more amenable to alternate delivery systems and formulations. It can also affect clinically important features such as pharmacokinetics. Residues in the buried core were selected for optimization to minimize changes to the surface, thereby maintaining the active site and limiting the designed protein's potential for antigenicity. Using a structure that was homology modeled from bovine G-CSF, core designs of 25-34 residues were completed, corresponding to 10(21)-10(28) sequences screened. The optimal sequence from each design was selected for biophysical characterization and experimental testing; each had 10-14 mutations. The designed proteins showed enhanced thermal stabilities of up to 13 degrees C, displayed five-to 10-fold improvements in shelf life, and were biologically active in cell proliferation assays and in a neutropenic mouse model. Pharmacokinetic studies in monkeys showed that subcutaneous injection of the designed analogs results in greater systemic exposure, probably attributable to improved absorption from the subcutaneous compartment. These results show that our computational method can be used to develop improved pharmaceuticals and illustrate its utility as a powerful protein design tool.