Is walking netball an effective, acceptable and feasible method to increase physical activity and improve health in middle- to older age women?: A RE-AIM evaluation.

BACKGROUND: Physical activity is a modifiable risk factor for health and wellbeing, all-cause mortality and healthy aging. However, for middle- to older-age females less is known about the benefits of sports participation on these outcomes. Further, the acceptability and feasibility of setting-up, implementing and maintaining sports-based programmes for an aging population is an understudied area of inquiry. The current study used the RE-AIM framework to investigate a nationwide Walking Netball (WN) programme. METHODS: The evaluation used a mixed-methods approach incorporating a multiple-baseline study, quasi-experimental study, programme monitoring data and qualitative studies to evaluate the programme in the Women's Institutes (WI) in England. Data were analysed using multilevel growth modelling, mixed-design ANOVAs, multilevel regression, t-testing, and thematic analysis. Data were triangulated to address each dimension of the RE-AIM framework. FINDINGS: The programme reached 1.4% (n = 3148) of the WI population across 82.0% of WI regions in England and attracted inactive members at risk of ill-health. WN contributed to adaptations in physical function, mental health and wellbeing, social isolation, quality of life and increased physical activity. The adoption of the programme was successful with 87.7% WN groups' maintaining participation beyond the 20-session initial delivery phase. Adoption was effective because of its set-up, peer-mentorship and long-term delivery; these factors likewise shaped implementation. Adapting and tailoring WN to the varying characteristics of participants within the WI and the facilities available, along with training delivery staff and providing resources are key programme components. The Walking Netball programme can be maintained through promotion within the local community, sustainable funding, inter-WI competitions, festivals and networks, multiple-hosts and continued host development. CONCLUSIONS: WN was found to be an acceptable, feasible and effective intervention to increase physical activity and improve health in middle- to older- aged women. Future programmes may consider adapted styles of set-up and delivery. These include adapting to people, places and spaces through personalised support and providing a range of resources. Future designs may seek to understand how participation can contribute to healthy aging through longitudinal research beyond 12-months. STUDY REGISTRATION: The evaluation protocol was published in Open Science Framework in December 2018 prior to follow-up data collection being collected ( https://www.osf.io/dcekz ). Date of registration: 17 December 2018.

'Test n Treat' (TnT): a cluster randomized feasibility trial of on-site rapid Chlamydia trachomatis tests and treatment in ethnically diverse, sexually active teenagers attending technical colleges.

OBJECTIVES: We conducted a cluster-randomized feasibility trial of 90-minute Chlamydia trachomatis tests and same day on-site treatment ('Test n Treat/TnT') in six technical colleges in London, England, to assess TnT uptake rates; follow-up rates; prevalence of C. trachomatis at baseline and 7 months; time to treatment; acceptability of TnT. METHODS: Participants completed questionnaires and provided genitourinary samples at baseline and 7 months. Participants were informed that baseline samples would not be tested for 7 months and were advised to get screened independently. Colleges were randomly allocated 1:1 to intervention (TnT) or control (no TnT). One month and 4 months post recruitment, participants at intervention colleges were texted invitations for on-site free C. trachomatis tests. A purposive sample of students who did/did not attend for screening were interviewed (n = 26). RESULTS: Five hundred and nine sexually active students were recruited: median age 17.9 years, 47% male, 50% black ethnicity, 55% reporting two or more sexual partners in the previous year. TnT uptake was 13% (33/259; 95% CI 8.9-17.4%) at 1 month and 10% (26/259; 6.7-14.4%) at 4 months with overall C. trachomatis positivity 5.1% (3/59; 1.1-14.2%). Follow-up at 7 months was 62% (317/509) for questionnaires and 52% (264/509) for samples. C. trachomatis prevalence was 6.2% (31/503) at baseline and 6.1% (16/264) at 7 months. Median time from test to treatment was 15 h. Interviews suggested low test uptake was associated with not feeling at risk, perceptions of stigma, and little knowledge of sexually transmitted infections (STIs). CONCLUSIONS: Despite high C. trachomatis rates at baseline and follow-up, uptake of testing was low. Like many countries, England urgently needs better sex education, including making STI testing routine/normal. Trial registration ISRCTN58038795.

MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates.

Studies on mucosal-associated invariant T cells (MAITs) in nonhuman primates (NHP), a physiologically relevant model of human immunity, are handicapped due to a lack of macaque MAIT-specific reagents. Here we show that while MR1 ligand-contact residues are conserved between human and multiple NHP species, three T-cell receptor contact-residue mutations in NHP MR1 diminish binding of human MR1 tetramers to macaque MAITs. Construction of naturally loaded macaque MR1 tetramers facilitated identification and characterization of macaque MR1-binding ligands and MAITs, both of which mirrored their human counterparts. Using the macaque MR1 tetramer we show that NHP MAITs activated in vivo in response to both Bacillus Calmette-Guerin vaccination and Mycobacterium tuberculosis infection. These results demonstrate that NHP and human MR1 and MAITs function analogously, and establish a preclinical animal model to test MAIT-targeted vaccines and therapeutics for human infectious and autoimmune disease.

The financial and service implications of splitting fixed-dose antiretroviral drugs - a case study.

In 2010/2011, regional commissioners withdrew payment for the fixed-dose combination Combivir, forcing a switch to component drugs. This was deemed clinically acceptable and annual savings of £44 k expected. We estimated the true costs of switching and examined patient outcomes. Information for 46 patients using Combivir was extracted from case notes for each clinical contact in the 12 months pre- and post-switch (clinician seen, tests, antiretrovirals). Post-switch care costs £93/patient more annually versus pre-switch (95% CI £424 to £609), yielding £4278/year more post-switch for all patients. Drug and pathology costs were more expensive post-switch and extra clinical visits required. None of these results were statistically significant. Forty-two per cent of patients switched directly or in the subsequent year to an alternative fixed-dose combination rather than generics. Costs in this group were significantly higher post-switch driven by drug cost. Six patients (13%) reported problems with the switch including confusion around dosing and new side effects. As less-expensive generic antiretroviral drugs become available, it may appear cheaper to switch from fixed-dose combinations to component drugs. However, the additional clinical costs involved may outweigh the initial cost savings of the drugs and switching may cause confusion for some patients, risking loss of adherence.

Impact of third- and fourth-degree perineal tears at first birth on subsequent pregnancy outcomes: a cohort study.

OBJECTIVE: To investigate, among women who have had a third- or fourth-degree perineal tear, the mode of delivery in subsequent pregnancies as well as the recurrence rate of third- or fourth-degree tears. DESIGN: A retrospective cohort study of deliveries using a national administrative database. SETTING: The English National Health Service between 1 April 2004 and 31 March 2012. POPULATION: A total of 639,402 primiparous women who had a singleton, term, vaginal live birth between April 2004 and March 2011, and a second birth before April 2012. METHODS: Multivariable logistic regression models were used to estimate odds ratios, adjusted for other risk factors. MAIN OUTCOME MEASURES: Mode of delivery and recurrence of tears at second birth. RESULTS: The rate of elective caesarean at second birth was 24.2% for women with a third- or fourth-degree tear at first birth, and 1.5% for women without (adjusted odds ratio, aOR 18.3, 95% confidence interval, 95% CI 16.4-20.4). Among women who had a vaginal delivery at second birth, the rate of third- or fourth-degree tears was 7.2% for women with a third- or fourth-degree tear at first birth, compared with 1.3% for women without (aOR 5.5, 95% CI 5.2-5.9). CONCLUSIONS: The risk of a severe perineal tear is increased five-fold in women who had a third- or fourth-degree tear in their first delivery. This increased risk should be taken into account when decisions about mode of delivery are made.

Third- and fourth-degree perineal tears among primiparous women in England between 2000 and 2012: time trends and risk factors.

OBJECTIVE: To describe the trends of severe perineal tears in England and to investigate to what extent the changes in related risk factors could explain the observed trends. DESIGN: A retrospective cohort study of singleton deliveries from a national administrative database. SETTING: The English National Health Service between 1 April 2000 and 31 March 2012. POPULATION: A cohort of 1 035 253 primiparous women who had a singleton, term, cephalic, vaginal birth. METHODS: Multivariable logistic regression was used to estimate the impact of financial year of birth (labelled by starting year), adjusting for major risk factors. MAIN OUTCOME MEASURE: The rate of third-degree (anal sphincter is torn) or fourth-degree (anal sphincter as well as rectal mucosa are torn) perineal tears. RESULTS: The rate of reported third- or fourth-degree perineal tears tripled from 1.8 to 5.9% during the study period. The rate of episiotomy varied between 30 and 36%. An increasing proportion of ventouse deliveries (from 67.8 to 78.6%) and non-instrumental deliveries (from 15.1 to 19.1%) were assisted by an episiotomy. A higher risk of third- or fourth-degree perineal tears was associated with a maternal age above 25 years, instrumental delivery (forceps and ventouse), especially without episiotomy, Asian ethnicity, a more affluent socio-economic status, higher birthweight, and shoulder dystocia. CONCLUSIONS: Changes in major risk factors are unlikely explanations for the observed increase in the rate of third- or fourth-degree tears. The improved recognition of tears following the implementation of a standardised classification of perineal tears is the most likely explanation.

Health care providers' attention to food insecurity in households with children.

OBJECTIVE: To determine the extent to which physicians and nurse practitioners monitor household food insecurity (FI) of families with children, and to examine factors that influence FI monitoring. METHOD: A 2007 mail survey of family practice and pediatric physicians and nurse practitioners in the Portland, Oregon, region yielded 186 responses. Factor analysis was used to identify barriers to asking about FI. Regression analysis was used to determine whether monitoring of household food status was predicted by those barriers, attentiveness to potential FI indicators, and other variables. RESULTS: Most respondents did not routinely inquire about household FI during clinic visits. However, 88.8% expressed willingness to use a standardized screening question, if available. Monitoring of household food nutritional quality was significantly predicted by one of three identified barriers (providers' time availability). Monitoring of household food sufficiency was predicted by years in practice, attentiveness to FI indicators, and the remaining two identified barriers (inadequate knowledge about FI, discomfort in discussing FI). CONCLUSION: Routine monitoring of patients' household FI by health care providers is an underutilized strategy for reducing this condition, which poses serious risks to children's health and development. Addressing providers' concerns and introducing standardized screening procedures can increase their monitoring behaviors.

Practical aspects of implementation of helical tomotherapy for intensity-modulated and image-guided radiotherapy.

AIMS: Image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT) represent two important technical developments that will probably improve patient outcome. Helical tomotherapy, provided by the TomoTherapy HiArt system, provides an elegant integrated solution providing both technologies, although others are available. Here we report our experience of clinical implementation of daily online IGRT and IMRT using helical tomotherapy. MATERIALS AND METHODS: Methods were needed to select patients who would probably benefit. Machine-specific commissioning, a quality assurance programme and patient-specific delivery quality assurance were also needed. The planning target volume dose was prescribed as the median dose, with the added criterion that the 95% isodose should cover 99% of the target volume. Although back-up plans, for delivery on conventional linear accelerators, were initially prepared, this practice was abandoned because they were used very rarely. RESULTS: In the first 12 months, 114 patients were accepted for treatment, and 3343 fractions delivered. New starts averaged 2.6 per week, with an average of 17.5 fractions treated per day, and the total number capped at 22. This has subsequently been raised to 24. Of the first 100 patients, 96 were treated with radical intent. Five were considered to have been untreatable on our standard equipment. IGRT is radiographer led and all patients were imaged daily, with positional correction made before treatment, using an action level of 1mm. A formal training programme was developed and implemented before installation. The in-room time fell significantly during the year, reflecting increasing experience and a software upgrade. More recently, after a couch upgrade in April 2009, the mean in-room time fell to 18.6 min. CONCLUSIONS: Successful implementation of tomotherapy was the result of careful planning and effective teamwork. Treatment, including daily image guidance, positional correction and intensity-modulated delivery, is fast and efficient, and can be integrated into routine service. This should encourage the adoption of these technologies.

Liverpool Ultrasound Pictorial Chart: the development of a new method of documenting anal sphincter injury diagnosed by endoanal ultrasound.

OBJECTIVE: To develop and validate a pictorial chart that documents ultrasound examination of the anal sphincter. DESIGN: A new pictorial chart (Liverpool Ultrasound Pictorial Chart [LUPIC]) depicting the normal anatomy of the anal sphincter was developed. METHODS: To validate LUPIC, two observers documented the findings of 296 endoanal scans. Reliability was assessed between observers using kappa agreement for presence and position of sphincter defects. To validate the use of LUPIC by different observers, a video of ten endoanal ultrasound scans was reviewed by our local expert (gold standard). Seven clinicians underwent test-retest analysis. Kappa agreement was calculated to assess intra-observer and gold standard versus observer agreement for the overall presence of sphincter defects and compared with the gold standard. Complete agreement for the position and level of sphincter defects was assessed for the five abnormal scans. MAIN OUTCOME MEASURES: Excellent agreement between the two observers was found for the presence (kappa 0.99), position and level of external anal sphincter defects documented using LUPIC. The intra-observer and gold standard versus observer kappa values of experienced clinicians (A-E) showed good agreement for the overall presence of sphincter defects. Complete agreement for the position and level of sphincter defects was found in 23 of 35 (66%) observations. CONCLUSIONS: LUPIC is designed and validated method of documenting anal sphincter injury diagnosed by endoanal ultrasound. Standardisation of endoanal ultrasound findings by using LUPIC may help correlate the degree of damage with patient symptoms.

An investigation into methods of IMRT planning applied to breast radiotherapy.

The purpose of this study was to investigate methods used to modulate dose distributions in radiotherapy planning, to determine the fundamental features of these and to establish the attainable dose uniformity. Published modulation methods were categorized, and a simple physical model devised to predict the weight of the wedged beam and the relative dose distribution for each category. Each technique was applied to patient data with planning target volume sizes ranging from below 500 cm(3) to 2200 cm(3). The spatial distribution of high-dose regions in the breast, and maximum dose for the heart and lung, were determined for each plan. The dose uniformity was analysed by evaluating the volume of the breast (V(I)) receiving <95% and <105% of the prescribed dose. The difference between V(105%) and V(95%) for each method for each patient data set was also calculated. The simple model predicted the trend in percentage weight of the wedge beam and the form of the dose distribution in the transverse plane with the modulation method. Improvements in the dose uniformity were seen for the majority of modulation methods. The magnitude of the change was between 5.6% and 11.1% (p<0.05) of the breast volume for breast sizes above 500 cm(3). Some modulation methods introduced high dose at the chest wall. In conclusion, the majority of the methods improved dose uniformity for breast sizes of 500 cm(3) or greater. No method showed a clear advantage over the others. The use of modulation methods should be governed by consideration of its effects relative to a simple wedge plan.

A comparison between cobalt and linear accelerator-based treatment plans for conformal and intensity-modulated radiotherapy.

The simplicity of cobalt units gives them the advantage of reduced maintenance, running costs and downtime when compared with linear accelerators. However, treatments carried out on such units are typically limited to simple techniques. This study has explored the use of cobalt beams for conformal and intensity-modulated radiotherapy (IMRT). Six patients, covering a range of treatment sites, were planned using both X-ray photons (6/10 MV) and cobalt-60 gamma rays (1.17 and 1.33 MeV). A range of conformal and IMRT techniques were considered, as appropriate. Conformal plans created using cobalt beams for small breast, meningioma and parotid cases were found to compare well with those created using X-ray photons. By using additional fields, acceptable conformal plans were also created for oesophagus and prostate cases. IMRT plans were found to be of comparable quality for meningioma, parotid and thyroid cases on the basis of dose-volume histogram analysis. We conclude that it is possible to plan high-quality radical radiotherapy treatments for cobalt units. A well-designed beam blocking/compensation system would be required to enable a practical and efficient alternative to multileaf collimator (MLC)-based linac treatments to be offered. If cobalt units were to have such features incorporated into them, they could offer considerable benefits to the radiotherapy community.

Surgical management of pelvic organ prolapse in women: a short version Cochrane review.

BACKGROUND: Pelvic organ prolapse may occur in up to 50% of parous women. A variety of urinary, bowel and sexual symptoms may be associated with prolapse. OBJECTIVES: To determine the effects of the many different surgeries in the management of pelvic organ prolapse. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 3 May 2006) and reference lists of relevant articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that included surgical operations for pelvic organ prolapse. DATA COLLECTION AND ANALYSIS: Trials were assessed and data extracted independently by two reviewers. Six investigators were contacted for additional information with five responding. MAIN RESULTS: Twenty two randomised controlled trials were identified evaluating 2368 women. Abdominal sacral colpopexy was better than vaginal sacrospinous colpopexy in terms of a lower rate of recurrent vault prolapse (RR 0.23, 95% CI 0.07 to 0.77) and less dyspareunia (RR 0.39, 95% CI 0.18 to 0.86), but the trend towards a lower re-operation rate for prolapse following abdominal sacrocolpopexy was not statistically significant (RR 0.46, 95% CI 0.19 to 1.11). However, the vaginal sacrospinous colpopexy was quicker and cheaper to perform and women had an earlier return to activities of daily living. The data were too few to evaluate other clinical outcomes and adverse events. The three trials contributing to this comparison were clinically heterogeneous. For the anterior vaginal wall prolapse, standard anterior repair was associated with more recurrent cystoceles than when supplemented by polyglactin mesh inlay (RR 1.39, 95% CI 1.02 to 1.90) or porcine dermis mesh inlay (RR 2.72, 95% CI 1.20 to 6.14), but data on morbidity, other clinical outcomes and for other mesh or graft materials were too few for reliable comparisons. For posterior vaginal wall prolapse, the vaginal approach was associated with a lower rate of recurrent rectocele and/or enterocele than the transanal approach (RR 0.24, 95% CI 0.09 to 0.64), although there was a higher blood loss and postoperative narcotic use. However, data on the effect of surgery on bowel symptoms and the use of polyglactin mesh inlay or porcine small intestine graft inlay on the risk of recurrent rectocele were insufficient for meta-analysis.Meta-analysis on the impact of pelvic organ prolapse surgery on continence issues was limited and inconclusive, although about 10% of women developed new urinary symptoms after surgery. Although the addition of tension-free vaginal tape to endopelvic fascia plication (RR 5.5, 95% CI 1.36 to 22.32) and Burch colposuspension to abdominal sacrocolpopexy (RR 2.13, 95% CI 1.39 to 3.24) were followed by a lower risk of women developing new postoperative stress incontinence, but other outcomes, particularly economic, remain to be evaluated. AUTHORS' CONCLUSIONS: Abdominal sacrocolpopexy is associated with a lower rate of recurrent vault prolapse and dyspareunia than the vaginal sacrospinous colpopexy. These benefits must be balanced against a longer operating time, longer time to return to activities of daily living and increased cost of the abdominal approach. The use of mesh or graft inlays at the time of anterior vaginal wall repair may reduce the risk of recurrent cystocele. Posterior vaginal wall repair may be better than transanal repair in the management of rectoceles in terms of recurrence of prolapse. The addition of a continence procedure to a prolapse repair operation may reduce the incidence of postoperative urinary incontinence but this benefit needs to be balanced against possible differences in costs and adverse effects. Adequately powered randomised controlled clinical trials are urgently needed.

Surgical management of pelvic organ prolapse in women.

BACKGROUND: Pelvic organ prolapse may occur in up to 50% of parous women. A variety of urinary, bowel and sexual symptoms may be associated with prolapse. OBJECTIVES: To determine the effects of the many different surgeries in the management of pelvic organ prolapse. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 3 May 2006) and reference lists of relevant articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that included surgical operations for pelvic organ prolapse. DATA COLLECTION AND ANALYSIS: Trials were assessed and data extracted independently by two reviewers. Six investigators were contacted for additional information with five responding. MAIN RESULTS: Twenty two randomised controlled trials were identified evaluating 2368 women. Abdominal sacral colpopexy was better than vaginal sacrospinous colpopexy in terms of a lower rate of recurrent vault prolapse (RR 0.23, 95% CI 0.07 to 0.77) and less dyspareunia (RR 0.39, 95% CI 0.18 to 0.86), but the trend towards a lower re-operation rate for prolapse following abdominal sacrocolpopexy was not statistically significant (RR 0.46, 95% CI 0.19 to 1.11). However, the vaginal sacrospinous colpopexy was quicker and cheaper to perform and women had an earlier return to activities of daily living. The data were too few to evaluate other clinical outcomes and adverse events. The three trials contributing to this comparison were clinically heterogeneous. For the anterior vaginal wall prolapse, standard anterior repair was associated with more recurrent cystoceles than when supplemented by polyglactin mesh inlay (RR 1.39, 95% CI 1.02 to 1.90) or porcine dermis mesh inlay (RR 2.72, 95% CI 1.20 to 6.14), but data on morbidity, other clinical outcomes and for other mesh or graft materials were too few for reliable comparisons. For posterior vaginal wall prolapse, the vaginal approach was associated with a lower rate of recurrent rectocele and/or enterocele than the transanal approach (RR 0.24, 95% CI 0.09 to 0.64), although there was a higher blood loss and postoperative narcotic use. However, data on the effect of surgery on bowel symptoms and the use of polyglactin mesh inlay or porcine small intestine graft inlay on the risk of recurrent rectocele were insufficient for meta-analysis.Meta-analysis on the impact of pelvic organ prolapse surgery on continence issues was limited and inconclusive, although about 10% of women developed new urinary symptoms after surgery. Although the addition of tension-free vaginal tape to endopelvic fascia plication (RR 5.5, 95% CI 1.36 to 22.32) and Burch colposuspension to abdominal sacrocolpopexy (RR 2.13, 95% CI 1.39 to 3.24) were followed by a lower risk of women developing new postoperative stress incontinence, but other outcomes, particularly economic, remain to be evaluated. AUTHORS' CONCLUSIONS: Abdominal sacrocolpopexy is associated with a lower rate of recurrent vault prolapse and dyspareunia than the vaginal sacrospinous colpopexy. These benefits must be balanced against a longer operating time, longer time to return to activities of daily living and increased cost of the abdominal approach. The use of mesh or graft inlays at the time of anterior vaginal wall repair may reduce the risk of recurrent cystocele. Posterior vaginal wall repair may be better than transanal repair in the management of rectoceles in terms of recurrence of prolapse. The addition of a continence procedure to a prolapse repair operation may reduce the incidence of postoperative urinary incontinence but this benefit needs to be balanced against possible differences in costs and adverse effects. Adequately powered randomised controlled clinical trials are urgently needed.

Modelling the effectiveness of chlamydia screening in England.

BACKGROUND: Several developed countries have initiated chlamydia screening programmes. Screening for a sexually transmitted infection has both direct individual and indirect population-wide effects. Mathematical models can incorporate these non-linear effects and estimate the likely impact of different screening programmes and identify areas where more data are needed. METHODS: A stochastic, individual based dynamic network model, parameterised from UK screening studies and data on sexual behaviour and chlamydia epidemiology, was used to investigate the likely impact of opportunistic screening on chlamydia prevalence. Three main strategies were considered for <25 year olds: (1) annual offer to women; (2) annual offer to women or if changed partner within last 6 months; (3) annual offer to men and women. Sensitivity analyses were performed for key screening parameters including uptake rate, targeted age range, percentage of partners notified, and screening interval. RESULTS: Under strategy 1, continuous opportunistic screening of women <25 years of age is expected to reduce the population prevalence by over 50% after 5 years. Prevalence is also expected to decrease in unscreened older women and in men. For all three strategies screening those aged over 25 results in small additional reductions in prevalence. Including men led to a faster and greater reduction in overall prevalence, but involved approximately twice as many tests as strategy 1 and 10% more than strategy 2. The frequency of attendance at healthcare sites limits the number of opportunities to screen and the effect of changing the screening interval. CONCLUSIONS: The model suggests that continuous opportunistic screening at high uptake rates could significantly reduced chlamydia prevalence within a few years. Opportunistic programmes depend on regular attendance at healthcare providers, but there is a lack of high quality data on patterns of attendance. Inequalities in coverage may result in a less efficient and less equitable outcome.

Re-engineering the target specificity of Clostridial neurotoxins - a route to novel therapeutics.

The ability to chemically couple proteins to LH(N)-fragments of clostridial neurotoxins and create novel molecules with selectivity for cells other than the natural target cell of the native neurotoxin is well established. Such molecules are able to inhibit exocytosis in the target cell and have the potential to be therapeutically beneficial where secretion from a particular cell plays a causative role in a disease or medical condition. To date, these molecules have been produced by chemical coupling of the LH(N)-fragment and the targeting ligand. This is, however, not a suitable basis for producing pharmaceutical agents as the products are ill defined, difficult to control and heterogeneous. Also, the molecules described to date have targeted neuroendocrine cells that are susceptible to native neurotoxins, and therefore the benefit of creating a molecule with a novel targeting domain has been limited. In this paper, the production of a fully recombinant fusion protein from a recombinant gene encoding both the LH(N)-domain of a clostridial neurotoxin and a specific targeting domain is described, together with the ability of such recombinant fusion proteins to inhibit secretion from non-neuronal target cells. Specifically, a novel protein consisting of the LH(N)-domains of botulinum neurotoxin type C and epidermal growth factor (EGF) that is able to inhibit secretion of mucus from epithelial cells is reported. Such a molecule has the potential to prevent mucus hypersecretion in asthma and chronic obstructive pulmonary disease.

An investigation of dose calculation accuracy in intensity-modulated radiotherapy of sites in the head & neck.

Knowledge of the accuracy of dose calculations in intensity-modulated radiotherapy of the head and neck is essential for clinical confidence in these highly conformal treatments. High dose gradients are frequently placed very close to critical structures, such as the spinal cord, and good coverage of complex shaped nodal target volumes is important for long term-local control. A phantom study is presented comparing the performance of standard clinical pencil-beam and collapsed-cone dose algorithms to Monte Carlo calculation and three-dimensional gel dosimetry measurement. Calculations and measurements are individually normalized to the median dose in the primary planning target volume, making this a purely relative study. The phantom simulates tissue, air and bone for a typical neck section and is treated using an inverse-planned 5-field IMRT treatment, similar in character to clinically used class solutions. Results indicate that the pencil-beam algorithm fails to correctly model the relative dose distribution surrounding the air cavity, leading to an cverestimate of the target coverage. The collapsed-cone and Monte Carlo results are very similar, indicating that the clinical collapsed-cone algorithm is perfectly sufficient for routine clinical use. The gel measurement shows generally good agreement with the collapsed-cone and Monte Carlo calculated dose, particularly in the spinal cord dose and nodal target coverage, thus giving greater confidence in the use of this class solution.

Surgical management of pelvic organ prolapse in women.

BACKGROUND: Pelvic organ prolapse may occur in up to 50% of parous women. A variety of urinary, bowel and sexual symptoms may be associated with prolapse. OBJECTIVES: To determine the effects of surgery in the management of pelvic organ prolapse. SEARCH STRATEGY: We searched the Cochrane Incontinence Group trials register (8 June 2004) and reference lists of relevant articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that included surgical operations for pelvic organ prolapse. DATA COLLECTION AND ANALYSIS: Trials were assessed and data extracted independently by at least two reviewers. Four investigators were contacted for additional information with two responding. MAIN RESULTS: Fourteen randomised controlled trials were identified evaluating 1004 women. Abdominal sacral colpopexy was better than vaginal sacrospinous colpopexy in terms of a lower rate of recurrent vault prolapse (RR 0.23, 95% CI 0.07 to 0.77) and less dyspareunia (RR 0.39, 95% CI 0.18 to 0.86), but the trend towards a lower re-operation rate for prolapse following abdominal sacrocolpopexy was not statistically significant (RR 0.46, 95% CI 0.19 to 1.11). However, the vaginal sacrospinous colpopexy was quicker and cheaper to perform and women had an earlier return to activities of daily living. The data were to evaluate other clinical outcomes and adverse events. For the anterior vaginal wall prolapse, standard anterior repair was associated with more recurrent cystoceles than when supplemented by Vicryl mesh overlay (RR 1.39, 95% CI 1.02 to 1.90) but data on morbidity and other clinical outcomes were too few for reliable comparisons. For posterior vaginal wall prolapse, the vaginal approach was associated with a lower rate of recurrent rectocele and/or enterocele than the transanal approach (RR 0.24, 95% CI 0.09 to 0.64), although there was a higher blood loss and postoperative narcotic use. However, data on the effect of surgery on bowel symptoms and the use of polyglactin mesh overlay on the risk of recurrent rectocele were insufficient for meta-analysis.Meta-analysis on the impact of pelvic organ prolapse surgery on continence issues was limited and inconclusive, although about 10% of women developed new symptoms after surgery. However, more women with occult stress urinary incontinence developed postoperative stress urinary incontinence after endopelvic fascia plication alone than after endopelvic fascia plication and tension-free vaginal tape (RR 5.5, 95% CI 1.36 to 22.32). REVIEWERS' CONCLUSIONS: Abdominal sacrocolpopexy is associated with a lower rate of recurrent vault prolapse and dyspareunia than the vaginal sacrospinous colpopexy. These benefits must be balanced against a longer operating time, longer time to return to activities of daily living and increased cost of the abdominal approach. The use of a polyglactin mesh overlay at the time of anterior vaginal wall repair may reduce the risk of recurrent cystocele. Posterior vaginal wall repair may be better than transanal repair in the management of rectoceles in terms of recurrence of prolapse. Adequately powered randomised controlled clinical trials are urgently needed.

Modelling the healthcare costs of an opportunistic chlamydia screening programme.

OBJECTIVES: To estimate the average cost per screening offer, cost per testing episode and cost per chlamydia positive episode for an opportunistic chlamydia screening programme (including partner management), and to explore the uncertainty of parameter assumptions, based on the costs to the healthcare system. METHODS: A decision tree was constructed and parameterised using empirical data from a chlamydia screening pilot study and other sources. The model was run using baseline data from the pilot, and univariate and multivariate sensitivity analyses were conducted. RESULTS: The total estimated cost for offering screening over 12 months to 33,215 females aged 16-24 was 493,412 pounds . The average cost (with partner management) was 14.88 pounds per screening offer (90% credibility interval (CI) 10.34 to 18.56), 21.83 pounds per testing episode (90% CI 18.16 to 24.20), and 38.36 pounds per positive episode (90% CI 33.97 to 42.25). The proportion of individuals accepting screening, the clinician (general practitioner/nurse) time and their relative involvement in discussing screening, the test cost, the time to notify patients of their results, and the receptionist time recruiting patients had the greatest impact on the outcomes in both the univariate and multivariate sensitivity analyses. CONCLUSIONS: Results from this costing study may be used to inform resource allocation for current and future chlamydia screening programme implementation.

Chlamydia trachomatis in the United Kingdom: a systematic review and analysis of prevalence studies.

OBJECTIVES: To undertake a systematic review to obtain estimates of genital Chlamydia trachomatis prevalence in various populations in the United Kingdom and Ireland; to determine which populations have the highest rates of infection; and to explore the most important determinants of infection. METHODS: Electronic databases were searched using the keywords "chlamydia" and "England," "Wales," "UK," "Scotland," "Ireland," or "Britain." Additional unpublished data and references were solicited from experts. Studies were included in the analysis if C trachomatis prevalence was reported, and if they met inclusion criteria. Nine variables identified as potentially important descriptors of chlamydia prevalence were extracted from each study and analysed using various logistic regression models. Only studies reporting prevalence in female populations were included in the models, because there were few data from males. RESULTS: 357 studies were identified using the search methods, 90 of which met inclusion criteria, and 19 of which contributed to the final model. The most influential variables on prevalence were age and setting of the population tested. In general practice surgeries, the under 20 year old age group had an estimated prevalence of 8.1% (95% CI 6.5 to 9.9), 20-24 year olds 5.2% (95% CI 4.3 to 6.3), 25-29 year olds 2.6% (95% CI 2.0 to 3.3), decreasing to 1.4% (95% CI 1.0 to 1.9) in those aged over 30 years. Overall, healthcare settings had higher prevalence estimates than population based studies. For example, among under 20 year olds, estimates were 17.3% (95% CI 13.6 to 21.8) in genitourinary medicine clinics, 12.6% (95% CI 6.4 to 23.2) in antenatal clinics, 12.3% (95% CI 9.8 to 15.3) in termination of pregnancy clinics, 10.7% (95% CI 8.3 to 13.8) in youth clinics, 10.0% (95% CI 8.7 to 11.5) in family planning clinics, and 8.1% (95% CI 6.5 to 9.9) in general practice, compared to 5.0% (95% CI 3.2 to 7.6) in population based studies. The type of test, specimen used, date, and location of test were not strongly associated with chlamydia prevalence. CONCLUSION: The chlamydia prevalence estimates by age and setting from the model may be used to inform chlamydia screening strategies. The systematic review revealed much heterogeneity in the studies identified, but with clear patterns of prevalence. It also indicated gaps in the knowledge about chlamydia prevalence in certain subgroups such as men and the general population.

Implementation of IMRT in the radiotherapy department.

This paper describes the implementation of intensity modulated radiotherapy (IMRT) in a radiotherapy department. When preparing to set-up an IMRT programme, it is important to review departmental protocols with regard to immobilization, CT planning, treatment planning and verification. Any additional quality assurance steps also need to be fully understood. A new IMRT programme is most likely to be successful if it builds on established clinical experience with three-dimensional conformal radiotherapy (CRT). Training of radiographers, clinicians and physicists is critical, and both team-work and communication are vital to ensure a smooth transition from 3DCRT to IMRT delivery in the clinic.