Female Urgency, Trial of Urodynamics as Routine Evaluation (FUTURE study): a superiority randomised clinical trial to evaluate the effectiveness and cost-effectiveness of invasive urodynamic investigations in management of women with refractory overactive bladder symptoms.

BACKGROUND: Overactive bladder (OAB) syndrome is a symptom complex affecting 12-14% of the UK adult female population. Symptoms include urinary urgency, with or without urgency incontinence, increased daytime urinary frequency and nocturia. OAB has a negative impact on women's social, physical, and psychological wellbeing. Initial treatment includes lifestyle modifications, bladder retraining, pelvic floor exercises and pharmacological therapy. However, these measures are unsuccessful in 25-40% of women (refractory OAB). Before considering invasive treatments, such as Botulinum toxin injection or sacral neuromodulation, most guidelines recommend urodynamics to confirm diagnosis of detrusor overactivity (DO). However, urodynamics may fail to show evidence of DO in up to 45% of cases, hence the need to evaluate its effectiveness and cost-effectiveness. FUTURE (Female Urgency, Trial of Urodynamics as Routine Evaluation) aims to test the hypothesis that, in women with refractory OAB, urodynamics and comprehensive clinical assessment is associated with superior patient-reported outcomes following treatment and is more cost-effective, compared to comprehensive clinical assessment only. METHODS: FUTURE is a pragmatic, multi-centre, superiority randomised controlled trial. Women aged ≥ 18 years with refractory OAB or urgency predominant mixed urinary incontinence, and who have failed/not tolerated conservative and medical treatment, are considered for trial entry. We aim to recruit 1096 women from approximately 60 secondary/tertiary care hospitals across the UK. All consenting women will complete questionnaires at baseline, 3 months, 6 months and 15 months post-randomisation. The primary outcome is participant-reported success at 15 months post-randomisation measured using the Patient Global Impression of Improvement. The primary economic outcome is incremental cost per quality-adjusted life year gained at 15 months. The secondary outcomes include adverse events, impact on other urinary symptoms and health-related quality of life. Qualitative interviews with participants and clinicians and a health economic evaluation will also be conducted. The statistical analysis of the primary outcome will be by intention-to-treat. Results will be presented as estimates and 95% CIs. DISCUSSION: The FUTURE study will inform patients, clinicians and policy makers whether routine urodynamics improves treatment outcomes in women with refractory OAB and whether it is cost-effective. TRIAL REGISTRATION: ISRCTN63268739 . Registered on 14 September 2017.

Mesh inlay, mesh kit or native tissue repair for women having repeat anterior or posterior prolapse surgery: randomised controlled trial (PROSPECT).

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.

ELECtric Tibial nerve stimulation to Reduce Incontinence in Care homes: protocol for the ELECTRIC randomised trial.

BACKGROUND: Urinary incontinence (UI) is highly prevalent in nursing and residential care homes (CHs) and profoundly impacts on residents' dignity and quality of life. CHs predominantly use absorbent pads to contain UI rather than actively treat the condition. Transcutaneous posterior tibial nerve stimulation (TPTNS) is a non-invasive, safe and low-cost intervention with demonstrated effectiveness for reducing UI in adults. However, the effectiveness of TPTNS to treat UI in older adults living in CHs is not known. The ELECTRIC trial aims to establish if a programme of TPTNS is a clinically effective treatment for UI in CH residents and investigate the associated costs and consequences. METHODS: This is a pragmatic, multicentre, placebo-controlled, randomised parallel-group trial comparing the effectiveness of TPTNS (target n = 250) with sham stimulation (target n = 250) in reducing volume of UI in CH residents. CH residents (men and women) with self- or staff-reported UI of more than once per week are eligible to take part, including those with cognitive impairment. Outcomes will be measured at 6, 12 and 18 weeks post randomisation using the following measures: 24-h Pad Weight Tests, post void residual urine (bladder scans), Patient Perception of Bladder Condition, Minnesota Toileting Skills Questionnaire and Dementia Quality of Life. Economic evaluation based on a bespoke Resource Use Questionnaire will assess the costs of providing a programme of TPTNS. A concurrent process evaluation will investigate fidelity to the intervention and influencing factors, and qualitative interviews will explore the experiences of TPTNS from the perspective of CH residents, family members, CH staff and managers. DISCUSSION: TPTNS is a non-invasive intervention that has demonstrated effectiveness in reducing UI in adults. The ELECTRIC trial will involve CH staff delivering TPTNS to residents and establish whether TPTNS is more effective than sham stimulation for reducing the volume of UI in CH residents. Should TPTNS be shown to be an effective and acceptable treatment for UI in older adults in CHs, it will provide a safe, low-cost and dignified alternative to the current standard approach of containment and medication. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03248362. Registered on 14 August 2017. ISRCTN, ISRCTN98415244. Registered on 25 April 2018. https://www.isrctn.com/.

Application of Hyperspectral imaging to predict the pH, intramuscular fatty acid content and composition of lamb M. longissimus lumborum at 24h post mortem.

Cost-effective, rapid and objective measurement of lamb quality on a routine basis is an important step for lamb value chains wishing to manage lamb product quality. Hyperspectral imaging (HSI) technology has shown promise as a solution for objective non-invasive prediction of meat quality. The performance of HSI applied 24h post mortem to lamb M. longissimus lumborum (LL) within a processing plant environment was assessed over two sampling years to evaluate its suitability for an objective lamb meat quality assurance tool. Calibration and validation steps were undertaken to evaluate HSI prediction performance for predicting fatty acid content and composition (n=1020 lambs) and pH (n=2406 lambs). Practical considerations of reference meat quality data quality and validation strategies are discussed. HSI can be used to predict meat quality parameters of lamb LL with varying accuracy levels, but ongoing calibration and validation across seasons is required to improve robustness of HSI for objective non-invasive assessment of lamb meat quality.

Reporting and dealing with missing quality of life data in RCTs: has the picture changed in the last decade?

PURPOSE: Missing data are a major problem in the analysis of data from randomised trials affecting power and potentially producing biased treatment effects. Specifically focussing on quality of life outcomes, we aimed to report the amount of missing data, whether imputation was used and what methods and was the missing mechanism discussed from four leading medical journals and compare the picture to our previous review nearly a decade ago. METHODS: A random selection (50 %) of all RCTS published during 2013-2014 in BMJ, JAMA, Lancet and NEJM was obtained. RCTs reported in research letters, cluster RCTs, non-randomised designs, review articles and meta-analysis were excluded. RESULTS: We included 87 RCTs in the review of which 35 % the amount of missing primary QoL data was unclear, 31 (36 %) used imputation. Only 23 % discussed the missing data mechanism. Nearly half used complete case analysis. Reporting was more unclear for secondary QoL outcomes. Compared to the previous review, multiple imputation was used more prominently but mainly in sensitivity analysis. CONCLUSIONS: Inadequate reporting and handling of missing QoL data in RCTs are still an issue. There is a large gap between statistical methods research relating to missing data and the use of the methods in applications. A sensitivity analysis should be undertaken to explore the sensitivity of the main results to different missing data assumptions. Medical journals can help to improve the situation by requiring higher standards of reporting and analytical methods to deal with missing data, and by issuing guidance to authors on expected standard.

Behavioural recovery after treatment for varicose veins.

BACKGROUND: The aim of this study was to assess behavioural recovery from the patient's perspective as a prespecified secondary outcome in a multicentre parallel-group randomized clinical trial comparing ultrasound-guided foam sclerotherapy (UGFS), endovenous laser ablation (EVLA) and surgery for the treatment of primary varicose veins. METHODS: Participants were recruited from 11 UK sites as part of the CLASS trial, a randomized trial of UGFS, EVLA or surgery for varicose veins. Patients were followed up 6 weeks after treatment and asked to complete the Behavioural Recovery After treatment for Varicose Veins (BRAVVO) questionnaire. This is a 15-item instrument that covers eight activity behaviours (tasks or actions an individual is capable of doing in an idealized situation) and seven participation behaviours (what the individual does in an everyday, real-world situation) that were identified to be important from the patient's perspective. RESULTS: A total of 798 participants were recruited. Both UGFS and EVLA resulted in a significantly quicker recovery compared with surgery for 13 of the 15 behaviours assessed. UGFS was superior to EVLA in terms of return to full-time work (hazard ratio 1·43, 95 per cent c.i. 1·11 to 1·85), looking after children (1·45, 1·04 to 2·02) and walks of short (1·48, 1·19 to 1·84) and longer (1·32, 1·05 to 1·66) duration. CONCLUSION: Both UGFS and EVLA resulted in more rapid recovery than surgery, and UGFS was superior to EVLA for one-quarter of the behaviours assessed. The BRAVVO questionnaire has the potential to provide important meaningful information to patients about their early recovery and what they may expect to be able to achieve after treatment.

Metabolic syndrome, inflammation and lower urinary tract symptoms: possible translational links.

BACKGROUND: Epidemiological data suggest that lower urinary tract symptoms (LUTSs) may be associated with metabolic syndrome (MetS). Inflammation has been proposed as a candidate mechanism at the crossroad between these two clinical entities. The aim of this review article is to evaluate the role of MetS-induced inflammation in the pathogenesis and progression of LUTS. METHODS: A systematic review was conducted using the keywords 'metabolic syndrome and lower urinary tract symptoms' within the title search engines including PubMed, Web of Science and the Cochrane Library for relevant research work published between 2000 and January 2015. The obtained literature was reviewed by the primary author (QH) and was assessed for eligibility and standard level of evidence. RESULTS: Total of 52 articles met the eligibility criteria. On the basis of database search during the past 15 years and our systematic review of prospective and retrospective cohorts, case-control trials, observational studies and animal data identified a possible link between MetS-induced inflammation and LUTS including BPH, bladder outlet obstruction, overactive bladder, urinary incontinence and other possible urinary tract abnormalities. CONCLUSIONS: There is convincing evidence to suggest that MetS and inflammation could be important contributors to LUTS in men, particularly in the development of BPH. However, the role of MetS-induced inflammation remains unclear in overactive bladder, urinary incontinence and etiology of LUTS progression.

Effect of forage and retail packaging types on meat quality of long-term chilled lamb loins.

The objectives of this study were to determine the effects of different forage regimes and modified atmosphere packaging (MAP) systems [high oxygen (HiOx-MAP): 80% O2 and 20% CO2; and CO2-MAP: 20% CO2 and 80% N2] on color and lipid oxidation stability and sensory attributes of long-term chilled lamb loins during retail display. Lambs (n = 124) were randomly assigned to several pasture-feeding regimes for 12 wk before slaughter. Some had ryegrass (n = 18), lucerne (n = 18), chicory (n = 19), plantain (n = 16), or red clover (Clover 12; n = 17) for all 12 wk. Some were assigned a regime of red clover for 11 wk and pasture for 1 wk (Clover 11; n = 18), with others on red clover for 9 wk and pasture for 3 wk (Clover 9; n = 18). After the lambs were slaughtered, the paired loins (M. longissimus dorsi) were excised at 24 h postmortem, vacuum-packed and stored at -1.5 °C for 9 wk. Cuts were then made from each loin and randomly allocated to either HiOx-MAP or CO2-MAP, and displayed for 7 d at 4 °C under light. Chemical attributes including lipid oxidation, surface color-reversing ability, oxygen consumption, and meat quality attributes (color stability and sensory characteristics) were determined. Among the different forage types, the loins from lambs finished on ryegrass appeared to have greater color stability and less lipid oxidation than the loins from lambs finished on other forage types (P < 0.05). On the other hand, the loins from lambs finished on lucerne had the least color and lipid oxidation stabilities and least color-reversing ability (P < 0.05). The loins from lambs finished on chicory had higher aroma and flavor scores than other pasture types in general (P < 0.05). HiOx-MAP negatively influenced meat quality attributes of lamb loins during display, as substantial increases in surface discoloration and lipid oxidation were observed, along with significant decreases in aroma and flavor during retail display compared with the loins in CO2-MAP. These results suggest that different forage types and packaging conditions could result in substantial impacts on meat quality attributes of long-term chilled lamb loins by affecting oxidation stability. Furthermore, the present study suggests that CO2-MAP could provide beneficial effects on the eating quality of long-term chilled lamb loins by suppressing oxidation-related defects during display without compromising the ability of blooming for meat display.

Five-year results of a randomised controlled trial comparing mobile and fixed bearings in total knee replacement.

There is conflicting evidence about the merits of mobile bearings in total knee replacement, partly because most randomised controlled trials (RCTs) have not been adequately powered. We report the results of a multicentre RCT of mobile versus fixed bearings. This was part of the knee arthroplasty trial (KAT), where 539 patients were randomly allocated to mobile or fixed bearings and analysed on an intention-to-treat basis. The primary outcome measure was the Oxford Knee Score (OKS) plus secondary measures including Short Form-12, EuroQol EQ-5D, costs, cost-effectiveness and need for further surgery. There was no significant difference between the groups pre-operatively: mean OKS was 17.18 (sd 7.60) in the mobile-bearing group and 16.49 (sd 7.40) in the fixed-bearing group. At five years mean OKS was 33.19 (sd 16.68) and 33.65 (sd 9.68), respectively. There was no significant difference between trial groups in OKS at five years (-1.12 (95% confidence interval -2.77 to 0.52) or any of the other outcome measures. Furthermore, there was no significant difference in the proportion of patients with knee-related re-operations or in total costs. In this appropriately powered RCT, over the first five years after total knee replacement functional outcomes, re-operation rates and healthcare costs appear to be the same irrespective of whether a mobile or fixed bearing is used.

Types of urethral catheter for reducing symptomatic urinary tract infections in hospitalised adults requiring short-term catheterisation: multicentre randomised controlled trial and economic evaluation of antimicrobial- and antiseptic-impregnated urethral catheters (the CATHETER trial).

BACKGROUND: Catheter-associated urinary tract infection (CAUTI) is a major preventable cause of harm for patients in hospital and incurs significant costs for health-care providers such as the UK NHS. Many preventative strategies and measures have been introduced to minimise CAUTI risk, including the use of antimicrobial catheters. However, there is considerable uncertainty regarding their usefulness in terms of reducing symptomatic CAUTI, and whether or not they are cost-effective. OBJECTIVES: Do antimicrobial catheters reduce the rate of symptomatic urinary tract infection (UTI) during short-term hospital use and is their use cost-effective for the UK NHS? DESIGN: A pragmatic multicentre UK randomised controlled trial comparing three catheters as they would be used in the UK NHS: antimicrobial-impregnated (nitrofurazone) and antiseptic-coated (silver alloy) catheters with the standard polytetrafluoroethylene (PTFE)-coated catheters. Economic evaluation used a decision model populated with data from the trial. Sensitivity analysis was used to explore uncertainty. SETTING: Relevant clinical departments in 24 NHS hospitals throughout the UK. PARTICIPANTS: Adults requiring temporary urethral catheterisation for a period of between 1 and 14 days as part of their care, predominantly as a result of elective surgery. INTERVENTIONS: Eligible participants were randomised 1 : 1 : 1 to one of three types of urethral catheter in order to make the following pragmatic comparisons: nitrofurazone-impregnated silicone catheter compared with standard PTFE-coated latex catheter; and silver alloy-coated hydrogel latex catheter compared with standard PTFE-coated latex catheter. MAIN OUTCOME MEASURES: The primary outcome for clinical effectiveness was the incidence of UTI at any time up to 6 weeks post randomisation. This was defined as any symptom reported during catheterisation, up to 3 days or 1 or 2 weeks post catheter removal or 6 weeks post randomisation combined with a prescription of antibiotics, at any of these times, for presumed symptomatic UTI. The primary economic outcome was incremental cost per quality-adjusted life-year (QALY). Health-care costs were estimated from NHS sources with QALYs calculated from participant completion of the European Quality of Life-5 Dimensions (EQ-5D). RESULTS: Outcome analyses encompassed 6394 (90%) of 7102 participants randomised. The rate of symptomatic UTI within 6 weeks of randomisation was 10.6% in the nitrofurazone group (n = 2153; -2.1% absolute risk difference), 12.5% in the silver alloy group (n = 2097; -0.1% absolute risk difference) and 12.6% in the PTFE group (n = 2144). The effect size {odds ratio (OR) [97.5% confidence interval (CI)]} was 0.82 (97.5% CI 0.66 to 1.01) for nitrofurazone (p = 0.037) and 0.99 (97.5% CI 0.81 to 1.22) for silver alloy (p = 0.92) catheters. The nitrofurazone catheters were more likely to cause discomfort during use and on removal. The primary economic analysis suggested that nitrofurazone-impregnated catheters would be, on average, the least costly (> £7 less than PTFE) and most effective option at current NHS prices. There was a 73% chance that nitrofurazone would be cost saving and an 84% chance that the incremental cost per QALY would be < £30,000. At the trial price (£6.46), silver alloy catheters were very unlikely to be cost-effective. These results were unchanged in sensitivity analyses, although when the length of stay cost was excluded the incremental cost per QALY for nitrofurazone against PTFE was £28,602. CONCLUSIONS: The trial estimate of clinical effectiveness for nitrofurazone-impregnated catheters was less than the pre-specified minimum absolute risk difference that we considered important (-3.3%), and the surrounding CI included zero, indicating that any reduction in catheter-associated UTI was uncertain. Economic analysis, although associated with uncertainty, suggested that nitrofurazone-impregnated catheters may be cost-effective for the NHS. The trial ruled out the possibility that silver alloy-coated catheters might reach the pre-set degree of clinical effectiveness and that their use was unlikely to be cost-effective. These findings should be considered by patients, clinicians and health-care policy-makers to determine whether or not a change in practice is worthwhile. Future research should be aimed at determining the minimum clinically important difference in terms of CAUTI prevention in comparative trials, and to identify reliable methods which can detect the impact of the intervention on quality of life and other drivers of cost, when the intervention is a subsidiary part of overall treatment plans.

The clinical effectiveness and cost-effectiveness of different surveillance mammography regimens after the treatment for primary breast cancer: systematic reviews registry database analyses and economic evaluation.

BACKGROUND: Following primary breast cancer treatment, the early detection of ipsilateral breast tumour recurrence (IBTR) or ipsilateral secondary cancer in the treated breast and detection of new primary cancers in the contralateral breast is beneficial for survival. Surveillance mammography is used to detect these cancers, but the optimal frequency of surveillance and the length of follow-up are unclear. OBJECTIVES: To identify feasible management strategies for surveillance and follow-up of women after treatment for primary breast cancer in a UK setting, and to determine the effectiveness and cost-effectiveness of differing regimens. METHODS: A survey of UK breast surgeons and radiologists to identify current surveillance mammography regimens and inform feasible alternatives; two discrete systematic reviews of evidence published from 1990 to mid 2009 to determine (i) the clinical effectiveness and cost-effectiveness of differing surveillance mammography regimens for patient health outcomes and (ii) the test performance of surveillance mammography in the detection of IBTR and metachronous contralateral breast cancer (MCBC); statistical analysis of individual patient data (West Midlands Cancer Intelligence Unit Breast Cancer Registry and Edinburgh data sets); and economic modelling using the systematic reviews results, existing data sets, and focused searches for specific data analysis to determine the effectiveness and cost-utility of differing surveillance regimens. RESULTS: The majority of survey respondents initiate surveillance mammography 12 months after breast-conserving surgery (BCS) (87%) or mastectomy (79%). Annual surveillance mammography was most commonly reported for women after BCS or after mastectomy (72% and 53%, respectively). Most (74%) discharge women from surveillance mammography, most frequently 10 years after surgery. The majority (82%) discharge from clinical follow-up, most frequently at 5 years. Combining initiation, frequency and duration of surveillance mammography resulted in 54 differing surveillance regimens for women after BCS and 56 for women following mastectomy. The eight studies included in the clinical effectiveness systematic review suggest surveillance mammography offers a survival benefit compared with a surveillance regimen that does not include surveillance mammography. Nine studies were included in the test performance systematic review. For routine IBTR detection, surveillance mammography sensitivity ranged from 64% to 67% and specificity ranged from 85% to 97%. For magnetic resonance imaging (MRI), sensitivity ranged from 86% to 100% and specificity was 93%. For non-routine IBTR detection, sensitivity and specificity for surveillance mammography ranged from 50% to 83% and from 57% to 75%, respectively, and for MRI from 93% to 100% and from 88% to 96%, respectively. For routine MCBC detection, one study reported sensitivity of 67% and specificity of 50% for both surveillance mammography and MRI, although this was a highly select population. Data set analysis showed that IBTR has an adverse effect on survival. Furthermore, women experiencing a second tumour measuring >20 mm in diameter were at a significantly greater risk of death than those with no recurrence or those whose tumour was <10 mm in diameter. In the base-case analysis, the strategy with the highest net benefit, and most likely to be considered cost-effective, was surveillance mammography alone, provided every 12 months at a societal willingness to pay for a quality-adjusted life-year of either £20,000 or £30,000. The incremental cost-effectiveness ratio for surveillance mammography alone every 12 months compared with no surveillance was £4727. LIMITATIONS: Few studies met the review inclusion criteria and none of the studies was a randomised controlled trial. The limited and variable nature of the data available precluded any quantitative analysis. There was no useable evidence contained in the Breast Cancer Registry database to assess the effectiveness of surveillance mammography directly. The results of the economic model should be considered exploratory and interpreted with caution given the paucity of data available to inform the economic model. CONCLUSIONS: Surveillance is likely to improve survival and patients should gain maximum benefit through optimal use of resources, with those women with a greater likelihood of developing IBTR or MCBC being offered more comprehensive and more frequent surveillance. Further evidence is required to make a robust and informed judgement on the effectiveness of surveillance mammography and follow-up. The utility of national data sets could be improved and there is a need for high-quality, direct head-to-head studies comparing the diagnostic accuracy of tests used in the surveillance population. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Spontaneous metastasis in mouse models of testicular germ-cell tumours.

Testicular germ-cell tumours (TGCTs) are the most common cancer in young men; the incidence is increasing worldwide and they have an unusually high rate of metastasis. Despite significant work on TGCTs and their metastases in humans, absence of a mouse model of spontaneous metastasis has greatly limited our understanding of the mechanisms by which metastatic potential is acquired and on their modes of dissemination. We report a new model of spontaneous TGCT metastasis in the 129 family of mice and provide evidence that these are true metastases derived directly from primary testicular cancers rather than independently from ectopic stem cells. These putative metastases (pMETs) occur at similar frequencies among TGCT-affected males in six genetically distinct TGCT-susceptible strains and were largely found in anatomical sites that are consistent with patterns of TGCT metastasis in humans. Various lines of evidence support their pluripotency and germ-cell origin, including presence of multiple endodermal, mesodermal and ectodermal derivatives as well as cells showing OCT4 and SSEA-1 pluripotency markers. In addition, pMETs were never found in males that did not have a TGCT, suggesting that metastases are derived from primary tumours. Finally, pMETS and primary TGCTs shared several DNA copy number variants suggesting a common cellular and developmental origin. Together, these results provide the first evidence for spontaneous TGCT metastasis in mice and show that these metastases originate from primary TGCTs rather than independently from ectopic stem cells.

Factors influencing the participation of older people in clinical trials - data analysis from the MAVIS trial.

BACKGROUND: Older people are less likely to be included in clinical trials. Little is known about factors influencing older people's decisions about participating in clinical trials. OBJECTIVES: To examine the views of older people about participating in clinical trials. METHODS: Postal questionnaire to 801 participants who had completed the MAVIS nutrition trial, aged 65 yrs and older. Closed and open questions sought participants' views about factors important to them when deciding to take part in a trial, features of the MAVIS trial they liked and disliked and changes they would suggest. RESULTS: 540 (59% of MAVIS trial participants) returned the questionnaire. The most important reasons reported for taking part in the trial were helping the research team and medical knowledge, and helping other older people. Participants valued good communication with the trial staff and good organisation. Participants reported concerns about swallowing pills and taking a placebo. Participants reported that future participation in trials could be influenced by poor health status. LIMITATIONS: This questionnaire surveyed older participants who had taken part in a randomised controlled trial. It did not elicit the views of people who had withdrawn or never decided to take part in the trial. CONCLUSIONS: Older people report altruistic reasons for taking part in trials. Simple trial designs, which minimise demands on participants and maintain good communications should be preferred. Explaining the need for older people, despite poor health, to participate in trials may help the generalisability of clinical trials.

PET imaging of hepatocellular carcinoma with 2-deoxy-2[18F]fluoro-D-glucose, 6-deoxy-6[18F] fluoro-D-glucose, [1-11C]-acetate and [N-methyl-11C]-choline.

AIM: This study was designed to investigate the performance of positron emission tomography (PET) imaging for hepatocellular carcinoma (HCC) on a hepatitis viral infection-induced woodchuck model using existing tracers such as 2-deoxy-2[(18)F]fluoro-D-glucose (2FDG), 6-deoxy-6[(18)F]fluoro-D-glucose (6FDG), [1(-11)C]acetate (acetate) and [N-methyl(-11)C]choline (choline). METHODS: Fourteen woodchucks with HCC were imaged with different radiotracers: 13 (10 with HCC and 3 controls) with 2FDG; 4 (3 with HCC and 1 control) with 6FDG; 13 (10 with HCC and 3 controls) with acetate; 4 (2 with HCC and 2 controls) with choline. The woodchucks were euthanized after imaging experiments and liver tissues were harvested for histology, for enzymatic activities including hexokinase (HK), glucose-6-phosphatase, acetyl-CoA synthetase (ACAS) and choline kinase (CK), and for differential gene expressions between the HCCs and the surrounding hepatic tissues. RESULTS: 2FDG detected 7/13 tumors with a tumor-to-liver uptake ratio (T/L) of 1.36+/-0.13. Five of these HCCs were moderately- or poorly-differentiated. The HK/glucose-6-phosphatase ratio was significantly higher in HCCs compared to the surrounding liver tissues (P=0.05). None of the HCCs imaged with 6FDG were detected by PET (T/L=1.01+/-0.11). Acetate detected 16/17 HCCs (T/L=2.02+/-0.7). ACAS activity was significantly higher in HCCs (P=0.01) and lipids-related genes were found up-regulated. Choline imaging detected all HCCs (T/L=1.63+/-0.34). CK activity was significantly higher in HCCs (P=0.001). CONCLUSIONS: Well-differentiated and some moderately-differentiated HCCs do not uptake 2FDG more than the surrounding liver tissues, but display increased acetate uptake. There is no contrast between HCCs and the surrounding liver tissues on the 6FDG PET images. Despite elevated background signal from the liver, choline uptake seems to be detectable in the HCCs scanned in this study.

Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

OBJECTIVES: To determine the clinical effectiveness and cost utility of procedures alternative to TURP (transurethral resection of the prostate) for benign prostatic enlargement (BPE) unresponsive to expectant, non-surgical treatments. DATA SOURCES: Electronic searches of 13 databases to identify relevant randomised controlled trials (RCTs). REVIEW METHODS: Two reviewers independently assessed study quality and extracted data. The International Prostate Symptom Score/American Urological Association (IPSS/AUA) symptom score was the primary outcome; others included quality of life, peak urine flow rate and adverse effects. Cost-effectiveness was assessed using a Markov model reflecting likely care pathways. RESULTS: 156 reports describing 88 RCTs were included. Most had fewer than 100 participants (range 12-234). TURP provided consistent, high-level, long-term symptomatic improvement. Minimally invasive procedures resulted in less marked improvement. Ablative procedures gave improvements equivalent to TURP. Holmium laser enucleation of the prostate (HoLEP) additionally resulted in greater improvement in flow rate. HoLEP is unique amongst the newer technologies in offering an advantage in urodynamic outcomes over TURP, although long-term follow-up data are lacking. Severe blood loss was more common following TURP. Rates of incontinence were similar across all interventions other than transurethral needle ablation (TUNA) and laser coagulation, for which lower rates were reported. Acute retention and reoperation were commoner with newer technologies, especially minimally invasive interventions. The economic model suggested that minimally invasive procedures were unlikely to be cost-effective compared with TURP. Transurethral vaporisation of the prostate (TUVP) was both less costly and less effective than TURP. HoLEP was estimated to be more cost-effective than a single TURP but less effective than a strategy involving repeat TURP if necessary. The base-case analysis suggested an 80% chance that TUVP, followed by HoLEP if required, would be cost-effective at a threshold of 20,000 pounds per quality-adjusted life-year. At a 50,000 pounds threshold, TUVP, followed by TURP as required, would be cost-effective, although considerable uncertainty surrounds this finding. The main limitations are the quantity and quality of the data available, in the context of multiple comparisons. CONCLUSIONS: In the absence of strong evidence in favour of newer methods, the standard--TURP--remains both clinically effective and cost-effective. There is a need for further research to establish (i) how many years of medical treatment are necessary to offset the cost of treatment with a minimally invasive or ablative intervention; (ii) more cost-effective alternatives to TURP; and (iii) strategies to improve outcomes after TURP.

Efficacy and safety of using mesh or grafts in surgery for anterior and/or posterior vaginal wall prolapse: systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of mesh/graft in surgery for anterior or posterior pelvic organ prolapse is uncertain. OBJECTIVES: To systematically review the efficacy and safety of mesh/graft for anterior or posterior vaginal wall prolapse surgery. SEARCH STRATEGY: Electronic databases and conference proceedings were searched, experts and manufacturers contacted, and reference lists of retrieved papers scanned. SELECTION CRITERIA: Randomised controlled trials (RCTs), nonrandomised comparative studies, registries, case series involving at least 50 women, and RCTs published as conference abstracts from 2005 onwards. DATA COLLECTION AND ANALYSIS: One reviewer screened titles/abstracts, undertook data extraction, and assessed study quality. Data analysis was conducted for three subgroups: anterior, posterior, and anterior and/or posterior repair (not reported separately). RESULTS: Forty-nine studies involving 4569 women treated with mesh/graft were included. Study quality was generally high. Median follow up was 13 months (range 1-51 months). In anterior repair, there was short-term evidence that mesh/graft (any type) significantly reduced objective prolapse recurrence rates compared with no mesh/graft (relative risk 0.48, 95% CI 0.32-0.72). Nonabsorbable synthetic mesh had a significantly lower objective prolapse recurrence rate (8.8%, 48/548) than absorbable synthetic mesh (23.1%, 63/273) and biological graft (17.9%, 186/1041), but a higher erosion rate (10.2%, 68/666) than absorbable synthetic mesh (0.7%, 1/147) and biological graft (6.0%, 35/581). There was insufficient information to compare any of the other outcomes regardless of prolapse type. CONCLUSIONS: Evidence for most outcomes was too sparse to provide meaningful conclusions. Rigorous long-term RCTs are required to determine the comparative efficacy of using mesh/graft.

Changing clinicians' behavior: a randomized controlled trial of fees and education.

The fissure-sealing of newly erupted molars is an effective caries prevention treatment, but remains underutilized. Two plausible reasons are the financial disincentive produced by the dental remuneration system, and dentists' lack of awareness of evidence-based practice. The primary hypothesis was that implementation strategies based on remuneration or training in evidence-based healthcare would produce a higher proportion of children receiving sealed second permanent molars than standard care. The four study arms were: fee per sealant treatment, education in evidence-based practice, fee plus education, and control. A cost-effectiveness analysis was conducted. Analysis was based on 133 dentists and 2833 children. After adjustment for baseline differences, the primary outcome was 9.8% higher when a fee was offered. The education intervention had no statistically significant effect. 'Fee only' was the most cost-effective intervention. The study contributes to the incentives in health care provision debate, and led to the introduction of a direct fee for this treatment.

The accuracy of accredited glaucoma optometrists in the diagnosis and treatment recommendation for glaucoma.

AIM: To compare the diagnostic performance of accredited glaucoma optometrists (AGO) for both the diagnosis of glaucoma and the decision to treat with that of routine hospital eye care, against a reference standard of expert opinion (a consultant ophthalmologist with a special interest in glaucoma). METHODS: A directly comparative, masked, performance study was undertaken in Grampian, Scotland. Of 165 people invited to participate, 100 (61%) were examined. People suspected of having glaucoma underwent, within one month, a full ophthalmic assessment in both a newly established community optometry led glaucoma management scheme and a consultant led hospital eye service. RESULTS: Agreement between the AGO and the consultant ophthalmologist in diagnosing glaucoma was substantial (89%; kappa = 0.703, SE = 0.083). Agreement over the need for treatment was also substantial (88%; kappa = 0.716, SE = 0.076). The agreement between the trainee ophthalmologists and the consultant ophthalmologist in the diagnosis of glaucoma and treatment recommendation was moderate (83%, kappa = 0.541, SE = 0.098, SE = 0.98; and 81%, kappa = 0.553, SE = 0.90, respectively). The diagnostic accuracy of the optometrists in detecting glaucoma in this population was high for specificity (0.93 (95% confidence interval, 0.85 to 0.97)) but lower for sensitivity (0.76 (0.57 to 0.89)). Performance was similar when accuracy was assessed for treatment recommendation (sensitivity 0.73 (0.57 to 0.85); specificity 0.96 (0.88 to 0.99)). The differences in sensitivity and specificity between AGO and junior ophthalmologist were not statistically significant. CONCLUSIONS: Community optometrists trained in glaucoma provided satisfactory decisions regarding diagnosis and initiation of treatment for glaucoma. With such additional training in glaucoma, optometrists are at least as accurate as junior ophthalmologists but some cases of glaucoma are missed.

The S100 proteins for screening and prognostic grading of bladder cancer.

The S100 gene family, which is composed of at least 24 members carrying the Ca2+ binding EF-hand motif, has been implicated in both intracellular and extracellular functions, including enzyme activities, immune responses, cytoskeleton dynamics, Ca2+ homeostasis, cell growth and cell differentiation. Altered S100 protein levels are associated with a broad range of diseases, including cardiomyopathy, inflammatory and immune disorders, neurodegenerative disorders and cancer. Although the precise role of S100 protein in carcinogenesis is poorly understood, it seems that formation of homo- and hetero-dimers, binding of Ca2+ and interaction with effector molecules are essential for the development and progression of many cancers. Several studies have suggested that S100 proteins promote cancer progression and metastasis through cell survival and apoptosis pathways. In animal models of bladder cancer, several S100 proteins are differentially expressed in bladder tumors relative to normal urothelium. In human bladder cancer, overexpression of S100A4, S100A8 or S100A11 are associated with stage progression, invasion, metastasis and poor survival. This review summarizes these findings and evaluates their implications for human bladder cancer management.

Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation.

The histogenesis of sarcomatoid urothelial carcinoma, a rare neoplasm with bidirectional epithelial and mesenchymal differentiation, has been a matter of controversy. To clarify its origin, we analysed the status of X-chromosome inactivation in sarcomatoid urothelial carcinomas from 10 female patients and examined losses of heterozygosity (LOH) in these specimens and in additional 20 tumours from male patients. Six polymorphic microsatellite markers where genetic alterations occur frequently in early or advanced stages of urothelial carcinomas, including D3S3050, D8S261, IFNA, D9S177, D11S569 and TP53, were investigated in the current study. The identical pattern of non-random X-chromosome inactivation in both carcinomatous and sarcomatous components was identified in five of eight informative female patients, and the remaining three informative cases showed a random, but concordant, pattern of X-chromosome inactivation. The concordant X-chromosome inactivation results in all eight informative cases support the concept of a monoclonal origin of both components of this biphasic neoplasm. Among the tumours demonstrating loss of heterozygosity, high incidences of an identical pattern of allelic loss between carcinomatous and sarcomatous components were identified in genetic alterations associated with early carcinogenesis: 86% at D8S261, 78% at D11S569, 75% at D9S177 and 57% at IFNA. In contrast, concordant LOH patterns were less frequently observed for microsatellites related to advanced carcinogenesis: only 40% at D3S3050 and 40% at TP53. The significant overlap of loss of heterozygosity supports a monoclonal cell origin and suggests that clonal divergence may occur during tumour progression and differentiation. Divergent patterns of discordant allelic loss of microsatellite markers imply that heterogeneous pathogenetic pathways may exist in the evolution of this enigmatic neoplasm.