Long-term cost-effectiveness of screening for fracture risk in a UK primary care setting: the SCOOP study.

Community-based screening and treatment of women aged 70-85 years at high fracture risk reduced fractures; moreover, the screening programme was cost-saving. The results support a case for a screening programme of fracture risk in older women in the UK. INTRODUCTION: The SCOOP (screening for prevention of fractures in older women) randomized controlled trial investigated whether community-based screening could reduce fractures in women aged 70-85 years. The objective of this study was to estimate the long-term cost-effectiveness of screening for fracture risk in a UK primary care setting compared with usual management, based on the SCOOP study. METHODS: A health economic Markov model was used to predict the life-time consequences in terms of costs and quality of life of the screening programme compared with the control arm. The model was populated with costs related to drugs, administration and screening intervention derived from the SCOOP study. Fracture risk reduction in the screening arm compared with the usual management arm was derived from SCOOP. Modelled fracture risk corresponded to the risk observed in SCOOP. RESULTS: Screening of 1000 patients saved 9 hip fractures and 20 non-hip fractures over the remaining lifetime (mean 14 years) compared with usual management. In total, the screening arm saved costs (£286) and gained 0.015 QALYs/patient in comparison with usual management arm. CONCLUSIONS: This analysis suggests that a screening programme of fracture risk in older women in the UK would gain quality of life and life years, and reduce fracture costs to more than offset the cost of running the programme.

Systematic screening using FRAX® leads to increased use of, and adherence to, anti-osteoporosis medications: an analysis of the UK SCOOP trial.

In the large community-based SCOOP trial, systematic fracture risk screening using FRAX® led to greater use of AOM and greater adherence, in women at high fracture risk, compared with usual care. INTRODUCTION: In the SCreening of Older wOmen for Prevention of fracture (SCOOP) trial, we investigated the effect of the screening intervention on subsequent long-term self-reported adherence to anti-osteoporosis medications (AOM). METHODS: SCOOP was a primary care-based UK multicentre trial of screening for fracture risk. A total of 12,483 women (70-85 years) were randomised to either usual NHS care, or assessment using the FRAX® tool ± dual-energy X-ray absorptiometry (DXA), with medication recommended for those found to be at high risk of hip fracture. Self-reported AOM use was obtained by postal questionnaires at 6, 12, 24, 36, 48 and 60 months. Analysis was limited to those who initiated AOM during follow-up. Logistic regression was used to explore baseline determinants of adherence (good ≥ 80%; poor < 80%). RESULTS: The mean (SD) age of participants was 75.6 (4.2) years, with 6233 randomised to screening and 6250 to the control group. Of those participants identified at high fracture risk in the screening group, 38.2% of those on treatment at 6 months were still treated at 60 months, whereas the corresponding figure for the control group was 21.6%. Older age was associated with poorer adherence (OR per year increase in age 0.96 [95% CI 0.93, 0.99], p = 0.01), whereas history of parental hip fracture was associated with greater rate adherence (OR 1.67 [95% CI 1.23, 2.26], p < 0.01). CONCLUSIONS: Systematic fracture risk screening using FRAX® leads to greater use of AOM and greater adherence, in women at high fracture risk, compared with usual care.

Screening for high hip fracture risk does not impact on falls risk: a post hoc analysis from the SCOOP study.

A reduction in hip fracture incidence following population screening might reflect the effectiveness of anti-osteoporosis therapy, behaviour change to reduce falls, or both. This post hoc analysis demonstrates that identifying high hip fracture risk by FRAX was not associated with any alteration in falls risk. INTRODUCTION: To investigate whether effectiveness of an osteoporosis screening programme to reduce hip fractures was mediated by modification of falls risk in the screening arm. METHODS: The SCOOP study recruited 12,483 women aged 70-85 years, individually randomised to a control (n = 6250) or screening (n = 6233) arm; in the latter, osteoporosis treatment was recommended to women at high risk of hip fracture, while the control arm received usual care. Falls were captured by self-reported questionnaire. We determined the influence of baseline risk factors on future falls, and then examined for differences in falls risk between the randomisation groups, particularly in those at high fracture risk. RESULTS: Women sustaining one or more falls were slightly older at baseline than those remaining falls free during follow-up (mean difference 0.70 years, 95%CI 0.55-0.85, p < 0.001). A higher FRAX 10-year probability of hip fracture was associated with increased likelihood of falling, with fall risk increasing by 1-2% for every 1% increase in hip fracture probability. However, falls risk factors were well balanced between the study arms and, importantly, there was no evidence of a difference in falls occurrence. In particular, there was no evidence of interaction (p = 0.18) between baseline FRAX hip fracture probabilities and falls risk in the two arms, consistent with no impact of screening on falls in women informed to be at high risk of hip fracture. CONCLUSION: Effectiveness of screening for high FRAX hip fracture probability to reduce hip fracture risk was not mediated by a reduction in falls.

Young people's experiences of managing Type 1 diabetes at university: a national study of UK university students.

AIM: Little is known about the challenges of transitioning from school to university for young people with Type 1 diabetes. In a national survey, we investigated the impact of entering and attending university on diabetes self-care in students with Type 1 diabetes in all UK universities. METHODS: Some 1865 current UK university students aged 18-24 years with Type 1 diabetes, were invited to complete a structured questionnaire. The association between demographic variables and diabetes variables was assessed using logistic regression models. RESULTS: In total, 584 (31%) students from 64 hospitals and 37 university medical practices completed the questionnaire. Some 62% had maintained routine diabetes care with their home team, whereas 32% moved to the university provider. Since starting university, 63% reported harder diabetes management and 44% reported higher HbA1c levels than before university. At university, 52% had frequent hypoglycaemia, 9.6% reported one or more episodes of severe hypoglycaemia and 26% experienced diabetes-related hospital admissions. Female students and those who changed healthcare provider were approximately twice as likely to report poor glycaemic control, emergency hospital admissions and frequent hypoglycaemia. Females were more likely than males to report stress [odds ratio (OR) 4.78, 95% confidence interval (CI) 3.19-7.16], illness (OR 3.48, 95% CI 2.06-5.87) and weight management issues (OR 3.19, 95% CI 1.99-5.11) as barriers to self-care. Despite these difficulties, 91% of respondents never or rarely contacted university support services about their diabetes. CONCLUSION: The study quantifies the high level of risk experienced by students with Type 1 diabetes during the transition to university, in particular, female students and those moving to a new university healthcare provider.

Assessing Pathogen Presence in an Intensively Tile Drained, Agricultural Watershed.

Increases in swine production and concomitant manure application provide beneficial nutrients for crops but also include the potential to spread pathogenic bacteria in the environment. While manure is known to contain a variety of pathogens, little is known regarding the long-term effect of manure application on fate and transport of this diverse set of pathogens into surrounding waterways. We report on the use of 16S-rRNA gene sequencing to detect pathogen-containing genera in the agriculturally dominated South Fork Iowa River watershed, home to approximately 840,000 swine in the 76,000-ha basin. DNA was extracted from monthly grab samples collected from three surface water sites and two main artificial drainage outlets. DNA sequences from water samples were matched with sequences from genera known to contain pathogens using targeted 16S rRNA amplicon sequencing. The specific genera known to contain pathogens were quantified by combining percentage of genera sequence matches with 16S rRNA gene quantitative polymerase chain reaction results. Specifically, abundances of , , and significantly increased in surface water after typical fall manure application. Additionally, the likely transport pathways for specific genera known to contain pathogens were identified. Surface water concentrations were influenced mainly by artificial drainage, whereas was primarily transported to surface waters by runoff events. The results of this study will help us to understand environmental pathways that may be useful for mitigation of the diverse set of pathogenic genera transported in agroecosystems and the capability of manure application to alter existing microbial community structures.

Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways.

The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10(-6)), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10(-5)) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.

Grazoprevir plus peginterferon and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection: a randomized trial.

UNLABELLED: Grazoprevir (MK-5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25-100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty-seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100-mg arm and 22 days in the 25- and 50-mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25-, 50- and 100-mg arms, respectively (per-protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25- and 100-mg arms). CONCLUSION: These data support further study of the grazoprevir 100-mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).

Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection.

Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

Effects of two different knee tape procedures on lower-limb kinematics and kinetics in recreational runners.

The purpose of this study was to compare the effects of Mulligan's tape (MT) and kinesio tape (KT) with no tape (NT) on hip and knee kinematics and kinetics during running. Twenty-nine female recreational runners performed a series of 'run-throughs' along a 10-m runway under the three taping conditions. Two force plates and a 14-camera Vicon motion analysis system (Oxford Metrics, Inc., Oxford, UK) captured kinematic and kinetic data for each dependent variable from ground contact to toe off. Comparisons of each dependent variable under three taping conditions were assessed through Statistical Package for the Social Sciences (SPSS; SPSS, Inc., Chicago, Illinois, USA; P-value < 0.01) using repeated measure analyses of variance. For each dependent variable with a P-value < 0.01, repeated measures with pairwise comparisons and Bonferroni adjustment were conducted to compare the three taping conditions. MT induced a significant reduction in anterior and posterior hip forces, knee flexion angular velocity, knee extensor moments, and hip flexion and extension moments compared with NT and KT (P = 0.001). There was no difference in hip or knee, kinematics or kinetics, between KT and NT (P = 1.000). MT appears to influence hip and knee biomechanics during running in an asymptomatic sample, whereas KT appeared to be biomechanically not different from NT.

The oncological outcome after right hemicolectomy and accuracy of CT scan as a preoperative tool for staging in right sided colonic cancers.

AIM: Neoadjuvant chemotherapy may have a role in the management of colonic carcinoma but clinical trials are required to determine whether this approach is superior to the standard policy of radical surgery, high-quality histopathology and selective postoperative chemotherapy. The selection of appropriate patients for such trials will depend on accurate locoregional staging of disease by preoperative CT scanning. We studied the outcome after radical right hemicolectomy and assessed the accuracy of preoperative CT scans in the prediction of postoperative pathology. METHOD: A retrospective analysis of right hemicolectomies performed with curative intent for colon cancer under the care of a single colorectal surgeon (D.J.A.) was performed. Preoperative CT-proven Dukes D patients were excluded. Patient demographics, postoperative histology, use of adjuvant chemotherapy and survival data were collected. Kaplan-Meier curves were constructed and log-rank testing was performed to compare cancer-specific survival. Fifty patients had their preoperative CT scan images reviewed by two radiologists both blinded to the results of the postoperative histology. The accuracy of preoperative CT for T and N staging was studied. A P-value of < 0.05 was significant. RESULTS: There were 136 patients (79 women). Median age was 76 (interquartile ratio 67-82) years. Median period of follow-up was 72 (interquartile ratio 39-92) months. There were 56 deaths (39 medical, 16 oncological and 1 postoperative). There were three groups of patients: node negative (n = 84), node positive with postoperative adjuvant chemotherapy (n = 30) and node positive without chemotherapy (n = 22). Five-year cancer-specific survival for node negative disease was 84% and was poorer for node positive patients who received adjuvant chemotherapy when compared with those who did not (62 vs 72%, P-value = 0.046 on log-rank testing). Sensitivity, specificity, positive and negative predictive value of CT scan for tumour (T) stage were 90, 33, 86 and 43% respectively, while that for nodal (N) stage was 83, 38, 57 and 69%, respectively. CONCLUSION: CT scan has limited accuracy in predicting those patients with advanced locoregional disease who might benefit from neoadjuvant treatment. When this finding is combined with relatively high cancer-specific survival with surgery alone the impact of adjuvant chemotherapy on survival after radical surgery for right colon carcinoma may be marginal.

A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of screening older women for the prevention of fractures: rationale, design and methods for the SCOOP study.

SCOOP is a UK seven-centre, pragmatic, randomised controlled trial with 5-year follow-up, including 11,580 women aged 70 to 85 years, to assess the effectiveness and cost-effectiveness of a community-based screening programme to reduce fractures. It utilises the FRAX algorithm and DXA to assess the 10-year probability of fracture. Introduction Osteoporotic, or low-trauma, fractures present a considerable burden to the National Health Service and have major adverse effects on quality of life, disability and mortality for the individual. Methods Given the availability of efficacious treatments and a risk assessment tool based upon clinical risk factors and bone mineral density, a case exists to undertake a community-based controlled evaluation of screening for subjects at high risk of fracture, under the hypothesis that such a screening programme would reduce fractures in this population. Results This study is a UK seven-centre, unblinded, pragmatic, randomised controlled trial with a 5-year follow-up period. A total of 11,580 women, aged 70 to 85 years and not on prescribed bone protective therapy will be consented to the trial by post via primary care providing 90% power to detect an 18% decrease in fractures. Conclusions Participants will be randomised to either a screening arm or control. Those undergoing screening will have a 10-year fracture probability computed from baseline risk factors together with bone mineral density measured by DXA in selected subjects. Individuals above an age-dependent threshold of fracture probability will be recommended for treatment for the duration of the trial. Subjects in the control arm will receive 'usual care'. Participants will be followed up 6 months after randomisation and annually by postal questionnaires with independent checking of hospital and primary care records. The primary outcome will be the proportion of individuals sustaining fractures in each group. An economic analysis will be carried out to assess cost-effectiveness of screening. A qualitative evaluation will be conducted to examine the acceptability of the process to participants.

Cell adhesion molecules, signal transduction and cell growth.

Signals from dynamic cellular interactions between the extracellular matrix and neighboring cells ultimately input into the cellular decision-making process. These interactions form the basis of anchorage-dependent growth. Recent advances have provided the mechanistic details behind the ability of integrins, and other cell adhesion molecules (CAMs), to regulate both early signal transduction events initiated by soluble factors and downstream events more proximally involved in cell cycle progression. These actions appear to depend on the ability of CAMs to initiate the formation of organized structures that permit the efficient flow of information.

Integrin signaling and cell growth control.

Integrins contribute to cell growth by providing a physical linkage between cytoskeletal structures and the extracellular matrix, and also by participating in various signal transduction processes. The interaction of integrins with matrix ligands can generate signals in and of itself, and can also modulate signals instigated by soluble factors such as peptide mitogens. Cellular events affected by integrin-mediated signaling include motility, cell division, differentiation and programmed cell death. Elucidation of how integrin-mediated cell adhesion controls cell growth is likely to be of fundamental importance in understanding complex biological processes, such as tissue morphogenesis and tumor progression.

Regulation of anchorage-dependent signal transduction by protein kinase A and p21-activated kinase.

Activation of the canonical mitogen-activated protein kinase (MAPK) cascade by soluble mitogens is blocked in non-adherent cells. It is also blocked in cells in which the cAMP-dependent protein kinase (PKA) is activated. Here we show that inhibition of PKA allows anchorage-independent stimulation of the MAPK cascade by growth factors. This effect is transient, and its duration correlates with sustained tyrosine phosphorylation of paxillin and focal-adhesion kinase (FAK) in non-adherent cells. The effect is sensitive to cytochalasin D, implicating the actin cytoskeleton as an important factor in mediating this anchorage-independent signalling. Interestingly, constitutively active p21-activated kinase (PAK) also allows anchorage-independent MAPK signalling. Furthermore, PKA negatively regulates PAK in vivo, and whereas the induction of anchorage-independent signaling resulting from PKA suppression is blocked by dominant negative PAK, it is markedly prolonged by constitutively active PAK. These observations indicate that PKA and PAK are important regulators of anchorage-dependent signal transduction.

Copy number variation of lipocalin family genes for male-specific proteins in tilapia and its association with gender.

Lipocalins are involved in the binding of small molecules like sex steroids. We show here that the previously reported tilapia male-specific protein (MSP) is a lipocalin encoded by a variety of paralogous and homologous genes in different tilapia species. Exon-intron boundaries of MSP genes were typical of the six-exon genomic structure of lipocalins, and the transcripts were capable of encoding 200 amino-acid polypeptides that consisted of a putative signal peptide and a lipocalin domain. Cysteine residues are conserved in positions analogous to those forming the three disulfide bonds characteristic of the ligand pocket. The calculated molecular mass of the secreted MSP (20.4 kDa) was less than half of that observed, suggesting that it is highly glycosylated like its homologue tributyltin-binding protein. Analysis of sequence variations revealed three types of paralogs MSPA, MSPB and MSPC. Expression of both MSPA and MSPB was detected in testis. In haploid Oreochromis niloticus embryos, each of these types consisted of two closely related paralogs, and asymmetry between MSP copy numbers on the maternal (six copies) and the paternal (three copies) chromosomes was observed. Using this polymorphism we mapped MSPA and MSPC to linkage group 12 of an F(2) mapping family derived from a cross between O. niloticus and Oreochromis aureus. Females with high MSP copy number were more frequent by more than twofold than males. Gender-MSPC combinations showed significant deviation from expected Mendelian segregation (P=0.009) suggesting elimination of males with MSPC copies. We discuss different hypotheses to explain this elimination, including possibility for allelic conflict resulted by the hybridization.

Depression in primary care: three key challenges.

The recognition and treatment of depression is a challenging area of clinical practice, especially in primary care where there are many patients with various presentations and a multitude of causes for distress. The prevalence of depression is increasing, and it is predicted to become second only to ischaemic heart disease as a cause of morbidity worldwide. Fortunately, the research evidence on effective approaches is increasing. This article looks at how we can best identify, treat and understand the perspectives of people with depression who are seen in primary care. Simple questionnaires can provide effective screening in generalist settings, particularly when targeting high-risk groups such as those with cardiovascular comorbidity or recurrent unexplained symptoms. Guidelines now exist for use of antidepressants and cognitive behavioural therapy for mild to moderate depression, although the latter needs effective policy implementation in clinical practice to maximise its impact for patients. However, there is also consistent evidence from service users that people with depression want individualised care which takes into account their preferences and concerns, even if this entails departure from guidelines. Adherence to treatment is low in many studies, and remodelling of services can easily lead to gaps in consistent approaches to personal care. The research challenges for the future include clarification of which patient groups merit proactive screening, how to enhance adherence, and the relative merits and outcomes of pharmacological versus behavioural therapies. Changes in policy and service configuration can improve or destabilise effective care, but high-quality and flexible intervention with patients with mild to moderate depression is likely to be cost-effective in view of the high prevalence and disease burden of this distressing problem.

A substitution at a non-glycine position in the triple-helical domain of pro alpha 2(I) collagen chains present in an individual with a variant of the Marfan syndrome.

A substitution for a highly conserved non-glycine residue in the triple-helical domain of the pro alpha 2(I) collagen molecule was found in an individual with a variant of the Marfan syndrome. A single base change resulted in substitution of arginine618 by glutamine at the Y position of a Gly-X-Y repeat, and is responsible for the decreased migration in SDS-polyacrylamide gels of some pro alpha 2(I) chains of type I collagen synthesized by dermal fibroblasts from this individual. Family studies suggest that this substitution was inherited from the individual's father who also produces abnormally migrating pro alpha 2(I) collagen chains and shares some of the abnormal skeletal features. This single base change creates a new Bsu36 I (Sau I, Mst II) restriction site detectable in genomic DNA by Southern blot analysis when probed with a COL1A2 fragment. The analysis of 52 control individuals (103 chromosomes) was negative for the new Bsu36 I site, suggesting that the substitution is not a common polymorphism.

Contamination in trials of educational interventions.

OBJECTIVES: To consider the effects of contamination on the magnitude and statistical significance (or precision) of the estimated effect of an educational intervention, to investigate the mechanisms of contamination, and to consider how contamination can be avoided. DATA SOURCES: Major electronic databases were searched up to May 2005. METHODS: An exploratory literature search was conducted. The results of trials included in previous relevant systematic reviews were then analysed to see whether studies that avoided contamination resulted in larger effect estimates than those that did not. Experts' opinions were elicited about factors more or less likely to lead to contamination. We simulated contamination processes to compare contamination biases between cluster and individually randomised trials. Statistical adjustment was made for contamination using Complier Average Causal Effect analytic methods, using published and simulated data. The bias and power of cluster and individually randomised trials were compared, as were Complier Average Causal Effect, intention-to-treat and per protocol methods of analysis. RESULTS: Few relevant studies quantified contamination. Experts largely agreed on where contamination was more or less likely. Simulation of contamination processes showed that, with various combinations of timing, intensity and baseline dependence of contamination, cluster randomised trials might produce biases greater than or similar to those of individually randomised trials. Complier Average Causal Effect analyses produced results that were less biased than intention-to-treat or per protocol analyses. They also showed that individually randomised trials would in most situations be more powerful than cluster randomised trials despite contamination. CONCLUSIONS: The probability, nature and process of contamination should be considered when designing and analysing controlled trials of educational interventions in health. Cluster randomisation may or may not be appropriate and should not be uncritically assumed always to be a solution. Complier Average Causal Effect models are an appropriate way to adjust for contamination if it can be measured. When conducting such trials in future, it is a priority to report the extent, nature and effects of contamination.

Learning to work together - lessons from a reflective analysis of a research project on public involvement.

PLAIN ENGLISH SUMMARY: Patient and public involvement (PPI) in research is very important, and funders and the NHS all expect this to happen. What this means in practice, and how to make it really successful, is therefore an important research question. This article analyses the experience of a research team using PPI, and makes recommendations on strengthening PPI in research. There were different PPI roles in our study - some people were part of the research team: some were on the advisory group; and there were patient groups who gave specific feedback on how to make research work better for their needs. We used minutes, other written documents, and structured individual and group reflections to learn from our own experiences over time. The main findings were:- for researchers and those in a PPI role to work in partnership, project structures must allow flexibility and responsiveness to different people's ideas and needs; a named link person can ensure support; PPI representatives need to feel fully included in the research; make clear what is expected for all roles; and ensure enough time and funding to allow meaningful involvement. Some roles brought more demands but also more rewards than others - highlighting that it is important that people giving up their time to help with research experience gains from doing so. Those contributing to PPI on a regular basis may want to learn new skills, rather than always doing the same things. Researchers and the public need to find ways to develop roles in PPI over time. We also found that, even for a team with expertise in PPI, there was a need both for understanding of different ways to contribute, and an evolving 'normalisation' of new ways of working together over time, which both enriched the process and the outputs. ABSTRACT: Background Patient and public involvement (PPI) is now an expectation of research funders, in the UK, but there is relatively little published literature on what this means in practice - nor is there much evaluative research about implementation and outputs. Policy literature endorses the need to include PPI representation at all stages of planning, performing and research dissemination, and recommends resource allocation to these roles; but details of how to make such inputs effective in practice are less common. While literature on power and participation informs the debate, there are relatively few published case studies of how this can play out through the lived experience of PPI in research; early findings highlight key issues around access to knowledge, resources, and interpersonal respect. This article describes the findings of a case study of PPI within a study about PPI in research. Methods The aim of the study was to look at how the PPI representatives' inputs had developed over time, key challenges and changes, and lessons learned. We used realist evaluation and normalisation process theory to frame and analyse the data, which was drawn from project documentation, minutes of meetings and workshops, field notes and observations made by PPI representatives and researchers; documented feedback after meetings and activities; and the structured feedback from two formal reflective meetings. Results Key findings included the need for named contacts who support, integrate and work with PPI contributors and researchers, to ensure partnership working is encouraged and supported to be as effective as possible. A structure for partnership working enabled this to be enacted systematically across all settings. Some individual tensions were nonetheless identified around different roles, with possible implications for clarifying expectations and deepening understandings of the different types of PPI contribution and of their importance. Even in a team with research expertise in PPI, the data showed that there were different phases and challenges to 'normalising' the PPI input to the project. Mutual commitment and flexibility, embedded through relationships across the team, led to inclusion and collaboration. Conclusion Work on developing relationships and teambuilding are as important for enabling partnership between PPI representatives and researchers as more practical components such as funding and information sharing. Early explicit exploration of the different roles and their contributions may assist effective participation and satisfaction.

Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

OBJECTIVES: To estimate the costs of commonly used treatments for cutaneous warts, as well as their health benefits and risk. To create an economic decision model to evaluate the cost-effectiveness of these treatments, and, as a result, assess whether a randomised controlled trial (RCT) would be feasible and cost-effective. DATA SOURCES: Focus groups, structured interviews and observation of practice. Postal survey sent to 723 patients. A recently updated Cochrane systematic review and published cost and prescribing data. REVIEW METHODS: Primary and secondary data collection methods were used to inform the development of an economic decision model. Data from the postal survey provided estimates of the effectiveness of wart treatments in a primary care setting. These estimates were compared with outcomes reported in the Cochrane review of wart treatment, which were largely obtained from RCTs conducted in secondary care. A decision model was developed including a variety of over-the-counter (OTC) and GP-prescribed treatments. The model simulated 10,000 patients and adopted a societal perspective. RESULTS: OTC treatments were used by a substantial number of patients (57%) before attending the GP surgery. By far the most commonly used OTC preparation was salicylic acid (SA). The results of the economic model suggested that of the treatments prescribed by a GP, the most cost-effective treatment was SA, with an incremental cost-effectiveness ratio (ICER) of 2.20 pound/% cured. The ICERs for cryotherapy varied widely (from 1.95 to 7.06 pound/% cured) depending on the frequency of applications and the mode of delivery. The most cost-effective mode of delivery was through nurse-led cryotherapy clinics (ICER = 1.95 pound/% cured) and this could be a cost-effective alternative to GP-prescribed SA. Overall, the OTC therapies were the most cost-effective treatment options. ICERs ranged from 0.22 pound/% cured for OTC duct tape and 0.76 pound/% cured for OTC cryotherapy to 1.12 pound/% cured for OTC SA. However, evidence in support of OTC duct tape and OTC cryotherapy is very limited. Side-effects were commonly reported for both SA and cryotherapy, particularly a burning sensation, pain and blistering. CONCLUSIONS: Cryotherapy delivered by a doctor is an expensive option for the treatment of warts in primary care. Alternative options such as GP-prescribed SA and nurse-led cryotherapy clinics provide more cost-effective alternatives, but are still expensive compared with self-treatment. Given the minor nature of most cutaneous warts, coupled with the fact that the majority spontaneously resolve in time, it may be concluded that a shift towards self-treatment is warranted. Although both duct tape and OTC cryotherapy appear promising new self-treatment options from both a cost and an effectiveness perspective, more research is required to confirm the efficacy of these two methods of wart treatment. If these treatments are shown to be as cost-effective as or more cost-effective than conventional treatments, then a shift in service delivery away from primary care towards more OTC treatment is likely. A public awareness campaign would be useful to educate patients about the self-limiting nature of warts and the possible alternative OTC treatment options available. Two future RCTs are recommended for consideration: a trial of SA compared with nurse-led cryotherapy in primary care, and a trial of home treatments. Greater understanding of the efficacy of these home treatments will give doctors a wider choice of treatment options, and may help to reduce the overall demand for cryotherapy in primary care.