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1.  Regression to the Mean and Predictors of MRI Disease Activity in RRMS Placebo Cohorts - Is There a Place for Baseline-to-Treatment Studies in MS? 
PLoS ONE  2015;10(2):e0116559.
Background
Gadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials.
Objectives
To quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts.
Methods
21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression.
Results
The mean number of GD+-lesions per scan was similar after 6 months (1.19, 95%CI: 0.87-1.51) and 2 years (1.19, 95%CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95%CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months.
Conclusion
Baseline GD-enhancing lesions predict evolution of Gd- and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+lesions per scan within 6 months.
doi:10.1371/journal.pone.0116559
PMCID: PMC4319835  PMID: 25659100
2.  Primum non nocere: shared informed decision making in low back pain – a pilot cluster randomised trial 
Background
Low back pain is a common and disabling condition leading to large health service and societal costs. Although there are several treatment options for back pain little is known about how to improve patient choice in treatment selection. The purpose of this study was to pilot a decision support package to help people choose between low back pain treatments.
Methods
This was a single-centred pilot cluster randomised controlled trial conducted in a community physiotherapy service. We included adults with non-specific low back pain referred for physiotherapy. Intervention participants were sent an information booklet prior to their first consultation. Intervention physiotherapists were trained to enhance their skills in shared informed decision making. Those in the control arm received care as usual. The primary outcome was satisfaction with the treatment received at four months using a five-point Likert Scale dichotomised into “satisfaction” (very satisfied or somewhat satisfied) and “non-satisfaction” (neither satisfied nor dissatisfied, somewhat dissatisfied or very dissatisfied).
Results
We recruited 148 participants. In the control arm 67% of participants were satisfied with their treatment and in the intervention arm 53%. The adjusted relative risk of being satisfied was 1.28 (95% confidence interval 0.79 to 2.09). For most secondary outcomes the trend was towards worse outcomes in the intervention group. For one measure; the Roland Morris Disability Questionnaire, this difference was clinically important (2.27, 95% confidence interval 0.08 to 4.47). Mean healthcare costs were slightly lower (£38 saving per patient) within the intervention arm but health outcomes were also less favourable (0.02 fewer QALYs); the estimated probability that the intervention would be cost-effective at an incremental threshold of £20,000 per QALY was 16%.
Conclusion
We did not find that this decision support package improved satisfaction with treatment; it may have had a substantial negative effect on clinical outcome, and is very unlikely to prove cost-effective. That a decision support package might have a clinically important detrimental effect is of concern. To our knowledge this has not been observed previously. Decision support packages should be formally tested for clinical and cost-effectiveness, and safety before implementation.
Trial registration
Current Controlled Trials ISRCTN46035546 registered on 11/02/10.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2474-15-282) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2474-15-282
PMCID: PMC4247192  PMID: 25146587
Back pain; Randomised control trial; Decision making
3.  Adhesion Maturation of Neutrophils on Nanoscopically Presented Platelet Glycoprotein Ibα 
ACS Nano  2013;7(11):9984-9996.
Neutrophilic granulocytes play a fundamental role in cardiovascular disease. They interact with platelet aggregates via the integrin Mac-1 and the platelet receptor glycoprotein Ibα (GPIbα). In vivo, GPIbα presentation is highly variable under different physiological and pathophysiological conditions. Here, we quantitatively determined the conditions for neutrophil adhesion in a biomimetic in vitro system, which allowed precise adjustment of the spacings between human GPIbα presented on the nanoscale from 60 to 200 nm. Unlike most conventional nanopatterning approaches, this method provided control over the local receptor density (spacing) rather than just the global receptor density. Under physiological flow conditions, neutrophils required a minimum spacing of GPIbα molecules to successfully adhere. In contrast, under low-flow conditions, neutrophils adhered on all tested spacings with subtle but nonlinear differences in cell response, including spreading area, spreading kinetics, adhesion maturation, and mobility. Surprisingly, Mac-1-dependent neutrophil adhesion was very robust to GPIbα density variations up to 1 order of magnitude. This complex response map indicates that neutrophil adhesion under flow and adhesion maturation are differentially regulated by GPIbα density. Our study reveals how Mac-1/GPIbα interactions govern cell adhesion and how neutrophils process the number of available surface receptors on the nanoscale. In the future, such in vitro studies can be useful to determine optimum therapeutic ranges for targeting this interaction.
doi:10.1021/nn403923h
PMCID: PMC4122703  PMID: 24093566
biomimetic surfaces; nanopatterning; biofunctionalization; cell adhesion; neutrophils; platelets
4.  Work-related outcomes in randomised placebo-controlled pain trials: a systematic review and meta-analysis 
Background
Chronic painful conditions have an important influence on the ability to work. Work-related outcomes, however, are not commonly reported in publications on trials investigating the treatment of chronic painful conditions. We aim to provide an overview of the reporting of work-related outcomes in such trials and investigate the relationship between work-related outcomes and pain outcomes.
Methods
We conducted a systematic literature search in PubMed with the aim of identifying randomised placebo-controlled clinical trials investigating treatments for chronic painful conditions or rheumatic diseases that also reported on work-related outcomes. Methodological study quality was assessed with the Oxford Quality Scale (OQS). Meta-analyses were conducted for the outcomes of interference with work and number of patients with at least 30% reduction in pain intensity (30% pain responders). The correlation between work-related and pain outcomes was investigated with regression analyses.
Results
We included 31 publications reporting on 27 datasets from randomised placebo-controlled trials (with a total of 11,434 study participants) conducted in chronic painful or rheumatic diseases and reporting on work-related outcomes. These 31 publications make up only about 0.2% of all publications on randomised placebo-controlled trials in such conditions. The methodological quality of the included studies was high; only nine studies scored less than four (out of a maximum five) points on the OQS. Sixteen different work-related outcomes were reported on in the studies. Of 25 studies testing for the statistical significance of changes in work-related outcomes over the course of the trials, 14 (56%) reported a significant improvement; the others reported non-significant changes. Eight studies reported data on both interference with work and 30% pain responders: meta-analyses demonstrated similar, statistically significant improvements in both these outcomes with active therapy compared to placebo and regression analysis showed that these outcomes were correlated.
Conclusions
Despite the importance of pain as a reason for decreased ability to work, work-related outcomes are reported in substantially less than 1% of publications on placebo-controlled trials in chronic painful and rheumatic diseases. Work-related outcomes and pain responder outcomes are closely related.
doi:10.1186/1745-6673-9-25
PMCID: PMC4107475  PMID: 25057282
Chronic painful conditions; Rheumatic diseases; Randomised controlled trials; Work-related outcomes
5.  Safety relevant knowledge of orally anticoagulated patients without self-monitoring: a baseline survey in primary care 
BMC Family Practice  2014;15:104.
Background
Effective and safe management of oral anticoagulant treatment (OAT) requires a high level of patient knowledge and adherence. The aim of this study was to assess patient knowledge about OAT and factors associated with patient knowledge.
Methods
This is a baseline survey of a cluster-randomized controlled trial in 22 general practices with an educational intervention for patients or their caregivers. We assessed knowledge about general information on OAT and key facts regarding nutrition, drug-interactions and other safety precautions of 345 patients at baseline.
Results
Participants rated their knowledge about OAT as excellent to good (56%), moderate (36%) or poor (8%). However, there was a discrepancy between self-rated knowledge and evaluated actual knowledge and we observed serious knowledge gaps. Half of the participants (49%) were unaware of dietary recommendations. The majority (80%) did not know which non-prescription analgesic is the safest and 73% indicated they would not inform pharmacists about OAT. Many participants (35-75%) would not recognize important emergency situations. After adjustment in a multivariate analysis, older age and less than 10 years education remained significantly associated with lower overall score, but not with self-rated knowledge.
Conclusions
Patients have relevant knowledge gaps, potentially affecting safe and effective OAT. There is a need to assess patient knowledge and for structured education programs.
Trial registration
Deutsches Register Klinischer Studien (German Clinical Trials Register): DRKS00000586.
Universal Trial Number (UTN U1111-1118-3464).
doi:10.1186/1471-2296-15-104
PMCID: PMC4045910  PMID: 24885192
6.  Efficacy of Ambroxol lozenges for pharyngitis: a meta-analysis 
BMC Family Practice  2014;15:45.
Background
Ambroxol has a local anaesthetic action and is marketed for pain relief for sore throat. The objective is to examine the efficacy and safety of ambroxol for the relief of pain associated with acute uncomplicated sore throat.
Methods
A systematic review of the literature and meta-analysis. Selection criteria consisted of randomized controlled trials which compared ambroxol to placebo or any other treatment for sore throat. Two reviewers independently assessed for relevance, inclusion, and risk of bias. Weighted mean differences (WMDs) were calculated and are reported with corresponding 95% confidence intervals (CIs).
Results and conclusion
From 14 potentially relevant citations, five trials reported in three publications met the inclusion criteria, three of them were published twice. Ambroxol lozenges were compared in different dosages (5–30 mg) with mint flavoured lozenges and once with benzocaine. Main outcome was a ratio of pain reduction measured repeatedly over 3 h compared to baseline on 6-item verbal rating scale. A total of 1.772 adult patients participated in the trials. Pain intensity decreased in both study arms. A meta-analysis of the 5 controlled trials resulted in a difference in pain reduction compared to placebo of -0.11 (95% CI [-0.15, -0.07]; p < 0.0001) favouring ambroxol 20 mg. Quality of reporting of the studies was low. Ambroxol is slightly more effective in relieving pain in acute sore throat than mint flavoured lozenges over a period of 3 h. However, the additional benefits of ambroxol beyond three hours, remain unclear given that more than 50% of patients using mint flavoured lozenges for pain relief reported good or very good efficacy after 1 day compared to 69% with ambroxol. Ambroxol is a safe option for individual patients with mainly local symptoms asking for treatment.
doi:10.1186/1471-2296-15-45
PMCID: PMC3975147  PMID: 24621446
Pharyngitis; Sore throat; Mint flavoured lozenges; Ambroxol; Primary care; Pain relief; Meta-analysis
7.  Sources of Information and Behavioral Patterns in Online Health Forums: Observational Study 
Background
Increasing numbers of patients are raising their voice in online forums. This shift is welcome as an act of patient autonomy, reflected in the term “expert patient”. At the same time, there is considerable concern that patients can be easily misguided by pseudoscientific research and debate. Little is known about the sources of information used in health-related online forums, how users apply this information, and how they behave in such forums.
Objective
The intent of the study was to identify (1) the sources of information used in online health-related forums, and (2) the roles and behavior of active forum visitors in introducing and disseminating this information.
Methods
This observational study used the largest German multiple sclerosis (MS) online forum as a database, analyzing the user debate about the recently proposed and controversial Chronic Cerebrospinal Venous Insufficiency (CCSVI) hypothesis. After extracting all posts and then filtering relevant CCSVI posts between 01 January 2008 and 17 August 2012, we first identified hyperlinks to scientific publications and other information sources used or referenced in the posts. Employing k-means clustering, we then analyzed the users’ preference for sources of information and their general posting habits.
Results
Of 139,912 posts from 11,997 threads, 8628 posts discussed or at least mentioned CCSVI. We detected hyperlinks pointing to CCSVI-related scientific publications in 31 posts. In contrast, 2829 different URLs were posted to the forum, most frequently referring to social media, such as YouTube or Facebook. We identified a total of 6 different roles of hyperlink posters including Social Media Fans, Organization Followers, and Balanced Source Users. Apart from the large and nonspecific residual category of the “average user”, several specific behavior patterns were identified, such as the small but relevant groups of CCSVI-Focused Responders or CCSVI Activators.
Conclusions
The bulk of the observed contributions were not based on scientific results, but on various social media sources. These sources seem to contain mostly opinions and personal experience. A small group of people with distinct behavioral patterns played a core role in fuelling the discussion about CCSVI.
doi:10.2196/jmir.2875
PMCID: PMC3958625  PMID: 24425598
Internet utilization; information dissemination; data mining; social media; social networks; multiple sclerosis; CCSVI
9.  Cross cultural evaluation of the Warwick-Edinburgh mental well-being scale (WEMWBS) -a mixed methods study 
Background
We aimed to validate the Warwick-Edinburgh Mental Well-being Scale (WEMWBS) among English speaking adults representing two of the minority ethnic groups living in the UK, self-identified as Chinese or Pakistani by background, in a mixed methods study.
Methods
Quantitative data were collected in two cities in the West Midlands, UK. Item response, dimensionality, internal consistency, and construct validity of the WEMWBS were assessed in Chinese and Pakistani groups separately, using data from both cities combined.
Qualitative data were collected in the first city in eight focus groups of different ages recruited by the community workers. Three mixed sex Chinese and five single sex Pakistani groups discussed ease of completion and comprehension of items, together with overall reactions to the scale and underlying concept.
Results of quantitative and qualitative analysis were examined for commonalities and differences.
Results
Item completion and item total correlations were satisfactory in both groups. In the Chinese data, Exploratory Factor Analysis showed a single factor with loadings ranging from 0.60 to 0.82 for all 14 items. In the Pakistani data, three factors reached statistical significance; however, a substantial drop in eigenvalues between the first and second factors and the limited variance explained by the second and third factors supported a one-factor model. All items loaded on this factor from 0.51 to 0.83.
In the Chinese and Pakistani data respectively, Cronbach’s alpha was 0.92 (0.89 – 0.94) and 0.91 (0.88 – 0.94); Spearman’s correlation with GHQ-12 was - 0.63 (−0.73 to −0.49) and −0.55 (−0.70 to −0.36), and with the WHO-5 0.62 (0.46-0.75) and 0.64 (0.50 to 0.76).
Qualitative analysis revealed good comprehension and ease of completion of almost all items. Some culturally determined differences in understanding of mental well-being, which varied both between and within communities, emerged.
Conclusions
The WEMWBS was well received by members of both Pakistani and Chinese communities. It showed high levels of consistency and reliability compared with accepted criteria. Data were sufficiently strong to recommend the WEMWBS for use in general population surveys.
doi:10.1186/1477-7525-11-27
PMCID: PMC3610169  PMID: 23445544
Mental well-being; WEMWBS; Cross cultural; Validation; PROMS (patient reported outcome measures); Ethnicity (MeSH: ethnic groups)
10.  Safety and Efficacy of the ACE-Inhibitor Ramipril in Alport Syndrome: The Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase III EARLY PRO-TECT Alport Trial in Pediatric Patients 
ISRN Pediatrics  2012;2012:436046.
Introduction. Retrospective observational data show that ACE-inhibitor therapy delays renal failure and improves life expectancy in Alport patients with proteinuria. The EARLY PRO-TECT Alport trial assesses the safety and efficacy of early therapy onset with ramipril in pediatric Alport patients. Methods and analysis. This double-blind, randomized, placebo-controlled, multicenter phase III trial (NCT01485978; EudraCT-number 2010-024300-10) includes 120 pediatric patients aged 24 months to 18 years with early stages of Alport syndrome (isolated hematuria or microalbuminuria). From March 2012, up to 80 patients will be randomized 1:1 to ramipril or placebo. In the event of disease progression during 3-year treatment, patients are unblinded and ramipril is initiated, if applicable. Approximately 40 patients receive open-label ramipril contributing to the safety database. Primary end-points are “time to progression to next disease level” and “incidence of adverse drug events before disease progression.” Treatment effect estimates from the randomized comparison and Alport registry data will be combined in supportive analyses to maximize evidence. Conclusion. Without this trial, ACE inhibitors may become standard off-label treatment in Alport syndrome without satisfactory evidence base. The results are expected to be of relevance for therapy of all pediatric patients with kidney disease, and the trial protocol might serve as a model for other rare pediatric glomerulopathies.
doi:10.5402/2012/436046
PMCID: PMC3395192  PMID: 22811928
12.  Rationale, objectives, and design of the EUTrigTreat clinical study: a prospective observational study for arrhythmia risk stratification and assessment of interrelationships among repolarization markers and genotype 
Europace  2011;14(3):416-422.
Aims
The EUTrigTreat clinical study has been designed as a prospective multicentre observational study and aims to (i) risk stratify patients with an implantable cardioverter defibrillator (ICD) for mortality and shock risk using multiple novel and established risk markers, (ii) explore a link between repolarization biomarkers and genetics of ion (Ca2+, Na+, K+) metabolism, (iii) compare the results of invasive and non-invasive electrophysiological (EP) testing, (iv) assess changes of non-invasive risk stratification tests over time, and (v) associate arrythmogenomic risk through 19 candidate genes.
Methods and results
Patients with clinical ICD indication are eligible for the trial. Upon inclusion, patients will undergo non-invasive risk stratification, including beat-to-beat variability of repolarization (BVR), T-wave alternans, T-wave morphology variables, ambient arrhythmias from Holter, heart rate variability, and heart rate turbulence. Non-invasive or invasive programmed electrical stimulation will assess inducibility of ventricular arrhythmias, with the latter including recordings of monophasic action potentials and assessment of restitution properties. Established candidate genes are screened for variants. The primary endpoint is all-cause mortality, while one of the secondary endpoints is ICD shock risk. A mean follow-up of 3.3 years is anticipated. Non-invasive testing will be repeated annually during follow-up. It has been calculated that 700 patients are required to identify risk predictors of the primary endpoint, with a possible increase to 1000 patients based on interim risk analysis.
Conclusion
The EUTrigTreat clinical study aims to overcome current shortcomings in sudden cardiac death risk stratification and to answer several related research questions. The initial patient recruitment is expected to be completed in July 2012, and follow-up is expected to end in September 2014.
Clinicaltrials.gov identifier: NCT01209494.
doi:10.1093/europace/eur352
PMCID: PMC3283222  PMID: 22117037
Sudden cardiac death risk stratification; Implantable cardioverter defibrillator; Cardiomyocyte ion metabolism; Ventricular repolarization; Electrocardiogram; Programmed electrical stimulation; Repolarization alternans
13.  Reporting FDR analogous confidence intervals for the log fold change of differentially expressed genes 
BMC Bioinformatics  2011;12:288.
Background
Gene expression experiments are common in molecular biology, for example in order to identify genes which play a certain role in a specified biological framework. For that purpose expression levels of several thousand genes are measured simultaneously using DNA microarrays. Comparing two distinct groups of tissue samples to detect those genes which are differentially expressed one statistical test per gene is performed, and resulting p-values are adjusted to control the false discovery rate. In addition, the expression change of each gene is quantified by some effect measure, typically the log fold change. In certain cases, however, a gene with a significant p-value can have a rather small fold change while in other cases a non-significant gene can have a rather large fold change. The biological relevance of the change of gene expression can be more intuitively judged by a fold change then merely by a p-value. Therefore, confidence intervals for the log fold change which accompany the adjusted p-values are desirable.
Results
In a new approach, we employ an existing algorithm for adjusting confidence intervals in the case of high-dimensional data and apply it to a widely used linear model for microarray data. Furthermore, we adopt a concept of different relevance categories for effects in clinical trials to assess biological relevance of genes in microarray experiments. In a brief simulation study the properties of the adjusting algorithm are maintained when being combined with the linear model for microarray data. In two cancer data sets the adjusted confidence intervals can indicate significance of large fold changes and distinguish them from other large but non-significant fold changes. Adjusting of confidence intervals also corrects the assessment of biological relevance.
Conclusions
Our new combination approach and the categorization of fold changes facilitates the selection of genes in microarray experiments and helps to interpret their biological relevance.
doi:10.1186/1471-2105-12-288
PMCID: PMC3154206  PMID: 21756370
14.  Warwick-Edinburgh Mental Well-being Scale (WEMWBS): Validated for teenage school students in England and Scotland. A mixed methods assessment 
BMC Public Health  2011;11:487.
Background
Understanding and measuring mental health and wellbeing amongst teenagers has recently become a priority. The Warwick-Edinburgh Mental Well-being Scale (WEMWBS) is validated for measuring mental wellbeing in populations aged 16 years and over in the UK. We report here a study designed to establish the validity and reliability of WEMWBS in teenagers in the UK.
Methods
WEMWBS and comparator scales, together with socio-demographic information and self-reported health, were incorporated into a self-administered questionnaire given to pupils aged 13 to 16 years in six schools in Scotland and England. Psychometric properties including internal consistency, correlations with comparator scales, test-retest stability and unidimensionality were investigated for WEMWBS. Twelve focus groups were undertaken to assess acceptability and comprehensibility of WEMWBS and were taped, transcribed and analysed thematically.
Results
A total of 1,650 teenagers completed the questionnaire (response rate 80.8%). Mean WEMWBS score was 48.8 (SD 6.8; median 49). Response scores covered the full range (from 14 to 70). WEMWBS demonstrated strong internal consistency and a high Cronbach's alpha of 0.87 (95% CI (0.85-0.88), n = 1517). Measures of construct validity gave values as predicted. The correlation coefficient for WEMWBS total score and psychological wellbeing domain of the Kidscreen-27 was 0.59 (95% CI [0.55; 0.62]); for the Mental Health Continuum Short Form (MHC-SF) was 0.65, 95% CI [0.62; 0.69]; and for the WHO (WHO-5) Well-being Index 0.57 (95% CI [0.53; 0.61]). The correlation coefficient for the Strengths and Difficulties Questionnaire (SDQ) was -0.44 (95% CI [-0.49; -0.40]) and for the 12-item General Health Questionnaire (GHQ12) -0.45 (95% CI [-0.49; -0.40]). Test-retest reliability was acceptable (Intraclass correlation coefficient (ICC) 0.66 (95% CI [0.59; 0.72] n = 212)). Confirmatory factor analysis demonstrated one underlying factor.
WEMWBS was significantly associated with the Family Affluence Score (WEMWBS increased with increasing household socio-economic status) and had a positive association with the physical health dimension of the Kidscreen-27, but was unrelated to age, gender or location/school. Eighty students took part in focus groups. In general, although some students considered some items open to misunderstanding or misinterpretation, WEMWBS was received positively and was considered comprehensible, and acceptable.
Conclusions
WEMWBS is a psychometrically strong population measure of mental wellbeing, and can be used for this purpose in teenagers aged 13 and over.
doi:10.1186/1471-2458-11-487
PMCID: PMC3141456  PMID: 21693055
15.  Development of oral immunomodulatory agents in the management of multiple sclerosis 
The emergence of oral disease-modifying therapies in multiple sclerosis (MS) will have a significant impact on the evolving scenario of immunomodulatory treatments in MS where current therapies are all injectable. Reducing relapses in trials translates for individuals with MS into a therapeutic aim of stopping future events. Thus the possible absence of any perceived benefits to the individual together with the long disease course, variable outcome, and a younger age group affected in MS makes side effects the major issue. The use of disease-modifying therapies as a whole needs to be placed in the context of a widening therapeutic indication where the use of these therapies is being justified at an increasingly early stage and in pre-MS syndromes such as clinically isolated and radiologically isolated syndromes where no fixed disability is likely to have accumulated. The five oral therapies discussed (cladribine, fingolimod, laquinimod, BG-12, and teriflunomide) have just completed Phase III studies and some have just been licensed. New oral drugs for MS need to be placed within this evolving marketplace where ease of delivery together with efficacy and side effects needs to be balanced against the known issues but also the known long-term safety of standard injectables.
doi:10.2147/DDDT.S10498
PMCID: PMC3100222  PMID: 21625416
multiple sclerosis; immunomodulatory treatment; cladribine; fingolimod; laquinimod; BG-12; teriflunomide
16.  Practice nursed-based, individual and video-assisted patient education in oral anticoagulation - Protocol of a cluster-randomized controlled trial 
BMC Family Practice  2011;12:17.
Background
Managing oral anticoagulant treatment (OAT) is a challenge for patients and primary care providers. It requires a high level of patient knowledge and adherence. Studies have shown that insufficient adherence and a low level of patient knowledge about OAT are primary causes for complications. This trial is the first to evaluate the long-term effects of a complex practice nurse-based patient education program in comparison to a patient brochure only.
Methods and design
This trial will be a cluster-randomized controlled trial in 22 general practices (GPs) recruiting 360 patients with OAT. GPs will be randomized into an intervention group or a control group. A baseline questionnaire will assess pre-existing knowledge about OAT. The patients in the intervention group will be educated by a complex education program which consists of a video, a brochure and individual training by a practice nurse. The video gives information about OAT, nutrition, and instructions about how to manage critical situations. The brochure repeats the content of the video. After 4 to 6 weeks, the intervention will be recapitulated. The control group will receive the brochure only. After 6 months, questionnaires will be used in both groups to assess patient knowledge about OAT as well as patients' subjective feelings of safety. Separately, we will evaluate patient records, looking for documented complications and the time spent in the therapeutic range.
Discussion
This trial will start in January 2011. This trial will evaluate the long-term effectiveness of a video-assisted education program on patients with OAT in comparison to a patient information brochure. Most previous studies have evaluated knowledge directly after an educational intervention. Our trial will look for long-term differences in basic knowledge of OAT. We expect that our complex patient education program effectively increases long-term basic knowledge about OAT. Although the population of our study is too small to observe differences in adverse effects, we expect to discover differences in secondary outcomes, such as the time spent in the therapeutic range.
Trial registration
Deutsches Register Klinischer Studien (German Clinical Trials Register): DRKS00000586
Universal Trial Number (UTN U1111-1118-3464)
doi:10.1186/1471-2296-12-17
PMCID: PMC3089775  PMID: 21477372
17.  Automated electronic reminders to facilitate primary cardiovascular disease prevention: randomised controlled trial 
The British Journal of General Practice  2010;60(573):e137-e143.
Background
Primary care databases contain cardiovascular disease risk factor data, but practical tools are required to improve identification of at-risk patients.
Aim
To test the effects of a system of electronic reminders (the ‘e-Nudge’) on cardiovascular events and the adequacy of data for cardiovascular risk estimation.
Design of study
Randomised controlled trial.
Setting
Nineteen general practices in the West Midlands, UK.
Method
The e-Nudge identifies four groups of patients aged over 50 years on the basis of estimated cardiovascular risk and adequacy of risk factor data in general practice computers. Screen messages highlight individuals at raised risk and prompt users to complete risk profiles where necessary. The proportion of the study population in the four groups was measured, as well as the rate of cardiovascular events in each arm after 2 years.
Results
Over 38 000 patients' electronic records were randomised. The intervention led to an increase in the proportion of patients with sufficient data who were identifiably at risk, with a difference of 1.94% compared to the control group (95% confidence interval [CI] = 1.38 to 2.50, P<0.001). A corresponding reduction occurred in the proportion potentially at risk but requiring further data for a risk estimation (difference = –3.68%, 95% CI = –4.53 to –2.84, P<0.001). No significant difference was observed in the incidence of cardiovascular events (rate ratio = 0.96, 95% CI = 0.85 to 1.10, P = 0.59).
Conclusion
Automated electronic reminders using routinely collected primary care data can improve the adequacy of cardiovascular risk factor information during everyday practice and increase the visibility of the at-risk population.
doi:10.3399/bjgp10X483904
PMCID: PMC2845504  PMID: 20353659
cardiovascular diseases; primary prevention; reminder systems; risk assessment; informatics
18.  Study protocol: Improving patient choice in treating low back pain (IMPACT - LBP): A randomised controlled trial of a decision support package for use in physical therapy 
Background
Low back pain is a common and costly condition. There are several treatment options for people suffering from back pain, but there are few data on how to improve patients' treatment choices. This study will test the effects of a decision support package (DSP), designed to help patients seeking care for back pain to make better, more informed choices about their treatment within a physiotherapy department. The package will be designed to assist both therapist and patient.
Methods/Design
Firstly, in collaboration with physiotherapists, patients and experts in the field of decision support and decision aids, we will develop the DSP. The work will include: a literature and evidence review; secondary analysis of existing qualitative data; exploration of patients' perspectives through focus groups and exploration of experts' perspectives using a nominal group technique and a Delphi study.
Secondly, we will carry out a pilot single centre randomised controlled trial within NHS Coventry Community Physiotherapy. We will randomise physiotherapists to receive either training for the DSP or not. We will randomly allocate patients seeking treatment for non specific low back pain to either a physiotherapist trained in decision support or to receive usual care. Our primary outcome measure will be patient satisfaction with treatment at three month follow-up. We will also estimate the cost-effectiveness of the intervention, and assess the value of conducting further research.
Discussion
Informed shared decision-making should be an important part of any clinical consultation, particularly when there are several treatments, which potentially have moderate effects. The results of this pilot will help us determine the benefits of improving the decision-making process in clinical practice on patient satisfaction.
Trial registration
Current Controlled Trials ISRCTN46035546
doi:10.1186/1471-2474-12-52
PMCID: PMC3063252  PMID: 21352528
19.  Design and Development of a Decision Support Package for Low Back Pain 
Arthritis Care & Research  2014;66(6):925-933.
Objective
To develop a decision support package for people with low back pain (LBP) referred for physiotherapy.
Methods
We used a program of exploratory work, including literature reviews, a Delphi study, a nominal group with physiotherapists, focus groups with patients, and secondary analysis of existing interview data.
Results
We developed an information booklet describing the evidence-based treatment modalities available in a physiotherapy department. This includes data on likely benefits and risks and how the intervention is delivered. The booklet specifically addresses questions identified as important in our exploratory work. Space is provided for patients to note down the pros and cons of each treatment and what matters to them when choosing treatments. The patient is subsequently directed to a section that explores any gaps in knowledge, values, support, and choice before finally clarifying if a treatment decision is possible. At this stage they are encouraged to note down any questions or concerns they have to be discussed at the first physiotherapy consultation. This overall package includes patient material in the form of a booklet posted prior to their consultation, plus the enhanced consultation with the specially trained physiotherapist. Patients then receive their chosen treatment. In addition we developed a training package for physiotherapists that explains the content of the booklet and supports them in using informed, shared decision making in their consultation.
Conclusion
This package has the potential to improve effectiveness of treatments and patient satisfaction for LBP by facilitating patient choice and therefore matching patients more effectively to different treatments.
doi:10.1002/acr.22252
PMCID: PMC4153953  PMID: 24339441
20.  Data-driven treatment selection for seamless phase II/III trials incorporating early-outcome data 
Pharmaceutical Statistics  2014;13(4):238-246.
Seamless phase II/III clinical trials are conducted in two stages with treatment selection at the first stage. In the first stage, patients are randomized to a control or one of k > 1 experimental treatments. At the end of this stage, interim data are analysed, and a decision is made concerning which experimental treatment should continue to the second stage. If the primary endpoint is observable only after some period of follow-up, at the interim analysis data may be available on some early outcome on a larger number of patients than those for whom the primary endpoint is available. These early endpoint data can thus be used for treatment selection. For two previously proposed approaches, the power has been shown to be greater for one or other method depending on the true treatment effects and correlations. We propose a new approach that builds on the previously proposed approaches and uses data available at the interim analysis to estimate these parameters and then, on the basis of these estimates, chooses the treatment selection method with the highest probability of correctly selecting the most effective treatment. This method is shown to perform well compared with the two previously described methods for a wide range of true parameter values. In most cases, the performance of the new method is either similar to or, in some cases, better than either of the two previously proposed methods. © 2014 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.
doi:10.1002/pst.1619
PMCID: PMC4283755  PMID: 24789367
adaptive seamless design; multi-arm multi-stage trial; surrogate endpoint
21.  Spline-based procedures for dose-finding studies with active control 
Statistics in Medicine  2014;34(2):232-248.
In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose–response relationship and to find the smallest target dose concentration d*, which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose–response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose–response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs. © 2014 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
doi:10.1002/sim.6320
PMCID: PMC4288315  PMID: 25319931
dose-finding study; active control; spline interpolation; design considerations

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