Depression in small-vessel disease relates to white matter ultrastructural damage, not disability.

OBJECTIVE: To determine whether cerebral small-vessel disease (SVD) is a specific risk factor for depression, whether any association is mediated via white matter damage, and to study the role of depressive symptoms and disability on quality of life (QoL) in this patient group. METHODS: Using path analyses in cross-sectional data, we modeled the relationships among depression, disability, and QoL in patients with SVD presenting with radiologically confirmed lacunar stroke (n = 100), and replicated results in a second SVD cohort (n = 100). We then compared the same model in a non-SVD stroke cohort (n = 50) and healthy older adults (n = 203). In a further study, to determine the role of white matter damage in mediating the association with depression, a subgroup of patients with SVD (n = 101) underwent diffusion tensor imaging (DTI). RESULTS: Reduced QoL was associated with depression in patients with SVD, but this association was not mediated by disability or cognition; very similar results were found in the replication SVD cohort. In contrast, the non-SVD stroke group and the healthy older adult group showed a direct relationship between disability and depression. The DTI study showed that fractional anisotropy, a marker of white matter damage, was related to depressive symptoms in patients with SVD. CONCLUSION: These results suggest that in stroke patients without SVD, disability is an important causal factor for depression, whereas in SVD stroke, other factors specific to this stroke subtype have a causal role. White matter damage detected on DTI is one factor that mediates the association between SVD and depression

The Brief Memory and Executive Test (BMET) for detecting vascular cognitive impairment in small vessel disease: a validation study.

Cognitive impairment is common in patients with cerebral small vessel disease, but is not well detected using common cognitive screening tests which have been primarily devised for cortical dementias. We developed the Brief Memory and Executive Test (BMET); a rapid screening measure sensitive to the impaired executive function and processing speed characteristic of small vessel disease (SVD). To assess the BMET's validity for general use, we evaluated it when administered by non-psychologists in a multicentre study and collected control data to derive normative scores.The BMET study was funded by The Stroke Association (TSA2010/08). Recruitment to BMET was supported by the NIHR Stroke Clinical Research Network. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospitals NIHR Comprehensive BRC. Matthew Hollocks is supported by a Stroke Association/British Heart Foundation Grant (TSA BHF 2010/01). Robin Morris receives consultancy fees for P1Vital Limited. The authors disclose no competing interests financial or otherwise

Design considerations in a clinical trial of a cognitive behavioural intervention for the management of low back pain in primary care : Back Skills Training Trial

Background Low back pain (LBP) is a major public health problem. Risk factors for the development and persistence of LBP include physical and psychological factors. However, most research activity has focused on physical solutions including manipulation, exercise training and activity promotion. Methods/Design This randomised controlled trial will establish the clinical and cost-effectiveness of a group programme, based on cognitive behavioural principles, for the management of sub-acute and chronic LBP in primary care. Our primary outcomes are disease specific measures of pain and function. Secondary outcomes include back beliefs, generic health related quality of life and resource use. All outcomes are measured over 12 months. Participants randomised to the intervention arm are invited to attend up to six weekly sessions each of 90 minutes; each group has 6–8 participants. A parallel qualitative study will aid the evaluation of the intervention. Discussion In this paper we describe the rationale and design of a randomised evaluation of a group based cognitive behavioural intervention for low back pain

Quality of medication use in primary care - mapping the problem, working to a solution: a systematic review of the literature

Background: The UK, USA and the World Health Organization have identified improved patient safety in healthcare as a priority. Medication error has been identified as one of the most frequent forms of medical error and is associated with significant medical harm. Errors are the result of the systems that produce them. In industrial settings, a range of systematic techniques have been designed to reduce error and waste. The first stage of these processes is to map out the whole system and its reliability at each stage. However, to date, studies of medication error and solutions have concentrated on individual parts of the whole system. In this paper we wished to conduct a systematic review of the literature, in order to map out the medication system with its associated errors and failures in quality, to assess the strength of the evidence and to use approaches from quality management to identify ways in which the system could be made safer. Methods: We mapped out the medicines management system in primary care in the UK. We conducted a systematic literature review in order to refine our map of the system and to establish the quality of the research and reliability of the system. Results: The map demonstrated that the proportion of errors in the management system for medicines in primary care is very high. Several stages of the process had error rates of 50% or more: repeat prescribing reviews, interface prescribing and communication and patient adherence. When including the efficacy of the medicine in the system, the available evidence suggested that only between 4% and 21% of patients achieved the optimum benefit from their medication. Whilst there were some limitations in the evidence base, including the error rate measurement and the sampling strategies employed, there was sufficient information to indicate the ways in which the system could be improved, using management approaches. The first step to improving the overall quality would be routine monitoring of adherence, clinical effectiveness and hospital admissions. Conclusion: By adopting the whole system approach from a management perspective we have found where failures in quality occur in medication use in primary care in the UK, and where weaknesses occur in the associated evidence base. Quality management approaches have allowed us to develop a coherent change and research agenda in order to tackle these, so far, fairly intractable problems

Postural control is not systematically related to reading skills:implications for the assessment of balance as a risk factor for developmental dyslexia

Impaired postural control has been associated with poor reading skills, as well as with lower performance on measures of attention and motor control variables that frequently co-occur with reading difficulties. Measures of balance and motor control have been incorporated into several screening batteries for developmental dyslexia, but it is unclear whether the relationship between such skills and reading manifests as a behavioural continuum across the range of abilities or is restricted to groups of individuals with specific disorder phenotypes. Here were obtained measures of postural control alongside measures of reading, attention and general cognitive skills in a large sample of young adults (n = 100). Postural control was assessed using centre of pressure (CoP) measurements, obtained over 5 different task conditions. Our results indicate an absence of strong statistical relationships between balance measures with either reading, cognitive or attention measures across the sample as a whole. © 2014 Loras et al

A review of reporting of participant recruitment and retention in RCTs in six major journals

<p>Abstract</p> <p>Background</p> <p>Poor recruitment and retention of participants in randomised controlled trials (RCTs) is problematic but common. Clear and detailed reporting of participant flow is essential to assess the generalisability and comparability of RCTs. Despite improved reporting since the implementation of the CONSORT statement, important problems remain. This paper aims: (i) to update and extend previous reviews evaluating reporting of participant recruitment and retention in RCTs; (ii) to quantify the level of participation throughout RCTs.</p> <p>Methods</p> <p>We reviewed all reports of RCTs of health care interventions and/or processes with individual randomisation, published July–December 2004 in six major journals. Short, secondary or interim reports, and Phase I/II trials were excluded. Data recorded were: general RCT details; inclusion of flow diagram; participant flow throughout trial; reasons for non-participation/withdrawal; target sample sizes.</p> <p>Results</p> <p>133 reports were reviewed. Overall, 79% included a flow diagram, but over a third were incomplete. The majority reported the flow of participants at each stage of the trial after randomisation. However, 40% failed to report the numbers assessed for eligibility. Percentages of participants retained at each stage were high: for example, 90% of eligible individuals were randomised, and 93% of those randomised were outcome assessed. On average, trials met their sample size targets. However, there were some substantial shortfalls: for example 21% of trials reporting a sample size calculation failed to achieve adequate numbers at randomisation, and 48% at outcome assessment. Reporting of losses to follow up was variable and difficult to interpret.</p> <p>Conclusion</p> <p>The majority of RCTs reported the flow of participants well after randomisation, although only two-thirds included a complete flow chart and there was great variability over the definition of "lost to follow up". Reporting of participant eligibility was poor, making assessments of recruitment practice and external validity difficult. Reporting of participant flow throughout RCTs could be improved by small changes to the CONSORT chart.</p

Multivariable risk prediction can greatly enhance the statistical power of clinical trial subgroup analysis

BACKGROUND: When subgroup analyses of a positive clinical trial are unrevealing, such findings are commonly used to argue that the treatment's benefits apply to the entire study population; however, such analyses are often limited by poor statistical power. Multivariable risk-stratified analysis has been proposed as an important advance in investigating heterogeneity in treatment benefits, yet no one has conducted a systematic statistical examination of circumstances influencing the relative merits of this approach vs. conventional subgroup analysis. METHODS: Using simulated clinical trials in which the probability of outcomes in individual patients was stochastically determined by the presence of risk factors and the effects of treatment, we examined the relative merits of a conventional vs. a "risk-stratified" subgroup analysis under a variety of circumstances in which there is a small amount of uniformly distributed treatment-related harm. The statistical power to detect treatment-effect heterogeneity was calculated for risk-stratified and conventional subgroup analysis while varying: 1) the number, prevalence and odds ratios of individual risk factors for risk in the absence of treatment, 2) the predictiveness of the multivariable risk model (including the accuracy of its weights), 3) the degree of treatment-related harm, and 5) the average untreated risk of the study population. RESULTS: Conventional subgroup analysis (in which single patient attributes are evaluated "one-at-a-time") had at best moderate statistical power (30% to 45%) to detect variation in a treatment's net relative risk reduction resulting from treatment-related harm, even under optimal circumstances (overall statistical power of the study was good and treatment-effect heterogeneity was evaluated across a major risk factor [OR = 3]). In some instances a multi-variable risk-stratified approach also had low to moderate statistical power (especially when the multivariable risk prediction tool had low discrimination). However, a multivariable risk-stratified approach can have excellent statistical power to detect heterogeneity in net treatment benefit under a wide variety of circumstances, instances under which conventional subgroup analysis has poor statistical power. CONCLUSION: These results suggest that under many likely scenarios, a multivariable risk-stratified approach will have substantially greater statistical power than conventional subgroup analysis for detecting heterogeneity in treatment benefits and safety related to previously unidentified treatment-related harm. Subgroup analyses must always be well-justified and interpreted with care, and conventional subgroup analyses can be useful under some circumstances; however, clinical trial reporting should include a multivariable risk-stratified analysis when an adequate externally-developed risk prediction tool is available

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Competing risk and heterogeneity of treatment effect in clinical trials

It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks – which may or may not be correlated – may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend