Established corticosteroid creams should be applied only once daily in patients with atopic eczema

Atopic eczema affects many adults and up to 20% of children,1 with health costs comparable to diabetes2 and asthma.3 One community survey of 1760 young children in the United Kingdom found that 84% had mild eczema, 14% moderate, and 2% severe eczema.4 Topical corticosteroids are a mainstay of treatment for inflammatory episodes.5 Most long established topical corticosteroids such as betamethasone valerate or hydrocortisone are applied at least twice daily, but three newer preparations (mometasone, fluticasone, and methylprednisolone) have been developed for once daily application. Here, I propose that established preparations need be applied only once daily.

Feasibility study to inform the design of a UK multi-centre randomised controlled trial of prophylactic antibiotics for the prevention of recurrent cellulitis of the leg

Background: This paper describes the results of a feasibility study for a randomised controlled trial (RCT). Methods: Twenty-nine members of the UK Dermatology Clinical Trials Network (UK DCTN) expressed an interest in recruiting for this study. Of these, 17 obtained full ethics and Research & Development (R&D) approval, and 15 successfully recruited patients into the study. A total of 70 participants with a diagnosis of cellulitis of the leg were enrolled over a 5-month period. These participants were largely recruited from medical admissions wards, although some were identified from dermatology, orthopaedic, geriatric and general surgery wards. Data were collected on patient demographics, clinical features and willingness to take part in a future RCT. Results: Despite being a relatively common condition, cellulitis patients were difficult to locate through our network of UK DCTN clinicians. This was largely because patients were rarely seen by dermatologists, and admissions were not co-ordinated centrally. In addition, the impact of the proposed exclusion criteria was high; only 26 (37%) of those enrolled in the study fulfilled all of the inclusion criteria for the subsequent RCT, and were willing to be randomised to treatment. Of the 70 participants identified during the study as having cellulitis of the leg (as confirmed by a dermatologist), only 59 (84%) had all 3 of the defining features of: i) erythema, ii) oedema, and iii) warmth with acute pain/tenderness upon examination. Twenty-two (32%) patients experienced a previous episode of cellulitis within the last 3 years. The median time to recurrence (estimated as the time since the most recent previous attack) was 205 days (95% CI 102 to 308). Service users were generally supportive of the trial, although several expressed concerns about taking antibiotics for lengthy periods, and felt that multiple morbidity/old age would limit entry into a 3-year study. Conclusion: This pilot study has been crucial in highlighting some key issues for the conduct of a future RCT. As a result of these findings, changes have been made to i) the planned recruitment strategy, ii) the proposed inclusion criteria and ii) the definition of cellulitis for use in the future trial.

Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema

Objective To determine whether a three day burst of a potent corticosteroid is more effective than a mild preparation used for seven days in children with mild or moderate atopic eczema. Design Randomised, double blind, parallel group study of 18 weeks' duration. Setting 13 general practices and a teaching hospital in the Nottingham area. Participants 174 children with mild or moderate atopic eczema recruited from general practices and 33 from a hospital outpatient clinic. Interventions 0.1% betamethasone valerate applied for three days followed by the base ointment for four days versus 1% hydrocortisone applied for seven days. Main outcome measures Primary outcomes were total number of scratch­free days and number of relapses. Secondary outcomes were median duration of relapses, number of undisturbed nights, disease severity (six area, six sign atopic dermatitis severity scale), scores on two quality of life measures (children's life quality index and dermatitis family impact questionnaire), and number of patients in whom treatment failed in each arm. Results No differences were found between the two groups. This was consistent for all outcomes. The median number of scratch­free days was 118.0 for the mild group and 117.5 for the potent group (difference 0.5, 95% confidence interval - 2.0 to 4.0, P = 0.53). The median number of relapses for both groups was 1.0. Both groups showed clinically important improvements in disease severity and quality of life compared with baseline. Conclusion A short burst of a potent topical corticosteroid is just as effective as prolonged use of a milder preparation for controlling mild or moderate atopic eczema in children.

Home based exercise programme for knee pain and knee osteoarthritis: randomised controlled trial

Objectives To determine whether a home based exercise programme can improve outcomes in patients with knee pain. Design Pragmatic, factorial randomised controlled trial of two years' duration. Setting Two general practices in Nottingham. Participants 786 men and women aged >45 years with self reported knee pain. Interventions Participants were randomised to four groups to receive exercise therapy, monthly telephone contact, exercise therapy plus telephone contact, or no intervention. Patients in the no intervention and combined exercise and telephone groups were randomised to receive or not receive a placebo health food tablet. Main outcome measures Primary outcome was self reported score for knee pain on the Western Ontario and McMaster universities (WOMAC) osteoarthritis index at two years. Secondary outcomes included knee specific physical function and stiffness (scored on WOMAC index), general physical function (scored on SF­36 questionnaire), psychological outlook (scored on hospital anxiety and depression scale), and isometric muscle strength. Results 600 (76.3%) participants completed the study. At 24 months, highly significant reductions in knee pain were apparent for the pooled exercise groups compared with the non­exercise groups (mean difference –0.82, 95% confidence interval –1.3 to –0.3). Similar improvements were observed at 6, 12, and 18 months. Regular telephone contact alone did not reduce pain. The reduction in pain was greater the closer patients adhered to the exercise plan. Conclusions A simple home based exercise programme can significantly reduce knee pain. The lack of improvement in patients who received only telephone contact suggests that improvements are not just due to psychosocial effects because of contact with the therapist.

Should eye protection be worn during dermatological surgery: prospective observational study

Background There is a potential risk of infection with blood-borne viruses if a doctor receives a blood splash to a mucous membrane. The quantification of facial contamination with blood has never been documented in the context of dermatological surgery. Objectives (i) To identify the number of facial blood splashes that occur during skin surgery and to identify the procedures that present higher risks for the operator and assistant. (ii) To assess the provision of eye protection and attitudes to its use in dermatological surgery in the U.K. Methods (i) Prospective, observational study in the skin surgery suite of a U.K. teaching hospital assessing 100 consecutive dermatological surgery procedures, plus 100 consecutive operations in which an assistant was present. Primary outcome: number of face-mask visors with at least one blood splash. Secondary outcomes: to identify if any of the following variables influenced the occurrence of a blood splash: grade of operator, site and type of procedure, and the use of electrocautery. (ii) A postal survey of all U.K.-based members of the British Society of Dermatological Surgery (BSDS) was conducted assessing facilities available and the attitudes of U.K.-based clinicians to the use of face masks during surgery. Results (i) In 33% of all surgical procedures there was at least one facial splash to the operator (range 1–75) and in 15% of procedures the assistant received at least one splash (range 1–11). Use of monopolar electrocautery was significantly less likely to result in splashes to the mask compared with bipolar electrocautery [odds ratio (OR) 0Æ04; 95% confidence interval (CI) 0Æ01–0Æ19]. Compared with the head/neck, operations on the body were significantly more likely to result in splashes to the mask (OR 6Æ52) (95% CI 1Æ7–25Æ07). The type of procedure and the status of the operator did not have a bearing on the likelihood of receiving a splash to the mask. (ii) From the survey, 33 of 159 (20Æ8%) of BSDS members had no face masks available and 54 of 159 (34Æ0%) did not wear any facial protection while operating. The majority (53Æ5%) thought they received a splash in £ 1% of procedures. Conclusions There is a substantial risk of a splash of blood coming into contact with the face during dermatological surgery for both the operator and assistant, regardless of the procedure. The risk of receiving a blood splash to the face may be substantially underestimated by U.K.-based dermatologists. The use of protective eyewear is advisable at all times, but particularly when using bipolar electrocautery, or when operating on high-risk individuals.

Intelligent pipeline control - a simulation study in the automotive sector

Automotive producers are aiming to make their order fulfilment processes more flexible. Opening the pipeline of planned products for dynamic allocation to dealers/ customers is a significant step to be more flexible but the behaviour of such Virtual-Build-To-Order systems are complex to predict and their performance varies significantly as product variety levels change. This study investigates the potential for intelligent control of the pipeline feed, taking into account the current status of inventory (level and mix) and of the volume and mix of unsold products in the planning pipeline, as well as the demand profile. Five ‘intelligent’ methods for selecting the next product to be planned into the production pipeline are analysed using a discrete event simulation model and compared to the unintelligent random feed. The methods are tested under two conditions, firstly when customers must be fulfilled with the exact product they request, and secondly when customers trade-off a shorter waiting time for compromise in specification. The two forms of customer behaviour have a substantial impact on the performance of the methods and there are also significant differences between the methods themselves. When the producer has an accurate model of customer demand, methods that attempt to harmonise the mix in the system to the demand distribution are superior.

Sensory gating and its modulation by cannabinoids: electrophysiological, computational and mathematical analysis

Gating of sensory information can be assessed using an auditory conditioning-test paradigm which measures the reduction in the auditory evoked response to a test stimulus following an initial conditioning stimulus. Recording brainwaves from specific areas of the brain using multiple electrodes is helpful in the study of the neurobiology of sensory gating. In this paper, we use such technology to investigate the role of cannabinoids in sensory gating in the CA3 region of the rat hippocampus. Our experimental results show that application of the exogenous cannabinoid agonist WIN55,212-2 can abolish sensory gating. We have developed a phenomenological model of cannabinoid dynamics incorporated within a spiking neural network model of CA3 with synaptically interacting pyramidal and basket cells. Direct numerical simulations of this model suggest that the basic mechanism for this effect can be traced to the suppression of inhibition of slow GABAB synapses. Furthermore, by working with a simpler mathematical firing rate model we are able to show the robustness of this mechanism for the abolition of sensory gating.

The bimodal regulation of vascular function by superoxide anion: role of endothelium

Reactive oxygen species (ROS) are implicated in vascular homeostasis. This study investigated whether O2 .

Empirical evidence of bias in the design of experimental stroke studies: a metaepidemiologic approach

Background and Purpose: At least part of the failure in the transition from experimental to clinical studies in stroke has been attributed to the imprecision introduced by problems in the design of experimental stroke studies. Using a metaepidemiologic approach, we addressed the effect of randomization, blinding, and use of comorbid animals on the estimate of how effectively therapeutic interventions reduce infarct size. Methods: Electronic and manual searches were performed to identify meta-analyses that described interventions in experimental stroke. For each meta-analysis thus identified, a reanalysis was conducted to estimate the impact of various quality items on the estimate of efficacy, and these estimates were combined in a meta meta-analysis to obtain a summary measure of the impact of the various design characteristics. Results: Thirteen meta-analyses that described outcomes in 15 635 animals were included. Studies that included unblinded induction of ischemia reported effect sizes 13.1% (95% CI, 26.4% to 0.2%) greater than studies that included blinding, and studies that included healthy animals instead of animals with comorbidities overstated the effect size by 11.5% (95% CI, 21.2% to 1.8%). No significant effect was found for randomization, blinded outcome assessment, or high aggregate CAMARADES quality score. Conclusions: We provide empirical evidence of bias in the design of studies, with studies that included unblinded induction of ischemia or healthy animals overestimating the effectiveness of the intervention. This bias could account for the failure in the transition from bench to bedside of stroke therapies.

Neuronal networks with gap junctions: A study of piece-wise linear planar neuron models

The presence of gap junction coupling among neurons of the central nervous systems has been appreciated for some time now. In recent years there has been an upsurge of interest from the mathematical community in understanding the contribution of these direct electrical connections between cells to large-scale brain rhythms. Here we analyze a class of exactly soluble single neuron models, capable of producing realistic action potential shapes, that can be used as the basis for understanding dynamics at the network level. This work focuses on planar piece-wise linear models that can mimic the firing response of several different cell types. Under constant current injection the periodic response and phase response curve (PRC) is calculated in closed form. A simple formula for the stability of a periodic orbit is found using Floquet theory. From the calculated PRC and the periodic orbit a phase interaction function is constructed that allows the investigation of phase-locked network states using the theory of weakly coupled oscillators. For large networks with global gap junction connectivity we develop a theory of strong coupling instabilities of the homogeneous, synchronous and splay state. For a piece-wise linear caricature of the Morris-Lecar model, with oscillations arising from a homoclinic bifurcation, we show that large amplitude oscillations in the mean membrane potential are organized around such unstable orbits.

Calculation of sample size for stroke trials assessing functional outcome: comparison of binary and ordinal approaches

Background Many acute stroke trials have given neutral results. Sub-optimal statistical analyses may be failing to detect efficacy. Methods which take account of the ordinal nature of functional outcome data are more efficient. We compare sample size calculations for dichotomous and ordinal outcomes for use in stroke trials. Methods Data from stroke trials studying the effects of interventions known to positively or negatively alter functional outcome – Rankin Scale and Barthel Index – were assessed. Sample size was calculated using comparisons of proportions, means, medians (according to Payne), and ordinal data (according to Whitehead). The sample sizes gained from each method were compared using Friedman 2 way ANOVA. Results Fifty-five comparisons (54 173 patients) of active vs. control treatment were assessed. Estimated sample sizes differed significantly depending on the method of calculation (Po00001). The ordering of the methods showed that the ordinal method of Whitehead and comparison of means produced significantly lower sample sizes than the other methods. The ordinal data method on average reduced sample size by 28% (inter-quartile range 14–53%) compared with the comparison of proportions; however, a 22% increase in sample size was seen with the ordinal method for trials assessing thrombolysis. The comparison of medians method of Payne gave the largest sample sizes. Conclusions Choosing an ordinal rather than binary method of analysis allows most trials to be, on average, smaller by approximately 28% for a given statistical power. Smaller trial sample sizes may help by reducing time to completion, complexity, and financial expense. However, ordinal methods may not be optimal for interventions which both improve functional outcome

Predicting long-term outcome after acute ischemic stroke: a simple index works in patients from controlled clinical trials

Background and Purpose—An early and reliable prognosis for recovery in stroke patients is important for initiation of individual treatment and for informing patients and relatives. We recently developed and validated models for predicting survival and functional independence within 3 months after acute stroke, based on age and the National Institutes of Health Stroke Scale score assessed within 6 hours after stroke. Herein we demonstrate the applicability of our models in an independent sample of patients from controlled clinical trials. Methods—The prognostic models were used to predict survival and functional recovery in 5419 patients from the Virtual International Stroke Trials Archive (VISTA). Furthermore, we tried to improve the accuracy by adapting intercepts and estimating new model parameters. Results—The original models were able to correctly classify 70.4% (survival) and 72.9% (functional recovery) of patients. Because the prediction was slightly pessimistic for patients in the controlled trials, adapting the intercept improved the accuracy to 74.8% (survival) and 74.0% (functional recovery). Novel estimation of parameters, however, yielded no relevant further improvement. Conclusions—For acute ischemic stroke patients included in controlled trials, our easy-to-apply prognostic models based on age and National Institutes of Health Stroke Scale score correctly predicted survival and functional recovery after 3 months. Furthermore, a simple adaptation helps to adjust for a different prognosis and is recommended if a large data set is available. (Stroke. 2008;39:000-000.)

"Ordinary people only": knowledge, representativeness and the publics of public participation in healthcare

Public involvement in healthcare is a prominent policy in countries across the economically developed world. A growing body of academic literature has focused on public participation, often presenting dichotomies between good and bad practice: between initiatives that offer empowerment and those constrained by consumerism, or between those which rely for recruitment on self-selecting members of the public, and those including a more broad-based, statistically representative group. In this paper I discuss the apparent tensions between differing rationales for participation, relating recent discussions about the nature of representation in public involvement to parallel writings about the contribution of laypeople’s expertise and experience. In the academic literature, there is, I suggest, a thin line between democratic justifications for involvement, suggesting a representative role for involved publics, and technocratic ideas about the potential ‘expert’ contributions of particular subgroups of the public. Analysing recent policy documents on participation in healthcare in England, I seek moreover to show how contemporary policy transcends both categories, demanding complex roles of involved publics which invoke various qualities seen as important in governing the interface between state and society. I relate this to social-theoretical perspectives on the relationship between governmental authority and citizens in late-modern society.

Gap junctions and emergent rhythms

Gap junction coupling is ubiquitous in the brain, particularly between the dendritic trees of inhibitory interneurons. Such direct non-synaptic interaction allows for direct electrical communication between cells. Unlike spike-time driven synaptic neural network models, which are event based, any model with gap junctions must necessarily involve a single neuron model that can represent the shape of an action potential. Indeed, not only do neurons communicating via gaps feel super-threshold spikes, but they also experience, and respond to, sub-threshold voltage signals. In this chapter we show that the so-called absolute integrate-and-fire model is ideally suited to such studies. At the single neuron level voltage traces for the model may be obtained in closed form, and are shown to mimic those of fast-spiking inhibitory neurons. Interestingly in the presence of a slow spike adaptation current the model is shown to support periodic bursting oscillations. For both tonic and bursting modes the phase response curve can be calculated in closed form. At the network level we focus on global gap junction coupling and show how to analyze the asynchronous firing state in large networks. Importantly, we are able to determine the emergence of non-trivial network rhythms due to strong coupling instabilities. To illustrate the use of our theoretical techniques (particularly the phase-density formalism used to determine stability) we focus on a spike adaptation induced transition from asynchronous tonic activity to synchronous bursting in a gap-junction coupled network.