Natasha K Rogers

Review: the ubiquitin-proteasome system: contributions to cell death or survival in neurodegeneration.

N. Rogers, S. Paine, L. Bedford and R. Layfield (2010) Neuropathology and Applied Neurobiology36, 113–124
The ubiquitin‐proteasome system: contributions to cell death or survival in neurodegeneration

What is the evidence-base for atopic eczema treatments? A summary of published randomised controlled trials

Atopic eczema (AE) is a common chronic inflammatory skin condition. While many AE treatment options are available, the evidence to support their efficacy varies in depth and quality. In 2000, a National Institute for Health Research (NIHR) Health Technology Assessment systematic review identified and evaluated existing randomized controlled trials (RCTs) of AE treatments. To ensure continuing utility, the NIHR commissioned an update to the review. Here, we present an overview of the updated report and its key findings. Systematic reviews and RCTs of AE treatments that included participants with AE (criteria based or diagnosed) were identified using Medline, Embase, CENTRAL, Latin American and Caribbean Health Sciences, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature and Cochrane Skin Group Specialised Register [searched to 31 August 2013 (RCTs) and 31 December 2015 (systematic reviews)]. Outcome measures included symptoms, AE severity, quality of life and adverse effects. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Of the 287 new RCTs identified, only 22 (8%) were judged to have a low risk of bias. When combined with RCTs from the previous review (n = 254), we found ‘reasonable evidence of benefit’ for corticosteroids, calcineurin inhibitors, Atopiclair®, ciclosporin, azathioprine, ultraviolet radiation and education programmes. Interventions with reasonable evidence of ‘no benefit’ included some dietary interventions, ion exchange water softeners, multiple daily applications of topical corticosteroids and antibiotic‐containing corticosteroids for noninfected AE. Many common treatments lack evidence of efficacy and warrant further evaluation. The evidence base for AE is still hampered by poor trial design and reporting. The trials included in this review were used to establish the Global Resource of EczemA Trials (GREAT) database.

Extra-cellular matrix proteins induce matrix metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma.

Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms.

Reporting of symptoms in randomized controlled trials of atopic eczema treatments: a systematic review.

‘Symptoms’ is a core outcome domain for atopic eczema (AE) trials, agreed by consensus as part of the Harmonising Outcome Measures for Eczema (HOME) initiative. To standardize and validate the core domain symptoms and symptom instruments for AE trials the HOME roadmap is followed. Its first step is to establish if and how symptoms have been measured in published AE treatment trials. Therefore the Global Resource for Eczema Trials database was used to collect all randomized controlled trials (RCTs) of treatments for AE between January 2000 and April 2014. Study selection and data extraction were performed by three reviewers independently. We identified the use of symptoms in 295 of 378 trials (78%). Symptoms as a primary end point were applied by 147 RCTs (50%). Seventeen different symptoms were measured, but mostly itch and sleep loss. Symptoms were assessed by only 37% of trials by a stand‐alone symptom measurement. Overall 63% of RCTs used a composite instrument, and 30 different instruments were identified. The Scoring Atopic Dermatitis (SCORAD) index was the most commonly applied, but only 23% of RCTs reported the SCORAD symptom score separately. This systematic review demonstrates that symptoms, most frequently itch and sleep loss, are commonly reported in AE treatment trials, but are measured using many different instruments. Often symptoms are evaluated as part of a composite instrument, and currently it is not possible to extract symptoms‐only data from most published studies. Future trials should report symptom scores to permit meta‐analysis of the core outcomes.

What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 1. Epidemiology, risk factors and outcomes

This review summarizes key findings from nine systematic reviews on atopic eczema (AE) published or first indexed in 2014. It focuses on epidemiology, disease processes and methodological issues. There is reasonable evidence to conclude that high birth weight (> 4000 g) is a risk factor for the development of AE. A lower socioeconomic position is associated with lower prevalence of AE. The effect of exposure to traffic‐related air pollution in childhood on the development of AE is uncertain. CD14 polymorphisms do not appear to have an effect in AE. There may be a role for interleukin‐18 in AE development. Patients with AE are at decreased risk of brain tumours, but at increased risk of developing attention deficit hyperactivity disorder. Evidence supports the view that normal‐appearing skin in AE is in fact structurally abnormal. Lower success rates at inducing remission in AE are associated with increased risk of relapse during long‐term follow‐up. The Eczema Area Severity Index (EASI) has been agreed as the preferred core instrument to measure clinical signs in future research. There remains a lack of consensus on the definition of an AE flare.

What's new in atopic eczema? An analysis of systematic reviews published in 2014. Part 2. Treatment and prevention

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE). It provides a summary of key findings from 12 systematic reviews (SRs) that were published or indexed during 2014, and focuses on the treatment and prevention of AE. For an update of SRs on the epidemiology, mechanisms of disease and methodological issues, see Part 1 of this update. Although phototherapy and various systemic medications (including ciclosporin, azathioprine and methotrexate) are commonly used to treat AE, many of these have not been robustly assessed in head‐to‐head randomized controlled trials. Educational interventions may improve AE severity and quality of life for children and their families. Intake of probiotics prenatally and postnatally may help prevent AE, but there is little evidence to suggest a role in the treatment of AE. Although no benefit was found for allergen avoidance in preventing AE, the use of immunotherapy to treat AE‐associated aeroallergen sensitivity requires further evaluation. There is insufficient evidence for Vitamin D supplementation for the treatment of AE This overview of reviews provides a succinct guide for clinicians and patients wishing to remain up to date with the most recent evidence for the treatment and prevention of AE.

Risk of bias does not differ between full papers and letters reporting dermatological randomized controlled trials.

DEAR EDITOR, Results of randomized controlled trials (RCTs) are often reported in letters rather than published within full papers. Trial results that are published as letters are often missed from bibliographic searches, especially if the term ‘randomized controlled trial’ is not included in the title of the letter. Such RCT letters generally require ‘hand searching’ in order to identify them. Based on our experience of critically appraising hundreds of RCTs when conducting systematic reviews, we hypothesized that the reporting quality of trial results in letters would be poorer than that of trials reported fully as original articles. We came to this view based on a perception that trials published as letters occupied a middle ground between not being good enough to be published as a full report, but not bad enough to be rejected completely by journals. It is also clear that less printed journal space is available for trials submitted as letters, which would probably influence the degree to which essential items are included in trial reports. Such deficiencies mean that systematic reviewers would usually need to contact authors to obtain further details. As authors may not respond effectively to the systematic reviewers, this would increase the number of ‘unclear’ risk-of-bias assessments. We aimed to examine the risk of bias of RCTs reported as letters in published Cochrane Skin Group systematic reviews, and to compare the results with full papers published in the same year and journal. To perform this assessment, we searched the Cochrane Skin Group’s Cochrane Register of Studies database using the freetext term ‘letter’. We limited any results generated from these searches to records linked to a Cochrane review. We crosschecked the results of the Cochrane Register of Studies search against Medline to confirm that they were indexed by the National Library of Medicine in America with the publication type as ‘letter’. We excluded letters that were not the primary reference to a study in the Cochrane review, not RCTs, or not included in the published Cochrane review. For each trial published as a letter, we identified two trials published in full, matched on Cochrane review paper and on year of publication to the identified letter ( 4 years). The rationale for the 1 : 2 letters to full report ratio was based on a preliminary samplesize calculation whereby we hypothesized that low risk of bias would be recorded in 10% of letters and 30% of full papers. Assuming 80% power and a 5% significance level we would require 56 letters and 111 full papers. Using the risk-of-bias tables included in the individual Cochrane reviews, two authors independently obtained the Cochrane risk-of-bias assessment (low, high or unclear) for the following three areas: (i) random sequence generation and allocation concealment, (ii) blinding of participants/personnel and outcome assessments and (iii) incomplete outcome data. For studies where risk-of-bias information was missing from the Cochrane review, the risk of bias was determined independently by two authors, with discrepancies resolved by a third party. We retrieved each letter and full paper in order to assess whether the trial reported a statistically significant result. Analysis was performed to compare the proportion of letters with low, high or unclear risk of bias with that of full papers. In total we identified 31 letters reporting RCTs across 20 different Cochrane Skin Group systematic reviews between the years 1980 and 2010. We matched these 31 letters to 62 full papers. The full papers were published between 1978 and 2011. Only eleven (35%) of the letters compared with 42 (68%) of the full papers reported statistically significant results, confirming our suspicion that ‘positive’ results were more likely to be published as full papers. We assessed the risk of bias for allocation concealment, blinding and incomplete data for all publications (Table 1; Fig. 1). A greater proportion of letters were assessed as having an unclear risk of bias for allocation concealment compared with full

What's new in atopic eczema? An analysis of systematic reviews published in 2015. Part 2: prevention and treatment

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE), providing a succinct guide for clinicians and patients. It provides a summary of key findings from 26 systematic reviews that were published during 2015, and focuses on the treatment and prevention of AE. For systematic reviews on the epidemiology and methodological issues, see Part 1 of this update. Topical corticosteroid withdrawal syndrome, ‘steroid addiction’, has been evaluated in a high‐quality systematic review, which helps better define this entity and the risk factors for it. A Cochrane Review has not demonstrated any association between topical corticosteroid use in pregnancy and adverse outcomes, although very large quantities of potent/very potent topical corticosteroids may be associated with reduced birth weight. House dust mite avoidance strategies do not appear to prevent AE. Exposure to probiotics prenatally and in early infancy may help prevent AE, but there is no evidence that maternal diet or supplementation has a preventative effect.

What's new in atopic eczema? An analysis of systematic reviews published in 2015. Part 1: epidemiology and methodology

This review forms part of a series of annual updates that summarize the evidence base for atopic eczema (AE), providing a succinct guide for clinicians and patients. It provides a summary of key findings from 15 systematic reviews that were published during 2015, and focuses on the epidemiology and methodology issues of AE. For systematic reviews on the prevention and treatment of AE, see Part 2 of this update. The worldwide prevalence of AE during childhood has been calculated to be 7.89% (95% CI 7.88–7.89), based on studies of 1 430 329 children from 102 countries. Children with AE are four times more likely than controls to have allergic rhinitis and asthma [relative risk (RR) = 4.24, 95% CI 3.75–4.79]. Twin studies show the heritability of AE to be about 75%. AE is more prevalent in patients with vitiligo and alopecia, and is positively associated with a high body mass index in America and Asia but not in Europe. Possible relationships between AE and exercise, maternal folate supplementation, maternal stress and autism spectrum disorder (ASD) have been assessed, but more high‐quality studies are needed for definitive conclusions. The Harmonising Outcomes Measures for Eczema (HOME) Initiative is developing a core set of outcome measures for AE trials. Suitable instruments for measuring quality of life are yet to be agreed, and use of Investigator Global Assessment in trials requires standardization. Transparent reporting of AE trials remains problematic.