Do patient characteristics matter when calculating sample size for eczema clinical trials?

Background: The Patient-Oriented Eczema Measure (POEM) is the core outcome instrument recommended for measuring patient-reported atopic eczema symptoms in clinical trials. To ensure that the statistical significance of clinical trial results is meaningful, trials are often designed by specifying the target difference in the primary outcome as part of the sample size calculation. One method used to specify the target difference is a score that corresponds to a standardized effect size. Objectives: to assess how the standardized effect size of POEM scores vary across age, gender, ethnicity and disease severity. Methods: This study combined data from five UK-based randomized clinical trials of eczema treatments in order to assess differences in self-reported eczema symptoms (POEM) corresponding to a standardized effect size (0.5 SD of baseline POEM scores) across age, gender, ethnicity and disease severity. Results: POEM scores corresponding to 0.5 SD(baseline) were remarkably consistent across participants of varying ages, gender, ethnicity and disease severity from datasets of five UK trials in children (range 2.99-3.45). Conclusions: This study provides information that can support those designing clinical trials to determine their sample size and can aid individuals interpreting trial results. Further exploration of differences in populations beyond the United Kingdom is needed.

Views and experiences of managing eczema: systematic review and thematic synthesis of qualitative studies.

BACKGROUND: The number of qualitative studies on eczema has increased rapidly in recent years. Systematically reviewing these can provide greater understandings of people's perceptions of eczema and eczema treatments. OBJECTIVES: We sought to systematically review and thematically synthesize qualitative studies exploring views and experiences of people with eczema and parents/carers of children with eczema. METHODS: We searched MEDLINE, EMBASE, PsycINFO and CINAHL from the earliest date available to February 2019. We selected papers focusing on views and experiences of eczema and eczema treatments, and barriers/facilitators to eczema self-management. We excluded papers focusing on health service provision models or health professionals' views. RESULTS: We synthesized 39 papers (reporting 32 studies) from 13 countries. We developed four analytical themes: (1) Eczema not viewed as a long-term condition; (2) Significant psychosocial impact not acknowledged by others; (3) Hesitancy (patient/carer uncertainty) about eczema treatments; and (4) Insufficient information and advice. Our findings suggest that people with eczema and their carers experience frustration at having to manage a condition that is often seen by others as mundane but has significant psychosocial impact and is difficult to manage due to concerns about, and burden of, treatment. This frustration can be exacerbated by experiences of conflicting and/or insufficient information and advice from health professionals, family and others. CONCLUSIONS: Effective self-management of eczema could be supported by addressing beliefs and concerns about treatments; seeking positive ways to promote a 'control not cure' message; acknowledging psychosocial impacts of eczema and treatment burden; and providing clear consistent advice or signposting towards reliable information.

Development and initial testing of a new instrument to measure the experience of eczema control in adults and children: Recap of atopic eczema (RECAP).

BACKGROUND: Eczema control has been identified as an important outcome by key stakeholders in eczema research (including patients, carers, healthcare professionals and researchers) but no validated instruments for the domain have been identified. OBJECTIVES: To develop a measurement instrument to capture a patient's perspective of eczema control that is suitable for use in eczema clinical trials. METHODS: Best practice for the development of a patient-reported outcome was followed. A mixed-methods approach was used to develop and refine a conceptual framework, generate, refine and select items and to test the distribution and construct validity of the final scale. The mixed-methods approach involved expert panel meetings (including patient representatives, healthcare professionals and methodologists), and data collection using a focus group, cognitive interviews and an online survey with people with eczema and caregivers. Multivariable linear regression was used in the item selection process. RESULTS: Fourteen expert panel members co-produced the instrument, with input from people with eczema and caregivers via a focus group (n = 6), cognitive interviews (n = 13) and an online survey (n = 330). The resulting instrument, Recap of atopic eczema (RECAP), is a seven-item questionnaire that captures eczema control via self or caregiver report. The development process aimed to ensure good content validity and feasibility. Initial testing suggested no floor or ceiling effects and good construct validity. Hypothesized correlation with the Patient-Oriented Eczema Measure was confirmed [r(258) = 0·83, P < 0·001]. CONCLUSIONS: RECAP has the potential to improve reporting of eczema control in research and clinical practice. Further exploration of measurement properties is required. Linked Comment: Pattinson and Bundy. Br J Dermatol 2020; 183:418-419. What's already known about this topic? Eczema control has been identified as an important outcome by key stakeholders in eczema research (including patients, carers, healthcare professionals and researchers). Qualitative studies suggest eczema control is a multifaceted and individual experience and no instrument has been identified that captures eczema control in this way. What does this study add? We have developed Recap of atopic eczema (RECAP), a seven-item questionnaire to capture the experience of eczema control in all ages and eczema severities; there are two versions: a self-reported version for adults and older children with eczema, and a caregiver-reported version for younger children with eczema. Designed with input from people with eczema, caregivers and healthcare professionals to ensure good content validity. Initial testing of score distributions and construct validity suggests good measurement properties. What are the clinical implications of the work? The RECAP instrument is appropriate and feasible for measuring eczema control in clinical trials and may also be useful in routine practice.

Beliefs and practices among adults with eczema and carers of children with eczema regarding the role of food allergy.

In this study, 211 carers of children and adults with atopic eczema/dermatitis (AE) completed an online questionnaire about diet and allergy. The study group comprised 106 children [mean age 5 years, Patient-Oriented Eczema Measure (POEM) score mean ± SD 13.8 ± 7.8] and 105 adults (mean age 35 years, POEM score 14.5 ± 7.5). We found that 57% of respondents had discussed the role of diet in AE with a health professional and 38% felt this discussion was unhelpful or very unhelpful. Regarding testing, 54% reported having had an allergy test. Food exclusion was common; 68% of children and 46% of adults excluded one or more foods from their diet, with 40% of children and 52% of adults doing so to reduce AE symptoms. The most commonly avoided food among both children (63%) and adults (50%) was cow's milk. Only 17% of adults with modified diets had received dietary advice from a dietitian, compared with 57% of children. Clinicians should routinely ask patients about their views of diet in eczema and any changes that they have made, offering objective assessment where appropriate.

Comparison of patient (POEM), observer (EASI, SASSAD, TIS) and corneometry measures of emollient effectiveness in children with eczema: findings from the COMET feasibility trial.

BACKGROUND: Eczema affects around 20% of children, but multiple different outcome measures have hampered research into the effectiveness of different treatments. OBJECTIVES: To compare the change in scores and correlations within and between five measures of eczema severity: Patient-Orientated Eczema Measure (POEM), Eczema Area and Severity Index (EASI), Six Area, Six Sign Atopic Dermatitis (SASSAD), Three Item Severity (TIS) and skin hydration (corneometry). METHODS: Data from a feasibility trial that randomized young children with eczema to one of four emollients were used. Participants were followed for 3 months (84 days). Descriptive statistics (by emollient over time) and Spearman's correlation coefficients comparing scores at each time point and absolute change (between adjacent time points) for each outcome measure were calculated. RESULTS: In total, 197 children, mean ± SD age 21·7 ± 12·8 months, were randomized. POEM and TIS appeared to capture a range of eczema severity at baseline, but only POEM had close approximation to normal distribution. Mean POEM, EASI, SASSAD and TIS scores improved month by month, with POEM showing the greatest sensitivity (effect size 0·42). Correlations within POEM, EASI, SASSAD and TIS were moderate to good, decreasing over time. Correlations between measures were strongest for EASI, SASSAD and TIS. By contrast, corneometry scores were more variable, correlated less well over time and were poorly correlated with the other measures. CONCLUSIONS: Except for corneometry, all measures appear to change in relation to emollient use over time and correlate well with themselves. POEM demonstrated the greatest range of scores at baseline and change in eczema severity over the first 28 days.

Systematic review of self-management interventions for people with eczema.

Eczema is a common long-term condition, but inadequate support and information can lead to poor adherence and treatment failure. We have reviewed the international literature of interventions designed to promote self-management in adults and children with eczema. MEDLINE, MEDLINE in process, Embase, CINAHL and the Global Resource for EczemA Trials database were searched from their inception to August 2016, for randomized controlled trials. Two authors independently applied eligibility criteria, assessed risk of bias for all included studies and extracted data. Twenty studies (3028 participants) conducted in 11 different countries were included. The majority (n = 18) were based in secondary care and most (n = 16) targeted children with eczema. Reporting of studies, including descriptions of the interventions and the outcomes themselves, was generally poor. Thirteen studies were face-to-face educational interventions, five were delivered online and two were studies of written action plans. Follow-up in most studies (n = 12) was short term (up to 12 weeks). Only six trials specified a single primary outcome. There was limited evidence of effectiveness. Only three studies collected and reported outcomes related to cost and just one study undertook any formal cost-effectiveness analysis. In summary, we have identified a general absence of well-conducted and well-reported randomized controlled trials with a strong theoretical basis. Therefore, there is still uncertainty about how best to support self-management of eczema in a clinically effective and cost-effective way. Recommendations on design and conduct of future trials are presented.

The Eczema Priority Setting Partnership: a collaboration between patients, carers, clinicians and researchers to identify and prioritize important research questions for the treatment of eczema.

BACKGROUND: Eczema is a common condition, yet there are uncertainties regarding many frequently used treatments. Knowing which of these uncertainties matter to patients and clinicians is important, because they are likely to have different priorities from those of researchers and funders. OBJECTIVES: To identify the uncertainties in eczema treatment that are important to patients who have eczema, their carers and the healthcare professionals (HCPs) who treat them. METHODS: An eczema Priority Setting Partnership was established, including patients, HCPs and researchers. Eczema treatment uncertainties were gathered from patients and clinicians, and then prioritized in a transparent process, using a methodology advocated by the James Lind Alliance. RESULTS: In the consultation stage 493 participants (including 341 patients/carers) made 1070 submissions, of which 718 were uncertainties relating to the treatment of eczema. Treatment uncertainties with more than one submission were grouped into 52 'indicative uncertainties', which were then ranked by 514 participants (including 399 patients/carers). The top 14 treatment uncertainties were prioritized for research. The first four were common to patients/carers and HCPs (shared uncertainties): (i) the best and safest way of using topical steroids (including frequency of application, potency, length of time, alternation with other topical treatments and age limits); (ii) the long-term safety of topical steroids; (iii) the role of food allergy tests; and (iv) the most effective and safe emollients in treating eczema. The remaining 10 of the top 14 uncertainties comprised the next five highest ranked uncertainties for patients and the next five highest ranked uncertainties for HCPs. At a workshop involving 40 participants (patients, HCPs and researchers), shared uncertainties were formulated into possible research questions. CONCLUSIONS: The top 14 treatment uncertainties around the treatment of eczema provide guidance for researchers and funding bodies to ensure that future research answers questions that are important to both clinicians and patients.

The effects of copper on the microbial community of a coral reef sponge.

Marine sponges often harbour communities of symbiotic microorganisms that fulfil necessary functions for the well-being of their hosts. Microbial communities associated with the sponge Rhopaloeides odorabile were used as bioindicators for sublethal cupric ion (Cu2+) stress. A combined strategy incorporating molecular, cultivation and electron microscopy techniques was adopted to monitor changes in microbial diversity. The total density of sponge-associated bacteria and counts of the predominant cultivated symbiont (alpha-proteobacterium strain NW001) were significantly reduced in response to Cu2+ concentrations of 1.7 microg l(-1) and above after 14 days of exposure. The number of operational taxonomic units (OTUs) detected by restriction fragment length polymorphism (RFLP) decreased by 64% in sponges exposed to 223 microg l(-1) Cu2+ for 48 h and by 46% in sponges exposed to 19.4 microg l(-1) Cu2+ for 14 days. Electron microscopy was used to identify 17 predominant bacterial morphotypes, composing 47% of the total observed cells in control sponges. A reduction in the proportion of these morphotypes to 25% of observed cells was evident in sponges exposed to a Cu2+ concentration of 19.4 microg l(-1). Although the abundance of most morphotypes decreased under Cu2+ stress, three morphotypes were not reduced in numbers and a single morpho-type actually increased in abundance. Bacterial numbers, as detected using fluorescence in situ hybridization (FISH), decreased significantly after 48 h exposure to 19.4 microg l(-1) Cu2+. Archaea, which are normally prolific in R. odorabile, were not detected after exposure to a Cu2+ concentration of 19.4 microg l(-1) for 14 days, indicating that many of the microorganisms associated with R. odorabile are sensitive to free copper. Sponges exposed to a Cu2+ concentration of 223 microg l(-1) became highly necrosed after 48 h and accumulated 142 +/- 18 mg kg(-1) copper, whereas sponges exposed to 19.4 microg l(-1) Cu2+ accumulated 306 +/- 15 mg kg(-1) copper after 14 days without apoptosis or mortality. Not only do sponges have potential for monitoring elevated concentrations of heavy metals but also examining changes in their microbial symbionts is a novel and sensitive bioindicator for the assessment of pollution on important microbial communities.

Ginkgo biloba abolishes aggression in mice lacking MAO A.

Mice deficient in monoamine oxidase A (MAO A) have increased brain levels of serotonin (5-HT) and norepinephrine and show enhanced aggression. We used MAO A knock-out (KO) mice as a model to study the effect of ginkgo biloba (EGb) on aggression. When EGb was administered to MAO A KO mice, their aggressive behavior in resident-intruder confrontations was reduced to levels seen in wild types. EGb did not affect the locomotive behavior of MAO A KO mice, which suggests that its effects on aggression were not due to sedation. EGb caused a significant 16.9% decrease in [3H]ketanserin binding to 5-HT2A receptors in the frontal cortex of MAO A KO mice but did not change the receptor affinity for [3H]ketanserin. This suggests that the antiaggressive effect of EGb may be mediated by 5-HT2A receptors and that EGb may be developed as a novel antiaggressive agent.

Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A.

Mice deficient in monoamine oxidase A (MAO A) have elevated brain levels of 5-HT and manifest enhanced aggression. We used these mice as a model to study the role of 5-HT in aggression. Our results show that ketanserin and tetrabenazine (TBZ) strikingly abolished the aggressive behavior of MAO A-deficient mice. The anti-aggressive effect of ketanserin may be primarily mediated by 5-HT(2A) receptors. Another specific 5-HT(2A) antagonist, [R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methan ol (MDL 100907), also blocks the aggression of mutant mice but was less dramatic. Ketanserin and TBZ are both antagonists of the vesicular monoamine transporter (VMAT2). The anti-aggressive effect of TBZ and part of the effect of ketanserin may be mediated by the VMAT2. Using radioligand binding and autoradiography, we also showed that the numbers of VMAT2, 5-HT(1A), 5-HT(2A) and 5-HT(2C) sites are decreased in brains of mutant mice, which may reflect down-regulation by excess 5-HT. This study suggests that ketanserin and TBZ may be developed as novel anti-aggressive agents.

Role of MAO A and B in neurotransmitter metabolism and behavior.

MAO (monoamine oxidase) A and B are key isoenzymes that degrade biogenic and dietary amines. MAO A preferentially oxidizes serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE), whereas MAO B preferentially oxidizes phenylethylamine (PEA). Both forms can oxidize dopamine (DA). However, the substrate specificity overlap and the in vivo function of these two isoenzymes is not clear. Recently, we have shown that MAO A and B knock-out (KO) mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A KO mice have elevated brain levels of 5-HT, NE and DA and manifest aggressive behavior similar to men with a deletion of MAO A. In contrast, MAO B KO mice do not exhibit aggression and only levels of PEA are increased. Both MAO A and B KO mice show increased reactivity to stress. Taken together, these results suggest that MAO A and B have distinctly different roles in monoamine metabolism. Further, these mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

Monoamine oxidase: from genes to behavior.

Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

The effect of acute kainic acid treatment on mu-opioid receptors in rat brain.

There is evidence that acute exposure to kainic acid (KA) induces the release of endogenous ligands for opioid receptors and that mu-opioid agonists intensify KA-induced neurodegeneration. The aim of the present study was to investigate any acute toxic effects of KA upon mu-opioid receptors labelled with [3H]-DAMGO. 200-250 g rats were injected intraperitoneally with either saline or 16 mg/kg KA and brains were removed after 4 h. Membrane homogenates were prepared from the cerebellum, cortex, hippocampus, medulla and pons, midbrain and hypothalamus and striatum and in separate studies, from whole brain. In addition, frozen coronal sections were processed for comparative quantitative autoradiography. KA produced a two-fold increase in receptor affinity for [3H]-DAMGO in all regions and significant increases in receptor number in cortex, medulla and pons and striatum. Quantitative autoradiography showed similar significantly increased mu-labelling of structures comprising these gross anatomical regions. The findings demonstrate region specific changes in rat brain mu-opioid receptors after acute KA treatment which may be functionally related to the convulsant effects of this excitotoxin.

The effect of acute kainic acid treatment on dopamine D2 receptors in rat brain.

Acute exposure to kainic acid (KA) induces neurochemical changes in dopaminergic systems in the brain and the aim of the present study was to investigate the acute toxicity of KA upon dopamine D2 receptors. Adult rats were injected intraperitoneally with either saline or 16 mg/kg KA. Brains were removed after 4 h. Membrane homogenates were prepared from seven brain regions and in addition, frozen coronal sections were sectioned for comparative quantitative autoradiographic analysis. Dopamine D2 receptors were characterised by saturation studies using [125I]iodosulpiride, [3H]raclopride and [3H]spiperone. KA produced a 2-fold decrease in receptor affinity for [125I]iodosulpiride and a 2-fold increase in receptor density in all regions studied except striatum. Quantitative autoradiography with [125I]iodosulpiride showed similar increases in D2 labelling following KA except in caudate putamen, nucleus accumbens and olfactory tubercle. In contrast, there was no change in [3H]spiperone binding in whole brain minus striatum nor in striatum alone after KA treatment. KA produced a significant increase in Bmax for [3H]raclopride in whole brain minus striatum and in striatum alone with minimal changes in affinity. These findings demonstrate acute changes in rat brain dopamine D2 receptors labelled with [125I]iodosulpiride and [3H]raclopride but not [3H]spiperone after KA treatment predominantly in extra striatal regions.