Search

Little attention is paid to disease definition in dermatology and how such definitions come about, yet defining a disease is a fundamental step upon which all subsequent clinical management and prognostic judgements depend. Developing diagnostic criteria is also a critically important step for research purposes so that studies referring to groups of people can be compared in a meaningful way. This short review introduces the concepts of regressive and progressive nosology, and how definitions of a dermatological disease can evolve in a useful way as knowledge about that disease increases. It also highlights the dangers of panchrestons – names that try to explain all yet end up explaining very little. It also considers approaches to disease definition, such as whether a binary yes/no or continuous approach is more appropriate. Conceptual frameworks including essentialistic vs. nominalistic approaches using the biomedical or biopsychosocial perspectives are articulated. The review then illustrates hazards of underdiagnosis and overdiagnosis, and introduces the notion of ‘disease mongering’ – the selling of disease in order to promote the use of medicines. The review concludes with a reaffirmation of the importance of defining dermatological disease, and why any new diagnostic criteria must be shown to increase predictive ability before they are assimilated into clinical practice and research.

Background: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Methods: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Findings: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314–26 796) in the suspend methotrexate group and 10 798 U/mL (8970–12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57–3·04; p

The UK Dermatology Clinical Trials Network (UK DCTN) was formed in 2002 with the aim of developing and supporting high-quality independent national clinical trials that address prioritized research questions for people with skin disease. Its philosophy is to democratize UK dermatological clinical research and to tackle important clinical questions that industry has no incentive to answer. The network also plays a key role in training and capacity development. Its membership of over 1000 individuals includes dermatology consultants, trainees, dermatology nurses, general practitioners, methodologists and patients. Its organizational structures are lean and include a co-ordinating team based at the Centre of Evidence-Based Dermatology in Nottingham, and an executive with independent members to ensure probity and business progression. A prioritization panel and steering group enable a pipeline of projects to be prioritized and refined for external funding from independent sources. The UK DCTN has supported and completed 12 national clinical trials, attracting investment of over £15 million into UK clinical dermatology research. Trials have covered a range of interventions from drugs such as doxycycline (BLISTER), silk clothing for eczema (CLOTHES) and surgical interventions for hidradenitis suppurativa (THESEUS). Trial results are published in prestigious journals and have global impact. Genuine partnership with patients and carers has been a strong feature of the network since its inception. The UK DCTN is proud of its first 20 years of collaborative work, and aims to remain at the forefront of independent dermatological health technology assessment, as well as expanding into areas including diagnostics, artificial intelligence, efficient studies and innovative designs.

Introduction It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions. Methods and analysis An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status. Ethics and dissemination This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers. Trial registration number ISRCTN11442263.

In Part 1 of this 2-part review of the 20th anniversary of the UK Dermatology Clinical Trials Network (UK DCTN), we described its role in developing and supporting clinical trial proposals, elaborating on structure, process and clinical trials activity. This review describes the diverse educational and training activities that the UK DCTN supports. Although not primarily set up as an educational organization, an education and training function emerged organically as the network grew. Education and training also embodies the democratization principle that drove the formation of the UK DCTN, allowing participation from a much wider group of individuals than just senior academics. Far from being a sideline, education and training has now become a major component of the UK DCTN that evolves constantly through changing training curricula and trial methodology developments. Formal UK DCTN training opportunities started in 2007 with competitively awarded annual fellowships for dermatology trainees, followed by similar schemes for general practitioners, Staff and Associate Specialist clinicians and dermatology nurses. These were followed in 2013 by larger groups of trainees who work up specific trial proposals with senior mentors. Finally, a virtual journal club emerged during the pandemic in 2020 in order to reach trainees with little access to academic training. Focused activities with dermatological nurses and patients/carers also take place. Such activities require considerable organization and volunteerism from the co-ordinating centre and former fellows. Education and training has become an essential component for capacity building to develop clinical trials and succession planning for the UK DCTN.

RATIONALE: Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up. APPROACH: The National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for 'data-enabled clinical trials'. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation. REFLECTION: Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a 'route map' to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution. DISCUSSION: EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial's specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR's funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.

Objective: An umbrella review summarising all safety data from systematic reviews of topical corticosteroids (TCS) in adults and children with atopic eczema .Methods: Embase, MEDLINE, PubMed, Cochrane Database of Systematic Reviews and the Centre of Evidence Based Dermatology map of eczema systematic reviews searched until 7th November 2018 and Epistemonikos until 2nd March 2021. Reviews were included if they assessed safety of TCS in atopic eczema and searched >1 database using a reproducible search strategy. Review quality assessed using AMSTAR-2. PROSPERO registration: CRD42018079409. Results: 38 systematic reviews included, 34 low/critically low quality. Treatment and follow-up usually short (2-4 weeks). Key findings: TCS versus emollient/vehicle: No meta-analyses identified for skin-thinning. Two 2-week randomised controlled trials (RCTs) found no significant increased risk with very potent TCS (0/196 TCS vs 0/33 vehicle in children and 6/109 TCS vs 2/50 vehicle, age unknown). Biochemical adrenal suppression (cortisol) was 3.8% (95% CI 2.4%-5.8%) in a meta-analysis of 11 uncontrolled observational studies (any potency TCS, 522 children). Effects reversed when treatment ceased. TCS versus topical calcineurin inhibitors (TCIs): Meta-analysis showed higher relative risk of skin-thinning with TCS (RR 4.86, 95% CI 1.06-22.28, n=4128, four RCTs, including one 5-year RCT). Eight cases in 2068 participants, 7 using potent TCS. No evidence of growth suppression.Once daily versus more frequent TCS: No meta-analyses identified. No skin-thinning in one RCT (3 weeks potent TCS, n=94) or biochemical adrenal suppression in two RCTs (up to 2 weeks very potent/moderate TCS, n=129).TCS twice/week to prevent flares (‘weekend therapy’) versus vehicle: No meta-analyses identified. No evidence of skin-thinning in five RCTs. One RCT found biochemical adrenal suppression (2/44 children, potent TCS).Conclusions: We found no evidence of harm when TCS used intermittently “as required” to treat flares or “weekend therapy” to prevent flares. However, long-term safety data was limited.

Rationale: Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile, and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHR). Opportunities exist to utilise these in innovative ways to decrease duplication of effort, and speed trial recruitment, conduct and follow-up.Approach: The National Institute of Health Research (NIHR), Health Data Research UK (HDR UK) and Clinical Practice Research Datalink (CPRD) co-organised a national workshop to accelerate the agenda for “data-enabled clinical trials”. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation.Reflection: Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a “route map” to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution.Discussion: EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial’s specific challenges. The short-term emphasis should be on facilitating patient recruitment and for post-marketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR’s funding call. ambitious data-enabled trials at scale. There is the opportunity for the United Kingdom to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.

BackgroundFood allergy is thought to develop through transcutaneous sensitization, especially in the presence of skin barrier impairment and inflammation. Regular moisturizer application to infant skin could potentially promote transcutaneous sensitization and the development of food allergy.ObjectivesWe tested this hypothesis in the Enquiring About Tolerance (EAT) study population.MethodsThe EAT study was a population-based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, and recruited 1303 exclusively breastfed 3-month-old infants and their families from England and Wales. At enrollment at 3 months, families completed a questionnaire that included questions about frequency and type of moisturizer applied, use of corticosteroid creams, and parental report of dry skin or eczema. Infants were examined for visible eczema at the enrollment visit.ResultsA statistically significant dose-response relationship was observed between parent-reported moisturization frequency at 3 months of age and the subsequent development of food allergy. Each additional moisturization per week was associated with an adjusted odds ratio of 1.20 (95% CI, 1.13-1.27; P [less than].0005) for developing food allergy. For infants with no visible eczema at the enrollment visit, the corresponding adjusted odds ratio was 1.18 (95% CI, 1.07-1.30; P = .001) and for those with eczema at the enrollment visit, 1.20 (95% CI, 1.11-1.31; P [less than] .0005). Moisturizer frequency showed similar dose-response relationships with the development of both food and aeroallergen sensitization at 36 months.ConclusionsThese findings support the notion that regular application of moisturizers to the skin of young infants may promote the development of food allergy through transcutaneous sensitization.

Importance: Extenuating circumstances can trigger unplanned changes to randomized trials and introduce methodological, ethical, feasibility, and analytical challenges that can potentially compromise the validity of findings. Numerous randomized trials have required changes in response to the COVID-19 pandemic, but guidance for reporting such modifications is incomplete. Objective: As a joint extension for the CONSORT and SPIRIT reporting guidelines, CONSERVE (CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances) aims to improve reporting of trial protocols and completed trials that undergo important modifications in response to extenuating circumstances. Evidence: A panel of 37 international trial investigators, patient representatives, methodologists and statisticians, ethicists, funders, regulators, and journal editors convened to develop the guideline. The panel developed CONSERVE following an accelerated, iterative process between June 2020 and February 2021 involving (1) a rapid literature review of multiple databases (OVID Medline, OVID EMBASE, and EBSCO CINAHL) and gray literature sources from 2003 to March 2021; (2) consensus-based panelist meetings using a modified Delphi process and surveys; and (3) a global survey of trial stakeholders. Findings: The rapid review yielded 41 673 citations, of which 38 titles were relevant, including emerging guidance from regulatory and funding agencies for managing the effects of the COVID-19 pandemic on trials. However, no generalizable guidance for all circumstances in which trials and trial protocols might face unanticipated modifications were identified. The CONSERVE panel used these findings to develop a consensus reporting guidelines following 4 rounds of meetings and surveys. Responses were received from 198 professionals from 34 countries, of whom 90% (n = 178) indicated that they understood the concept definitions and 85.4% (n = 169) indicated that they understood and could use the implementation tool. Feedback from survey respondents was used to finalize the guideline and confirm that the guideline's core concepts were applicable and had utility for the trial community. CONSERVE incorporates an implementation tool and checklists tailored to trial reports and trial protocols for which extenuating circumstances have resulted in important modifications to the intended study procedures. The checklists include 4 sections capturing extenuating circumstances, important modifications, responsible parties, and interim data analyses. Conclusions and Relevance: CONSERVE offers an extension to CONSORT and SPIRIT that could improve the transparency, quality, and completeness of reporting important modifications to trials in extenuating circumstances such as COVID-19.

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease with periods of flares and remission. Designing personalised treatment strategies for AD is challenging, given the apparent unpredictability and large variation in AD symptoms and treatment responses within and across individuals. Better prediction of AD severity over time for individual patients could help to select optimum timing and type of treatment for improving disease control.ObjectiveWe aimed to develop a proof?of?principle mechanistic machine learning model that predicts the patient?specific evolution of AD severity scores on a daily basis.MethodsWe designed a probabilistic predictive model and trained it using Bayesian inference with the longitudinal data from two published clinical studies. The data consisted of daily recordings of AD severity scores and treatments used by 59 and 334 AD children over 6 months and 16 weeks, respectively. Validation of the predictive model was conducted in a forward?chaining setting.ResultsOur model was able to predict future severity scores at the individual level and improved chance?level forecast by 60%. Heterogeneous patterns in severity trajectories were captured with patient?specific parameters such as the short?term persistence of AD severity and responsiveness to topical steroids, calcineurin inhibitors and step?up treatment.ConclusionsOur proof of principle model successfully predicted the daily evolution of AD severity scores at an individual level, and could inform the design of personalised treatment strategies that can be tested in future studies. Our model?based approach can be applied to other diseases such as asthma with apparent unpredictability and large variation in symptoms and treatment responses

© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd. Background: Food allergy diagnosis in clinical studies can be challenging. Oral food challenges (OFC) are time-consuming, carry some risk and may, therefore, not be acceptable to all study participants. Objective: To design and evaluate an algorithm for detecting IgE-mediated food allergy in clinical study participants who do not undergo OFC. Methods: An algorithm for trial participants in the Barrier Enhancement for Eczema Prevention (BEEP) study who were unwilling or unable to attend OFC was developed. BEEP is a pragmatic, multi-centre, randomized-controlled trial of daily emollient for the first year of life for primary prevention of eczema and food allergy in high-risk infants (ISRCTN21528841). We built on the European iFAAM consensus guidance to develop a novel food allergy diagnosis algorithm using available information on previous allergenic food ingestion, food reaction(s) and sensitization status. This was implemented by a panel of food allergy experts blind to treatment allocation and OFC outcome. We then evaluated the algorithm's performance in both BEEP and Enquiring About Tolerance (EAT) study participants who did undergo OFC. Results: In 31/69 (45%) BEEP and 44/55 (80%) EAT study control group participants who had an OFC the panel felt confident enough to categorize children as “probable food allergy” or “probable no food allergy”. Algorithm-derived panel decisions showed high sensitivity 94% (95%CI 68, 100) BEEP; 90% (95%CI 72, 97) EAT and moderate specificity 67% (95%CI 39, 87) BEEP; 67% (95%CI 39, 87) EAT. Sensitivity and specificity were similar when all BEEP and EAT participants with OFC outcome were included. Conclusion: We describe a new algorithm with high sensitivity for IgE-mediated food allergy in clinical study participants who do not undergo OFC. Clinical Relevance: This may be a useful tool for excluding food allergy in future clinical studies where OFC is not conducted.

Additional file 1. Sensitivity analyses, secondary outcomes and interim analyses.

BackgroundAtopic eczema onset is described primarily in early childhood; the frequency and characteristics of adult-onset disease remain controversial.ObjectiveTo determine the proportion of individuals who report atopic eczema symptoms between birth and mid adulthood, and to examine demographic, immunologic, and genetic factors associated with period of symptom onset.MethodsWe conducted a longitudinal study using data from two nationally representative community-based birth cohorts from the United Kingdom: the British Cohort Studies 1958 and 1970. Individuals were followed from birth through age 42-50. The primary outcome was the age period of self-reported atopic eczema symptom onset based on repeated measures of self-reported atopic eczema at each survey wave.ResultsThe annual period prevalence of atopic eczema ranged from 5-15% in two cohorts of over 17,000 participants each followed from birth through mid-age. There was no clear trend in prevalence by age, and among adults reporting active atopic eczema during a given year, only 38% had symptom onset reported in childhood. When compared with individuals whose eczema started in childhood, those with adult-onset disease were more likely to be women, from Scotland or Northern England, of lower childhood socio-economic group, smokers in adulthood, and less likely to have a history of asthma. In a sub-analysis using data from the 1958 cohort only, genetic mutations previously associated with atopic eczema, including filaggrin null mutations, and allergen-specific IgE were more common among those with childhood-onset disease.ConclusionRates of self-reported atopic eczema remain high after childhood, and adult-onset atopic eczema has different risk factor associations than childhood-onset eczema.

Background Atopic eczema onset is described primarily in early childhood, and the frequency and characteristics of adult-onset disease remain controversial. Objective We sought to determine the proportion of subjects who report atopic eczema symptoms between birth and midadulthood and to examine demographic, immunologic, and genetic factors associated with period of symptom onset. Methods We conducted a longitudinal study using data from 2 nationally representative community-based birth cohorts from the United Kingdom: the British Cohort Studies 1958 and 1970. Subjects were followed from birth through age 42 to 50 years. The primary outcome was the age period of self-reported atopic eczema symptom onset based on repeated measures of self-reported atopic eczema at each survey wave. Results The annual period prevalence of atopic eczema ranged from 5% to 15% in 2 cohorts of more than 17,000 participants each followed from birth through middle age. There was no clear trend in prevalence by age, and among adults reporting active atopic eczema during a given year, only 38% had symptom onset reported in childhood. When compared with subjects whose eczema started in childhood, those with adult-onset disease were more likely to be women, from Scotland or Northern England, of lower childhood socioeconomic group, smokers in adulthood, and less likely to have a history of asthma. In a subanalysis using data from the 1958 cohort only, genetic mutations previously associated with atopic eczema, including filaggrin-null mutations, and allergen-specific IgE were more common among those with childhood-onset disease. Conclusion Rates of self-reported atopic eczema remain high after childhood, and adult-onset atopic eczema has different risk factor associations than childhood-onset eczema., Graphical abstract

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6–7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37–1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10–2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34–1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21–1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00–1.82 and OR = 0.94, 95% CI = 0.69–1.28, respectively). At ages 13–14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51–1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33–1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84–3.59 and OR = 2.38, 95% CI = 1.52–3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27–1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07–1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6-7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37-1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10-2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34-1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21-1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00-1.82 and OR = 0.94, 95% CI = 0.69-1.28, respectively). At ages 13-14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51-1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33-1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84-3.59 and OR = 2.38, 95% CI = 1.52-3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27-1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07-1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6–7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37–1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10–2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34–1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21–1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00–1.82 and OR = 0.94, 95% CI = 0.69–1.28, respectively). At ages 13–14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51–1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33–1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84–3.59 and OR = 2.38, 95% CI = 1.52–3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27–1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07–1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation. Revisión por pares

BACKGROUND: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high-risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Teledermatology provides a way for generalist clinicians to access the opinion of a specialist dermatologist for skin lesions that they consider to be suspicious without referring the patients through the normal referral pathway. Teledermatology consultations can be 'store-and-forward' with electronic digital images of a lesion sent to a dermatologist for review at a later time, or can be live and interactive consultations using videoconferencing to connect the patient, referrer and dermatologist in real time. OBJECTIVES: To determine the diagnostic accuracy of teledermatology for the detection of any skin cancer (melanoma, BCC or cutaneous squamous cell carcinoma (cSCC)) in adults, and to compare its accuracy with that of in-person diagnosis. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, CPCI, Zetoc, Science Citation Index, US National Institutes of Health Ongoing Trials Register, NIHR Clinical Research Network Portfolio Database and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies evaluating skin cancer diagnosis for teledermatology alone, or in comparison with face-to-face diagnosis by a specialist clinician, compared with a reference standard of histological confirmation or clinical follow-up and expert opinion. We also included studies evaluating the referral accuracy of teledermatology compared with a reference standard of face-to-face diagnosis by a specialist clinician. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where there were information related to the target condition of any skin cancer missing. Data permitting, we estimated summary sensitivities and specificities using the bivariate hierarchical model. Due to the scarcity of data, we undertook no covariate investigations for this review. For illustrative purposes, we plotted estimates of sensitivity and specificity on coupled forest plots for diagnostic threshold and target condition under consideration. MAIN RESULTS: The review included 22 studies reporting diagnostic accuracy data for 4057 lesions and 879 malignant cases (16 studies) and referral accuracy data for reported data for 1449 lesions and 270 'positive' cases as determined by the reference standard face-to-face decision (six studies). Methodological quality was variable with poor reporting hindering assessment. The overall risk of bias was high or unclear for participant selection, reference standard, and participant flow and timing in at least half of all studies; the majority were at low risk of bias for the index test. The applicability of study findings were of high or unclear concern for most studies in all domains assessed due to the recruitment of participants from secondary care settings or specialist clinics rather than from primary or community-based settings in which teledermatology is more likely to be used and due to the acquisition of lesion images by dermatologists or in specialist imaging units rather than by primary care clinicians.Seven studies provided data for the primary target condition of any skin cancer (1588 lesions and 638 malignancies). For the correct diagnosis of lesions as malignant using photographic images, summary sensitivity was 94.9% (95% confidence interval (CI) 90.1% to 97.4%) and summary specificity was 84.3% (95% CI 48.5% to 96.8%) (from four studies). Individual study estimates using dermoscopic images or a combination of photographic and dermoscopic images generally suggested similarly high sensitivities with highly variable specificities. Limited comparative data suggested similar diagnostic accuracy between teledermatology assessment and in-person diagnosis by a dermatologist; however, data were too scarce to draw firm conclusions. For the detection of invasive melanoma or atypical intraepidermal melanocytic variants both sensitivities and specificities were more variable. Sensitivities ranged from 59% (95% CI 42% to 74%) to 100% (95% CI 48% to 100%) and specificities from 30% (95% CI 22% to 40%) to 100% (95% CI 93% to 100%), with reported diagnostic thresholds including the correct diagnosis of melanoma, classification of lesions as 'atypical' or 'typical, and the decision to refer or to excise a lesion.Referral accuracy data comparing teledermatology against a face-to-face reference standard suggested good agreement for lesions considered to require some positive action by face-to-face assessment (sensitivities of over 90%). For lesions considered of less concern when assessed face-to-face (e.g. for lesions not recommended for excision or referral), agreement was more variable with teledermatology specificities ranging from 57% (95% CI 39% to 73%) to 100% (95% CI 86% to 100%), suggesting that remote assessment is more likely recommend excision, referral or follow-up compared to in-person decisions. AUTHORS' CONCLUSIONS: Studies were generally small and heterogeneous and methodological quality was difficult to judge due to poor reporting. Bearing in mind concerns regarding the applicability of study participants and of lesion image acquisition in specialist settings, our results suggest that teledermatology can correctly identify the majority of malignant lesions. Using a more widely defined threshold to identify 'possibly' malignant cases or lesions that should be considered for excision is likely to appropriately triage those lesions requiring face-to-face assessment by a specialist. Despite the increasing use of teledermatology on an international level, the evidence base to support its ability to accurately diagnose lesions and to triage lesions from primary to secondary care is lacking and further prospective and pragmatic evaluation is needed.

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual-and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6-7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37-1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10-2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34-1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21-1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00-1.82 and OR = 0.94, 95% CI = 0.69-1.28, respectively). At ages 13-14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51-1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33-1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84-3.59 and OR = 2.38, 95% CI = 1.52-3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27-1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07-1.82). Most individual-and school-level effects were consistent, tending to exclude reverse causation.

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Ultrasound is a non-invasive imaging technique which relies on the measurement of sound wave reflections from the tissues of the body. At lower frequencies, the deeper structures of the body such as the internal organs can be visualised, while high frequency ultrasound (HFUS) with transducer frequencies of at least 20MHz, has a much lower depth of tissue penetration but produces a higher resolution image of tissues and structures closer to the skin surface. Used in conjunction with clinical or dermoscopic examination of suspected skin cancer, or both, HFUS may offer additional diagnostic information compared to other technologies.Objectives: To determine the diagnostic accuracy of HFUS to assist in the diagnosis of (a) melanoma and intraepidermal melanocytic variants, (b) cutaneous squamous cell carcinoma (cSCC), and (c) basal cell carcinoma (BCC) in adults.Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria: Studies evaluating HFUS (>= 20 MHz) in adults with lesions suspicious for melanoma, cSCC or BCC, compared with a reference standard of histological confirmation or clinical follow-up.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and poor quality of studies, no meta-analysis was undertaken for this review. For illustrative purposes, estimates of sensitivity and specificity were plotted on coupled forest plots.Main results: Six studies were included, providing 29 datasets, 20 for diagnosis of melanoma (1125 lesions and 242 melanomas) and 9 for diagnosis of BCC (993 lesions and 119 BCCs). No data relating to the diagnosis of cSCC were identified. Studies were generally poorly reported limiting judgements of methodological quality. Half of studies did not set out to establish test accuracy and all should be considered preliminary evaluations of the potential usefulness of HFUS. There were particularly high concerns for applicability of findings due to selective study populations and data driven thresholds for test positivity. Studies reporting qualitative assessments of HFUS images excluded up to 22% of lesions (including some melanomas) due to them not being visualised by the test. Derived sensitivities for qualitative HFUS characteristics were at least 83% (95% CI 75% to 90%) for the detection of melanoma; the combination of three features (lesions appearing hypoechoic, homogenous and well defined) demonstrating 100% sensitivity in two studies, with variable corresponding specificities of 33% (95% CI 20% to 48%) and 73% (95% CI 57% to 85%) (Lower limits of the 95% CIs for sensitivities were 94% and 82% respectively). Quantitative measurement of HFUS outputs in two studies enabled decision thresholds to be set to achieve 100% sensitivity; specificities were 93% (95% CI 77% to 99%) and 65% (95% CI 51% to 76%). It was not possible to make summary statements regarding HFUS accuracy for the diagnosis of BCC due to highly variable sensitivities and specificities.Authors' conclusions: Insufficient data are available on the potential value of HFUS in the diagnosis of melanoma or BCC. Given the between study heterogeneity, unclear to low methodological quality and limited volume of evidence, no implications for practice can be drawn. The main value of the preliminary studies included may be in provision of guidance on the possible components of future diagnostic rules for diagnosis of melanoma or BCC using HFUS that require future evaluation. A prospective evaluation of HFUS added to visual inspection and dermoscopy alone in a standard health care setting with a clearly defined and representative population of participants would be required for a full and proper evaluation of accuracy.

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and cutaneous squamous cell carcinoma (cSCC) are high‐risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Computer‐assisted diagnosis (CAD) systems use artificial intelligence to analyse lesion data and arrive at a diagnosis of skin cancer. When used in unreferred settings ('primary care'), CAD may assist general practitioners (GPs) or other clinicians to more appropriately triage high‐risk lesions to secondary care. Used alongside clinical and dermoscopic suspicion of malignancy, CAD may reduce unnecessary excisions without missing melanoma cases.Objectives: To determine the accuracy of CAD systems for diagnosing cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, BCC or cSCC in adults, and to compare its accuracy with that of dermoscopy.Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria: Studies of any design that evaluated CAD alone, or in comparison with dermoscopy, in adults with lesions suspicious for melanoma or BCC or cSCC, and compared with a reference standard of either histological confirmation or clinical follow‐up.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS‐2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities separately by type of CAD system, using the bivariate hierarchical model. We compared CAD with dermoscopy using (a) all available CAD data (indirect comparisons), and (b) studies providing paired data for both tests (direct comparisons). We tested the contribution of human decision‐making to the accuracy of CAD diagnoses in a sensitivity analysis by removing studies that gave CAD results to clinicians to guide diagnostic decision‐making.Main results: We included 42 studies, 24 evaluating digital dermoscopy‐based CAD systems (Derm–CAD) in 23 study cohorts with 9602 lesions (1220 melanomas, at least 83 BCCs, 9 cSCCs), providing 32 datasets for Derm–CAD and seven for dermoscopy. Eighteen studies evaluated spectroscopy‐based CAD (Spectro–CAD) in 16 study cohorts with 6336 lesions (934 melanomas, 163 BCC, 49 cSCCs), providing 32 datasets for Spectro–CAD and six for dermoscopy. These consisted of 15 studies using multispectral imaging (MSI), two studies using electrical impedance spectroscopy (EIS) and one study using diffuse‐reflectance spectroscopy. Studies were incompletely reported and at unclear to high risk of bias across all domains. Included studies inadequately address the review question, due to an abundance of low‐quality studies, poor reporting, and recruitment of highly selected groups of participants.Across all CAD systems, we found considerable variation in the hardware and software technologies used, the types of classification algorithm employed, methods used to train the algorithms, and which lesion morphological features were extracted and analysed across all CAD systems, and even between studies evaluating CAD systems. Meta–analysis found CAD systems had high sensitivity for correct identification of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in highly selected populations, but with low and very variable specificity, particularly for Spectro–CAD systems. Pooled data from 22 studies estimated the sensitivity of Derm–CAD for the detection of melanoma as 90.1% (95% confidence interval (CI) 84.0% to 94.0%) and specificity as 74.3% (95% CI 63.6% to 82.7%). Pooled data from eight studies estimated the sensitivity of multispectral imaging CAD (MSI–CAD) as 92.9% (95% CI 83.7% to 97.1%) and specificity as 43.6% (95% CI 24.8% to 64.5%). When applied to a hypothetical population of 1000 lesions at the mean observed melanoma prevalence of 20%, Derm–CAD would miss 20 melanomas and would lead to 206 false‐positive results for melanoma. MSI–CAD would miss 14 melanomas and would lead to 451 false diagnoses for melanoma. Preliminary findings suggest CAD systems are at least as sensitive as assessment of dermoscopic images for the diagnosis of invasive melanoma and atypical intraepidermal melanocytic variants. We are unable to make summary statements about the use of CAD in unreferred populations, or its accuracy in detecting keratinocyte cancers, or its use in any setting as a diagnostic aid, because of the paucity of studies.Authors' conclusions: In highly selected patient populations all CAD types demonstrate high sensitivity, and could prove useful as a back‐up for specialist diagnosis to assist in minimising the risk of missing melanomas. However, the evidence base is currently too poor to understand whether CAD system outputs translate to different clinical decision–making in practice. Insufficient data are available on the use of CAD in community settings, or for the detection of keratinocyte cancers. The evidence base for individual systems is too limited to draw conclusions on which might be preferred for practice. Prospective comparative studies are required that evaluate the use of already evaluated CAD systems as diagnostic aids, by comparison to face–to–face dermoscopy, and in participant populations that are representative of those in which the test would be used in practice.

Background:Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high-risk skin cancers, which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised, with potential to infiltrate and damage surrounding tissue. Anxiety around missing early cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Optical coherence tomography (OCT) is a microscopic imaging technique, which magnifies the surface of a skin lesion using near-infrared light. Used in conjunction with clinical or dermoscopic examination of suspected skin cancer, or both, OCT may offer additional diagnostic information compared to other technologies.Objectives:To determine the diagnostic accuracy of OCT for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, basal cell carcinoma (BCC), or cutaneous squamous cell carcinoma (cSCC) in adults.Search methods:We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria:Studies evaluating OCT in adults with lesions suspicious for invasive melanoma and atypical intraepidermal melanocytic variants, BCC or cSCC, compared with a reference standard of histological confirmation or clinical follow-up.Data collection and analysis:Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Our unit of analysis was lesions. Where possible, we estimated summary sensitivities and specificities using the bivariate hierarchical model.Main results:Five studies including 529 cutaneous lesions (273 malignant lesions) were included, providing nine datasets for OCT, two for visual inspection alone, and two for visual inspection plus dermoscopy. Studies were of moderate to poor quality using data driven thresholds for test positivity and giving poor accounts of reference standard interpretation and blinding. Studies maynot be representative of populations eligible for OCT in practice, for example due to high disease prevalence in study populations, and may not reflect how OCT is used in practice, for example by using previously acquired OCT images.It is not possible to make summary statements regarding accuracy of detection of melanoma or of cSCC because of the paucity of studies, small sample sizes, and for melanoma differences in the OCT technologies used (high-definition versus conventional resolution OCT), and differences in the degree of testing performed prior to OCT (i.e. visual inspection alone or visual inspection plus dermoscopy).Pooled data from two studies using conventional swept-source OCT alongside visual inspection and dermoscopy for the detection of BCC estimated the sensitivity and specificity of OCT as 95% (95% CI: 91, 97%) and 77% (95% CI: 69, 83%), respectively.When applied to a hypothetical population of 1000 lesions at the mean observed BCC prevalence of 60%, OCT would miss 31 BCCs (91 fewer than would be missed by visual inspection alone and 53 fewer than would be missed by visual inspection and dermoscopy), and OCT would lead to 93 false positive results for BCC (a reduction in unnecessary excisions of 159 compared to using visual inspection alone and of 87 compared to visual inspection and dermoscopy).Authors' conclusions:Insufficient data are available on the use of OCT for the detection of melanoma or cSCC. Initial data suggests conventional OCT may have a role for the diagnosis of BCC in clinically challenging lesions, our meta-analysis showing a higher sensitivity and higher specificity when compared to visual inspection and dermoscopy. However the small number of studies and varying methodological quality means implications to guide practice cannot currently be drawn. Appropriately designed prospective comparative studies are required, given the paucity of data comparing OCT with dermoscopy and indeed other similar diagnostic aids such as reflectance confocal microscopy.

BACKGROUND: Early accurate detection of all skin cancer types is important to guide appropriate management, to reduce morbidity and to improve survival. Basal cell carcinoma (BCC) is almost always a localised skin cancer with potential to infiltrate and damage surrounding tissue, whereas a minority of cutaneous squamous cell carcinomas (cSCCs) and invasive melanomas are higher-risk skin cancers with the potential to metastasise and cause death. Dermoscopy has become an important tool to assist specialist clinicians in the diagnosis of melanoma, and is increasingly used in primary-care settings. Dermoscopy is a precision-built handheld illuminated magnifier that allows more detailed examination of the skin down to the level of the superficial dermis. Establishing the value of dermoscopy over and above visual inspection for the diagnosis of BCC or cSCC in primary- and secondary-care settings is critical to understanding its potential contribution to appropriate skin cancer triage, including referral of higher-risk cancers to secondary care, the identification of low-risk skin cancers that might be treated in primary care and to provide reassurance to those with benign skin lesions who can be safely discharged. OBJECTIVES: To determine the diagnostic accuracy of visual inspection and dermoscopy, alone or in combination, for the detection of (a) BCC and (b) cSCC, in adults. We separated studies according to whether the diagnosis was recorded face-to-face (in person) or based on remote (image-based) assessment. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated visual inspection or dermoscopy or both in adults with lesions suspicious for skin cancer, compared with a reference standard of either histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic thresholds were missing. We estimated accuracy using hierarchical summary ROC methods. We undertook analysis of studies allowing direct comparison between tests. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely-developed algorithm to assist diagnosis; and observer expertise. MAIN RESULTS: We included 24 publications reporting on 24 study cohorts, providing 27 visual inspection datasets (8805 lesions; 2579 malignancies) and 33 dermoscopy datasets (6855 lesions; 1444 malignancies). The risk of bias was mainly low for the index test (for dermoscopy evaluations) and reference standard domains, particularly for in-person evaluations, and high or unclear for participant selection, application of the index test for visual inspection and for participant flow and timing. We scored concerns about the applicability of study findings as of 'high' or 'unclear' concern for almost all studies across all domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic.The detection of BCC was reported in 28 datasets; 15 on an in-person basis and 13 image-based. Analysis of studies by prior testing of participants and according to observer expertise was not possible due to lack of data. Studies were primarily conducted in participants referred for specialist assessment of lesions with available histological classification. We found no clear differences in accuracy between dermoscopy studies undertaken in person and those which evaluated images. The lack of effect observed may be due to other sources of heterogeneity, including variations in the types of skin lesion studied, in dermatoscopes used, or in the use of algorithms and varying thresholds for deciding on a positive test result.Meta-analysis found in-person evaluations of dermoscopy (7 evaluations; 4683 lesions and 363 BCCs) to be more accurate than visual inspection alone for the detection of BCC (8 evaluations; 7017 lesions and 1586 BCCs), with a relative diagnostic odds ratio (RDOR) of 8.2 (95% confidence interval (CI) 3.5 to 19.3; P < 0.001). This corresponds to predicted differences in sensitivity of 14% (93% versus 79%) at a fixed specificity of 80% and predicted differences in specificity of 22% (99% versus 77%) at a fixed sensitivity of 80%. We observed very similar results for the image-based evaluations.When applied to a hypothetical population of 1000 lesions, of which 170 are BCC (based on median BCC prevalence across studies), an increased sensitivity of 14% from dermoscopy would lead to 24 fewer BCCs missed, assuming 166 false positive results from both tests. A 22% increase in specificity from dermoscopy with sensitivity fixed at 80% would result in 183 fewer unnecessary excisions, assuming 34 BCCs missed for both tests. There was not enough evidence to assess the use of algorithms or structured checklists for either visual inspection or dermoscopy.Insufficient data were available to draw conclusions on the accuracy of either test for the detection of cSCCs. AUTHORS' CONCLUSIONS: Dermoscopy may be a valuable tool for the diagnosis of BCC as an adjunct to visual inspection of a suspicious skin lesion following a thorough history-taking including assessment of risk factors for keratinocyte cancer. The evidence primarily comes from secondary-care (referred) populations and populations with pigmented lesions or mixed lesion types. There is no clear evidence supporting the use of currently-available formal algorithms to assist dermoscopy diagnosis.

BACKGROUND: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. History-taking and visual inspection of a suspicious lesion by a clinician is usually the first in a series of 'tests' to diagnose skin cancer. Establishing the accuracy of visual inspection alone is critical to understating the potential contribution of additional tests to assist in the diagnosis of melanoma. OBJECTIVES: To determine the diagnostic accuracy of visual inspection for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults with limited prior testing and in those referred for further evaluation of a suspicious lesion. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: CENTRAL; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Test accuracy studies of any design that evaluated visual inspection in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. We excluded studies reporting data for 'clinical diagnosis' where dermoscopy may or may not have been used. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities per algorithm and threshold using the bivariate hierarchical model. We investigated the impact of: in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; and observer expertise. MAIN RESULTS: We included 49 publications reporting on a total of 51 study cohorts with 34,351 lesions (including 2499 cases), providing 134 datasets for visual inspection. Across almost all study quality domains, the majority of study reports provided insufficient information to allow us to judge the risk of bias, while in three of four domains that we assessed we scored concerns regarding applicability of study findings as 'high'. Selective participant recruitment, lack of detail regarding the threshold for deciding on a positive test result, and lack of detail on observer expertise were particularly problematic.Attempts to analyse studies by degree of prior testing were hampered by a lack of relevant information and by the restricted inclusion of lesions selected for biopsy or excision. Accuracy was generally much higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio of 8.54, 95% CI 2.89 to 25.3, P < 0.001). Meta-analysis of in-person evaluations that could be clearly placed on the clinical pathway showed a general trade-off between sensitivity and specificity, with the highest sensitivity (92.4%, 95% CI 26.2% to 99.8%) and lowest specificity (79.7%, 95% CI 73.7% to 84.7%) observed in participants with limited prior testing (n = 3 datasets). Summary sensitivities were lower for those referred for specialist assessment but with much higher specificities (e.g. sensitivity 76.7%, 95% CI 61.7% to 87.1%) and specificity 95.7%, 95% CI 89.7% to 98.3%) for lesions selected for excision, n = 8 datasets). These differences may be related to differences in the spectrum of included lesions, differences in the definition of a positive test result, or to variations in observer expertise. We did not find clear evidence that accuracy is improved by the use of any algorithm to assist diagnosis in all settings. Attempts to examine the effect of observer expertise in melanoma diagnosis were hindered due to poor reporting. AUTHORS' CONCLUSIONS: Visual inspection is a fundamental component of the assessment of a suspicious skin lesion; however, the evidence suggests that melanomas will be missed if visual inspection is used on its own. The evidence to support its accuracy in the range of settings in which it is used is flawed and very poorly reported. Although published algorithms do not appear to improve accuracy, there is insufficient evidence to suggest that the 'no algorithm' approach should be preferred in all settings. Despite the volume of research evaluating visual inspection, further prospective evaluation of the potential added value of using established algorithms according to the prior testing or diagnostic difficulty of lesions may be warranted.

Some previously described environmental associations for atopic eczema may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple atopic eczema risk factors. The International Study of Asthma and Allergies in Childhood (i.e, ISAAC) Phase Three surveyed children in schools (the sampling unit) regarding atopic eczema symptoms and potential risk factors. We assessed the effect of these risk factors on atopic eczema symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. Overall, 546,348 children from 53 countries were included. At ages 6-7 years, the strongest individual-level associations were with current paracetamol use (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.37-1.54), which persisted at school-level (OR = 1.55, 95% CI = 1.10-2.21), early-life antibiotics (OR = 1.41, 95% CI = 1.34-1.48), and early-life paracetamol use (OR = 1.28, 95% CI = 1.21-1.36), with the former persisting at the school level, whereas the latter was no longer observed (OR = 1.35, 95% CI = 1.00-1.82 and OR = 0.94, 95% CI = 0.69-1.28, respectively). At ages 13-14 years, the strongest associations at the individual level were with current paracetamol use (OR = 1.57, 95% CI = 1.51-1.63) and open-fire cooking (OR = 1.46, 95% CI = 1.33-1.62); both were stronger at the school level (OR = 2.57, 95% CI = 1.84-3.59 and OR = 2.38, 95% CI = 1.52-3.73, respectively). Association with exposure to heavy traffic (OR = 1.31, 95% CI = 1.27-1.36) also persisted at the school level (OR = 1.40, 95% CI = 1.07-1.82). Most individual- and school-level effects were consistent, tending to exclude reverse causation.

BackgroundEarly accurate detection of all skin cancer types is important to guide appropriate management and to improve morbidity and survival. Basal cell carcinoma (BCC) is usually a localised skin cancer but with potential to infiltrate and damage surrounding tissue, whereas squamous cell carcinoma (cSCC) and melanoma are higher risk skin cancers with the potential to metastasise and ultimately lead to death. When used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, reflectance confocal microscopy (RCM) may help to identify those eligible for non-surgical treatment without the need for a diagnostic biopsy, particularly in people with suspected BCC. Any potential benefit must be balanced against the risk of any misdiagnoses.Objectives1) To determine the diagnostic accuracy of RCM for the detection of BCC, cSCC, or any skin cancer in adults with a) suspicious lesion and b) lesions that are difficult to diagnose (equivocal); and 2) to compare its accuracy with that of usual practice (visual inspection or dermoscopy, or both).Search methodsWe undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteriaStudies of any design that evaluated the accuracy of RCM alone, or RCM in comparison to visual inspection or dermoscopy, or both, in adults with lesions suspicious for skin cancer compared with a reference standard of either histological confirmation or clinical follow-up, or both.Data collection and analysisTwo review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities using the bivariate hierarchical model. For computation of likely numbers of true positive, false positive, false negative, and true negative findings in the'Summary of findings' tables, summary sensitivity and specificity estimates were applied to lower quartile, median and upper quartiles of the prevalence observed in the study groups. We also investigated the impact of observer experience.Main resultsTen studies reporting on a total of 11 study cohorts were included. All 11 cohorts reported data for the detection of BCC, including 2037 lesions (464 with BCC); and four cohorts reported data for the detection of cSCC, including 834 lesions (71 with cSCC). Only one study also reported data for the detection of BCC or cSCC using dermoscopy, limiting comparisons between RCM and dermoscopy. Studies were at high or unclear risk of bias across almost all methodological quality domains, and were of high or unclear concern regarding applicability of the evidence. Selective participant recruitment, unclear blinding of the reference test, and exclusions due to image quality or technical difficulties were observed. It is unclear whether studies are representative of populations eligible for testing with RCM, and test interpretation was often undertaken using images, remotely from the patient and the interpreter blinded to clinical information that would normally be available in practice.Meta-analysis found RCM to be more sensitive but less specific for the detection of BCC in studies of participants with equivocal lesions (sensitivity 94%, 95% CI 79% to 98%; specificity 85%, 95% CI 72% to 92%; n = 3 studies) compared to studies that included any suspicious lesion (sensitivity 76%, 95% CI 45% to 92%; specificity 95%, 95% CI 66% to 99%; n = 4 studies), although confidence intervals were wide. At the median prevalence of disease of 12.5% observed in studies including any suspicious lesion, applying these results to a hypothetical population of 1000 lesions results in 30 BCCs missed with 44 false positive results (lesions misdiagnosed as BCCs). At the median prevalence of disease of 15% observed in studies of equivocal lesions, 9 BCCs would be missed with 128 false positive results in a population of 1000 lesions. Across both sets of studies, up to 15% of these false positive lesions were observed to be melanomas mistaken for BCCs. There was some suggestion of higher sensitivities in studies with more experienced observers. Summary sensitivity and specificity could not be estimated for the detection of cSCC due to paucity of data.Authors' conclusionsThere is insufficient evidence for the use of RCM for the diagnosis of BCC or cSCC in either population group. A possible role for RCM in clinical practice is as a tool to avoid diagnostic biopsies in lesions with a relatively high clinical suspicion of BCC. The potential for, and consequences of, misclassification of other skin cancers such as melanoma as BCCs requires further research. Importantly, data are lacking that compare RCM to standard clinical practice (with or without dermoscopy).

Background: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. History-taking and visual inspection of a suspicious lesion by a clinician is usually the first in a series of ‘tests’ to diagnose skin cancer. Establishing the accuracy of visual inspection alone is critical to understating the potential contribution of additional tests to assist in the diagnosis of melanoma.Objectives: To determine the diagnostic accuracy of visual inspection for the detection of cutaneous invasive melanoma and intraepidermal melanocytic variants in adults with limited prior testing and in those referred for further evaluation of a suspicious lesion. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment.Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria: Test accuracy studies of any design that evaluated visual inspection in adults with lesions suspicious for melanoma, compared with a reference standard of, either histological confirmation or clinical follow-up. Studies reporting data for ‘clinical diagnosis’ where dermoscopy may or may not have been used were excluded.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities per algorithm and threshold using the bivariate hierarchical model. We investigated the impact of: in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; and observer expertise.Main results: Forty-nine publications reporting on a total of 51 study cohorts with 34,351 lesions (including 2499 cases) were included, providing 134 datasets for visual inspection. Across almost all study quality domains, insufficient information was provided in the majority of study reports to allow the risk of bias to be judged, while concerns regarding applicability of study findings were scored as ‘High’ in three of four domains assessed. Selective participant recruitment, lack of detail regarding the threshold for deciding on a positive test result, and lack of detail on observer expertise were particularly problematic. Attempts to analyse studies by degree of prior testing were hampered by a lack of relevant information and by the restricted inclusion of lesions selected for biopsy or excision. Accuracy was generally much higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio of 8.54, 95% CI 2.89, 25.3, P

Background: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of ‘tests’ to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other highresolution image analysis techniques.Objectives: To determine the diagnostic accuracy of dermoscopy for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults, and to compare its accuracy with that of visual inspection alone. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment.Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria: Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary ROC methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training.Main results: A total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases) were included, providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as ‘High’ concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic. The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in-person (dermoscopy added to visual inspection) and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) of 4.6; 95% CI 2.4, 9.0, P

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to reduce morbidity and improve survival. Basal cell carcinoma (BCC) is usually localised to the skin with potential to infiltrate and damage surrounding tissue, while cutaneous squamous cell carcinoma (cSCC) and melanoma have a much higher potential to metastasise and ultimately lead to death. Exfoliative cytology is a non–invasive test that uses the Tzanck smear technique to identify disease by examining the structure of cells obtained from scraped samples. This simple procedure is a less invasive diagnostic test than a skin biopsy, and for BCC has the potential to provide an immediate diagnosis that avoids an additional visit to clinic to receive skin biopsy results. This may benefit patients scheduled for either Mohs micrographic surgery or non–surgical treatments such as radiotherapy. A cytology scrape can never give the same information as a skin biopsy, however, so it is important to know more about which skin cancer situations it may be helpful.Objectives: The primary objective was to determine the diagnostic accuracy of exfoliative cytology for the detection of basal cell carcinoma (BCC) in adults. Secondary objectives were to determine diagnostic accuracy for the detection of i) cutaneous squamous cell carcinoma, ii) invasive melanoma and atypical intraepidermal melanocytic variants, and iii) any skin cancer, including keratinocyte skin cancer, invasive melanoma and atypical intraepidermal melanocytic variants, or any other skin cancer.Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We also studied the reference lists of published systematic review articles.Selection criteria: Studies evaluating exfoliative cytology in adults with lesions suspicious for BCC, cSCC or melanoma, compared with a reference standard of histological confirmation.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Where possible we estimated summary sensitivities and specificities using the bivariate hierarchical model.Main results: This review reports on nine studies with a total of 1655 lesions including 1120 BCCs (14 datasets), 401 lesions with 44 cSCCs (two datasets), and 200 lesions with 10 melanomas (one dataset). Three of these datasets (one each for BCC, melanoma, and any malignant condition) were derived from one study which also performed a direct comparison with dermoscopy. Studies were of moderate to poor quality providing inadequate descriptions of participant selection, thresholds used to make cytological and histological diagnoses, and blinding. Reporting of patients’ prior referral pathways was particularly poor, as were descriptions of the cytodiagnostic criteria used to make diagnoses. No studies evaluated the use of exfoliative cytology as a primary diagnostic test for detecting BCC or other skin cancers in lesions suspicious for skin cancer. Pooled data from seven studies using standard cytomorphological criteria (but various stain methods) to detect BCC in patients with a high clinical suspicion of BCC estimated the sensitivity and specificity of exfoliative cytology as 97.5% (95% CI: 94.5 to 98.9%) and 90.1% (95% CI: 81.1 to 95.1%) respectively. When applied to a hypothetical population of 1000 clinically suspected BCC lesions with a median observed BCC prevalence of 86%, exfoliative cytology would miss 21 BCCs and would lead to 14 false positive diagnoses of BCC. No false positive cases were histologically confirmed to be melanoma. Insufficient data are available to make summary statements regarding the accuracy of exfoliative cytology to detect melanoma or cSCC, or its accuracy compared to dermoscopy.Authors' conclusions: The utility of exfoliative cytology for the primary diagnosis of skin cancer is unknown, as all included studies focused on the use of this technique for confirming strongly suspected clinical diagnoses. For the confirmation of BCC in lesions with a high clinical suspicion, there is evidence of high sensitivity and specificity for exfoliative cytology. Since decisions to treat low riskBCCs are unlikely in practice to require diagnostic confirmation given that clinical suspicion is already high, exfoliative cytology might be most useful for cases of BCC where the treatments being contemplated require a tissue diagnosis (e.g. radiotherapy). The small number of included studies, poor reporting and varying methodological quality means that no strong conclusions can currently be drawn to guide clinical practice. Despite insufficient data on the use of cytology for cSCC or melanoma, it is unlikely that cytology would be useful in these scenarios since preservation of the architecture of the whole lesion that would be available from a biopsy provides crucial diagnostic information. Given the paucity of good quality data, appropriately designed prospective comparative studies may be required to evaluate both the diagnostic value of exfoliative cytology by comparison to dermoscopy, and its confirmatory value in adequately reported populations with a high probability of BCC scheduled for further treatment requiring a tissue diagnosis.

Background: Melanoma accounts for a small proportion of all skin cancer cases but is responsible for the majority of skin cancer-related deaths. Early detection and treatment can improve survival. Smartphone applications are readily accessible and potentially offer an instant risk assessment of the likelihood of malignancy, so that the right people seek further medical attention from a clinician for more detailed assessment of the lesion. There is, however, a risk that melanomas will be missed and treatment delayed if the application reassures the user that their lesion is low risk.Objectives: To determine the diagnostic accuracy of smartphone applications to rule out cutaneous invasive melanoma and intraepidermal melanocytic variants in adults with concerns about suspicious skin lesions. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria: Studies of any design evaluating smartphone applications intended for use by individuals in a community setting who have lesions that might be suspicious for melanoma or intraepidermal melanocytic variants compared with a reference standard of histological confirmation or clinical follow-up and expert opinion.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and poor quality of studies, no meta-analysis was undertaken for this review. For illustrative purposes, estimates of sensitivity and specificity were plotted on coupled forest plots for each application under consideration.Main results: This review reports on two cohorts of lesions published in two studies. Both studies were at high risk of bias from selective participant recruitment, and high rates of non-evaluable images. Concerns about applicability of findings were high due to inclusion only of lesions already selected for excision in a dermatology clinic setting, and image acquisition by clinicians rather than by smartphone app users. Data for five mobile phone applications were reported for 332 suspicious skin lesions with 86 melanomas across the two studies. Across the four artificial intelligence-based applications which classified lesion images (photographs) as melanomas (one application) or as high risk or ‘problematic’ lesions (three applications) using a pre-programmed algorithm, sensitivities ranged from 7% (95% CI: 2%, 16%) to 73% (95% CI: 52%, 88%) and specificities from 37% (95% CI: 29% to 46%) to 94% (95% CI: 87%, 97%). The single application using store-and-forward review of lesion images by a dermatologist had a sensitivity of 98% (95% CI: 90%, 100%) and specificity 30% (95% CI: 22%, 40%). The number of test failures (lesion images analysed by the applications but classed as ‘not evaluable’ and excluded by the study authors) ranged from 3 to 31 (or 2% to 18% of lesions analysed). The store-and-forward application had one of the highest rates of test failure (15%). At least one melanoma was classed as ‘not evaluable’ in three of the four application evaluations.Authors' conclusions: Smartphone applications using artificial intelligence-based analysis have not yet demonstrated sufficient promise in terms of accuracy, and are associated with a high likelihood of missing melanomas. Applications based on store-and-forward images could have a potential role in the timely presentation of people with potentially malignant lesions by facilitating active self-management health practices and early engagement of those with suspicious skin lesions; however, they may incur a significant increase in resource and workload. Given the paucity of evidence and low methodological quality, no implications for practice can be drawn. Nevertheless, this is a rapidly advancing field and new and better applications with robust reporting of studies could change these conclusions substantially.

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Teledermatology provides a way for generalist clinicians to access the opinion of a specialist dermatologist for skin lesions that they consider to be suspicious without referring the patients concerned through the normal referral pathway. Teledermatology consultations can be ‘store-and-forward’ with electronic digital images of a lesion sent to a dermatologist for review at a later time, or can be live and interactive consultations using video conferencing to connect the patient, referrer and dermatologist in real time.Objectives: To determine the diagnostic accuracy of teledermatology for the detection of any skin cancer (melanoma, BCC or cSCC) in adults, and to compare its accuracy with that of in-person diagnosis.Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria: Studies evaluating skin cancer diagnosis for teledermatology alone, or in comparison with face-to-face diagnosis by a specialist clinician, compared with a reference standard of histological confirmation or clinical follow-up and expert opinion. Studies evaluating the referral accuracy of teledermatology compared with a reference standard of face-to-face diagnosis by a specialist clinician were also included.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition of any skin cancer was missing. Data permitting, we estimated summary sensitivities and specificities using the bivariate hierarchical model. Due to scarcity of data, no covariate investigations were undertaken for this review. For illustrative purposes, estimates of sensitivity and specificity were plotted on coupled forest plots for diagnostic threshold and target condition under consideration.Main results: Twenty-two studies were included reporting diagnostic accuracy data for 4057 lesions and 879 malignant cases (16 studies) and referral accuracy data for reported data for 1449 lesions and 270 ‘positive’ cases as determined by the reference standard face-to-face decision (six studies). Methodological quality was variable with poor reporting hindering assessment. The overall risk of bias was rated as high or unclear for participant selection, reference standard and participant flow and timing in at least half of all studies; the majority were considered at low risk of bias for the index test. The applicability of study findings were of high or unclear concern for the majority of studies in all domains assessed due to the recruitment of study participants from secondary care settings or specialist clinics rather than from the primary or community-based settings in which teledermatology is more likely to be used and due to the acquisition of lesion images by dermatologists or in specialist imaging units rather than by primary care clinicians. Seven studies provided data for the primary target condition of any skin cancer (1588 lesions and 638 malignancies). For the correct diagnosis of lesions as malignant using photographic images, summary sensitivity was 94.9% (95% CI 90.1 to 97.4%) and summary specificity 84.3% (95% CI 48.5 to 96.8%) (from four studies). Individual study estimates using dermoscopic images or a combination of photographic and dermoscopic images generally suggested similarly high sensitivities with highly variable specificities. Limited comparative data suggested similar diagnostic accuracy between teledermatology assessment and in-person diagnosis by a dermatologist; however, data were too scarce to draw firm conclusions. For the detection of invasive melanoma or atypical intraepidermal melanocytic variants both sensitivities and specificities were more variable. Sensitivities ranged from 59% (95% CI 42% to 74%) to 100% (95% CI 54% to 100%) and specificities from 30% (95% CI 22% to 40%) to 100% (95% CI 93% to 100%), with reported diagnostic thresholds including the correct diagnosis of melanoma, classification of lesions as ‘atypical’ or ‘typical as well as the decision to refer or to excise a lesion. Referral accuracy data comparing teledermatology against a face-to-face reference standard suggested good agreement for lesions considered to require some positive action by face to face assessment (sensitivities of over 90%). For lesions considered of less concern when assessed face-to-face (e.g. for those not recommended for excision or referral), agreement was more variable with teledermatology specificities ranging from 57% (95% CI 39 to 73%) to 100% (95% CI 86% to 100%), suggesting that remote assessment is more likely recommend excision, referral or follow-up compared to in-person decisions.Authors' conclusions: Studies were generally small and heterogeneous and methodological quality was difficult to judge due to poor reporting. Bearing in mind concerns regarding the applicability of study participants and of lesion image acquisition in specialist settings, our results suggest that teledermatology can correctly identify the majority of malignant lesions. Using a more widely defined threshold to identify ‘possibly’ malignant cases or lesions that should be considered for excision is likely to appropriately triage those lesions requiring face-to-face assessment by a specialist. Despite the increasing use of teledermatology on an international level, the evidence base to support its ability to accurately diagnose lesions and to triage lesions from primary to secondary care is lacking and further prospective and pragmatic evaluation is needed.

Correction in: LANCET Volume: 390 Issue: 10106 Pages: E38-E38 Published: OCT 28 2017, Background Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. Findings The highest globally observed HALE at birth for both women and men was in Singapore, at 75.2 years (95% uncertainty interval 71.9-78.6) for females and 72.0 years (68.8-75.1) for males. The lowest for females was in the Central African Republic (45.6 years [42.0-49.5]) and for males was in Lesotho (41.5 years [39.0-44.0]). From 1990 to 2016, global HALE increased by an average of 6.24 years (5.97-6.48) for both sexes combined. Global HALE increased by 6.04 years (5.74-6.27) for males and 6.49 years (6.08-6.77) for females, whereas HALE at age 65 years increased by 1.78 years (1.61-1.93) for males and 1.96 years (1.69-2.13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2.3% [-5.9 to 0.9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16.1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. Interpretation At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support., Bill & Melinda Gates Foundation

BACKGROUND: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of 'tests' to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other high-resolution image analysis techniques. OBJECTIVES: To determine the diagnostic accuracy of dermoscopy alone, or when added to visual inspection of a skin lesion, for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults. We separated studies according to whether the diagnosis was recorded face-to-face (in-person), or based on remote (image-based), assessment. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: CENTRAL; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary receiver operating characteristic (SROC),methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training. MAIN RESULTS: We included a total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases), providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as 'high' concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic.The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in person (dermoscopy added to visual inspection), and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) 4.6, 95% confidence interval (CI) 2.4 to 9.0; P < 0.001).We compared accuracy for (a), in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas),versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas), and for (b), image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas),versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a), 4.7 (95% CI 3.0 to 7.5; P < 0.001), and (b), 5.6 (95% CI 3.7 to 8.5; P < 0.001). For a), the predicted difference in sensitivity at a fixed specificity of 80% was 16% (95% CI 8% to 23%; 92% for dermoscopy + visual inspection versus 76% for visual inspection), and predicted difference in specificity at a fixed sensitivity of 80% was 20% (95% CI 7% to 33%; 95% for dermoscopy + visual inspection versus 75% for visual inspection). For b) the predicted differences in sensitivity was 34% (95% CI 24% to 46%; 81% for dermoscopy versus 47% for visual inspection), at a fixed specificity of 80%, and predicted difference in specificity was 40% (95% CI 27% to 57%; 82% for dermoscopy versus 42% for visual inspection), at a fixed sensitivity of 80%.Using the median prevalence of disease in each set of studies ((a), 12% for in-person and (b), 24% for image-based), for a hypothetical population of 1000 lesions, an increase in sensitivity of (a), 16% (in-person), and (b), 34% (image-based), from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a), 19 and (b), 81 with (a), 176 and (b), 152 false positive results. An increase in specificity of (a), 20% (in-person), and (b), 40% (image-based), at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a), 176 and (b), 304 with (a), 24 and (b), 48 melanomas missed.The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis), had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34 to 5.6; P = 0.17), or image-based (RDOR 1.4, 95% CI 0.60 to 3.3; P = 0.22), evaluations. This result was supported by subgroup analysis according to algorithm used. We observed higher accuracy for observers reported as having high experience and for those classed as 'expert consultants' in comparison to those considered to have less experience in dermoscopy, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity. AUTHORS' CONCLUSIONS: Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care are limited, however, it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in person are lacking.

BackgroundPrevious studies have reported national and regional Global Burden of Disease (GBD) estimates for the UK. Because of substantial variation in health within the UK, action to improve it requires comparable estimates of disease burden and risks at country and local levels. The slowdown in the rate of improvement in life expectancy requires further investigation. We use GBD 2016 data on mortality, causes of death, and disability to analyse the burden of disease in the countries of the UK and within local authorities in England by deprivation quintile.MethodsWe extracted data from the GBD 2016 to estimate years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and attributable risks from 1990 to 2016 for England, Scotland, Wales, Northern Ireland, the UK, and 150 English Upper-Tier Local Authorities. We estimated the burden of disease by cause of death, condition, year, and sex. We analysed the association between burden of disease and socioeconomic deprivation using the Index of Multiple Deprivation. We present results for all 264 GBD causes of death combined and the leading 20 specific causes, and all 84 GBD risks or risk clusters combined and 17 specific risks or risk clusters.FindingsThe leading causes of age-adjusted YLLs in all UK countries in 2016 were ischaemic heart disease, lung cancers, cerebrovascular disease, and chronic obstructive pulmonary disease. Age-standardised rates of YLLs for all causes varied by two times between local areas in England according to levels of socioeconomic deprivation (from 14 274 per 100 000 population [95% uncertainty interval 12 791–15 875] in Blackpool to 6888 [6145–7739] in Wokingham). Some Upper-Tier Local Authorities, particularly those in London, did better than expected for their level of deprivation. Allowing for differences in age structure, more deprived Upper-Tier Local Authorities had higher attributable YLLs for most major risk factors in the GBD. The population attributable fractions for all-cause YLLs for individual major risk factors varied across Upper-Tier Local Authorities. Life expectancy and YLLs have improved more slowly since 2010 in all UK countries compared with 1990–2010. In nine of 150 Upper-Tier Local Authorities, YLLs increased after 2010. For attributable YLLs, the rate of improvement slowed most substantially for cardiovascular disease and breast, colorectal, and lung cancers, and showed little change for Alzheimer's disease and other dementias. Morbidity makes an increasing contribution to overall burden in the UK compared with mortality. The age-standardised UK DALY rate for low back and neck pain (1795 [1258–2356]) was higher than for ischaemic heart disease (1200 [1155–1246]) or lung cancer (660 [642–679]). The leading causes of ill health (measured through YLDs) in the UK in 2016 were low back and neck pain, skin and subcutaneous diseases, migraine, depressive disorders, and sense organ disease. Age-standardised YLD rates varied much less than equivalent YLL rates across the UK, which reflects the relative scarcity of local data on causes of ill health.InterpretationThese estimates at local, regional, and national level will allow policy makers to match resources and priorities to levels of burden and risk factors. Improvement in YLLs and life expectancy slowed notably after 2010, particularly in cardiovascular disease and cancer, and targeted actions are needed if the rate of improvement is to recover. A targeted policy response is also required to address the increasing proportion of burden due to morbidity, such as musculoskeletal problems and depression. Improving the quality and completeness of available data on these causes is an essential component of this response.

This review provides a summary of key findings from 27 systematic reviews of 51 articles first published or indexed during 2015, focusing on the treatment of psoriasis as well as precision medicine in psoriasis. Evidence supports weight loss interventions by dieting and exercise for the improvement in disease severity in overweight and obese patients with psoriasis. No significant increased risk of serious infections were reported for the biologic therapies adalimumab, etanercept and ustekinumab when compared with appropriate comparators. Evidence could not provide reliable estimates of rare adverse events, underscoring the need for large prospective registries. Polymorphisms in the tumour necrosis factor (TNF) alpha gene may confer improved responses to TNF inhibitor (TNFI) therapy, but studies to date lack power to detect true association. From limited available evidence, multidisciplinary management is both more effective and more satisfactory for patients with psoriasis and psoriatic arthritis than conventional consultations. This summary of reviews provides a succinct guide for clinicians and patients wishing to remain up?to?date with high quality evidence for the treatment of psoriasis.

INTRODUCTION: Atopic dermatitis is a complex disease with differing clinical presentations. Many attempts have been made to identify uniform subtypes, or phenotypes, of atopic dermatitis in order to identify different aetiologies, improve diagnosis, estimate more accurate clinical prognoses, inform treatment andmanagement or predict treatment efficacy andeffectiveness. However, no consensus yet exists on exactly what defines these phenotypes or how many there are and whether they are genuine or statistical artefacts. This review aims to identify previously reported phenotypes of atopic dermatitis, the features used to define them and any characteristics or clinical outcomes significantly associated with them. METHODS AND ANALYSIS: We will search Ovid Embase, Ovid MEDLINE and Web of Science from inception to the latest available date at the time of the search for studies attempting to classify atopic dermatitis in humans using any cross-sectional or longitudinal epidemiological or interventional design. Primary outcomes are atopic dermatitis phenotypes, features used to define them and characteristics associated with them in subsequent analyses. A secondary outcome is the methodological approach used to derive them. Two reviewers will independently screen titles and abstracts for inclusion, extract data and assess study quality. We will present the results of this review descriptively and with frequencies where possible. ETHICS AND DISSEMINATION: Ethical approval is not required for this study as it is a systematic review. We will report results from this systematic review in a peer-reviewed journal. The main value of this study will be to inform further research. PROSPERO REGISTRATION NUMBER: CRD42018087500.

Objectives: To determine the clinical and cost-effectiveness of including emollient bath additives in the management of childhood eczema. Trial design: Pragmatic randomised open-label superiority trial with two parallel groups. Setting and recruitment: 96 general practices in Wales, West of England and Southern England. Invitation by personal letter or opportunistically by usual clinical team. Participants: Children were eligible to participate if aged over 12 months and less than 12 years, fulfilling UK Diagnostic Criteria for Atopic Dermatitis. Children with inactive or very mild eczema (5 or less on Nottingham Eczema Severity Scale) were excluded, as were children who bathed less than once a week, or whose carers were not willing to accept randomisation. 483 were randomised and one withdrew, leaving 482 children in the trial: 51% female, 84% white, mean age 5 years. Interventions: The intervention group were prescribed emollient bath additives by their usual clinical team and were asked to use them regularly for 12 months. The control group were asked to use no bath additives for 12 months. Both groups continued with standard eczema management and were given standardised advice on how to wash. Primary outcome: Eczema control measured by Patient Oriented Eczema Measure (POEM, range 0-28) weekly for 16 weeks. Secondary outcomes: Eczema severity over 1 year (4-weekly POEM from baseline to 52 weeks); number of eczema exacerbations resulting in primary healthcare consultation; disease-specific quality of life (QOL) (Dermatitis Family Impact); generic QoL (Child Health Utility-9D); resource utilisation; type and quantity of topical corticosteroid/calcineurin inhibitors prescribed. Randomisation: 483 children were randomised (1:1) using online software, stratified by recruiting centre. Results: 95.6% (461/482) of participants completed at least one post-baseline POEM, so were included in the analysis, and 76.8% (370/482) of participants completed questionnaires for more than 80% of the time points for the primary outcome (12/16 weekly questionnaires to 16 weeks). The mean Baseline POEM was 9.5 (s.d. 5.7) in the bath additives group and 10.1 (s.d. 5.8) in the no bath additives group. The mean POEM over the 16-week period was 7.5 (s.d. 6.0) in the bath additives group and 8.4 (6.0) in the no bath additives group. There was no statistically significant difference in weekly POEM scores between groups over 16 weeks. After controlling for baseline severity and confounders (ethnicity, topical corticosteroid use, soap substitute use) and allowing for clustering of participants within centres and responses within participants over time, POEM scores in the no bath additive group were 0.41 points higher than in the bath additive group (95% CI -0.27 to 1.10), below the published minimal clinically important difference for POEM of 3 points. There was no difference between groups in secondary outcomes, economic outcomes or in adverse effects. Conclusions: This trial found no evidence of clinical benefit from including emollient bath additives in the standard management of childhood eczema. Further research is needed into optimal regimens for leave-on emollient and use of soap substitutes for children with eczema.

Results of clinical trials are the most important information source for generating external clinical evidence. The use of different outcomes across trials, which investigate similar interventions for similar patient groups, significantly limits the interpretation, comparability and clinical application of trial results. Core outcome sets (COSs) aim to overcome this limitation. A COS is an agreed standardized collection of outcomes that should be measured and reported in all clinical trials for a specific clinical condition. The Core Outcome Set Initiative within the Cochrane Skin Group (CSG-COUSIN) supports the development of core outcomes in dermatology.In the second CSG-COUSIN meeting held in 2017, 11 COS development groups working on skin diseases presented their current work. The presentations and discussions identified the following overarching methodological challenges for COS development in dermatology: it is not always easy to define the disease focus of a COS; the optimal method for outcome domain identification and level of detail needed to specify such domains is challenging to many; decision rules within Delphi surveys need to be improved; appropriate ways of patient involvement are not always clear. In addition, there appear to be outcome domains that may be relevant as potential core outcome domains for the majority of skin diseases. The close collaboration between methodologists in the Core Outcome Set Initiative and the international Cochrane Skin Group has major advantages for trialists, systematic reviewers and COS developers.

Importance: The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. Objective: To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. Evidence Review: Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. Findings: In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, -1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. Conclusions and Relevance: Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.

IMPORTANCE The increasing burden due to cancer and other noncommunicable diseases poses a threat to human development, which has resulted in global political commitments reflected in the Sustainable Development Goals as well as the World Health Organization (WHO) Global Action Plan on Non-Communicable Diseases. To determine if these commitments have resulted in improved cancer control, quantitative assessments of the cancer burden are required. OBJECTIVE To assess the burden for 29 cancer groups over time to provide a framework for policy discussion, resource allocation, and research focus. EVIDENCE REVIEW Cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs) were evaluated for 195 countries and territories by age and sex using the Global Burden of Disease study estimation methods. Levels and trends were analyzed over time, as well as by the Sociodemographic Index (SDI). Changes in incident cases were categorized by changes due to epidemiological vs demographic transition. FINDINGS In 2016, there were 17.2 million cancer cases worldwide and 8.9 million deaths. Cancer cases increased by 28% between 2006 and 2016. The smallest increase was seen in high SDI countries. Globally, population aging contributed 17%; population growth, 12%; and changes in age-specific rates, -1% to this change. The most common incident cancer globally for men was prostate cancer (1.4 million cases). The leading cause of cancer deaths and DALYs was tracheal, bronchus, and lung cancer (1.2 million deaths and 25.4 million DALYs). For women, the most common incident cancer and the leading cause of cancer deaths and DALYs was breast cancer (1.7 million incident cases, 535 000 deaths, and 14.9 million DALYs). In 2016, cancer caused 213.2 million DALYs globally for both sexes combined. Between 2006 and 2016, the average annual age-standardized incidence rates for all cancers combined increased in 130 of 195 countries or territories, and the average annual age-standardized death rates decreased within that timeframe in 143 of 195 countries or territories. CONCLUSIONS AND RELEVANCE Large disparities exist between countries in cancer incidence, deaths, and associated disability. Scaling up cancer prevention and ensuring universal access to cancer care are required for health equity and to fulfill the global commitments for noncommunicable disease and cancer control.

Background:Because atopic dermatitis (AD) is a relapsing, remitting disease, assessing long?term control is important. Well controlled weeks (WCWs) have been used to assess asthma long?term control, but never validated for AD.Objectives: To assess feasibility, validity and interpretability of WCWs in AD patients.Methods: Three studies of patients with moderate?to?severe AD including 4?6 months of daily/weekly symptom and treatment use data were evaluated (Study A: n=336; Study B: n=60; Study C: n=224). WCWs were defined by worsening symptoms and increased medication use. Feasibility, construct validity and interpretability of WCWs were determined by assessing missing data, association with validated AD outcomes, and floor/ceiling effects. Analysis used linear and logistic regression.Results: WCWs were feasible to collect ? 95.2% (study A) and 94.7% (study B) contributed data for at least half of the weekly data?points, and 93.2% and 88.7% contributed to all data?points up to 4 months. WCWs were significantly associated with validated AD severity instruments including patient-reported (POEM) and objective signs (EASI, TIS and SASSAD). The odds of experiencing a WCW if AD severity was clear/mild was 5.8 (95% confidence interval (CI) 3.5 to 9.7), 1.9 (95%CI 0.8 to 4.4) and 8.1 (95%CI 4.5 to 14.6) in Studies A, B and C, respectively. WCWs were associated with ceiling effects? 31.6% (study A) and 37.5% (study B) of participants had no WCWs for >90% of the time.Conclusions: WCWs are valid and feasible for measuring long?term control in AD trials. However, ceiling effects and burden of data collection may limit use.

Background Because atopic dermatitis (AD) is a relapsing, remitting disease, assessing long-term control is important. Well controlled weeks (WCWs) have been used to assess asthma long-term control, but never validated for AD. Objectives: To assess feasibility, validity and interpretability of WCWs in AD patients.Methods Three studies of patients with moderate-to-severe AD including 4-6 months of daily/weekly symptom and treatment use data were evaluated (Study A: n=336; Study B: n=60; Study C: n=224). WCWs were defined by worsening symptoms and increased medication use. Feasibility, construct validity and interpretability of WCWs were determined by assessing missing data, association with validated AD outcomes, and floor/ceiling effects. Analysis used linear and logistic regression.Results WCWs were feasible to collect - 95.2% (study A) and 94.7% (study B) contributed data for at least half of the weekly data-points, and 93.2% and 88.7% contributed to all data-points up to 4 months. WCWs were significantly associated with validated AD severity instruments including patient-reported (POEM) and objective signs (EASI, TIS and SASSAD). The odds of experiencing a WCW if AD severity was clear/mild was 5.8 (95% confidence interval (CI) 3.5 to 9.7), 1.9 (95%CI 0.8 to 4.4) and 8.1 (95%CI 4.5 to 14.6) in Studies A, B and C, respectively. WCWs were associated with ceiling effects- 31.6% (study A) and 37.5% (study B) of participants had no WCWs for >90% of the time.Conclusions WCWs are valid and feasible for measuring long-term control in AD trials. However, ceiling effects and burden of data collection may limit use.

Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings We generated 9·3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17·2 billion, 95% uncertainty interval [UI] 15·4–19·2 billion) and diarrhoeal diseases (2·39 billion, 2·30–2·50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2·36 billion (2·35–2·37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20–30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Funding Bill & Melinda Gates Foundation. Open Access funded by Bill & Melinda Gates FoundationUnder a Creative Commons license Attribution 4.0 International (CC BY 4.0)

Background Healthy life expectancy (HALE) and disability-adjusted life-years (DALYs) provide summary measures of health across geographies and time that can inform assessments of epidemiological patterns and health system performance, help to prioritise investments in research and development, and monitor progress toward the Sustainable Development Goals (SDGs). We aimed to provide updated HALE and DALYs for geographies worldwide and evaluate how disease burden changes with development. Methods We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015. We calculated DALYs by summing years of life lost (YLLs) and years of life lived with disability (YLDs) for each geography, age group, sex, and year. We estimated HALE using the Sullivan method, which draws from age-specific death rates and YLDs per capita. We then assessed how observed levels of DALYs and HALE differed from expected trends calculated with the Socio-demographic Index (SDI), a composite indicator constructed from measures of income per capita, average years of schooling, and total fertility rate. Findings Total global DALYs remained largely unchanged from 1990 to 2015, with decreases in communicable, neonatal, maternal, and nutritional (Group 1) disease DALYs off set by increased DALYs due to non-communicable diseases (NCDs). Much of this epidemiological transition was caused by changes in population growth and ageing, but it was accelerated by widespread improvements in SDI that also correlated strongly with the increasing importance of NCDs. Both total DALYs and age-standardised DALY rates due to most Group 1 causes significantly decreased by 2015, and although total burden climbed for the majority of NCDs, age-standardised DALY rates due to NCDs declined. Nonetheless, age-standardised DALY rates due to several high-burden NCDs (including osteoarthritis, drug use disorders, depression, diabetes, congenital birth defects, and skin, oral, and sense organ diseases) either increased or remained unchanged, leading to increases in their relative ranking in many geographies. From 2005 to 2015, HALE at birth increased by an average of 2.9 years (95% uncertainty interval 2.9-3.0) for men and 3.5 years (3.4-3.7) for women, while HALE at age 65 years improved by 0.85 years (0.78-0.92) and 1.2 years (1.1-1.3), respectively. Rising SDI was associated with consistently higher HALE and a somewhat smaller proportion of life spent with functional health loss; however, rising SDI was related to increases in total disability. Many countries and territories in central America and eastern sub-Saharan Africa had increasingly lower rates of disease burden than expected given their SDI. At the same time, a subset of geographies recorded a growing gap between observed and expected levels of DALYs, a trend driven mainly by rising burden due to war, interpersonal violence, and various NCDs. Interpretation Health is improving globally, but this means more populations are spending more time with functional health loss, an absolute expansion of morbidity. The proportion of life spent in ill health decreases somewhat with increasing SDI, a relative compression of morbidity, which supports continued efforts to elevate personal income, improve education, and limit fertility. Our analysis of DALYs and HALE and their relationship to SDI represents a robust framework on which to benchmark geography-specific health performance and SDG progress. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform financial and research investments, prevention efforts, health policies, and health system improvement initiatives for all countries along the development continuum. Copyright (C) The Author(s). Published by Elsevier Ltd.

Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health. To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion. Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss. Global child and adolescent mortality decreased from 14.18 million (95% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75%) in 2015 than was the case in 1990 (61%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3% (95% UI, 3.1%-5.6%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries. Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.

© 2017 Thomas et al. Background: The role of clothing in the management of eczema (also called atopic dermatitis or atopic eczema) is poorly understood. This trial evaluated the effectiveness and cost-effectiveness of silk garments (in addition to standard care) for the management of eczema in children with moderate to severe disease. Methods and findings: This was a parallel-group, randomised, controlled, observer-blind trial. Children aged 1 to 15 y with moderate to severe eczema were recruited from secondary care and the community at five UK medical centres. Participants were allocated using online randomisation (1:1) to standard care or to standard care plus silk garments, stratified by age and recruiting centre. Silk garments were worn for 6 mo. Primary outcome (eczema severity) was assessed at baseline, 2, 4, and 6 mo, by nurses blinded to treatment allocation, using the Eczema Area and Severity Index (EASI), which was log-transformed for analysis (intention-to-treat analysis). A safety outcome was number of skin infections. Three hundred children were randomised (26 November 2013 to 5 May 2015): 42% girls, 79% white, mean age 5 y. Primary analysis included 282/300 (94%) children (n = 141 in each group). The garments were worn more often at night than in the day (median of 81% of nights [25th to 75th centile 57% to 96%] and 34% of days [25th to 75th centile 10% to 76%]). Geometric mean EASI scores at baseline, 2, 4, and 6 mo were, respectively, 9.2, 6.4, 5.8, and 5.4 for silk clothing and 8.4, 6.6, 6.0, and 5.4 for standard care. There was no evidence of any difference between the groups in EASI score averaged over all follow-up visits adjusted for baseline EASI score, age, and centre: adjusted ratio of geometric means 0.95, 95% CI 0.85 to 1.07, (p = 0.43). This confidence interval is equivalent to a difference of −1.5 to 0.5 in the original EASI units, which is not clinically important. Skin infections occurred in 36/142 (25%) and 39/141 (28%) of children in the silk clothing and standard care groups, respectively. Even if the small observed treatment effect was genuine, the incremental cost per quality-adjusted life year was £56,811 in the base case analysis from a National Health Service perspective, suggesting that silk garments are unlikely to be cost-effective using currently accepted thresholds. The main limitation of the study is that use of an objective primary outcome, whilst minimising detection bias, may have underestimated treatment effects. Conclusions: Silk clothing is unlikely to provide additional benefit over standard care in children with moderate to severe eczema. Trial registration: Current Controlled Trials ISRCTN77261365.