ObjectivesWe aimed to determine age-specific rates of delirium and associated factors in acute medicine, and the impact of delirium on mortality and re-admission on long-term follow-up.DesignObservational study. Consecutive patients over two 8-week periods (2010, 2012) were screened for delirium on admission, using the confusion assessment method (CAM), and reviewed daily thereafter. Delirium diagnosis was made using the Diagnostic and Statistical Manual Fourth Edition (DSM IV) criteria. For patients aged ≥65 years, potentially important covariables identified in previous studies were collected with follow-up for death and re-admission until January 2014.Participants503 consecutive patients (age median=72, range 16–99 years, 236 (48%) male).SettingAcute general medicine.ResultsDelirium occurred in 101/503 (20%) (71 on admission, 30 during admission, 17 both), with risk increasing from 3% (6/195) at <65 years to 14% (10/74) for 65–74 years and 36% (85/234) at ≥75 years (p<0.0001). Among 308 patients aged >65 years, after adjustment for age, delirium was associated with previous falls (OR=2.47, 95% CI 1.45 to 4.22, p=0.001), prior dementia (2.08, 1.10 to 3.93, p=0.024), dependency (2.58, 1.48 to 4.48, p=0.001), low cognitive score (5.00, 2.50 to 9.99, p<0.0001), dehydration (3.53, 1.91 to 6.53, p<0.0001), severe illness (1.98, 1.17 to 3.38, p=0.011), pressure sore risk (5.56, 2.60 to 11.88, p<0.0001) and infection (4.88, 2.85 to 8.36, p<0.0001). Patients with delirium were more likely to fall (OR=4.55, 1.47 to 14.05, p=0.008), be incontinent of urine (3.76, 2.15 to 6.58, p<0.0001) or faeces (3.49, 1.81–6.73, p=0.0002) and be catheterised (5.08, 2.44 to 10.54, p<0.0001); and delirium was associated with stay >7 days (2.82, 1.68 to 4.75, p<0.0001), death (4.56, 1.71 to 12.17, p=0.003) and an increase in dependency among survivors (2.56, 1.37 to 4.76, p=0.003) with excess mortality still evident at 2-year follow-up. Patients with delirium had fewer re-admissions within 30-days (OR=0.32, 95% CI 0.09 to 1.1, p=0.07) and in total (median, IQR total re-admissions=0, 0–1 vs 1, 0–2, p=0.01).ConclusionsDelirium affected a fifth of acute medical admissions and a third of those aged ≥75 years, and was associated with increased mortality, institutionalisation and dependency, but not with increased risk of re-admission on follow-up.

Atopic dermatitis is a common pruritic skin disease in which barrier dysfunction and cutaneous inflammation play a role in pathogenesis. Mechanisms underlying the associated inflammation are not fully understood, and while CD1a-expressing Langerhans cells are known to be enriched within lesions, their role in clinical disease pathogenesis has not been studied. Here we observed that house dust mite (HDM) generates neolipid antigens for presentation by CD1a to T cells in the blood and skin lesions of affected individuals. HDM-responsive CD1a-reactive T cells increased in frequency after birth and showed rapid effector function, consistent with antigen-driven maturation. To define the underlying mechanisms, we analyzed HDM-challenged human skin and observed allergen-derived phospholipase (PLA2) activity in vivo. CD1a-reactive T cell activation was dependent on HDM-derived PLA2 and such cells infiltrated the skin after allergen challenge. Filaggrin insufficiency is associated with atopic dermatitis, and we observed that filaggrin inhibits PLA2 activity and inhibits CD1a-reactive PLA2-generated neolipid-specific T cell activity from skin and blood. The most widely used classification schemes of hypersensitivity, such as Gell and Coombs are predicated on the idea that non-peptide stimulants of T cells act as haptens that modify peptides or proteins. However our results point to a broader model that does not posit haptenation, but instead shows that HDM proteins generate neolipid antigens which directly activate T cells. Specifically, the data identify a pathway of atopic skin inflammation, in which house dust mite-derived phospholipase A2 generates antigenic neolipids for presentation to CD1a-reactive T cells, and define PLA2 inhibition as a function of filaggrin, supporting PLA2 inhibition as a therapeutic approach.

Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti–IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8–induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.

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BackgroundAdvanced resuscitation skills training is an important and enjoyable part of medical training, but requires small group instruction to ensure active participation of all students. Increases in student numbers have made this increasingly difficult to achieve.MethodsA single-blind randomised controlled trial of peer-led vs. expert-led resuscitation training was performed using a group of sixth-year medical students as peer instructors. The expert instructors were a senior and a middle grade doctor, and a nurse who is an Advanced Life Support (ALS) Instructor.A power calculation showed that the trial would have a greater than 90% chance of rejecting the null hypothesis (that expert-led groups performed 20% better than peer-led groups) if that were the true situation. Secondary outcome measures were the proportion of High Pass grades in each groups and safety incidents.The peer instructors designed and delivered their own course material. To ensure safety, the peer-led groups used modified defibrillators that could deliver only low-energy shocks.Blinded assessment was conducted using an Objective Structured Clinical Examination (OSCE). The checklist items were based on International Liaison Committee on Resuscitation (ILCOR) guidelines using Ebel standard-setting methods that emphasised patient and staff safety and clinical effectiveness.The results were analysed using Exact methods, chi-squared and t-test.ResultsA total of 132 students were randomised: 58 into the expert-led group, 74 into the peer-led group. 57/58 (98%) of students from the expert-led group achieved a Pass compared to 72/74 (97%) from the peer-led group: Exact statistics confirmed that it was very unlikely (p = 0.0001) that the expert-led group was 20% better than the peer-led group.There were no safety incidents, and High Pass grades were achieved by 64 (49%) of students: 33/58 (57%) from the expert-led group, 31/74 (42%) from the peer-led group. Exact statistics showed that the difference of 15% meant that it was possible that the expert-led teaching was 20% better at generating students with High Passes.ConclusionsThe key elements of advanced cardiac resuscitation can be safely and effectively taught to medical students in small groups by peer-instructors who have undergone basic medical education training.

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These data would support a model where barrier dysfunction possibly promotes greater allergen penetration and delivery to drive allergen-specific CD4+ T cells. This could further contribute to respiratory and cutaneous inflammatory disease.

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