Summary
Background
Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP).
...Objectives
To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases primarily GPP and palmoplantar pustular psoriasis (PPP) for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN.
Methods
Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients – 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy‐number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype–phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort.
Results
The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype–phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers.
Conclusions
The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease‐causing genetic factors outside IL36RN.
What's already known about this topic?
The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role.
Most studies have analysed variants in different genes separately.
Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease‐contributing.
What does this study add?
Intragenic copy‐number variants or noncoding mutations in carriers of single IL36RN mutations were not found.
In total, 15% of patients with generalized pustular psoriasis (GPP) with IL36RN mutations carried variants in CARD14 or AP1S3, providing evidence for a complex inheritance.
Lack of causal /disease‐contributing variants in 64% of GPP patients suggests a role for other, not yet identified genes.
Genotype–phenotype correlation did not reveal significant correlations aside from the presence of IL36RN mutations with age at onset.
What is the translational message?
This study of three genes provides evidence that the inheritance of GPP is more complex than previously understood.
The role of known genes in GPP is rather limited, as almost two‐thirds of patients do not carry a variant in any of these genes.
In palmoplantar pustular psoriasis, the percentage of noncarriers is even lower.
Further genetic studies will reveal the diseases’ pathogenesis and provide a basis to use/develop more specific treatments.
Linked Comment: Capon. Br J Dermatol 2018; 178:589–590
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Summary
Background In previous studies, etanercept significantly improved plaque psoriasis and was well tolerated.
Objectives To examine further the efficacy and safety of etanercept and to assess ...maintenance of treatment effect after dose reduction of etanercept.
Methods In this multicentre 24‐week study in the U.S.A., Canada and Western Europe, patients were at least 18 years old; had active, clinically stable plaque psoriasis involving at least 10% of body surface area; had a minimum Psoriasis Area and Severity Index (PASI) of 10 at screening; and had received or were a candidate to receive systemic psoriasis therapy or phototherapy. During the first 12 weeks of the study, patients were randomly assigned to receive by subcutaneous injection etanercept twice weekly (BIW) at a dose of 50 mg or 25 mg, or placebo BIW in a double‐blind fashion. During the second 12 weeks, all patients received etanercept 25 mg BIW. The primary endpoint was a 75% or greater improvement from baseline in PASI (PASI 75) at 12 weeks.
Results Five hundred and eighty‐three subjects were randomized and received at least one dose of study drug. At week 12, a PASI 75 was achieved by 49% of patients in the etanercept 50 mg BIW group, 34% in the 25 mg BIW group, and 3% in the placebo group (P < 0·0001 for each etanercept group compared with placebo). At week 24 (after 12 weeks of open‐label 25 mg etanercept BIW), a PASI 75 was achieved by 54% of patients whose dose was reduced from 50 mg BIW to 25 mg BIW, by 45% of patients in the continuous 25 mg BIW group, and by 28% in the group that received placebo followed by etanercept 25 mg BIW. Etanercept was well tolerated throughout the study.
Conclusions Etanercept provided clinically meaningful benefit to patients with chronic plaque psoriasis, with no apparent decrease in efficacy after dose reduction.
Abstract Two studies investigated the effect of a food's viscosity on bite size, bite effort and food intake using a standardized protocol in which subjects sipped through a straw every 20 s for a ...period of 15 min from one of two products, a chocolate-flavored dairy drink and a chocolate-flavored dairy semi-solid, matched for energy density. In the first study, subjects consumed 47% more from the liquid than from the semi-solid to reach the same degree of satiation, with larger bite sizes for the liquid throughout the 15 minute period (8.7 ± 0.45 g) compared to the semi-solid (5.8 ± 0.3 g, p < 0.01). In the second study bite effort was eliminated by using a peristaltic pump to present the products every 20 s. Oral processing time before swallowing was set at 5 s (both products) or 8 s (semi-solid). With the elimination of bite effort and a standardized oral processing time, subjects consumed as much from the semi-solid as from the liquid to reach the same degree of satiation. Bite size for liquids started relatively small and grew gradually over successive bites, whereas the bite size for the semi-solid food started relatively large and became gradually smaller. The latter effect was even more pronounced when the oral processing time was increased from 5 to 8 s. In conclusion, semi-solids resulted in smaller bite sizes and lower intake than liquids, but these differences disappeared when differences in bite effort were eliminated.
Evidence-based treatments and preventive interventions in the child and family area have not met with widespread adoption by practitioners. Despite the high prevalence of child behavioral and ...emotional problems, many parents and families in need are not receiving or participating in services, and when they do, the most efficacious interventions are not what is usually provided. Simultaneously addressing the issues of low penetration and insufficient dissemination of evidence-based programming requires a population approach to parenting and family support and intervention. Process issues are important, particularly in relation to engagement of stakeholders, recruitment of practitioners, consideration of organizational factors, and use of media and communication strategies. This article discusses why there is a need for a population-based approach, provides a framework of how to conceptualize such an approach, and describes an example from our own work of a recently initiated prevention trial that illustrates a population-based approach in action. The rationale, structure, and goals of the Triple P System Population Trial are described in the context of the aforementioned population framework.
Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is ...associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.
The chronic nature of psoriasis means that patients often require lifetime treatment. Over this time, treatment frequently has to be adapted to meet variable demands resulting from changes in life ...course and life events. Biological drugs used to treat psoriasis vary in their dosing regimens, convenience and flexibility. Dermatologists need to understand which biologic agent is best suited for each individual patient. A wealth of evidence supports the safe and effective use of etanercept, which offers a rapid and sustained response, flexibility of dosing, maintenance of response after dose reduction or interruption, and efficacy against non‐skin manifestations such as psoriatic arthritis. An expert panel met to agree the typical patient profile of a psoriasis patient treated with etanercept, the main benefits of etanercept in psoriasis, and the patient group most likely to benefit from its use. They agreed that flexibility of dosing, the potential to individualize therapy by stopping and starting treatment while maintaining efficacy, and the possibility of cost saving through the use of flexible treatment regimens were important benefits supporting the use of etanercept in many patients with psoriasis.
Abstract
Psoriasis is an immune-mediated inflammatory disease (IMID) which may have a major impact on a patient's life, especially when the disease is moderate to severe. There is evidence that ...treatment of psoriasis during the first years is conservative and frequently based on topical agents which rarely clear lesions. Treatment with systemic agents including biologics is often undertaken only when topical agents have proved unsuitable, even in patients with moderate to severe disease. However, there is evidence that in other IMIDs (rheumatoid arthritis and Crohn's disease), targeted systemic treatment given early in the treatment pathway may improve long-term patient outcomes. We hypothesize that a patient-centered therapeutic approach, undertaken early in the psoriasis treatment pathway ("early intervention") with the goal of complete clearance, may improve control of cutaneous symptoms and may also modify disease course and burden. Critical points to address when designing an early intervention study would include: the definition of psoriasis disease activity; patient selection; intervention selection; and dosing strategies.
Summary
Background The pathogenesis of chronic hand eczema (CHE) is multifactorial and involves both endogenous predisposition and environmental triggers.
Objectives Filaggrin is a structural ...protein of the cornified envelope and important for the formation of the epidermal skin barrier. The aim of this investigation was to evaluate the role of mutations in the filaggrin gene (FLG) in the development of CHE.
Methods In total, 122 German patients with clearly defined CHE subtypes were screened for the FLG variants R501X and 2282del4 by polymerase chain reaction and restriction enzyme digest analysis. The prevalence of these variants in CHE patients was compared with that in 95 healthy individuals.
Results Overall, allele frequency and the number of mutation carriers were similar in both the CHE and control groups. When classified according to clearly defined CHE subtypes, however, the nonfunctional FLG variants showed an association with CHE involving an aetiological combination of contact allergy and irritant factors P = 0·04; P (exact test) = 0·06; P (difference in rates) = 0·09; 95% confidence interval (CI) 0–56·8), or with excessive daily exposure to water and irritants P = 0·003; P (difference in rates) < 0·001; 95% CI 29·3–67·9.
Conclusion Heterozygosity for nonfunctional mutations in the FLG gene may contribute to the manifestation and maintenance of a particular CHE subtype that is characterized by the combination of allergic and irritant contact dermatitis.
A number of in vitro and in vivo instrumental tests have been developed to reflect various aspects of the perceived oral texture of starch-based vanilla custard desserts. These tests include ...measurements of the food's infra-red reflectance (IRR), of the turbidity of spat-out rinse water, and of the friction between the food and the oral tissue. Also, images of spat-out foods have been digitally processed and image-processing parameters extracted. These tests, together with conventional rheological tests, were carried out on a set of vanilla custard desserts that varied systematically with respect to fat content (0–15%), starch content (3.3–5.1%), and type of modified starch (potato, tapioca, and waxy maize starch with various degrees of cross-liking) judged by nine highly trained QDA panelists. Three sensory dimensions could be identified from principal component analysis to summarize the sensory texture space of the custards. The results from instrumental measurements, together with the effects of ingredients, indicated that the fist dimension, running from roughness to creaminess, was related to lubrication. The second dimension, running from melting to thickness, was related to stimulus viscosity. Finally, the third dimension, running from airy to heterogeneous, was related to starch type. The results indicate that each sensory dimension has attributes that are either related to surface properties or to bulk properties of the food bolus and that saliva—and starch break-down by salivary amylase—should be incorporated into instrumental measurements. Key sensory attributes from all three dimensions were predicted well from instrumental measurements.
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