Are Small Hyperbolic Universes Observationally Detectable?

Using recent observational constraints on cosmological density parameters, together with recent mathematical results concerning small volume hyperbolic manifolds, we argue that, by employing pattern repetitions, the topology of nearly flat small hyperbolic universes can be observationally undetectable. This is important in view of the facts that quantum cosmology may favour hyperbolic universes with small volumes, and from the expectation coming from inflationary scenarios, that $\Omega_0$ is likely to be very close to one.Comment: 5 pages, 1 figure, LaTeX2e. A reference and two footnotes added. To appear in Class. Quantum Grav. 18 (2001) in the present for

Psoriasis and Genetics

Psoriasis is a common inflammatory skin disease caused by the interplay between multiple genetic and environmental risk factors. This review summarises recent progress in elucidating the genetic basis of psoriasis, particularly through large genome-wide association studies. We illustrate the power of genetic analyses for disease stratification. Psoriasis can be stratified by phenotype (common plaque versus rare pustular variants), or by outcome (prognosis, comorbidities, response to treatment); recent progress has been made in delineating the genetic contribution in each of these areas. We also highlight how genetic data can directly inform the development of effective psoriasis treatments.</p

Comorbidities of Keloid and Hypertrophic Scars Among Participants in UK Biobank

Importance: Keloids and hypertrophic scars (excessive scarring) are relatively understudied disfiguring chronic skin conditions with high treatment resistance. // Objective: To evaluate established comorbidities of excessive scarring in European individuals, with comparisons across ethnic groups, and to identify novel comorbidities via a phenome-wide association study (PheWAS). // Design, Setting, and Participants: This multicenter cross-sectional population-based cohort study used UK Biobank (UKB) data and fitted logistic regression models for testing associations between excessive scarring and a variety of outcomes, including previously studied comorbidities and 1518 systematically defined disease categories. Additional modeling was performed within subgroups of participants defined by self-reported ethnicity (as defined in UK Biobank). Of 502 701 UKB participants, analyses were restricted to 230078 individuals with linked primary care records. // Exposures: Keloid or hypertrophic scar diagnoses. // Main Outcomes and Measures: Previously studied disease associations (hypertension, uterine leiomyoma, vitamin D deficiency, atopic eczema) and phenotypes defined in the PheWAS Catalog. // Results: Of the 972 people with excessive scarring, there was a higher proportion of female participants compared with the 229 106 controls (65% vs 55%) and a lower proportion of White ethnicity (86% vs 95%); mean (SD) age of the total cohort was 64 (8) years. Associations were identified with hypertension and atopic eczema in models accounting for age, sex, and ethnicity, and the association with atopic eczema (odds ratio [OR], 1.68; 95% CI, 1.36-2.07; P < .001) remained statistically significant after accounting for additional potential confounders. Fully adjusted analyses within ethnic groups revealed associations with hypertension in Black participants (OR, 2.05; 95% CI, 1.13-3.72; P = .02) and with vitamin D deficiency in Asian participants (OR, 2.24; 95% CI, 1.26-3.97; P = .006). The association with uterine leiomyoma was borderline significant in Black women (OR, 1.93; 95% CI, 1.00-3.71; P = .05), whereas the association with atopic eczema was significant in White participants (OR, 1.68; 95% CI, 1.34-2.12; P < .001) and showed a similar trend in Asian (OR, 2.17; 95% CI, 1.01-4.67; P = .048) and Black participants (OR, 1.89; 95% CI, 0.83-4.28; P = .13). The PheWAS identified 110 significant associations across disease systems; of the nondermatological, musculoskeletal disease and pain symptoms were prominent. // Conclusions and Relevance: This cross-sectional study validated comorbidities of excessive scarring in UKB with comprehensive coverage of health outcomes. It also documented additional phenome-wide associations that will serve as a reference for future studies to investigate common underlying pathophysiologic mechanisms

Psoriasis treat to target:defining outcomes in psoriasis using data from a real world, population-based cohort study (the British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR)

BACKGROUND: The 'treat to target' paradigm improves outcomes and reduces costs in chronic disease management but is not yet established in psoriasis.OBJECTIVE: To identify treatment targets in psoriasis using the common measures of disease activity: Psoriasis Area and Severity Index (PASI) and Physician Global Assessment (PGA).METHODS: Data from a multicentre longitudinal UK cohort of psoriasis patients receiving systemic/biologic therapies (British Association of Dermatologists Biologics and Immunomodulators Register) were used to identify absolute PASI thresholds for 90% (PASI 90) and 75% (PASI 75) improvements in baseline disease activity, using receiver operating characteristic curves. The relationship between PGA (clear/almost clear/mild/moderate/moderate-severe/severe) and PASI (range 0-72) was described, and the concordance between absolute and relative definitions of response was determined. The same approach was used to establish treatment response and eligibility definitions based on PGA.RESULTS: Data from 13,422 patients were available (58% male, 91% white ethnicity, mean age 44·9 years), including over 23,000 longitudinal PASI and PGA scores. An absolute PASI &lt; 2 was concordant with PASI 90 and an absolute PASI &lt; 4 was concordant with PASI 75 in 90% and 88% of cases, respectively. These findings were robust to subgroups of timing of assessment, baseline disease severity and treatment modality. PASI and PGA were strongly correlated (Spearman's rank correlation coefficient 0·92). The median PASI increased from 0 (IQR 0-0, range 0-23) to 19 (IQR 15-25, range 0-64) for PGA clear to severe, respectively. PGA clear/almost clear was concordant with PASI &lt; 2 in 90% of cases, and PGA moderate-severe/severe was concordant with NICE PASI eligibility criteria for biologics in 81% of cases.CONCLUSIONS: An absolute PASI &lt; 2 and PGA clear/almost clear represent relevant disease endpoints to inform treat to target management strategies in psoriasis. This article is protected by copyright. All rights reserved.</p

An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target

Interleukin (IL)-36a, IL-36b, and IL-36g are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (TH17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associatedwith the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists

Network-Informed Gene Ranking Tackles Genetic Heterogeneity in Exome-Sequencing Studies of Monogenic Disease

Whole-exome sequencing studies of monogenic diseases can be hindered by genetic heterogeneity because different genes can harbour the disease-causing mutation in affected individuals. We show that interaction networks can help overcome genetic heterogeneity because many genes responsible for the same or very similar monogenic disease phenotypes interact. We present HetRank, a flexible gene-ranking method which incorporates network information. Using simulated exome sequencing studies we demonstrate that HetRank performs well under high levels of genetic heterogeneity and improves on previous efforts to overcome heterogeneity in monogenic disease studies. We make available an implementation of HetRank via the website http://sourceforge.net/p/hetran

Author Correction: Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis.

Funder: Department of HealthBiologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome

Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk.

Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn’s disease via altered methylation and expression of EPHB4—a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10−4), Crohn’s disease (rg = 0.097 ± 0.06, P = 3.27 × 10−3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10–3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10−3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10–3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10–3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.This research was supported in part by a number of funding sources. This research uses resources provided by the Genetic Association Information Network (GAIN), obtained from the database of Genotypes and Phenotypes (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v3.p2; samples and associated phenotype data for this study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: Pablo V. Gejman, Evanston Northwestern Healthcare and Northwestern University, Evanston, IL, USA). Fulbright Canada, the Weston Foundation, and Brain Canada through the Canada Brain Research Fund—a public-private partnership established by the Government of Canada (to J.G.P.); the National Research Foundation of Korea (NRF) [grant 2016R1C1B2013126 to B.H.] and the Bio & Medical Technology Development Program of the NRF [grant 2017M3A9B6061852 to B.H.] funded by the Korean government, Ministry of Science and ICT; the Finnish Cultural Foundation and Academy of Finland [grant 309643 to H.M.O.]; the Spanish Ministry of Economy and Competitiveness and P12-BIO-1395 from Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) [grant SAF2015-66761-P to J.M.]; the US National Institutes of Health (NIH) [grants R01AR045584, R01AR056292, X01HG007484 and P30AR057212 to Y.J., S.A.S. and R.S.]; the US NIH [grants N01AR02251 and R01AR05528 to M.D.M.]; the US NIH [grants 1R01AR063759, 1R01AR062886, 1UH2AR067677-01 and U19AI111224-01 to S.R.] and Doris Duke Charitable Foundation [grant 2013097 to S.R.]. Funding for the GAIN schizophrenia sample was provided by the US NIH [grants R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469 and U01 MH79470] and the genotyping of samples was provided through GAIN. The funding sources did not influence the study design, data analysis or writing of this manuscript