Evolution: Complexity, uncertainty and innovation

Complexity science provides a general mathematical basis for evolutionary thinking. It makes us face the inherent, irreducible nature of uncertainty and the limits to knowledge and prediction. Complex, evolutionary systems work on the basis of on-going, continuous internal processes of exploration, experimentation and innovation at their underlying levels. This is acted upon by the level above, leading to a selection process on the lower levels and a probing of the stability of the level above. This could either be an organizational level above, or the potential market place. Models aimed at predicting system behaviour therefore consist of assumptions of constraints on the micro-level – and because of inertia or conformity may be approximately true for some unspecified time. However, systems without strong mechanisms of repression and conformity will evolve, innovate and change, creating new emergent structures, capabilities and characteristics. Systems with no individual freedom at their lower levels will have predictable behaviour in the short term – but will not survive in the long term. Creative, innovative, evolving systems, on the other hand, will more probably survive over longer times, but will not have predictable characteristics or behaviour. These minimal mechanisms are all that are required to explain (though not predict) the co-evolutionary processes occurring in markets, organizations, and indeed in emergent, evolutionary communities of practice. Some examples will be presented briefly

287 Effects of ruxolitinib cream on pruritus in black patients with atopic dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease that has phenotypic differences across race and can be more severe in Black patients. In two phase 3 identical design studies (TRuE-AD1/TRuE-AD2), patients (≥12 years old with AD for ≥2 years, Investigator’s Global Assessment [IGA] score 2/3, 3%–20% affected body surface area) were randomized (2:2:1) to twice-daily 0.75% or 1.5% ruxolitinib (Janus kinase [JAK]1/JAK 2 inhibitor) cream or vehicle for 8 weeks. Here we describe the effect of ruxolitinib cream on itch in Black patients using pooled data from the 2 studies (n=292). Mean itch numerical rating scale (NRS) score at baseline was 5.3/5.4 for ruxolitinib cream (0.75%/1.5%) and 5.7 for vehicle. Reductions in mean itch NRS score with ruxolitinib cream (0.75%/1.5%) were evident within approximately 12 hours of first application (–0.6/–0.7 vs −0.2 for vehicle), with statistically significant reductions by Day 4 vs vehicle (–1.4/–1.6 vs –0.6; both P\u3c0.05). For those with baseline itch NRS ≥4 (n=187; 64.0%), more patients achieved ≥4-point itch NRS improvement vs vehicle by Day 2 (6.1%/16.4% vs 0%); this increased to 15.9%/26.6% vs 3.0% on Day 7 and 30.1%/43.2% vs 17.5% at Week 8 (P=0.212/P=0.009). More patients applying 0.75%/1.5% ruxolitinib cream vs vehicle reported no days of itch per question 1 of the Patient-Oriented Eczema Measure (POEM) at Week 2 (19.0%/19.4% vs 5.3%); this increased at Week 8 (34.0%/30.8% vs 12.2%). In summary, ruxolitinib cream monotherapy over 8 weeks was associated with rapid and considerable itch relief in Black patients with AD

275 Effects of ruxolitinib cream on sleep and quality of life over 52 weeks in black patients with atopic dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease with phenotypic differences across race and can affect sleep and quality of life (QoL). In 2 phase 3 studies of identical design (TRuE-AD1/TRuE-AD2), patients (pts; ≥12 y with AD for ≥2 y; Investigator’s Global Assessment score 2/3; 3%–20% affected body surface area) were randomized (2:2:1) to twice-daily 0.75% or 1.5% ruxolitinib (RUX; Janus kinase [JAK]1/JAK2 inhibitor) cream or vehicle for 8 wk (continuous treatment), followed by a long-term safety period (LTS; as-needed treatment) up to Wk 52. Pts randomized to RUX cream remained on their regimen during the LTS; pts on vehicle were rerandomized to either RUX cream strength. For Black pts who were initially randomized to the 0.75% RUX cream/1.5% RUX cream/vehicle to 0.75% RUX cream/vehicle to 1.5% RUX cream groups and continued in the LTS (n=91/97/25/22), sleep-related impairment and sleep disturbance scores per Patient-Reported Outcomes Measurement Information System at baseline (BL) were 16.3/16.4/15.0/17.5 and 18.9/19.7/17.9/19.8, respectively. Scores had decreased (less impairment) at LTS start in the RUX cream groups (Wk 8; 14.2/14.7/16.1/15.5 and 16.7/17.5/19.0/19.4) and were below BL at Wk 52 in all groups (14.3/14.8/13.9/14.4 and 18.0/18.0/17.4/16.3). Dermatology Life Quality Index (DLQI) scores were decreased at Wk 8 (mean change from BL, −7.4/−6.6/−3.8/−4.8); decreased scores were maintained to Wk 52 (−7.1/−6.5/−5.6/−8.8). Results were similar for children’s DLQI (Wk 8, −4.0/−6.9/−4.0/−3.0 [n=12/9/1/3]; Wk 52, −5.6/−11.6/−12.0/−7.3 [n=9/7/1/4]). In summary, sleep and QoL improved with RUX cream; improvements were maintained for 44 wk with as-needed use in Black pts

Durability of Response to Abrocitinib in Patients with Moderate-to-Severe Atopic Dermatitis After Treatment Discontinuation in a Phase 2b Trial

ntroduction: Multiple clinical trials showed that 12 weeks of abrocitinib monotherapy was safe and effective for the treatment of moderateto-severe atopic dermatitis (AD). The reversibility of pharmacologic activity after abrocitinib discontinuation was not described. Methods: This post hoc analysis used data from a phase 2b study to evaluate maintenance of disease control during a 4-week drug-free follow-up period in patients with moderate-tosevere AD treated with once-daily abrocitinib (200 mg/100 mg) or placebo for 12 weeks. Proportions of patients who achieved and maintained 50% or 75% improvement in Eczema Area and Severity Index (EASI-50/EASI75), an Investigator’s Global Assessment (IGA) score of 0/1, or at least a 4-point improvement in the pruritus numeric rating scale (pruritus NRS4) were determined. Biomarkers of Janus kinase inhibition and AD disease were measured in blood samples. Results: Among week 12 responders to abrocitinib 200 mg, 77.4%, 42.3%, 21.1%, and 42.9% maintained their EASI-50, EASI-75, IGA, and pruritus NRS4 response at week 16; corresponding proportions of week 12 responders maintaining response to abrocitinib 100 mg were 51.9%, 35.0%, 33.3%, and 43.5%, respectively. Four weeks after abrocitinib discontinuation, all AD biomarkers reverted towar

The COBE Diffuse Infrared Background Experiment Search for the Cosmic Infrared Background: IV. Cosmological Implications

In this paper we examine the cosmological constraints of the recent DIRBE and FIRAS detection of the extragalactic background light between 125-5000 microns on the metal and star formation histories of the universe.Comment: 38 pages and 9 figures. Accepted for publications in The Astrophysical Journa

Global Skin Disease Morbidity and Mortality: An Update From the Global Burden of Disease Study 2013.

Importance: Disability secondary to skin conditions is substantial worldwide. The Global Burden of Disease Study 2013 includes estimates of global morbidity and mortality due to skin diseases. Objective: To measure the burden of skin diseases worldwide. Data Sources: For nonfatal estimates, data were found by literature search using PubMed and Google Scholar in English and Spanish for years 1980 through 2013 and by accessing administrative data on hospital inpatient and outpatient episodes. Data for fatal estimates were based on vital registration and verbal autopsy data. Study Selection: Skin disease data were extracted from more than 4000 sources including systematic reviews, surveys, population-based disease registries, hospital inpatient data, outpatient data, cohort studies, and autopsy data. Data metrics included incidence, prevalence, remission, duration, severity, deaths, and mortality risk. Data Extraction and Synthesis: Data were extracted by age, time period, case definitions, and other study characteristics. Data points were modeled with Bayesian meta-regression to generate estimates of morbidity and mortality metrics for skin diseases. All estimates were made with 95% uncertainty intervals. Main Outcomes and Measures: Disability-adjusted life years (DALYs), years lived with disability, and years of life lost from 15 skin conditions in 188 countries. Results: Skin conditions contributed 1.79% to the global burden of disease measured in DALYs from 306 diseases and injuries in 2013. Individual skin diseases varied in size from 0.38% of total burden for dermatitis (atopic, contact, and seborrheic dermatitis), 0.29% for acne vulgaris, 0.19% for psoriasis, 0.19% for urticaria, 0.16% for viral skin diseases, 0.15% for fungal skin diseases, 0.07% for scabies, 0.06% for malignant skin melanoma, 0.05% for pyoderma, 0.04% for cellulitis, 0.03% for keratinocyte carcinoma, 0.03% for decubitus ulcer, and 0.01% for alopecia areata. All other skin and subcutaneous diseases composed 0.12% of total DALYs. Conclusions and Relevance: Skin and subcutaneous diseases were the 18th leading cause of global DALYs in Global Burden of Disease 2013. Excluding mortality, skin diseases were the fourth leading cause of disability worldwide

Dupilumab provides rapid and sustained improvement in SCORAD outcomes in adults with moderate-to-severe atopic dermatitis: combined results of four randomized phase 3 trials

Background:Dupilumab, a first-in-class therapy targeting the two key cytokines involved in the persistent underlying inflammatory pathway in atopic dermatitis (AD), is approved for treatment of moderate-to-severe AD in Europe, USA, Japan and several other countries. Objective:To assess dupilumab effects on SCORing Atopic Dermatitis (SCORAD) and component scores (objective and subjective SCORAD) over time in adults with moderate-to-severe AD. Methods:Thispost hocanalysis included 2,444 patients in four placebo-controlled, double-blind, randomized, phase 3 trials. SOLO 1 and 2 (NCT02277743; NCT02277769) evaluated 16 weeks of dupilumab monotherapy against placebo. CAFe (NCT02755649) and CHRONOS (NCT02260986) evaluated dupilumab with concomitant topical corticosteroids (TCS) against TCS alone for 16 and 52 weeks, respectively. Results:2,444 patients randomized to treatment in SOLO 1 and 2 (N = 1,379), CAFe (N = 325) and CHRONOS (N = 740) were analyzed. Dupilumab treatment significantly improved overall SCORAD and individual components as early as Week 1 or 2, with significant and clinically meaningful differences vs. control through end of treatment (p < .0001). These results occurred irrespective of dupilumab regimen, 300 mg subcutaneously weekly or every 2 weeks. Conclusions:In four large phase 3 trials in adults with moderate-to-severe AD, dupilumab treatment with or without concomitant TCS resulted in rapid and sustained improvements in all SCORAD outcomes vs. placebo or TCS alone

A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease

Peer reviewedPublisher PD

HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons

Objective: Experimental studies suggested that HMG-CoA reductase inhibitors (&apos;statins&apos;) may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons. Design: A nested case-control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization. Methods: Cases were incident HIVþ NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanente&apos;s electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV þ NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT). Results: A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV þ NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31-0.95), 0.64 (0.31-1.28), and 0.50 (0.23-1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29)