Etanercept withdrawal and retreatment in nonradiographic axial spondyloarthritis: results of RE-EMBARK, an open-label phase IV trial

Clinical trial[Abstract] Objective: RE-EMBARK investigated etanercept (ETN) withdrawal and retreatment in patients with nonradiographic axial spondyloarthritis (nr-axSpA) achieving inactive disease. Methods: Patients received ETN and a background nonsteroidal antiinflammatory drug for 24 weeks in period 1 (P1); those achieving inactive disease (Ankylosing Spondylitis Disease Activity Score [ASDAS] with C-reactive protein [CRP] < 1.3) discontinued ETN for 40 weeks or less (period 2 [P2]). Patients who flared (ASDAS with erythrocyte sedimentation rate [ESR] ≥ 2.1) were retreated for 12 weeks in period 3 (P3). The primary endpoint was the proportion of patients with inactive disease who flared within 40 weeks of ETN withdrawal. Baseline characteristics were analyzed post hoc as predictors of maintenance and regaining of inactive disease, respectively, using univariate logistic and stepwise multivariable logistic regression models. Results: The proportion of patients experiencing flare following ETN withdrawal (P2) increased from 22.3% (25/112) after 4 weeks to 67% (77/115) after 40 weeks; 74.8% (86/115) experienced flare at any time during P2. Median time to flare was 16.1 weeks. Most patients (54/87, 62.1%) who were retreated with ETN in P3 reachieved inactive disease. Absence of both sacroiliitis detected on magnetic resonance imaging (MRI) and high-sensitivity CRP (hs-CRP) > 3 mg/L at baseline predicted inactive disease maintenance in P2 following ETN withdrawal in multivariable analysis; male sex and age younger than 40 years predicted regaining of inactive disease in P3 after flare/retreatment. There were no unexpected safety signals. Conclusion: Approximately 25% of patients maintained inactive disease for 40 weeks after discontinuing ETN. Absence of both MRI sacroiliitis and high hs-CRP at baseline predicted response maintenance after ETN withdrawal

` Adding value to the fish! ´ Business Strategies in Fish Farming and Small-Scale Fishery

The development of values-based supply chains for fish and fish products from fisheries and aquaculture is a strategy to add value to the fish. This benefit refers to the double meaning of ‘value’; premium prices for high-value products and at the same time, the incorporation of environmental, social, cultural or ethical values based on a sustainable use of resources. Although small-scale fish production and fisheries have a long tradition in many regions of the European Union, fishermen and fish farmers face strong competition with industrialized fishery fleets as well as imports from lowcosts aquaculture. At the same time, European consumer surveys prove evidence that a consumers show an overaverage Willingness to Pay (WTP) for fish produced locally and according to sustainability standards. With this paper, we aim to identify and discuss fish farmers’ and fishermen’s strategies ensuring the viability of their businesses by adding value to their fish utilizing this so far often unused market potential. Four case studies serve as the basis for the analysis. The German case studies examined traditional carp pond farming in Franconia and recirculation aquaculture systems in northern Germany. The Italian case studies focus on saline aquaculture (marine and on-shore) in Tuscany and mussel farming (inshore) in the Emilia-Romagna region. The English, Italian and Greek study cases analysed the situation of small-scale coastal fisheries in Cornwall, Tuscany and the Kavala region

The prevalence and clinical characteristics of nonradiographic axial spondyloarthritis among patients with inflammatory back pain in rheumatology practices: a multinational, multicenter study

BACKGROUND: Patients with ankylosing spondylitis (AS), who by definition have radiographic sacroiliitis, typically experience symptoms for a decade or more before being diagnosed. Yet, even patients without radiographic sacroiliitis (i.e., nonradiographic axial spondyloarthritis [nr-axSpA]) report a significant disease burden. The primary objective of this study was to estimate the prevalence and clinical characteristics of nr-axSpA among patients with inflammatory back pain (IBP) in rheumatology clinics in a number of countries across the world. A secondary objective was to estimate the prevalence of IBP among patients with chronic low back pain (CLBP). METHODS: Data were collected from 51 rheumatology outpatient clinics in 19 countries in Latin America, Africa, Europe, and Asia. As consecutive patients with CLBP (N = 2517) were seen by physicians at the sites, their clinical histories were evaluated to determine whether they met the new Assessment of SpondyloArthritis international Society criteria for IBP. For those who did, their available clinical history (e.g., family history, C-reactive protein [CRP] levels) was documented in a case report form to establish whether they met criteria for nr-axSpA, AS, or other IBP. Patients diagnosed with nr-axSpA or AS completed patient-reported outcome measures to assess disease activity and functional limitations. RESULTS: A total of 2517 patients with CLBP were identified across all sites. Of these, 974 (38.70 %) fulfilled the criteria for IBP. Among IBP patients, 29.10 % met criteria for nr-axSpA, and 53.72 % met criteria for AS. The prevalence of nr-axSpA varied significantly by region (p < 0.05), with the highest prevalence reported in Asia (36.46 %) and the lowest reported in Africa (16.02 %). Patients with nr-axSpA reported mean ± SD Ankylosing Spondylitis Disease Activity Scores based on erythrocyte sedimentation rate and CRP of 2.62 ± 1.17 and 2.52 ± 1.21, respectively, indicating high levels of disease activity (patients with AS reported corresponding scores of 2.97 ± 1.13 and 2.93 ± 1.18). Similarly, the overall Bath Ankylosing Spondylitis Disease Activity Index score of 4.03 ± 2.23 for patients with nr-axSpA (4.56 ± 2.17 for patients with AS) suggested suboptimal disease control. CONCLUSIONS: These results suggest that, in the centers that participated in the study, 29 % of patients with IBP met the criteria for nr-axSpA and 39 % of patients with CLBP had IBP. The disease burden in nr-axSpA is substantial and similar to that of AS, with both groups of patients experiencing inadequate disease control. These findings suggest the need for early detection of nr-axSpA and initiation of available treatment options to slow disease progression and improve patient well-being

Carbon budget of tidal wetlands, estuaries, and shelf waters of eastern North America

Author Posting. © American Geophysical Union, 2018. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Global Biogeochemical Cycles 32 (2018): 389-416, doi:10.1002/2017GB005790.Carbon cycling in the coastal zone affects global carbon budgets and is critical for understanding the urgent issues of hypoxia, acidification, and tidal wetland loss. However, there are no regional carbon budgets spanning the three main ecosystems in coastal waters: tidal wetlands, estuaries, and shelf waters. Here we construct such a budget for eastern North America using historical data, empirical models, remote sensing algorithms, and process‐based models. Considering the net fluxes of total carbon at the domain boundaries, 59 ± 12% (± 2 standard errors) of the carbon entering is from rivers and 41 ± 12% is from the atmosphere, while 80 ± 9% of the carbon leaving is exported to the open ocean and 20 ± 9% is buried. Net lateral carbon transfers between the three main ecosystem types are comparable to fluxes at the domain boundaries. Each ecosystem type contributes substantially to exchange with the atmosphere, with CO2 uptake split evenly between tidal wetlands and shelf waters, and estuarine CO2 outgassing offsetting half of the uptake. Similarly, burial is about equal in tidal wetlands and shelf waters, while estuaries play a smaller but still substantial role. The importance of tidal wetlands and estuaries in the overall budget is remarkable given that they, respectively, make up only 2.4 and 8.9% of the study domain area. This study shows that coastal carbon budgets should explicitly include tidal wetlands, estuaries, shelf waters, and the linkages between them; ignoring any of them may produce a biased picture of coastal carbon cycling.NASA Interdisciplinary Science program Grant Number: NNX14AF93G; NASA Carbon Cycle Science Program Grant Number: NNX14AM37G; NASA Ocean Biology and Biogeochemistry Program Grant Number: NNX11AD47G; National Science Foundation's Chemical Oceanography Program Grant Number: OCE‐12605742018-10-0

Developing a Personality Model for Speech-based Conversational Agents Using the Psycholexical Approach

We present the first systematic analysis of personality dimensions developed specifically to describe the personality of speech-based conversational agents. Following the psycholexical approach from psychology, we first report on a new multi-method approach to collect potentially descriptive adjectives from 1) a free description task in an online survey (228 unique descriptors), 2) an interaction task in the lab (176 unique descriptors), and 3) a text analysis of 30,000 online reviews of conversational agents (Alexa, Google Assistant, Cortana) (383 unique descriptors). We aggregate the results into a set of 349 adjectives, which are then rated by 744 people in an online survey. A factor analysis reveals that the commonly used Big Five model for human personality does not adequately describe agent personality. As an initial step to developing a personality model, we propose alternative dimensions and discuss implications for the design of agent personalities, personality-aware personalisation, and future research.Comment: 14 pages, 2 figures, 3 tables, CHI'2

Differential Coupling of Self-Renewal Signaling Pathways in Murine Induced Pluripotent Stem Cells

The ability to reprogram somatic cells to induced pluripotent stem cells (iPSCs), exhibiting properties similar to those of embryonic stem cells (ESCs), has attracted much attention, with many studies focused on improving efficiency of derivation and unraveling the mechanisms of reprogramming. Despite this widespread interest, our knowledge of the molecular signaling pathways that are active in iPSCs and that play a role in controlling their fate have not been studied in detail. To address this shortfall, we have characterized the influence of different signals on the behavior of a model mouse iPSC line. We demonstrate significant responses of this iPSC line to the presence of serum, which leads to profoundly enhanced proliferation and, depending on the medium used, a reduction in the capacity of the iPSCs to self-renew. Surprisingly, this iPSC line was less sensitive to withdrawal of LIF compared to ESCs, exemplified by maintenance of expression of a Nanog-GFP reporter and enhanced self-renewal in the absence of LIF. While inhibition of phosphoinositide-3 kinase (PI3K) signaling decreased iPSC self-renewal, inhibition of Gsk-3 promoted it, even in the absence of LIF. High passages of this iPSC line displayed altered characteristics, including genetic instability and a reduced ability to self-renew. However, this second feature could be restored upon inhibition of Gsk-3. Collectively, our data suggest modulation of Gsk-3 activity plays a key role in the control of iPSC fate. We propose that more careful consideration should be given to characterization of the molecular pathways that control the fate of different iPSC lines, since perturbations from those observed in naïve pluripotent ESCs could render iPSCs and their derivatives susceptible to aberrant and potentially undesirable behaviors

Sources and cycling of dissolved and particulate organic radiocarbon in the northwest Atlantic continental margin

Continental shelves and slopes are productive and dynamic ocean margin systems that also regulate the fluxes of terrestrial, riverine, and estuarine materials between the continents and oceans. In order to evaluate the ages, potential sources, and transformations of organic matter in an ocean margin system, we measured the radiocarbon (Delta (14)C and delta (13)C distributions of total dissolved organic carbon (DOC), suspended particulate organic carbon (POC), and dissolved inorganic carbon (DIC) in waters of the Middle Atlantic Bight (MAB) continental shelf and slope in April-May 1994. The Delta (14)C of DOC was greatest (as high as -39 parts per thousand) in surface waters of the shelf, decreasing rapidly offshore and with depth, even in relatively shallow (25-50 in depth) shelf waters. The lowest Delta (14)C-DOC values were observed in deep slope waters, where they were significantly lower than values measured previously for the deep Sargasso Sea. There was a strong inverse relationship between Delta (14)C-DOC and delta (-13)C-DOC in all shelf and surface slope waters of the MAB, which is likely attributable to varying contributions of young, (14)C-enriched organic matter of terrestrial and/or riverine origin. The more highly (14)C-depleted DOC in deep : slope waters (as low as -442 parts per thousand) generally had a correspondingly lower delta (13)C (as low as -22.3 parts per thousand) component. However, this must originate from relic terrestrial material either in the MAB itself or be discharged to the MAB from rivers and estuaries. The isotopic signatures of POC were clearly differentiable from DOC and indicate that this pool also contained a broad range of both old and young material of terrestrial (delta (13)C as low as -24.9 parts per thousand) and marine (delta (13)C as high as -19.9 parts per thousand) origin throughout the MAB shelf and slope. The highest Delta (14)C-POC values (up to 78 parts per thousand) were observed in shallow shelf waters of the southern MAR Conversely, the lowest Delta (14)C-POC values (as low as -394 parts per thousand) were found in MAB deep slope waters and were also significantly more depleted in (14)C than POC from the central north Atlantic (Sargasso Sea). A multiple-source isotopic mass balance model employing both (14)C and (13)C was used to evaluate the relative contributions of both young and old terrigenous versus marine organic matter to DOC and POC in the MAR The results indicate that shelf and slope DOC is comprised of an old marine fraction (represented by offshore Sargasso Sea material) and either a young terrestrial/riverine/estuarine (TRE) component (in shelf and shallow slope waters) or a relic TRE component (in deep and some shallow slope waters). In contrast, suspended POC from the MAB appears to originate predominantly from a mixture of recent MAB primary production and an old, TRE component, similar to that observed in one of the major subestuaries of the Chesapeake Bay. These results suggest that both young and old sources of terrestrial and riverine organic matter can comprise a significant fraction of the DOC and POC in ocean margins. Preliminary calculations indicate that the export of this compositionally unique DOC and suspended POC may be significant terms in the organic carbon budgets of the MAB and other margin systems

Beta-HPV 5 and 8 E6 Promote p300 Degradation by Blocking AKT/p300 Association

The E6 oncoprotein from high-risk genus alpha human papillomaviruses (α-HPVs), such as HPV 16, has been well characterized with respect to the host-cell proteins it interacts with and corresponding signaling pathways that are disrupted due to these interactions. Less is known regarding the interacting partners of E6 from the genus beta papillomaviruses (β-HPVs); however, it is generally thought that β-HPV E6 proteins do not interact with many of the proteins known to bind to α-HPV E6. Here we identify p300 as a protein that interacts directly with E6 from both α- and β-HPV types. Importantly, this association appears much stronger with β-HPV types 5 and 8-E6 than with α-HPV type 16-E6 or β-HPV type 38-E6. We demonstrate that the enhanced association between 5/8-E6 and p300 leads to p300 degradation in a proteasomal-dependent but E6AP-independent manner. Rather, 5/8-E6 inhibit the association of AKT with p300, an event necessary to ensure p300 stability within the cell. Finally, we demonstrate that the decreased p300 protein levels concomitantly affect downstream signaling events, such as the expression of differentiation markers K1, K10 and Involucrin. Together, these results demonstrate a unique way in which β-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the α-HPVs

Mouse models to unravel the role of inhaled pollutants on allergic sensitization and airway inflammation

Air pollutant exposure has been linked to a rise in wheezing illnesses. Clinical data highlight that exposure to mainstream tobacco smoke (MS) and environmental tobacco smoke (ETS) as well as exposure to diesel exhaust particles (DEP) could promote allergic sensitization or aggravate symptoms of asthma, suggesting a role for these inhaled pollutants in the pathogenesis of asthma. Mouse models are a valuable tool to study the potential effects of these pollutants in the pathogenesis of asthma, with the opportunity to investigate their impact during processes leading to sensitization, acute inflammation and chronic disease. Mice allow us to perform mechanistic studies and to evaluate the importance of specific cell types in asthma pathogenesis. In this review, the major clinical effects of tobacco smoke and diesel exhaust exposure regarding to asthma development and progression are described. Clinical data are compared with findings from murine models of asthma and inhalable pollutant exposure. Moreover, the potential mechanisms by which both pollutants could aggravate asthma are discussed