Journal articles on the topic 'Bristol Twp'

Background:In the ACTION (NCT02109666) study, multivariable Cox proportional hazards regression models showed that the predictors of 1-year retention to abatacept treatment were: patient global pain assessment, country, reason for stopping last biologic, number of prior biologic treatments, abatacept monotherapy, RF/anti-cyclic citrullinated peptide (CCP) status, previous neoplasms, psychiatric disorders and cardiac disorders.1 Machine learning techniques, using the gradient-boosting model, subsequently identified additional predictors of abatacept retention in patients with moderate-to-severe RA enrolled in ACTION; however, the analysis did not show the directionality of the predictors.2Objectives:To improve the clinical interpretability of the machine learning model in terms of directionality and the importance of each variable in predicting retention.Methods:Previous analyses using the gradient-boosting model to identify predictors of abatacept retention at 1 year in the ACTION study have been described.2 This analysis used SHapley Additive exPlanations (SHAP), a mathematical framework, to show how a particular predictor value influences prediction in the context of all other predictors. Higher SHAP values indicate a higher likelihood of retention. The contribution of every variable in the model’s prediction (with the exception of country variables) was computed for each data point to capture individual variable impact. This enabled interpretation for level of importance and directionality at a patient level.Results:Using data from 2350 patients enrolled in ACTION (May 2008 to December 2013), the mean retention rate at 1 year was 59.3% (n=1393). Overall variable importance is shown in Figure 1. After removal of country variables, the top five baseline predictors of retention were: no previous corticosteroid use, ACR functional class II, ≥2 prior biologic treatments prior to abatacept initiation, abatacept monotherapy and HAQ-DI. In terms of directionality, no previous corticosteroid use, ≥2 prior biologic treatments prior to abatacept initiation, abatacept monotherapy and a higher HAQ-DI score at baseline were associated with a lower likelihood of retention; ACR functional class II was associated with a higher likelihood of retention.Conclusion:The gradient-boosting model previously identified predictors of abatacept retention from ACTION;2 the addition of SHAP in this analysis has provided information on the importance and directionality of those predictors. The most important predictor of abatacept retention was no previous corticosteroid use, which was associated with lower retention. The models and predictors identified could be further refined by using additional datasets from clinical trials. Machine learning offers an innovative and complementary approach to biostatistics and could be used to identify treatment response predictors at an individual patient level, leading to a more personalised treatment approach.References:[1]Alten R, et al. RMD Open 2017;3:e000538.[2]Alten R, et al. Presented at the virtual ACR Convergence 2020; 5–9 November 2020. Poster number 1745.Acknowledgements:This study was supported by Bristol Myers Squibb. Professional medical writing and editorial assistance was provided by Claire Line, PhD, at Caudex and was funded by Bristol Myers Squibb.Disclosure of Interests:Rieke Alten Speakers bureau: AbbVie, Bristol Myers Squibb, Gilead, Janssen, Lilly, Pfizer, Consultant of: AbbVie, Bristol Myers Squibb, Gilead, Janssen, Lilly, Pfizer, Grant/research support from: AbbVie, Bristol Myers Squibb, Gilead, Janssen, Lilly, Pfizer, Claire Behar Shareholder of: I have not invested directly in pharmaceutical companies producing drugs/devices for use in rheumatology however I may have shares via the funds linked to my life insurance., Consultant of: Bristol Myers Squibb, Christine Boileau Consultant of: AstraZeneca, Bristol Myers Squibb, Nanobiotix, Pierre Merckaert Consultant of: Bristol Myers Squibb, Ebenezer Afari Consultant of: Bristol Myers Squibb, Virginie Vannier-Moreau Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Sean Connolly Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Aurelie Najm Speakers bureau: Bristol Myers Squibb, Consultant of: Bristol Myers Squibb, Pierre-Antoine Juge Consultant of: Bristol Myers Squibb, Angshu Rai Shareholder of: Amgen Inc, Consultant of: Amgen Inc, Employee of: Amgen Inc, Bristol Myers Squibb, Yedid Elbez Consultant of: Bristol Myers Squibb, Karissa Lozenski Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb

ABSTRACT While previous studies have shown that microtubules (MTs) are essential for maintaining the highly biased axial growth of the Drosophila bristle, the mechanism for this process has remained vague. We report that the MT minus-end marker, Nod-KHC, accumulates at the bristle tip, suggesting that the MT network in the bristle is organized minus end out. Potential markers for studying the importance of properly polarized MTs to bristle axial growth are Ik2 and Spindle-F (Spn-F), since mutations in spn-F and ik2 affect bristle development. We demonstrate that Spn-F and Ik2 are localized to the bristle tip and that mutations in ik2 and spn-F affect bristle MT and actin organization. Specifically, mutation in ik2 affects polarized bristle MT function. It was previously found that the hook mutant exhibited defects in bristle polarity and that hook is involved in endocytic trafficking. We found that Hook is localized at the bristle tip and that this localization is affected in ik2 mutants, suggesting that the contribution of MTs within the bristle shaft is important for correct endocytic trafficking. Thus, our results show that MTs are organized in a polarized manner within the highly elongated bristle and that this organization is essential for biased bristle axial growth.

Background:Although EULAR/ACR guidelines suggest tapering biologic treatment for RA following sustained remission in patients (pts), specific de-escalation (DE) regimens are not defined. The Phase IIIb Assessing Very Early Rheumatoid arthritis Treatment (AVERT)-2 trial (NCT02504268) is evaluating SC abatacept (ABA) + MTX versus ABA placebo (PBO) + MTX in Anti-Citrullinated Protein Antibody (ACPA)-positive pts with early (ACR/EULAR 2010 criteria; disease duration ≤6 mths), active RA (SDAI >11). AVERT-2 was designed to investigate achievement of SDAI remission and a clinically meaningful dose DE strategy among pts in sustained remission who completed induction with ABA + MTX. In moderately to severely active RA and JIA patients, a relationship between ABA Cmin and efficacy was observed. Therefore, this analysis in very early RA patients, reports on the pharmacokinetics (PK) and immunogenicity of ABA and the maintenance of remission during the DE period of AVERT-2.Objectives:To assess the relationship between changes in ABA exposure and the maintenance of remission and the effect of immunogenicity on exposure during the DE period of AVERT-2.Methods:Pts received blinded SC ABA (125 mg once wkly [QW]) + MTX or ABA PBO + MTX induction treatment for 56 wks. Pts who completed induction with ABA + MTX and had sustained SDAI remission (≤3.3 at Wks 40 and 52) were re-randomized 1:1:1 to ABA QW + MTX for 48 wks (Arm C), ABA every other wk (EOW) + MTX for 24 wks followed by ABA PBO + MTX for 24 wks (Arm D), or ABA QW + MTX PBO for 48 wks (Arm E) in the DE period. ABA trough (Cmin) and anti-drug antibody (ADA) samples were collected in all subjects during the DE period. Serum ABA concentrations and ADA were measured using a validated enzyme immunoassay method and an electrochemiluminescence assay, respectively. Efficacy endpoints included change from DE Day 1 in SDAI score, HAQ-DI score, Physician’s Global Assessment (PhGA), and tender (TJC) and swollen (SJC) joint counts. The relationship between ABA Cmin and efficacy endpoints were assessed. Additionally, the impact of immunogenicity on ABA Cmin was explored.Results:Mean ABA Cmin values remained stable throughout the DE period for subjects in Arms C and E. ABA Cmin values decreased by ~50% in subjects in Arm D for the first 24 weeks from the start of DE and were ~0 for weeks 24-48 consistent with the change in the frequency of ABA dosing from EOW to ABA withdrawal (Figure 1 top).Figure 1:Mean (SD) ABA Cmin values (top) and Mean Change From Baseline in SDAI (bottom) in Subjects in DE Arm C (ABA QW + MTX), D (ABA EOW + MTX followed by ABA placebo + MTX), and E (ABA QW + MTX placebo)The incidence of immunogenicity appeared to increase upon withdrawal of ABA in Arm D. ADA formation did not appear to affect ABA Cmin, as ABA Cmin remained consistent between pts with and without ADA.Upon withdrawal of ABA in Arm D, there appeared to be an increase in the mean change from baseline (Day 1 of DE) in SDAI over time, which followed a similar time course as the washout of ABA (Figure 1 bottom). Similar results were observed for other efficacy endpoints such as HAQ-DI, PhGA, TJC, and SJC.Conclusion:The PK data in these early onset, MTX-naive, ACPA+ RA pts correlated well with the maintenance of remission in Arms A and E. Tapering of ABA from EOW to MTX only in Arm D results in a corresponding decrease in ABA Cmin, an increase in positive antibody response, and loss of remission.References:[1]Emery et. al. ACR [Abstract L11]. Nov. 2019. Atlanta GA USA[2]Li et. al. J Clin Pharmacol. Vol 59(2). Feb 2019.Disclosure of Interests:Yash Gandhi Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Sean Connolly Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Kuan-Hsiang Gary Huang Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Robert Wong Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Shannon Chilewski Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Bindu Murthy Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb

The blade tip shroud brush seal is applied to replace the labyrinth seal for the aerodynamic performance improvement of turbine stage. The leakage flow characteristics of the brush seal are numerically predicted by using the Reynolds-Averaged Navier–Stokes equations and non-linear Darcian porous medium model. The numerical leakage flow rate of the brush seal is in well agreement with the experimental data. The last and first long teeth of the labyrinth seal were designed to bristle pack named as the postposed and preposed brush seals based on the 1.5 turbine stage. The leakage flow rate and aerodynamic performance of the turbine stage with blade tip shroud labyrinth seal and brush seal are numerically investigated. The effect of the sealing clearance between bristle pack and tip shroud on the aerodynamic performance of turbine stage is conducted which ranged from 0 mm to 0.4 mm. The axial deflection of the bristle pack is analyzed with consideration of the aerodynamic forces and contact frictional force. The obtained results show that the leakage flow rate of the tip shroud brush seals with bristle tip 0.4 mm clearance which decreases by up to 18% in comparison with the labyrinth seal, and the aerodynamic efficiency increases by 0.6%. Compared to the tip labyrinth seal, tip shroud brush seals can decrease the relative deflection angle of exit flow. This flow behavior results in reducing the mixing loss between the tip leakage flow and mainstream. The similar axial deflection of the bristle pack for two kinds of brush seals is observed at the same sealing clearance. The deflection of the bristle pack under the function of the aerodynamic forces is protected by the backing plate. This work provides the theoretical basis and technical support for the brush seal application in the turbine industries.

Abstract Introduction: The phase 2 CheckMate 205 study (NCT02181738) of nivolumab (nivo) has demonstrated high objective response rates, durable efficacy, and acceptable safety profiles in patients (pts) with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) regardless of prior brentuximab vedotin (BV) treatment (Younes A et al. Lancet Oncol 2016; Fanale M et al. ICML 2017 [Oral 125]). Recently proposed new response criteria aim to account for atypical patterns of response with checkpoint inhibitors which may not be fully captured by conventional response criteria (Cheson BD et al. Blood 2016; Younes A et al, Ann Oncol 2017). Studies in solid tumors have shown that pts may continue to derive clinical benefits from nivo beyond disease progression as defined by conventional criteria (George S et al, JAMA Oncol 2016; Long GV et al, JAMA Oncol 2017). Here we report outcomes among pts with R/R cHL treated beyond progression (TBP) in CheckMate 205. Methods: This single-arm, multicenter study enrolled pts (age ≥18 y) with R/R cHL after failure of auto-HCT into 3 independent cohorts (A: BV naïve, B: BV after auto-HCT, C: BV before and/or after auto-HCT). Nivo 3 mg/kg IV every 2 wk was given until disease progression or unacceptable toxicity. Response was assessed by 2007 International Working Group criteria. Best overall response (BOR) was assessed per investigator. A protocol amendment in July 2014 allowed pts to be TBP (investigator-assessed) if they met prespecified criteria, including deriving clinical benefit, stable performance status, and non-rapid progression. Pts TBP were required to discontinue in the event of further progression (≥10% increase in tumor burden). Tumor burden after initial progression was assessed in a prespecified analysis. Exploratory analyses assessed overall survival (OS) and time to next therapy (TTNT) in pts TBP. Results: In total, 70/243 (29%) pts were TBP: 19 in Cohort A, 23 in B, and 28 in C. Demographics were similar to the overall study population: 57% had stage IV disease at study entry, median (range) age was 37 (18-72) y, and median number of prior therapies was 3 (2-5). BOR prior to progression was complete remission (CR) in 5 (7%) pts, partial remission (PR) in 31 (44%), stable disease (SD) in 20 (29%), and progressive disease in 13 (19%) (BOR was non-evaluable in 1 pt). Among pts TBP, the initial cause of progression was a ≥50% increase in total tumor burden in 13 (19%) pts, non-target lesion progression in 17 (24%), and new lesions in 47 (67%) (pts could have multiple findings as reasons for progression). The median time to initial progression in pts TBP was 6 mo; 11 mo in pts with initial BOR of CR and 7 mo in pts with initial PR or SD. At December 2016 database lock, median (range) doses of nivo beyond progression were 8 (1-43), and median duration of treatment beyond progression was 5 (0-19) mo. Overall, 21 (30%) pts TBP remained on treatment; the most common reason for discontinuation was further disease progression (80%). The majority of pts TBP demonstrated stable reductions in tumor burden with continued treatment. Median (95% CI) TTNT from first study dose of nivo was 17 (14, not estimable) mo (Figure). Median OS from date of initial progression was not reached in pts TBP and OS was 84% (95% CI 70, 92) at 1 y. Treatment-related adverse events (TRAEs) occurred in 46% of pts (13% grade [G] 3-4) after progression, vs 64% (9% G3-4) prior to progression. Serious TRAEs after progression were aspartate aminotransferase increase (n=1) and hypercalcemia (n=1), both G3-4. Ten deaths occurred in pts TBP; 7 were due to disease progression and none were considered related to study drug. Conclusions: In total, 29% of pts from CheckMate 205 Cohort A/B/C were TBP. New lesions were the most common reason for initial progression in pts TBP. Stable reductions in tumor burden were seen with continued treatment in pts TBP, and median TTNT and OS remained high. Proposed updates to response criteria may help to better assess the long-term efficacy of checkpoint inhibitors. These data suggest that pts considered to show stable performance status, non-rapid progression, and clinical benefits despite progression according to conventional response criteria may derive long-term benefits from continued nivo treatment. Study funding: BMS. Writing support: Simon Wigfield, Caudex, funded by BMS. Disclosures Cohen: Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takada: Research Funding; Bristol Myers Squibb: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; LAM Therapeutics, Inc: Research Funding. Engert: Amgen: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Honoraria, Research Funding. Ansell: Merck: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding. Younes: Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Bayer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Research Funding; Janssen: Honoraria; Merck: Honoraria; Curis: Research Funding; Sanofi: Honoraria; Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Seattle Genetics: Honoraria; Incyte: Honoraria; Celgene: Honoraria. Trneny: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Savage: Roche: Research Funding; Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Consultancy. Ramchandren: Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Collins: ADC Therapeutics: Research Funding; Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Celgene: Research Funding; Celleron: Consultancy; MSD: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding. Fanale: AMGEN: Membership on an entity's Board of Directors or advisory committees; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; ONYX: Research Funding; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GENENTECH: Research Funding; ADC THERAPEUTICS: Research Funding. Armand: Bristol-Myers Squibb: Consultancy, Other: research funding (institutional); Merck: Consultancy, Other: research funding (institutional); Infinity: Consultancy; Pfizer: Consultancy, Other: research funding (institutional); Affimed: Other: research funding (institutional); Otsuka: Other: research funding (institutional); Sequenta: Other: research funding (institutional); Sigma Tau: Other: research funding (institutional); Roche: Other: research funding (institutional); Tensha: Other: research funding (institutional). Zinzani: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Boer: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Other: Non-restricted grant for research in head and neck cancer; Eisai: Membership on an entity's Board of Directors or advisory committees; Astellas: Other: member of Independent Data Monitoring Committee. Shipp: Cell Signaling: Honoraria; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Other: Scientific Advisory Board; Merck: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; AstraZeneca: Honoraria. Santoro: Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Timmerman: Seattle Genetics: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genmab: Consultancy, Equity Ownership; Kite Pharma: Research Funding; ImmuneGene: Research Funding. Sacchi: Bristol-Myers Squibb: Employment. Sy: Bristol-Myers Squibb: Employment. Kuruvilla: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy; Hoffman LaRoche: Consultancy; Seattle Genetics: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Merck: Honoraria; Karyopharm: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding.

The work to be described forms part of an experimental study into the overall influence that the end region of a flap has on the flow of a high lift wing system. Here, our attention will be restricted mainly, but not entirely, to the tip flow of the flap itself. The study has been a collaborative venture over the past three years between British Aerospace-Civil Aircraft Division and the Aerospace Engineering Department of Bristol University, the latter funded by an SER.C research grant. BAe's major contribution was the undertaking of the main test programme, with University participation, using a large swept wing, high lift half model in the Filton low speed wind tunnel. The model was loaned by RAE for the study.

AbstractThe paper examines the role of universities in city development under the Triple Helix model through case studies of Russian and British cities. The cases of Bristol and Sheffield illustrate that the implementation of the Triple Helix model can be achieved through different approaches. In Bristol, universities reached beyond their campuses to create a ground for cooperation with partners. In Sheffield, there was a platform for interaction with partners using the brand of a top university. Meanwhile, the examples of Tomsk and Novosibirsk provide some evidence for the growing importance of universities in the innovative urban economy. The comparative analysis provides recommendations for Russian universities, whose application of the Triple Helix model is prevented by the lack of experience in developing an effective marketing strategy and weak interactions between research and enterprises.

George Gabriel Stokes won the coveted title of Senior Wrangler in 1841, a year in which the examination papers for the Cambridge Mathematical Tripos were notoriously difficult. Coming top in the Mathematical Tripos was a notable achievement, but for Stokes it was a prize hard won after several years of preparation, and not only years spent at Cambridge. When Stokes arrived at Pembroke College, he had spent the previous two years at Bristol College, a school which prided itself on its success in preparing students for Oxford and Cambridge. This article follows Stokes' path to the senior wranglership, tracing his mathematical journey from his arrival in Bristol to the end of his final year of undergraduate study at Cambridge. This article is part of the theme issue ‘Stokes at 200 (Part 1)’.

On the afternoon of 14th April 1987, the Society held a half-day symposium on wing-tip flows and devices. Papers were presented by J. J. Spillman of Cranfield Institute of Technology on wing-tip sails, by A. C. Willmer of British Aerospace (in association with R. V. Barrett and J. D. Coleman of Bristol University) on the tip flow of part-span flaps, and by H. P. Horton of Queen Mary College on measurements in the viscous flow regions of streamlined tips. Written versions of two of these talks and a synopsis of the third* have been prepared and are being printed in the Journal following these introductory remarks. The contribution by J. S. Smith of RAE to the discussion session is appearing elsewhere.

Brush seals comprised of special-alloy wire bristles are currently being used in lieu of traditional labyrinth seals for turbomachinery applications. This advancement in seal technology utilizes close-packed bristles that readily undergo lateral deformation arising from aerodynamic loads as well as loads imparted by the rotor surface. Thus, during operation, filament tips remain in contact with the rotor surface, which, in turn, inhibits leakage between successive stages of the turbine, and increases engine efficiency. However, contact forces generated at the interface of the rotor and fiber tips can lead to eventual bristle fatigue and wear of the seal/rotor system. Therefore, it is important that reliable modeling techniques be developed that can help identify complex relationships among brush seal design parameters, in-service loads, and contact forces that arise during the operation of turbomachinery. This paper is concerned with modeling and evaluating bristle deformation, bending stress, and bristle/rotor contact forces that are generated at the interface of the fiber and rotor surface due to radial fluid flow, and augments previous work reported by the author’s, which assessed filament tip forces that arise solely due to interference between the bristle/rotor. The current problem derives its importance from aerodynamic forces that are termed “blow-down,” that is, the inward radial flow of gas in close proximity to the face of the seal. Thus, bristle deformation, bristle tip reaction force, and bristle bending stress is computed on the basis of an in-plane, large-displacement mechanics analysis of a cantilever beam that is subjected to a uniform radial load. Solutions to the problem are obtained for which the filament tip is constrained to lie on the rotor surface, and includes the effect of Coulombic friction at the interface of the fiber tip and rotor. Contact forces are obtained for a range of brush seal design parameters including fiber lay angle, flexural rigidity, and length. In addition, the governing equation is cast in non-dimensional form, which extends the range of applicability of solutions to brush seals having a more general geometry and material composition.

This paper analytically investigates the aerodynamic bristle force distributions in brush seals used in aircraft gas turbine engines. These forces are responsible for the onset of bristle tip lift-off from the rotor surface which significantly affects brush seal performance. In order to provide an enhanced understanding of the mechanisms governing the bristle force distributions, a full Navier-Stokes flow simulation is performed in a streamwise periodic module of bristles corresponding to the staggered square configuration. As is the case with a companion paper (Sharatchandra and Rhode, 1996), this study has the novel feature of considering the combined effects of axial (leakage) and tangential (swirl) flows. Specifically, the effects of intra-bristle spacing and bristle inclination angle are explored. The results indicate that the lifting bristle force increases with reduced intra-bristle spacing and increased inclination angle. It was also observed that increases in the axial or tangential flow rates increased the force component in the normal as well as the flow direction.

Abstract. The 100 000 m2 wave-cut pavement in the Bristol Channel near Lilstock, UK, is a world-class outcrop, perfectly exposing a very large fracture network in several thin limestone layers. We present an analysis based on manual interpretation of fracture generations in selected domains and compare it with automated fracture tracing. Our dataset of high-resolution aerial photographs of the complete outcrop was acquired by an unmanned aerial vehicle, using a survey altitude optimized to resolve all fractures. We map fractures and identify fracture generations based on abutting and overprinting criteria, and we present the fracture networks of five selected representative domains. Each domain is also mapped automatically using ridge detection based on the complex shearlet transform method. The automatic fracture detection technique provides results close to the manually traced fracture networks in shorter time but with a bias towards closely spaced Y over X nodes. The assignment of fractures into generations cannot yet be done automatically, because the fracture traces extracted by the automatic method are segmented at the nodes, unlike the manual interpretation in which fractures are traced as a path from fracture tip to fracture tip and consist of several connected segments. This segmentation makes an interpretation of relative age impossible, because the identification of correct abutting relationships requires the investigation of the complete fracture trace by following a clearly defined set of rules. Generations 1 and 2 are long fractures that traverse all domains. Generation 3 is only present in the southwestern domains. Generation 4 follows an ENE–WSW striking trend, is suborthogonal to generations 1 and 2, and abuts on them and generation 3, if present. Generations 5 is the youngest fracture set with a range of orientations, creating polygonal patterns by abutting at all other fracture generations. Our mapping results show that the northeastern domains only contain four fracture generations; thus, the five generations of the outcrop identified in the southwestern domains are either not all present in each of the five domains or vary locally in their geometry, preventing the interpreter from linking the fractures to their respective generation over several spatially separate mapping domains. Fracture intensities differ between domains where the lowest is in the NE with 7.3 m−1 and the highest is in the SW with 10 m−1, coinciding with different fracture orientations and distributions of abutting relationships. Each domain has slightly different fracture network characteristics, and greater connectivity occurs where the development of later shorter fractures is not affected by the stress shadowing of pre-existing longer fractures.

Brush seals have proven to be an attractive alternative to labyrinth seals for turbomachinery applications. This innovation in seal technology utilizes both the high temperature capability of special-alloy wire and the flexural adaptability of fibers to accommodate a wide range of operating conditions that are encountered during service. The effectiveness of the seal is principally derived from the bristles ability to endure forces imparted by both the fluid and shaft, and yet maintain contact between the filament tips and the surface of the rotor. Consequently, contact forces generated along the interface of the fiber tip and rotor are an important consideration for both the design and performance of the rotor-seal assembly. This paper focuses on evaluating brush seal forces that arise along the surface of the rotor due to the dimensional disparity or interference between the rotor-fiber. Filament tip contact forces are computed on the basis of an in-plane, large deformation mechanics analysis of a cantilever beam, and validation of the model is assessed by using an electronic balance for measuring the shear and normal force exerted by a bristle tip onto a flat, hardened surface. Formulation of the mechanics problem is briefly reviewed, and includes the effect of Coulombic friction at the interface of the fiber tip and rotor. Filament contact force is used as a basis for computing bearing stress along the fiber-rotor interface. Results are reported for a range of brush seal design parameters in order to provide a better understanding of the role that seal geometry, friction, and bristle flexural rigidity play in generating rotor contact force.

Brush seals are designed to survive transient rotor rubs. Inherent brush seal flexibility reduces frictional heat generation. However, high surface speeds combined with thin rotor sections may result in local hot spots. Considering large surface area and accelerated oxidation rates, frictional heat at bristle tips is another major concern especially in challenging high-temperature applications. This study investigates temperature distribution in a brush seal as a function of frictional heat generation at bristle tips. The two-dimensional axisymmetric computational fluid dynamics (CFD) analysis includes the permeable bristle pack as a porous medium allowing fluid flow throughout the bristle matrix. In addition to effective flow resistance coefficients, isotropic effective thermal conductivity as a function of temperature is defined for the bristle pack. Employing a fin approach for a single bristle, a theoretical analysis has been developed after outlining the brush seal heat transfer mechanism. Theoretical and CFD analysis results are compared. To ensure coverage for various seal designs and operating conditions, several frictional heat input cases corresponding to different seal stiffness values have been studied. Frictional heat generation is outlined to introduce a practical heat flux input into the analysis model. Effect of seal stiffness on nominal bristle tip temperature has been evaluated. Analyses show a steep temperature rise close to bristle tips that diminishes further away. Heat flux conducted through the bristles dissipates into the flow by a strong convection at the fence-height region.

This article compares statistical indicators of health with those of material and social deprivation for 28 wards of the city of Bristol, England. Four general indicators of health were examined—a combined rate per 1,000 live births of stillbirths and infant deaths; deaths of persons aged 15 to 64 per 1,000 of that age; deaths of persons aged 65 and over per 10,000 of that age, and numbers of babies born after 40 weeks gestation weighing less than 2,800 (and 2,500) grams per 1,000 births having that period of gestation. Measures of average and cumulative rank were used to augment tests of the significance of correlations between different indicators. The degree of rank consistency was high, and several wards at the top and the bottom of the rankings were clearly distinct on all indicators. Five indicators of deprivation were also examined—the percentages of: 1) households with fewer rooms than persons; 2) households lacking a car; 3) economically active persons seeking work; 4) children aged 5 to 15 who receive school meals free; and 5) households experiencing disconnection of electricity in the previous 12 months. Again the consistency of ranking according to the five indicators was high, with marked differences on all five indicators between the highest and lowest ranking wards. Between 1971 and 1981 some forms of deprivation increased in nearly all wards. According to some criteria, deprivation increased more inwards already most deprived in 1971 than in those least deprived. Finally, a strong association between the two sets of indicators was found. On the data available to health and planning authorities poor health is significantly correlated with deprivation. There are therefore implications for new forms of joint policy-making on the part of different departments of local and central government.

Brush seal is a novel type contact seal, and it is well-known due to its excellent performance. However, there are many intrinsic drawbacks, such as hysteresis, which need to be solved. This article focused on modeling hysteresis in both numerical way and analytic way without pressure differential. The numerical simulation was solved by the finite element method. General contact method was used to model the inter-bristle contact, bristle–rotor contact, and bristle–backplate contact. Bristle deformation caused by both vertical and axial tip force was used to validate the numerical model together with reaction force. An analytic model in respect of the strain energy was created. The influence of structure parameters on the hysteresis ratio, with the emphasis on the derivation of hysteresis ratio formula for brush seals, was also presented. Both numerical model and analytic model presented that cant angle is the most influential factor. The aim of the article is to provide a useful theoretical and numerical method to analyze and predict the hysteresis. This work contributes the basis for future hysteresis investigation with pressure differential.

A post-test analysis of a set of inside-diameter/outside-diameter (ID/OD) bidirectional brush seals used in three-port wave rotor tests was undertaken to determine brush bristle and configuration wear, pullout, and rotor coating wear. The results suggest that sharp changes in the pressure profiles were not well reflected in bristle tip configuration patterns or wear. Also, positive-to-negative changes in axial pressure gradients appeared to have little effect on the backing plates. Although the brushes had similar porosities, they had very different unpacked arrays. This difference could explain the departure of experimental data from computational fluid dynamics flow predictions for well-packed arrays at higher pressure drops. The rotor wear led to “car track” scars (upper and lower wear bands) with a whipped surface between the bands. Those bands may have resulted from bristle stiffening at the fence and gap plates during alternate portions of the rotor cycle. Within the bristle response range the wear surface reflected the pressure distribution effect on bristle motion. No sacrificial metallurgical data were taken. The bristles did wear, with correspondingly more wear on the ID brush configurations than on the OD configurations; the complexity in constructing the ID brush was a factor.

Introduction: Current classifications of low-grade B-cell lymphomas (LGL), including splenic marginal zone lymphomas (SMZL), nodal marginal zone lymphomas (NMZL), and Lymphoplasmacytic lymphomas (LPL) are based on a mixture of clinical features and morphologic, immunophenotypic, and genetic findings from the tumor biopsy specimen. While this approach to classification makes pathologic diagnosis more precise, the corresponding clinical impact for the timing and choice of treatment is limited, and differentiating between cases can be challenging. Although LGL are considered indolent and the 10-year overall survival (OS) is about 80%, 70% of cases will eventually require treatment and approximately 30% of patients display a more aggressive phenotype and have a poor prognosis. Consequently, further investigations into the driving genetic, biological, and immune mechanisms of LGL are essential for early identification of high-risk patients and design of personalized treatments. Materials and Methods: RNA-seq was performed on 63 newly diagnosed LGL patient samples from the Mayo Clinic/University of Iowa Lymphoma SPORE: SMZL (N=48), NMZL (N=6), LPL (N=5), MALT (N=2), and BCL (N=2) as well as 5 normal memory B cell controls (CD19+CD27+). For identification of biologic clusters, filtered RNA-seq data was analyzed using the Non-negative Matrix Factorization (NMF) clustering tool from the Broad Institute against the normal samples. Each cluster was analyzed for differential gene expression. This analysis generated cluster-specific T values for each gene. Genes that were significantly associated with a cluster (FDR<0.05) were analyzed for genetic ontology. Cibersort was used to deconvolute the tumor microenvironment (TME). We performed whole exome sequencing (WES) analyses on 60/63 matched LGL to characterize mutations and copy number alterations. Results: WES revealed the presence of previously reported mutations in genes such as MYD88, SPEN, NOTCH, and KLF2 as well as copy number alterations 7q31.2, BCL6, TNFAIP3, and BCL2. NMF clustering of RNA-seq data resulted in a best fit of 5 clusters, named LGL1 through LGL4 and "Normals". Pathologic subtypes were not exclusive to a specific cluster. Differential RNA expression analysis resulted in gene sets that were differentially expressed in each cluster. A cluster signature of the top 1% of associated genes (N=94) was created for each. LGL1 genes were associated with higher BCR signaling. LGL2 was characterized by regulatory dysfunction, particularly concerning mitochondrial integrity. LGL3 genes were associated with high TME and NOTCH and STAT signaling components. Specifically, LGL3 was associated with high CD8+ T-cell and M2 macrophage TME presence. LGL4 was distinguished by the presence of aggressive genetic programs related to B-cell activation such as NF-kB and IRF4. Consequently, LGL4 patients had significantly poorer rates of event-free survival (EFS) (P=0.029) and OS (P=0.006) when compared against the other groups. The top 1% gene signature (N=94) was next validated against an independent cohort of 84 LGL samples with gene expression data (SMZL [N=34], NZML [N=24], and LPL [N=24]). A similar cluster pattern emerged, with pathological subtypes distributing across LGL classifications based on respective transcriptomic signatures. Association of DNA variants within each cluster was also analyzed, but due to the low frequency of genomic variants detected in LGL, nothing was significantly associated. However, we did see an enrichment of BCL2, BCL6, and TNFAIP3 alterations in LGL4 and an overall lower driver gene mutation frequency in LGL2. Conclusions: Gaining a greater understanding of LGL based on their genetic, biologic, and immune profiles will establish a valuable platform for clinicians to identify high-risk cases and make better therapeutic decisions. Using a large cohort of well-annotated cases we identify novel clusters of LGL that present unique genomic and clinical profiles. Our study lays the groundwork for a precision therapy approach in LGL in which DNA or RNA profiles can be used to identify patients early in treatment who may not benefit from the current standard of care and who would benefit from closer monitoring and targeted agents. Disclosures Anagnostou: American Society of Hematology, Mayo Clinic/Iowa Lymphoma SPORE, Mayo Clinic Immune Monitoring Core, Mayo Clinic Hematology Small Grant: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment. Cerhan:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; NanoString: Research Funding. Novak:Celgene Coorperation: Research Funding.

The Bristow method, an electrical resistivity technique employing a pole‐dipole measurement array in conjunction with a simple graphical method of interpretation, has proven an effective means of locating subsurface cavities. There have been questions, however, regarding the limits of the method and whether the Bristow method is indeed the most suitable of the various electrical resistivity techniques for cavity detection. In hopes of resolving some of the controversy surrounding Bristow’s method, resistivity traverses are numerically modeled over spherical and cylindrical cavities given a variety of circumstances. Using a slight variation of Bristow’s original interpretive technique on modeled data, the size and location of subsurface cavities can be determined with surprising accuracy. However, when the simulation is altered to incorporate geologic noise, the maximum depth at which a cavity can be detected is found to be far less than has been reported in field investigations. In this instance the presence of a cylindrical cavity cannot be discerned beyond a depth to the top approximately equal to the diameter of the cavity, and spherical cavities are indistinguishable at depths much greater than the radius. One should note that the noise field generated for this model may not be representative of what would normally be found in the real earth. In the field, the maximum achievable depth of detection will vary depending on the actual geologic conditions and whether some technique is employed to reduce the effects of noise. In any case, a comparison of traverses using various electrode arrays confirms that the Bristow method is the most satisfactory of the applicable electrical resistivity techniques.

During a period of five years in the mid-1970s, fish were collected at weekly intervals from the Severn Estuary and Bristol Channel. The resultant data on the abundance and lengths of these fish have provided valuable information on the times when the juveniles of several marine species are recruited into the estuary and on their pattern of growth during the first years of life (Claridge & Gardner, 1977; Titmus, Claridge & Potter, 1978; Claridge & Potter, 1983, 1984, 1985; Potter & Claridge, 1985). One of the marine species found in the Severn Estuary for which no seasonal data on density or body size have been presented is the sole, Solea solea (L.), whose relative abundance ranked it amongst the top ten species in two of the five years of our study (Claridge, Potter & Hardisty, 1986).

Brush seals comprised of closely packed fine-diameter wires are an important innovation in seal technology for turbo-machinery. During service, brush seal bristles are subjected to a complex system of forces that are associated with various working loads including—but not limited to—aerodynamic forces, bristle tip∕rotor contact force, and interbristle interactions. The latter interactions are associated with contact forces that are exerted onto a bristle by adjacent fibers, as both forces and displacements are transmitted throughout the fibrous network. Such interbristle contact forces can be represented as uniformly distributed loads along the lateral surface of the fiber, or as applied discrete loads at various locations along the bristle length. In this paper, the role that uniformly distributed interbristle friction force plays in brush seal hysteresis is examined and reported. The origin of this frictional load is attributed to conjugate interbristle shear forces that arise due to compaction and aggregate displacement of the bristle pack during service. This, in turn, gives rise to a uniformly distributed internal micromoment that resists bending deformation. Numerical studies are reported for a brush seal whose bristle tips are subjected to rotor induced loading that is associated with bristle∕rotor interference or eccentric rotation of the shaft. In order to extend the range of applicability of numerical solutions, results are reported in terms of nondimensional brush seal design parameters. Results indicated that interbristle friction force can give rise to a delayed filament displacement as well as an incomplete bending recovery of bristles. The latter phenomenon can inevitably result in hysteretic “gapping,” i.e., the formation of an annular or crescent space between the rotor and bristle tips, thereby increasing vulnerability of the seal to leakage.

Paper deals with in-pipe machine which locomotes inside pipe for inspection purpose otherwise cable drawing into pipes. It uses bristled locomotion based on friction difference principle. The friction between bristle tip and inner pipe wall has anisotropic character. Knowledge of this anisotropic friction is a key to developing and optimizing of in-pipe machine based on this principle.

A five times scale model of an engine brush seal has been manufactured. The bristle stiffness and pressure were chosen to satisfy close similarity of the relevant non-dimensional parameters, and the choice of parameters is described. The comparison of flow characteristics for the model seal and an engine seal confirmed the non-dimensional similarity. Detailed pressure measurements were performed within the bristle pack by employing hollow bristles. This novel measurement allowed insight to be obtained into the operation of both clearance and interference seals. In particular, the measured pressure variation in the region of the bristle tips was significant. The deflection of the bristles was determined by comparing the bristle tip pressures with the static pressures along the shaft. Hence the compaction of the pack in this region was found directly. A numerical modeling of brush seals employing anisotropic flow resistance has been developed. Predictions were compared with the measured pressure distributions within the pack. This enabled sensible selection of the pack resistance distribution to be made. Although uniform anisotropic resistance throughout the pack gave reasonable flow rate characteristics, the pressure distribution was not reproduced. A variation of resistance coefficient consistent with the observed compaction was required to give a solution comparable with the experiments. [S0742-4795(00)01703-8]

The actin bundles in Drosophila bristles run the length of the bristle cell and are accordingly 65 microns (microchaetes) or 400 microns (macrochaetes) in length, depending on the bristle type. Shortly after completion of bristle elongation in pupae, the actin bundles break down as the bristle surface becomes chitinized. The bundles break down in a bizarre way; it is as if each bundle is sawed transversely into pieces that average 3 microns in length. Disassembly of the actin filaments proceeds at the "sawed" surfaces. In all cases, the cuts in adjacent bundles appear in transverse register. From these images, we suspected that each actin bundle is made up of a series of shorter bundles or modules that are attached end-to-end. With fluorescent phalloidin staining and serial thin sections, we show that the modular design is present in nondegenerating bundles. Decoration of the actin filaments in adjacent bundles in the same bristle with subfragment 1 of myosin reveals that the actin filaments in every module have the same polarity. To study how modules form developmentally, we sectioned newly formed and elongating bristles. At the bristle tip are numerous tiny clusters of 6-10 filaments. These clusters become connected together more basally to form filament bundles that are poorly organized, initially, but with time become maximally cross-linked. Additional filaments are then added to the periphery of these organized bundle modules. All these observations make us aware of a new mechanism for the formation and elongation of actin filament bundles, one in which short bundles are assembled and attached end-to-end to other short bundles, as are the vertical girders between the floors of a skyscraper.

Background/methods: Identifying relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) patients (pts) eligible for lower-intensity second-line therapy (SLT) will aid in improving short-term and long-term treatment-related toxicity. We conducted a phase II study evaluating PET-adapted SLT with single-agent brentuximab vedotin (BV) followed by augICE (augmented ifosfamide, carboplatin, etoposide) for BV-naïve patients with RR cHL (Lancet Oncology 2015). In this study, patients who failed 1 line of therapy for cHL were treated with 2 or 3 cycles of BV, 1.2mg/Kg, administered weekly, 3 weeks on and 1 week off. Those who achieved PET-normalization proceeded directly to consolidation with autologous stem cell transplantation (ASCT). Those with persistent abnormalities on PET received 2 cycles of augICE prior to consideration for ASCT. At 3-year follow-up, outcomes for patients who achieved PET-normalization following BV alone or BV followed by augICE were identical. Furthermore, baseline metabolic tumor volume (bMTV) predicted outcome and improved the prognostic significance of pre-ASCT PET (Blood 2017). We now report 6-year follow-up from this study evaluating PET-adapted SLT with BV and augICE. Results: 65 pts enrolled onto this protocol, of whom 18 achieved PET-normalization (Deauville ≤ 2) after single-agent BV. These 18 pts included 8 (44%) with primary refractory disease, 7 (39%) with advanced stage disease, and 8 (44%) with extranodal disease. 17 of the 18 pts proceeded directly to ASCT and 1 pt experienced delay resulting in disease progression. That individual achieved PET-normalization following additional salvage chemotherapy (gemcitabine/vinorelbine/liposomal doxorubicin) and proceeded to ASCT. Of the other 47 pts who remained PET-positive after single-agent BV, 35 achieved PET-normalization after augICE, 9 remained PET-positive after augICE, 2 received no additional treatment before proceeding to ASCT (1 pt with Deauville 3 response to BV, 1 with Deauville 4 response), and 1 pt withdrew consent and was lost to follow-up. 64 of 65 pts proceeded to transplant and median post-ASCT follow-up is 5.98 yrs (range 4.4-7.2 yrs). 6-yr overall survival is 86%, 6-yr progression free survival (PFS) is 73%, and 6-yr time to tumor progression (TTP) is 78%. Overall, there have been 8 deaths, which were due to disease progression (n=5), progressive multifocal leukencephalopathy (PML) (n=1), treatment-related respiratory failure (n=1), and myelodysplastic syndrome (MDS) (n=1). Pts who proceeded to ASCT following single-agent BV achieved durable remission with 6-year TTP of 80%. Outcomes for the BV-only group were similar to those who required BV and augICE to become PET-negative (6-yr TTP 82%) and were more favorable than for those who remained PET-positive after BV and augICE (6-yr TTP 56%, p=0.058) (Figure 1). With 6-yr follow-up, bMTV &gt; 109.5 cm3remained prognostic for the entire group and aided in predicting which pts ultimately developed disease progression. In particular, among the pts who achieved PET-normalization with BV alone prior to ASCT, 6-yr TTP was 92% vs 40% for low and high bMTV respectively, p=0.017 (Figure 2). Similarly, for pts who achieved PET-normalization following BV and augICE, 6-yr TTP was 85% vs 33% for low and high bMTV respectively, p=0.002. Conclusions: For pts with RR cHL, long-term remission can be achieved following lower-intensity SLT with single-agent BV followed by ASCT, provided PET-normalization is achieved after single-agent BV. bMTV identifies which pts within this favorable group are likely to develop disease progression and therefore treatment strategies using bMTV to direct intensity of therapy should be explored. Disclosures Moskowitz: Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Merck: Research Funding; Cell Medica: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Erytech Pharma: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Incyte: Research Funding; Cell Medica: Consultancy; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy. Horwitz:Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Trillium: Research Funding; Miragen: Consultancy; Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Innate Pharma: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Portola: Consultancy; Aileron: Research Funding; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Affimed: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; ADCT Therapeutics: Research Funding; Miragen: Consultancy; ADCT Therapeutics: Research Funding; Kyowa Hakko Kirin: Consultancy; ADCT Therapeutics: Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Consultancy; Astex: Consultancy; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Miragen: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Aileron: Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Astex: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Astex: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Aileron: Research Funding; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Innate Pharma: Consultancy; Trillium: Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Kura: Consultancy; Affimed: Consultancy; Kura: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding. Kumar:Seattle Genetics: Research Funding. Matasar:Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Daiichi Sankyo: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Other: Travel, accommodation, expenses. Noy:Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Janssen: Consultancy; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Palomba:Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights . Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Kyte/Gilead: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding; NexImmune: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy; GSK: Consultancy. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees. Younes:BMS: Research Funding; Syndax: Research Funding; Genentech: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Abbvie: Honoraria; Biopath: Consultancy; Xynomics: Consultancy; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; Takeda: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Research Funding. Zelenetz:MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moskowitz:Merck: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Genentech: Consultancy, Research Funding. OffLabel Disclosure: Brentuximab vedotin is not FDA approved for use in the second-line setting for Hodgkin lymphoma.

This article draws on research designed to explore aspects of social stratification within owner occupation. The research reconstructed and compared the housing, employment and family histories of two groups of home owners in two contrasting localities in Bristol. This article focuses on the top end of the owner occupied market, a neglected area in the sociology of housing, and explores the connections between bargaining power in the labour market and the shaping of housing histories. It is argued that core workers in the labour market exercise choice in the housing market within a framework of job determined constraints. These constraints are accompanied by a range of subsidies and benefits which are unavailable to the majority of households. As a consequence it is suggested that this group's housing histories are shaped by qualitatively distinct processes which go beyond the single fact that their earned incomes are relatively large.

Summary Common burdock (Arctium minus) is a common biennial weed of non-arable land in typical rural settings of Orestiada, Greece. The aim of this study was to describe the basic morphological traits of this species throughout the main phenological stages of its life cycle and to obtain some insight into its growth and productivity in Orestiada. Based on our observations, the plants occurred most commonly in moist and fertile soils, usually as isolated individuals or in small patches near the parent plants. The species is characterized by its large basal ‘elephant-ear’ leaves during the vegetative stage, appearing in alternate arrangement, with irregularly wavy and non-toothed edges, as well as with long hollow stalks forming a noticeable furrow on the top. By monitoring individual plants, it was found that fl owering (in the second year of growth) mostly occurred from late June up to early August. The fl owers were purple, occurring in bristly heads at the top of the stem. The bristly heads formed a fruit, containing small black seeds. The average number of capitula per plant, from randomly selected populations in Orestiada, was found to be 69.7 and 57.7 respectively, whereas the mean seed number per capitulum reached 30.3 and 33.3 seeds, respectively

This article reports on research undertaken to identify Malaysian nurses’ experiences of the part-time Transnational Higher Education post-registration top-up degree programmes delivered by one Australian and two UK universities. An interpretive paradigm and hermeneutic phenomenology and ethnographic principle of cultural interpretation research designs were used. A mixed methods approach was chosen, using both quantitative and qualitative methods. The Bristol Online Survey Questionnaire (BOS) and semi-structured interviews were initially selected to collect data. Pre-pilot testing refined the quantitative and qualitative data collection tools. However, the pilot study for BOS failed to elicit useful responses. This led to only the qualitative methodology being used to elicit participants’ views in a culturally sensitive way. The interview guide allowed nurses’ views of their experiences in relation to the research question to be obtained. This study adds to the knowledge and insight on pre-pilot and pilot studies in international multicultural studies in Asia.

Abstract Introduction: The phase 2 CheckMate 205 study (NCT02181738) of nivolumab (nivo) has demonstrated high objective response rates (ORRs), durable efficacy, prolonged overall survival (OS), and an acceptable safety profile in patients (pts) with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after failure of autologous hematopoietic cell transplantation (auto-HCT) irrespective of prior brentuximab vedotin (BV) treatment (Armand et al, J Clin Oncol 2018). Atypical response patterns have been observed with checkpoint inhibitors, and clinical benefits may be experienced by pts who are treated beyond progression (TBP) as defined by conventional criteria (Cheson et al, Blood 2016; Younes et al, Ann Oncol 2017). Stable reductions in tumor burden without symptoms of active disease were seen in pts TBP in CheckMate 205, suggesting that pts might continue to derive clinical benefits from nivo beyond disease progression. As TBP was an option for some pts in CheckMate 205, we report here updated outcomes of those pts. Methods: This single-arm, multicenter study enrolled pts (age ≥18 y) with R/R cHL after failure of auto-HCT into 3 cohorts (A: BV naïve; B: BV after auto-HCT; C: BV before and/or after auto-HCT). Nivo was administered at 3 mg/kg IV every 2 wk until disease progression or unacceptable toxicity (or after 1 year in complete response [CR] for cohort C). Response was assessed by 2007 International Working Group (IWG) criteria. A protocol amendment allowed pts with stable performance status and perceived clinical benefit to be TBP per investigator assessment. Tumor burden after initial progression was assessed; exploratory analyses included OS and time to next therapy (TTNT). Pts TBP were further categorized as PD-1 resistant (failure to achieve CR/partial response [PR] during initial treatment with nivo or CR/PR with subsequent progressive disease [PD] ≤90 d of response) and non-resistant pts (CR/PR followed by PD >90 d from response). Results: At data cutoff, 130 pts had PD, among whom 80 (62%) were TBP, and 50 (38%) were not (non-TBP). Demographics of pts TBP and non-TBP were similar to the overall study population, although more pts TBP had ECOG performance status of 0 at baseline (59% vs 36%) and stage IV disease at diagnosis (30% vs 22%), but fewer had B symptoms at baseline (23% vs 30%). In pts TBP vs non-TBP, the cause of initial progression was new lesions in 50 (63%) vs 23 (46%), increased total tumor burden in 17 (21%) vs 11 (22%), and non-target lesion progression in 19 (24%) vs 4 (8%) (pts could have multiple reasons for progression). ORR prior to progression was similar between TBP (54%) and non-TBP (64%) pts. At data cutoff, the median (range) doses of nivo given beyond progression was 11 (1-64) and median TBP duration was 5 (95% CI: 3, 7) mo. Nine (11%) pts TBP remained on treatment compared with 2 (4%) non-TBP. The most common reason for discontinuation was further disease progression in 55 (69%) and 28 (56%) pts TBP and non-TBP, respectively. The majority of pts TBP (37/67 evaluable pts) had stable or reduced target lesion tumor burden and most had sustained further reduction compared with the burden presented at the time of disease progression (Figure). There was no discernible difference in the response to TBP between PD-1 resistant vs non-resistant pts. Median OS for pts TBP was not reached; 1- and 2-yr OS (95% CI) was 94% (85, 97) and 87% (77, 93), respectively. Median TTNT was 20 (95% CI: 14, 24) mo for all pts TBP. Treatment-related adverse events (TRAEs) occurred in 50% of pts after progression vs 68% prior to progression. The most common TRAEs reported after progression were fatigue (8%) and increased lipase (6%). Treatment-related serious AEs after progression were reported in 2 (3%) pts: aspartate aminotransferase increase (n=1) and hypercalcemia (n=1). No deaths occurred in pts TBP. Conclusions: Among pts treated beyond investigator-assessed progression, most commonly due to development of new lesions, continued reductions in tumor burden were observed in a majority with further nivo treatment irrespective of prior PD-1 resistance status. Nivo continued to be well tolerated during TBP with no new safety signals. Pts who have stable performance status despite progression according to conventional criteria may derive continued clinical benefit from TBP. Future work will focus on identifying subsets of pts TBP who may benefit the most from continued nivo treatment. Study support: BMS. Disclosures Cohen: Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Leukemia and Lymphoma Society Canada: Research Funding; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria. Ansell:Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding. Younes:Abbvie: Honoraria; J&J: Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Curis: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Takeda: Honoraria; BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Bayer: Honoraria; Celgene: Honoraria; Astra Zeneca: Research Funding; Incyte: Honoraria; Genentech: Research Funding. Trněný:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ramchandren:Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Collins:BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Celgene Corporation: Research Funding; Amgen: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Zinzani:Astra Zeneca: Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Boer:EISA: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shipp:Merck: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bayer: Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sy:Bristol-Myers Squibb: Employment. Armand:Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Infinity: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding.

【Background】Triplet and quadruplet regimens of novel agents have improved the survival of patients with multiple myeloma (MM) and elicited deeper responses to treatment. Minimal residual disease (MRD) negativity is now used as a surrogate marker for longer progression-free survival. However, triplet and quadruplet regimens can cause severe toxicity especially for elderly frail patients and financial toxicity is now an issue. On the other hand, long duration of response is sometimes experienced to low-dose lenalidomide and dexamethasone (Ld) therapy. However, the predictors of long duration of response is unknown. Sustained response without severe toxicity even if not achieving the MRD negativity is beneficial in the treatment choice for some populations like frail elderly patients. Therefore, predicting the long-duration of response could lead to individualized therapy, reducing overtreatment. Here, we hypothesized that the immunomodulatory effects of lenalidomide correlates with a long duration of response. 【Methods】We have previously conducted a prospective trial of Ld therapy in 40 patients with newly diagnosed transplant-ineligible MM. Among them, the time to progression (TTP) was evaluated in 29 patients, excluding patients who discontinued Ld therapy before disease progression. In this study, we evaluated the correlation between immune profile changes and TTP in this study set. Immune profile was evaluated by flow cytometry using peripheral blood mononuclear cells (PBMCs) obtained before and during the first or second cycles of Ld therapy. We evaluated the T cell subset (CD4+ T cells, CD8+ T cells, regulatory T cells) and NK cells and NKT cells and myeloid-derived suppressor cells. Exhaustion markers of PD-1, Tim-3, CTLA-4 and the activation markers of 4-1BB in each lymphocyte subset and memory subset of T cells were evaluated. The cytokine production of granzyme B, IFN-γ, TNF-α and IL-2, was detected by intracellular cytokine staining after 6-h stimulation with phorbol 12-myristate 13-acetate (25 ng/mL) and ionomycin (1 μg/mL) in the presence of the protein transport inhibitor, Golgi stop (BD Bioscience). 【Results】The median age was 75 years old (range, 61-86) at the initiation of Ld therapy. Median TTP was 34 months (range, 1-70). We divided the cases into two groups using the median TTP as a cut-off point (Figure 1). There were no significant differences in baseline characteristics, male to female ratio, performance status, M-protein subtype, creatinine clearance, international staging system (ISS), and high risk cytogenetic profiles between these two subgroups, except for age (median age was 77 years old in subgroups with TTP < 34 months compared to 72 years old, p=0.04). Median initial dosage of lenalidomide was not statistically different (10 mg/day and 15 mg/day in subgroups with TTP < 34months and TTP > 34months, respectively) and dexamethasone dosage was 20 mg/day in both groups. The achievement of best response more than partial response was also comparable in both subgroups (71% and 93% in subgroups of TTP < 34months and TTP > 34months). We compared the immune profile changes in these subgroups. Consequently, we found that mean fluorescence intensity (MFI) ratio of granzyme B expression in NK and NKT cells (before and after Ld therapy) and ΔMFI of granzyme B expression in CD8+ T cells were significantly higher (p<0.05) in longer TTP subgroups (Figure 2). 【Conclusions】Our data suggest that early immune responses during the first or second cycle of Ld therapy could serve as the predictive marker of longer TTP following Ld therapy in patients with NDMM. This could benefit some patients, particularly frail elderly patients by helping them avoid unnecessary intensification of treatment. Disclosures Ikeda: Nippon Shinyaku Research Grant: Research Funding. Nishikawa:Daiichi Sankyo: Research Funding; Zennyaku: Research Funding; Kyowa Hakko Kirin: Research Funding; Taihou Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Ono Pharmaceutical: Research Funding, Speakers Bureau; Chugai Pharmaceuticals: Research Funding, Speakers Bureau; Sysmex: Research Funding; Asahikasei Pharma: Research Funding. Takahashi:Kyowa Hakko Kirin: Research Funding; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Ono Pharmaceutical: Research Funding; Asahi Kasei Pharma: Research Funding; Chug Pharmaceuticals: Research Funding; Eisai Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Research Funding, Speakers Bureau.

Abstract Abstract 890 Purpose: Nilotinib is a highly selective and potent BCR-ABL inhibitor, approved for the treatment of patients with newly diagnosed Ph+ CML in chronic phase (CP) and CML patients who fail imatinib. The long-term clinical outcome of nilotinib therapy in patients with imatinib-resistant or -intolerant CML has been reported recently in a 24-month follow-up. In contrast to imatinib, the cellular uptake of nilotinib is independent of active transporter expression, so that systemic exposure is likely to be more closely related to patient response. The purpose of this analysis is to evaluate the population pharmacokinetics (PK) of nilotinib and its potential relationship to efficacy and safety in patients with imatinib-resistant or -intolerant CML. Methods: A non-linear mixed effects modeling analysis was performed to determine nilotinib PK. Serum-concentration data from 495 CML patients in CP (n=235), accelerated phase (AP, n=135) or blast crisis (BC, n=125) from Ph I and II studies was used. An exposure-efficacy analysis was performed in patients with CML-CP in Ph II, where the steady-state trough concentrations (Cmin) of nilotinib were computed for individual patients, and then correlated to efficacy measures, including CCyR at 12 months, MMR at 12 and 24 months, time to CCyR, time to MMR, and time to progression (TTP). Patients with baseline T315I mutations or those who had dose escalation to nilotinib 600 mg twice daily prior to the efficacy endpoints were excluded from the analysis. Baseline prognostic factors and mutation status that were previously suggested to affect the clinical benefit of nilotinib therapy were also investigated as potential covariates in the exposure-efficacy analysis, according to Akaike Information Criteria (Kantarjian et al, ASH abstract 2009). The prognostic score was defined as follows: 0 when the patient had baseline HGB >120 g/L, baseline basophils < 4% and no insensitive mutation; 1 if the patient did not satisfy one of the criteria; and 2 if the patient did not satisfy 2 of the criteria. The relationship between nilotinib Cmin, UGT genotype, and total bilirubin levels over 24 months was assessed in all patients from Ph I and II studies. Results: Nilotinib PK was found to be similar in patients with CML-CP, -AP or -BC. Patient age, body weight, ethnicity, and racial group did not significantly affect nilotinib PK. Overall, patients with lower nilotinib Cmin (quartile Q1) tended to have lower CCyR at 12 months, lower MMR at 12 and 24 months, longer time to achieve CCyR and MMR, and shorter TTP compared with patients with higher nilotinib Cmin (quartiles Q2-Q4, Table). Logistic regression of CCyR at 12 months and Cox proportional hazard analysis of TTP demonstrated that in addition to nilotinib Cmin, baseline prognostic scores also significantly affected CCyR (57% and 21% for patients with prognostic scores of 0–1 and 2, respectively) and TTP (27.9 and 18.7 months for patients with prognostic scores of 0–1 and 2, respectively). Both nilotinib Cmin and UGT genotype were significantly associated with the occurrence of total bilirubin abnormality (both p<0.1). Patients with nilotinib Cmin in Q1 (<422 ng/ml, n = 122) had a lower incidence of grade 3/4 bilirubin abnormalities (5.7%) than patients with nilotinib Cmin in Q2 ([422,610) ng/mL, n=120, 9.2%), Q3 ([610,842) ng/mL, n=121, 10.9%), and Q4 (>=842 ng/mL, n = 121, 14.1%), respectively. The occurrence of grade 3/4 bilirubin abnormalities was 6%, 12% and 48% for patients with TA(6)/TA(6), TA(6)/TA(7), and TA(7)/TA(7) UGT genotypes, respectively. Conclusion: Patients with lower nilotinib Cmin and higher baseline prognostic risk score showed a higher risk of progression as well as a trend of poorer response. These data suggest that adherence to nilotinib dose in order to maintain sufficient Cmin is important in maximizing the clinical efficacy of nilotinib therapy. Disclosures: Giles: Novartis: Consultancy, Honoraria. Yin:Novartis : Employment, Equity Ownership. Chia:Novartis: Employment, Equity Ownership. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Woodman:Novartis: Employment. Ottmann:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Baccarani:Novartis, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

Introduction Waldenstrom macroglobulinemia (WM) is a rare, incurable, indolent non-Hodgkin lymphoma that is preceded by an IgM monoclonal gammopathy of undetermined significance (IgM MGUS). In recent years, better understanding of the pathobiology of WM and IgM MGUS has strengthened the hypothesis that they may represent different stages of the same disease. Studying the relationship between these two conditions is the essential first step to understanding the mechanisms driving the malignant transformation from IgM MGUS to WM. Recently long non-coding RNAs (lncRNAs) have garnered significant recognition for their roles in the regulation of gene expression and cellular function. lncRNA can regulate gene expression of neighboring protein-coding genes through multiple mechanisms such as by recruiting chromatin modifiers and increasing accessibility of genes to transcription proteins, or by directly binding to enhancers or promoters. Here we present the first analysis of the lncRNA expression profile in patients with WM compared to IgM MGUS. Methods Twenty-one patients with untreated WM (n=14) and IgM MGUS (n=7) seen at Mayo Clinic were included in this analysis. Malignant cells were isolated from bone marrow samples using CD19 and CD38 positive selection. Total RNA was extracted and sequencing was performed using the Illumina HiSeq4000 NGS platform. Differentially expressed lncRNAs in WM compared to IgM MGUS were defined as log2 fold change (FC) > 1.0 (upregulated) or < -1.0 (downregulated) and a false discovery rate (FDR) < 0.05. The nearest gene to each lncRNA was also identified and their gene expression was detected. Using the Ingenuity Pathway Analysis software and taking into account the transcriptional expression and known function of these genes, a correlation between cell function and disease analysis was performed. Results A total of 119 lncRNAs were differently expressed between WM and IgM MGUS (17 transcripts were upregulated in WM, while 102 were downregulated in WM). Sixteen unique genes were identified as the nearest gene to 17 upregulated lncRNAs, while 18 genes were identified as the nearest genes to the top 18 downregulated lncRNAs in WM compared to IgM MGUS. Several of the upregulated lncRNA in WM were in proximity to known oncogenes. The well-known oncogenic lncRNA PVT1 was found to be upregulated in WM compared to IgM MGUS (log2 FC 1.35, FRD 0.04). PVT1 is overexpressed in several malignancies and associated with inhibition of apoptosis and increased cell proliferation. PVT1 is in close proximity to MYC and co-expression of PVT1-MYC has been described in multiple cancers. PVT1 also potentiate MYC amplification by increasing MYC protein stability, therefore promoting malignant cell growth. The lncRNA TCB1D27, also upregulated in WM compared to IgM MGUS, is located in close proximity to the oncogene TNFRSF13B (TACI), which was found to be overexpressed in WM patients (log2 FC 1.61, FDR <0.001). TACI is a receptor for BLyS/BAFF, which modulates the development of normal B-cells and plays a role in various B-cell malignancies. In fact, BLyS/BAFF level is known to be increased in WM and to promote survival and proliferation of WM B cells. The upregulated lncRNA RP11-25K21.1 in WM is located in close proximity to the oncogene FCGR2B (CD32B), which was also upregulated in WM compared to IgM MGUS (log2 FC 1.59, FDR 0.001). Overexpression of CD32B was previously shown to be associated with inferior outcomes in DLBCL and FL patients, presumably secondary to an increased internalization and clearance of rituximab due to increased CD32B expression on malignant cells. Several other upregulated lncRNAs in WM compared to IgM MGUS are also in proximity of other oncogenes such as PCED1B, POLD3, CLLU1, and SMAD7. Finally, we considered the expression of the nearest genes and their reported cell function and association with diseases. Several genes that are known to have a role in the cell proliferation and/or neoplasm development were noted to be upregulated in WM (figure 1). Conclusion We present the first report of lncRNAs expression in WM and IgM MGUS in addition to a concurrent analysis of the gene expression of the nearest protein-coding genes. Several known oncogenes are in proximity of overexpressed lncRNAs in WM compared to IgM MGUS that could indicate potential implications in the pathobiology of these diseases and the mechanism driving the malignant transformation to WM. Disclosures Paludo: Celgene: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding. Dasari:The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Kapoor:Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding. Ailawadhi:Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Celgene: Consultancy. Gertz:Amyloidosis Foundation: Research Funding; i3Health: Other: Development of educational programs and materials; Medscape: Consultancy, Speakers Bureau; Ionis/Akcea: Consultancy; Celgene: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Teva: Speakers Bureau; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Springer Publishing: Patents & Royalties; International Waldenstrom Foundation: Research Funding. Novak:Celgene Coorperation: Research Funding. Ansell:Affimed: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding.

Nowadays, sodium hypochlorite is the irrigant of choice in endodontic therapy because of its characteristics. In the dental practice, the most often used are commercial solutions of different concentrations. The aim of this study was to investigate the possibility of using some home bleach solutions as possible agents for root canal irrigation. Sneznik (Panonija AD Pancevo) and Brekin ( Briskol Chemical Industry Vrsac ) were used as the materials in this study. The presence and concentration of hard metals were detected using atomic absorption spectrophotometry (AAS). The results have shown that the concentration of hard metals in the tested solutions, Sneznik and Berekin, was below maximum allowed concentrations for tap water. Tested solutions could be recommended for root canal irrigation but only after hard metal concentration is checked.

A new genus and six new species of nematodes (Ungellidae, Drilonematoidea) parasitic in earthworms deposited in the Muséum National d’Histoire Naturelle, Paris, are described. Except for Ungella haitiana sp. n., all nematodes were found in West African oligochaetes. Chabaudigella perforata gen. n., sp. n. is distinguished by having a single row of minute pores on each lateral chord, cephalic hooks in a subdorsal pit with cuticularised rims, excretory pore opposite pharyngeal base, post-uterine sac, pouch-like vagina, short, non-cephalate spicules, and bristle-like male caudal sensilla. Ungella haitiana sp. n. is distinguished by presence of large pocket-like amphids, excretory pore posterior to isthmus, slim pharynx, female body posteriorly expanded, ovary tip in tail, vulva post-median, asymmetrical caudal organs, long spicules; U. millsoniae sp. n. by its small size, indistinct amphids, excretory pore posterior to pharynx base, ovary tip posterior to mid-body, distal ovary portion reflexed, female caudal organs large, with cavity, spicules strongly bent; U. agastrodrilii sp. n. by cephalic hooks in subdorsal pit, male with swollen body, short conical tail and symmetrical caudal organs situated shortly posterior to anus. Ungella barbaulti sp. n. is distinguished by its small size, short and thin cephalic hooks, large amphids, vulva median, post-uterine sac absent, and short spicules; U. lamto sp. n. by its small size; cephalic hooks in subdorsal pit, indistinct amphids; post-uterine sac absent, ovary tip between vulva and anus, median vulva, oblique vagina, caudal organs prominent, spicules short, broadly cephalate, precloacal supplement and bristle-like male caudal sensilla present. Keys to genera of Ungellinae and Ungella are given.

Impatiens guiqingensis S. X. Yu (Balsaminaceae), a new species from Gansu Province, China, is described and illustrated. The new species is superficially similar to I. dicentra in having 1–2 flowered racemose inflorescences, lateral sepals with dentate margin, top of lower and upper petals of lateral united petals with bristle appendages, but differs from the latter by yellow flower, lower sepal without spur and dorsal petal with unapparent crest. Moreover, the occurrence of the new species is also different from the related one.

Sharing data openly has become a straightforward process at the University of Bristol. The University’s top funders mandate or recommend data sharing as a condition of funding, and many publishers require access to research data to enable results of published articles to be verified. The University has provided a dedicated data repository to support this since 2015, and demand for open publication has risen steadily since its inception. However, an increasing number of requests for sharing data relate to data that has ethical, legal or commercial sensitivities and so cannot be published openly. Rather than discuss the wide-ranging ethical implications of data sharing, this practice paper will focus on the secure sharing of sensitive data that has ethical approval and, where required, has the necessary consent in place, from the perspective of an institution that has already decided to undertake the work inherent in sharing sensitive data. The specific purpose is to detail the workflow and administrative tasks integral in this and to highlight the types of challenges encountered.

Awns are bristle‐like structures, typically extending from the tip end of the lemmas in the florets of cereal species, including such economically important crops as wheat (Triticum aestivum L., T. durum Desf.), barley (Hordeum vulgare L.), rice (Oryza sativa L.), and rye (Secale cereale L.). The presence of long awns adhered at tip end of glumes is a characteristic feature of “Persian wheat” T. carthlicum Nevski spike. Glume outgrowth of T. carthlicum Nevski spike passes into a long awn, equal in length to the lemma awn. Awned glumes can be formed in T. aestivum and T. aethiopicum wheats, however, such forms are rare. Features of the awned glume development and the genetic determinants of this trait have been little studied. In this paper, we described the features of the development and inheritance of the tetra-awness (awned glume) trait of the bread wheat T. aestivum line CD 1167-8, using classical genetic analysis, molecular genetic mapping, and scanning electron microscopy. It was shown that the trait is inherited as a recessive monogenic. The gene for the awned glume trait of CD 1167-8 was mapped in the long arm of chromosome 5A, using the Illumina Infinium 15K Wheat Array (TraitGenetics GmbH), containing 15,000 SNPs associated with wheat genes. Results of allelism test and molecular-genetic mapping suggest that the gene for awned glumes in bread wheat is a recessive allele of the B1 awn suppressor. This new allele was designated the b1.ag (b1. awned glume). Analysis of the CD 1167-8 inflorescence development, using scanning electron microscopy, showed that awns had grown from the top of the lemmas and glumes simultaneously, and no differences in patterns of their development were found.

Background:In the phase 3 double-blind SELECT-CHOICE study of patients (pts) with prior inadequate response (IR) or intolerance to biologic disease-modifying antirheumatic drugs (bDMARDs), upadacitinib (UPA) showed superiority to abatacept (ABA) in change from baseline in 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) and in the proportion of pts achieving DAS28(CRP) <2.6 at Week 12.Objectives:To describe clinical responses in pts receiving UPA or ABA by number and mechanism of action of prior bDMARDs.Methods:612 pts were randomized to once-daily UPA 15 mg or monthly intravenous ABA (<60 kg, 500 mg; 60–100 kg, 750 mg; >100 kg, 1000 mg). All pts continued background therapy with stable conventional synthetic DMARDs. From Week 12, pts who did not achieve ≥20% improvement in both tender and swollen joint counts vs baseline at 2 consecutive visits had background medication(s) adjusted or added. In this post hoc analysis, pts were grouped by the number and/or type of bDMARD received prior to enrollment: 1) lack of efficacy (LoE) to ≥1 tumor necrosis factor (TNF) inhibitor; 2) LoE to ≥1 interleukin-6 (IL-6) inhibitor; 3) intolerance to prior bDMARDs; 4) number of prior bDMARDs (1, 2, or ≥3). Mean change from baseline in DAS28(CRP) and DAS28(CRP) <2.6 and other clinical endpoints were evaluated at Weeks 12/24.Results:Most pts had LoE to ≥1 TNF inhibitor (536, 87.6%); 96 (15.7%) had LoE to an IL-6 inhibitor; 79 (12.9%) had intolerance to prior bDMARDs; 408 (66.7%), 134 (21.9%), and 64 (10.5%) had received 1, 2, or ≥3 prior bDMARDs, respectively. Mean change from baseline in DAS28(CRP) was generally greater with UPA vs ABA across the different pt subgroups at Weeks 12/24 (Figure 1). Across endpoints, regardless of prior bDMARD therapy (except in those who failed ≥3 prior bDMARDs), UPA and ABA demonstrated similar responses at Week 12 compared with those observed for the overall treatment groups, even with more stringent criteria such as ACR70 and Clinical Disease Activity Index (CDAI) ≤2.8 (Table 1. below) Responses at Week 24 followed a similar trend to those at Week 12 for DAS28(CRP) <2.6 and other endpoints (Table 1). The safety profile across subgroups was consistent with each respective treatment in the overall study population (data not shown).Table 1.Efficacy endpoints by prior bDMARD subgroup (Week 12 [top] and Week 24 [bottom])aACR20ACR50ACR70DAS28(CRP)≤3.2DAS28(CRP) <2.6CDAI ≤10CDAI ≤2.8HAQ-DIMCIDbLoE to ≥1 TNF inhibitorUPA 15 mg n=26375.377.944.959.722.838.849.061.230.446.840.758.69.122.875.574.3ABAn=27364.572.933.748.413.224.927.546.512.529.733.749.82.212.565.266.3LoE to ≥1 IL-6 inhibitorUPA 15 mg n=4870.885.437.566.720.829.245.866.725.041.741.758.36.316.778.378.3ABAn=4877.179.241.756.322.927.125.043.814.629.227.152.12.110.475.075.0Intolerance to prior bDMARDsUPA 15 mgn=4783.076.653.257.417.027.753.257.431.929.844.744.78.514.980.073.3ABAn=3262.571.928.150.00.031.321.956.36.331.321.956.33.19.461.367.71 priorbDMARDUPA 15 mgn=20677.281.151.963.121.838.852.466.032.547.641.761.29.220.979.676.6ABAn=20267.377.735.153.515.833.729.251.512.435.636.155.93.016.366.771.72 priorbDMARDsUPA 15 mgn=6478.176.634.456.323.439.151.662.526.650.045.354.74.723.473.870.5ABAn=7064.364.328.642.94.311.427.141.411.424.328.644.31.48.655.755.7≥3 prior bDMARDsUPA 15 mg n=2955.265.524.144.817.224.127.641.420.727.627.648.310.317.258.672.4ABAn=3565.771.440.040.020.017.128.637.120.020.037.140.02.98.677.174.3aMissing information was imputed using NRI. bHAQ-DI MCID=reduction from baseline of ≥0.22ACR20/50/70, 20/50/70% improvement in ACR criteria; HAQ-DI, Health Assessment Questionnaire-Disability IndexConclusion:Although sample sizes were small for some subgroups, treatment with UPA led to greater clinical responses vs ABA at Week 12, including in pts with LoE to TNF or IL-6 inhibitors, and those with IR or intolerance to 1, 2, or ≥3 prior bDMARDs.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Grant Kirkpatrick, MSc of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Andrea Rubbert-Roth Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Gilead, Janssen, Novartis, Roche, and Sanofi, Ricardo Xavier Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Boulos Haraoui Consultant of: AbbVie, Amgen, Eli Lilly, Gilead, MSD, Pfizer, Sandoz, and UCB, Herbert S.B. Baraf Consultant of: Gilead, Janssen, and UCB, Grant/research support from: AbbVie, Eli Lilly, Genentech, Gilead, and Janssen, Maureen Rischmueller Consultant of: AbbVie, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Gilead, Janssen, Pfizer, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, and UCB, Naomi Martin Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jessica Suboticki Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, John Cush Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, and Novartis.

BackgroundGypsies, Travellers and Roma (referred to as Travellers) are less likely to access health services, including immunisation. To improve immunisation rates, we need to understand what helps and hinders individuals in these communities in taking up immunisations.Aims(1) Investigate the barriers to and facilitators of acceptability and uptake of immunisations among six Traveller communities across four UK cities; and (2) identify possible interventions to increase uptake of immunisations in these Traveller communities that could be tested in a subsequent feasibility study.MethodsThree-phase qualitative study underpinned by the social ecological model. Phase 1: interviews with 174 Travellers from six communities: Romanian Roma (Bristol); English Gypsy/Irish Traveller (Bristol); English Gypsy (York); Romanian/Slovakian Roma (Glasgow); Scottish Showpeople (Glasgow); and Irish Traveller (London). Focus on childhood and adult vaccines. Phase 2: interviews with 39 service providers. Data were analysed using the framework approach. Interventions were identified using a modified intervention mapping approach. Phase 3: 51 Travellers and 25 service providers attended workshops and produced a prioritised list of potentially acceptable and feasible interventions.ResultsThere were many common accounts of barriers and facilitators across communities, particularly across the English-speaking communities. Scottish Showpeople were the most similar to the general population. Roma communities experienced additional barriers of language and being in a new country. Men, women and service providers described similar barriers and facilitators. There was widespread acceptance of childhood and adult immunisation, with current parents perceived as more positive than their elders. A minority of English-speaking Travellers worried about multiple/combined childhood vaccines, adult flu and whooping cough. Cultural concerns about vaccines offered during pregnancy and about human papillomavirus were most evident in the Bristol English Gypsy/Irish Traveller community. Language, literacy, discrimination, poor school attendance, poverty and housing were identified by Travellers and service providers as barriers for some. Trustful relationships with health professionals were important and continuity of care was valued. A few English-speaking Travellers described problems of booking and attending for immunisation. Service providers tailored their approach to Travellers, particularly the Roma. Funding cuts, NHS reforms and poor monitoring challenged their work. Five ‘top-priority’ interventions were agreed across communities and service providers to improve the immunisation among Travellers who are housed or settled on an authorised site: (1) cultural competence training for health professionals and frontline staff; (2) identification of Travellers in health records to tailor support and monitor uptake; (3) provision of a named frontline person in general practitioner practices to provide respectful and supportive service; (4) flexible and diverse systems for booking appointments, recall and reminders; and (5) protected funding for health visitors specialising in Traveller health, including immunisation.LimitationsNo Travellers living on the roadside or on unofficial encampments were interviewed. We should exert caution in generalising to these groups.Future workTo include development, implementation and evaluation of a national policy plan (and practice guidance plan) to promote the uptake of immunisation among Traveller communities.Study registrationCurrent Controlled Trials ISRCTN20019630 and UK Clinical Research Network Portfolio number 15182.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 72. See the NIHR Journals Library website for further project information.

THIS article takes a fresh look at the test for inducement of the insurer where there can be said to have been non-disclosure of a material fact by the insured. Specifically, the article questions the assumption that the test for inducement of the actual insurer operates in precisely the same way as it does under the general law of contract in misrepresentation. The speeches of the majority of the House of Lords in Pan Atlantic v. Pine Top (1995) appear to make no distinction between the operation of these concepts. Yet two recent Court of Appeal decisions (Downs v. Chappell; Bristol and West Building Society v. Mothew – both reported in 1997) would seem to suggest that there is a distinction to be made. The conclusion reached in this article is that evidence of actual inducement of the insurer in the sense of evidence that he would have refused to take the risk or would have taken it only on other terms is necessary when the case is put on the basis of “pure” non-disclosure. Where, in contrast, the case is properly framed in misrepresentation the insurer need only show that he acted in reliance or was induced to act by the representations actually made.

Critical commentaries have often treated the smart city as a potentially problematic ‘top down’ tendency within policy-making and urban planning, which appears to serve the interests of already powerful corporate and political actors. This article, however, positions the smart city as significant in its implicit rejection of the strong normativity of traditional technologies of planning, in favour of an ontology of efficiency and emergence. It explores a series of prominent UK smart city initiatives (in Bristol, Manchester and Milton Keynes) as bundles of experimental local practices, drawing on the literature pointing to a growing valorisation of the ‘experimental’ over strong policy commitments in urban governance. It departs from this literature, however, by reading contemporary ‘smart experiments’ through Shapin and Schafer’s work on the emergence of 17th-century science, to advance a transhistorical understanding of experimentation as oriented towards societal reordering. From this perspective, the UK smart city merits attention primarily as an indicator of a wider set of shifts in approaches to governance. Its pragmatic orientation sits uneasily alongside ambitions to ‘standardise’ smart and sustainable urban development; and raises questions about the conscious overlap between the stated practical ambitions of smart city initiatives and pre-existing environmental and social policies.

Actin filament bundles can shape cellular extensions into dramatically different forms. We examined cytoskeleton formation during wing hair morphogenesis using both confocal and electron microscopy. Hairs elongate with linear kinetics (∼1 μm/h) over the course of ∼18 h. The resulting structure is vividly asymmetric and shaped like a rose thorn—elongated in the distal direction, curved in two dimensions with an oval base and a round tip. High-resolution analysis shows that the cytoskeleton forms from microvilli-like pimples that project actin filaments into the cytoplasm. These filaments become cross-linked into bundles by the sequential use of three cross-bridges: villin, forked and fascin. Genetic loss of each cross-bridge affects cell shape. Filament bundles associate together, with no lateral membrane attachments, into a cone of overlapping bundles that matures into an oval base by the asymmetric addition of bundles on the distal side. In contrast, the long bristle cell extension is supported by equally long (up to 400 μm) filament bundles assembled together by end-to-end grafting of shorter modules. Thus, bristle and hair cells use microvilli and cross-bridges to generate the common raw material of actin filament bundles but employ different strategies to assemble these into vastly different shapes.

Background:The eRA (evolving the management of RA) programme was initiated in Europe to provide practical educational tools that address unmet needs in the management of rheumatoid arthritis (RA). Several eRA tools – covering early access to care, management of comorbidities, treat-to-target strategies, and patient empowerment – are available to the rheumatology community. Through ongoing activities, the eRA Steering Committee (SC) identified a need for tools on non-pharmacological management of RA.Objectives:To improve accessibility to eRA tools for rheumatology professionals; to review the evidence base of non-pharmacological interventions to create new eRA resources that may support management decisions.Methods:A web platform providing information on eRA programme and tools was developed in 2019. The platform collects survey-based metrics to quantify perception of eRA and use of eRA tools in clinical practice. Platform and tools are translated to further support access and use across Europe.To address unmet needs in non-pharmacological patient management, the eRA SC reviewed the core literature on agreed priority interventions, including physical activity, diet, patient education and self-management, psychosocial interventions, occupational therapy and orthotics, hand exercises, and hydrotherapy/balneotherapy. Available evidence for each intervention was assessed and graded according to the Oxford Centre for Evidence-based Medicine Levels of Evidence.Results:The eRA web platform is now live in 3 countries (www.evolvingthemanagementofRA.com), hosting translated copies of the eRA tools, with additional countries launching throughout 2020.From a review of core literature on non-pharmacological interventions, the eRA SC determined that strong evidence exists to support use of physical activity, patient education and self-management, psychosocial interventions, and occupational therapy and orthotics. Evidence was lacking or conflicting for diet and nutrition, hand exercises, and balneotherapy/hydrotherapy. A set of educational slides was produced by the eRA SC to summarise the evidence (Fig. 1) and provide top-line guidance on use of interventions in practice that should engage relevant members of the multi-disciplinary team. These slides are available through eRA dissemination activities.Conclusion:The eRA programme content is now freely available to health care professionals in several countries on a web platform, supported by translations of the eRA tools. An additional slide set on non-pharmacological management serves to further increase the practical guidance of this programme’s educational offering.Acknowledgments:The eRA programme is funded by Sanofi Genzyme. Programme direction and content creation are driven by an independent Steering CommitteeDisclosure of Interests:Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Jose-Maria Alvaro-Gracia Grant/research support from: Abbvie, Elli-Lilly, MSD, Novartis, Pfizer, Consultant of: Abbvie, BMS, Janssen-Cilag, Elli-Lilly, MSD, Novartis, Pfizer, Sanofi, Tigenix, Roche, UCB, Paid instructor for: Elli-Lilly, Pfizer, Roche, Speakers bureau: Abbvie, BMS, Janssen-Cilag, Elli-Lilly, Gedeon Richter, MSD, Novartis, Pfizer, Sanofi, Tigenix, Roche, UCB, Neil Betteridge Consultant of: Amgen, Eli Lilly and Company, Grunenthal, GSK, Sanofi Genzyme, Jaime Calvo Grant/research support from: Lilly, UCB, Consultant of: Abbvie, Jansen, Celgene, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Patrick Durez Speakers bureau: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Pfizer, Sanofi, Ricardo J. O. Ferreira Grant/research support from: Abbvie, Consultant of: Sanofi Genzyme, Amgen, MSD, Paid instructor for: UCB, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Annamaria Iagnocco Grant/research support from: Abbvie, MSD and Alfasigma, Consultant of: AbbVie, Abiogen, Alfasigma, Biogen, BMS, Celgene, Eli-Lilly, Janssen, MSD, Novartis, Sanofi and Sanofi Genzyme, Speakers bureau: AbbVie, Alfasigma, BMS, Eli-Lilly, Janssen, MSD, Novartis, Sanofi, Carlomaurizio Montecucco: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Sofia Ramiro Grant/research support from: MSD, Consultant of: Abbvie, Lilly, Novartis, Sanofi Genzyme, Speakers bureau: Lilly, MSD, Novartis, Andrea Rubbert-Roth Consultant of: Abbvie, BMS, Chugai, Pfizer, Roche, Janssen, Lilly, Sanofi, Amgen, Novartis, Tanja Stamm Grant/research support from: AbbVie, Roche, Consultant of: AbbVie, Sanofi Genzyme, Speakers bureau: AbbVie, Roche, Sanofi, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Mart van de Laar Consultant of: Sanofi Genzyme, Speakers bureau: Sanofi Genzyme

Background: Ankyloglossia is an anatomical alteration of the frenulum length, volume, compactness, and insertion. It can lead to alterations in the ability to swallow and chewing, and dysfunctional coordination amongst cranio-facial muscles; these alterations are often responsible for respiratory alterations, skeletal malocclusions and dyslalia or the delay of speech. The aim of this study is to estimate the efficacy of lingual frenulectomy with diode-laser technology through a qualitative and quantitative evaluation. Methods: One hundred and twenty-five pediatric patients were recruited: 100 with a lingual pathological frenulum were randomly divided into four operating groups; the other 25 with a borderline pathological frenulum were recruited as a control group. Each patient was included in a follow-up program (T0-T1-T2-T3-T4) for a quantitative and qualitative evaluation: the first through an accurate measurement of Kotlow’s free tongue measurement (≥16), Mouth Opening with Tongue Tip to incisive papilla (MOTTIP), Maximal Intercisal Mouth Opening (MIO) and Protrusion; and the second using the Assessment Tool for Lingual Frenulum Function (ATLFF), Bristol Tongue Assessment Tool (BTAT), and grade of tongue functionality. Results: The increase of the aforementioned quantitative parameters was circa 10 mm, and all patients reacquired full functionality of the tongue. Conclusions: Diode-laser technology is efficient and innovative in the treatment of pathological lingual frenulums.