Journal articles: 'Warren Grant' – Grafiati (2024)

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Since 1988, efforts have been underway to establish a nursery research station in McMinnville, Warren County, Tennessee. Approximately 80 acres of farm property adjacent to the Collins scenic river has been conveyed to Tennessee State University (TSU) for this purpose. Scientists at TSU, Tennessee Technological University, University of Tennessee, and USDA's National Arboretum and Shade Tree Laboratory have cooperated in obtaining grant funds via the Capacity Building Grants Program to initiate a plant evaluation and introduction program. Replicated trials of woody genera include Acer, Castanea, Cornus, Lagerstroemia, Quercus, Syringa, Ulmus. Herbaceous genera are Echinacea, Hemerocallis, Hosta. Plantings will be made over a three year period as infrastructure at the new station develops. Additional grant proposals have been recently submitted.

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SummaryMental health and substance use disorders are the leading cause of long-term disability and a cause of significant mortality, worldwide. However, it is widely recognised that clinical practice in psychiatry has not fundamentally changed for over half a century. The Royal College of Psychiatrists is reviewing its trainee curriculum to identify neuroscience that relates to psychiatric practice. To date though, neuroscience has had very little impact on routine clinical practice. We discuss how a pragmatic approach to neuroscience can address this problem together with a route to implementation in National Health Service care. This has implications for altered funding priorities and training future psychiatrists. Five training recommendations for psychiatrists are identified.Declaration of interestJ.D.S. receives direct funding from MRC Program Grant MR/S010351/1 aimed at developing machine learning-based methods for routinely acquired NHS data and indirect funding from the Wellcome Trust STRADL study. M.P.P. receives payments for an UpToDate chapter on methamphetamine and is principal investigator on the following grants: NIGMS P20GM121312 and NIDA U01 DA041089 and receives support from the William K. Warren Foundation.

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While enrollment is dropping in many commodity-based curriculums, one key program area of interest to many students is sustainable agriculture. Some land-grant universities are initiating undergraduate and graduate programs, or concentrations in Sustainable Agriculture, to meet this student demand. Many smaller colleges (for example, Delaware Valley College, Slippery Rock Univ., and Warren Wilson College) are also offering a focus in this area as well. These programs often include an experiential learning component through internships and other hands-on activities. Examples of some of the courses being offered include Principles and Practices of Sustainable Agriculture, Agricultural Ecosystems, Sustainable Agriculture Processes in Plant Horticulture and Animal Husbandry, and Fertility Considerations in Regenerative Agriculture. In this presentation, I summarize ongoing programs nationwide, and discuss the impact these programs are having on student enrollment.

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In October 1912 the first issue of Harriet Monroe's new journal, Poetry: A magazine of verse, appeared. The last has yet to come. In an era when little magazines came and went like mayflies, Poetry came and has refused to go. The journal had it all—in its early years it was at the forefront of debates about imagism, vers libre, and other issues concerning the “proper” form and content for poetry. Monroe, its editor, is still insufficiently appreciated as a major figure in literary modernism. We hope to change that. Supported by a grant from the National Endowment for the Humanities, the Modernist Journals Project (MJP) has completed a digital edition of the first eleven years of this distinguished journal, using original copies provided by the University of Chicago Library, supplemented in some instances by copies from the University of Wisconsin, Madison, and the University of Tulsa's McFarlin Library. Those of us working on this edition have discovered many interesting things, including the first publication of Joyce Kilmer's “Trees,” which Cleanth Brooks and Robert Penn Warren later used as the primary example of bad poetry in their New Critical textbook, Understanding Poetry (274–78).

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Background:IgA vasculitis (IgAV) in children is considered a mostly self-limiting disease. However, patients may require aggressive initial treatment, are prone to disease relapses and conceivably have a sustained abnormality in mucosal and /or circulating IgA responsiveness, that can predispose to the development of other conditions.Objectives:To determine whether childhood IgAV predisposes to comorbidity later in life.Methods:Observational cohort study examining rates of hospitalization, ED visits, procedures and accrual of comorbidity (by Charlson comorbidity index; CCI) comparing 494 IgAV patients <20 years at diagnosis with 1385 non-exposed matched controls over a 20-year period. Maximum likelihood estimates were used to obtain Odds (OR) and Rate ratios per 1000 person-years (RR).Results:Hospitalization was increased proportionally (73.5 vs 51.5%) and by rate (21.7 vs 18.9; rate ratio 1.15) (both p<0.01) for IgAV patients, who underwent more diagnostic and medical procedures whereas controls had higher rates of surgical interventions. IgAV patients had an higher overall ED attendance (25 vs 16%) and visit rate (10.8 vs 8.43, RR 1.29) (each p<0.01)) and accrued more often peptic ulcer and renal disease and developed severe comorbidity (CCI ≥3) at a higher rate (OR 2.9, 95% CI 0.79-11.6) than controls.Conclusion:A diagnosis of IgAV in childhood associates with increased risk and rate of subsequent hospital admission, ED attendance and severe comorbidity. The occurrence of childhood IgAV thus signifies the presence of a sustained predisposition to illness.Acknowledgments:Supported by an unrestricted grant from the Arthritis Foundation of Western AustraliaDisclosure of Interests:Johannes (“Hans”) Nossent Speakers bureau: Janssen, warren raymond: None declared, milica ognjenivic: None declared, Helen Keen Speakers bureau: Pfizer Austrlaia, Abbvie Australia, David Preen: None declared, Charles Inderjeeth Grant/research support from: UCB Australia, Speakers bureau: Eli Lilly

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Background:A significant proportion of patients with rheumatoid arthritis (RA) have additional considerations that must be taken into account for managing their disease.1These include; co-morbidities, extra-articular manifestations and poor prognostic factors.2-5Tailored management could reduce the burden on patients, the health system and wider society.The ‘complex’ RA patient group is ill-defined and no specific recommendations exist for their optimal management and treatment.Objectives:A group of UK Rheumatology experts aimed to provide a set of recommendations to support consistent and high quality management, grounded in current evidence, expert opinion and best practice.Methods:A steering group meeting identified priority topics associated with complex RA.Table 1.Topics for consensusTopicNo. of statementsDefinition of ‘complex’ RA from a medical perspective19Definition of patient factors that may contribute to ‘complex’ RA3Outcomes for RA patients with co-morbidities and/or extra articular manifestations5Prescribing options for ‘complex’ RA8Evidence vs. best practice requirements4Burden of ‘complex’ RA4TOTAL NUMBER OF STATEMENTS43For each topic, the group defined statements they all agreed with. Delphi methodology was used to ratify these statements with rheumatology peers.High levels of agreement (over 70%) were achieved in the first round, the group proceeded to formulate the recommendations.Figure 1.Responses received (n=163)Figure 2.Consensus Plot (total responses n=163)Conclusion:These recommendations are offered:Healthcare professionals (HCPs) should consider a patient’s complexity (including clinical co-morbidities, extra-articular manifestations and poor prognostic factors) prior to making treatment decisions;HCPs should take into account a patient’s psychosocial factors and health literacy prior to making treatment decisions;Patient specific outcomes for complex RA should always be proactively agreed with the individual and/or their carers;The local healthcare system should consider the overall costs of complex RA, beyond drug acquisition costs to allow flexibility of prescribing choices, as necessary in this group of patients;Local treatment pathways should reflect that treatments with particular modes of action are more suitable for individual patients with complex RA.Management of complex RA patients should extend beyond guidelines and recognise additional sources of evidence including; clinical studies, Real World Experience (RWE) and post-marketing surveillance.References:[1]Uhlig T, Moe RH, Kvien TK. The burden of disease in rheumatoid arthritis. Pharmacoeconomics 2014;32:841–51[2]Dougados M, et al. Ann Rheum Dis 2014;73:62–68.[3]Parodi M et al,Rheumatism, 2005, 57(3): 154-60.[4]Young A & Koduri G. Best Pract Res Clin Rheumatol. 2007 Oct;21(5):907-27.[5]Holroyd CR, et al. Rheumatology 2019;58:e3-e42Acknowledgments:Support for medical writing/editorial assistance, provided by Tim Warren at Triducive was funded by Roche Products Ltd. & Chugai Pharma Ltd. in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).Disclosure of Interests:Gurdeep Dulay Grant/research support from: Educational grants to attend congress meetings/conferences from Roche, Chugai, UCB, Internis, Pfizer, Lilly, Sandoz, Consultant of: Honoraria for advisory board services from Roche, Chugai, Novartis, Speakers bureau: Speaker fees from Roche, Chugai, Novartis, Amgen, Lilly, Sandoz, Ernest Choy Grant/research support from: Amgen, Bio-Cancer, Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Roche, UCB, Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmaceuticals, GlaxoSmithKline, Hospita, Ionis, Janssen, Jazz Pharmaceuticals, MedImmune, Merck Sharp & Dohme, Merrimack Pharmaceutical, Napp, Novartis, Novimmune, ObsEva, Pfizer, R-Pharm, Regeneron Pharmaceuticals, Inc., Roche, SynAct Pharma, Sanofi Genzyme, Tonix, UCB, Speakers bureau: Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly, Hospira, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Sanofi-Aventis, UCB, Theresa Barnes Consultant of: Ad boards for Roche, Actelion and Abbvie, Speakers bureau: Speaker for MSD, UCB, Pfizer, Abbvie, Actelion, Roche and BMS, Debbie Chagadama Consultant of: Roche, Chugai, BI, Speakers bureau: Roche, Chugai, BI, Zoe Cole Consultant of: Consultancy work for Roche, Lilly, Gilead, Abbvie, Pfizer, UCB, Speakers bureau: Lilly, BMS, Abbvie, Pfizer, UCB, Janssen, Anshuman Malaviya Consultant of: Roche, Chugai, MSD, Pfizer, Novartis, Lily, BMS, Speakers bureau: Roche, BMS, Pfizer, MSD, Sandra Robinson Consultant of: Eli Lilly for Education Nurse Meeting, David Walker Grant/research support from: Gilead, Consultant of: Gilead, Lilly, Pfizer, Roche, Speakers bureau: Lilly, Pfizer, Roche, Chris Daly Employee of: Roche, Nicola Savill Employee of: Roche, Tim Warren Consultant of: Roche, Employee of: AstraZeneca, Nick Williams Shareholder of: MSD, Consultant of: Roche, Employee of: MSD

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Abstract Background PSA with MDR and XDR are a growing threat, and appropriate initial treatment of this organism is critical. C/T is a novel antibiotic with broad gram-negative in vitro susceptibility among surveillance studies. However comprehensive susceptibility analyses of C/T among PSA clinical isolates in comparison with other anti-PSA antibiotics remain limited, since routine clinical C/T susceptibility testing is not typically performed. Methods This study assessed all adult inpatient cultures positive for PSA from 32 months at an academic health system. Antimicrobial susceptibility was prospectively performed using Kirby Bower disk diffusion and interpreted by BIOMIC V3 during routine clinical care. Initial susceptibility testing included C/T along with amikacin, aztreonam, cefepime, ciprofloxacin, doripenem, gentamicin, imipenem, meropenem, piperacillin/tazobactam, and tobramycin. MDR and XDR isolates were identified using established definitions. The primary outcome was to quantify C/T resistant PSA (includes intermediate and resistant strains). Secondary outcomes were to determine resistance to other anti-PSA antibiotics and to identify C/T activity among isolates with MDR, XDR and pan-β-lactam resistance (PBLR = all β-lactams except C/T). Results A total of 2990 PSA isolates from 2339 cultures in 1311 individual patients were collected. Most cultures were from the lung (45%), followed by urine (30%), and body fluids (10%). For the primary outcome, 121/2990 (4%) of PSA isolates were C/T resistant. All PSA blood cultures were susceptible to C/T. Table 1 summarizes in vitro activity of all anti-PSA agents evaluated. C/T had the greatest percent susceptibility across all culture locations including MDR/XDR PSA isolates with median MICs of 8 µg/mL. For PBLR strains 35/66 (53%) were susceptible to C/T with a median MIC of 8 µg/mL. Table 1 Conclusion C/T susceptibility testing during routine care over a 2.5-year period revealed 96% susceptibility among PSA. C/T showed the highest susceptibility among all anti-PSA antibiotics for all culture locations and for MDR and XDR isolates. Given the high rates of resistance to traditional anti-PSA agents, the value of new agents with high rates of in vitro susceptibility in the gram-negative armamentarium is high. Disclosures Warren Rose, PharmD, MPH, Merck (Grant/Research Support)Paratek (Grant/Research Support) Janet Radaatz, PharmD, Merck (Employee) Laura A. Puzniak, PhD, Merck (Employee) Ryan J. Dillon, MSc, Merck & Co., Inc., (Employee)

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Abstract Background MSSA Infective endocarditis (IE) is inherently a high-burden infection with up to a 30% mortality rate. Cefazolin is an appealing treatment option for IE with low toxicity and a favorable dosing scheme. However, cefazolin has been associated with treatment failure in IE, attributed to an inoculum effect. The specific mechanism underlying the cefazolin inoculum effect (CIE) remains undetermined, but CIE has been linked to both blaZ expression and agr dysfunction. This study aims to determine whether CIE is linked to reduced susceptibility to other antibiotics and worse outcomes regardless of therapy in MSSA endovascular infections. Methods Sixty-four MSSA strains were collected from patients with endovascular infections not treated with cefazolin. To determine CIE phenotype, strains were cultured and MICs assayed for cefazolin, nafcillin, and vancomycin at 107 CFU/mL for high-inocula (HI) and 105 CFU/mL for standard-inocula (SI). This study defined CIE as a ≥ 4-fold increase in MIC at HI compared to SI, with at least an MIC of 4 mg/L at HI. Nitrocefin disks identified blaZ expression, and beta lysin disks were used to determine hemolysin type and agr function. Patient outcomes of mortality and bacteremia duration were assessed across cohorts. Results Twenty-four strains exhibit a CIE (38%), with 10 strains having an MIC of ≥ 32mg/L at HI. Nafcillin and vancomycin also had an inoculum effect, uncoupled from the CIE and occurring at a lower frequency and amplitude at HI. Presence of CIE had a greater association with blaZ expression (71% vs 25%) than agr dysfunction (38% vs 20%). 50% (9/18) of CIE infections were cleared within 48 hours while 77% (20/26) of CIE-negative infections were cleared within 48 hours (P=0.106). However, presence of CIE was not associated with increased mortality (25% CIE-positive vs 35%; P=0.578) Conclusion Previous studies for CIE failed to enrich for isolates from endovascular sources, where inocula are known to be high. This study presents one of the largest endovascular source cohorts for CIE evaluation. It identifies that CIE prevalence (38%) is higher than reports from diverse infection sources (10-36%). CIE appears to predict bacteremia duration with other MSSA treatment options, suggesting mechanisms independent of blaZ and agr function for this phenomenon. Disclosures Warren Rose, PharmD, MPH, Merck (Grant/Research Support)Paratek (Grant/Research Support)

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Background:IL-4 and IL-13 are related Th2 cytokines, with documented roles in allergic inflammation such as atopic dermatitis (AD). Psoriatic Arthritis (PsA) is typically thought to be a result of Th1/Th17 driven response, and blockage of this pathway (IL-23, IL-17 and TNF) has proven successful. Despite this, there is a strong genetic risk association for IL-13 and PsA(1), however, the precise role of IL-13 in PsA is presently unknown. The enthesis is the region where tendons or ligaments attach to bone, and inflammation of this site (enthesitis) is thought to be the cardinal lesion of PsA, whereas as Rheumatoid Arthritis inflammation is more synovial centric. Dupilumab is a monoclonal antibody that works by blocking the common receptor chain (IL-4α) shared by both IL-13 and IL-4. Recent studies have reported that AD patients receiving dupilumab have developed clinical enthesitis(2).Objectives:To investigate whether IL-4 and IL-13 could modulate IL-23production from entheseal myeloid cells and IL-17 production from enthseal T-cells.Methods:Healthy enthesis samples from patients undergoing surgery for non-inflammatory conditions such a lumbar decompression or scoliosis were obtained. Enthesis samples were digested and stimulated (Fig 1A) with LPS and anti-CD3 to induce IL-23 and IL-17 respectively. Samples were pre-treated with IL-4 and IL-13 to ascertain whether this modulated entheseal cytokine production.Results:Both IL-23 and IL-17 were readily induced from enthesis samples with IL-23 coming predominantly from entheseal myeloid resident cells (Fig 1B) and IL-17A from T-cells (Fig 1C). Pre-treatment of entheseal digested material with either IL-4 or IL-13 attenuated IL-23 secretion (Fig 1D). Neither IL-4 nor IL-13 was able to significantly attenuate IL-17 secretion from enthesis T-cells, however IL-13 trended downwards and IL-4 surprisingly trended upwards (Fig 1E).Conclusion:Our clinical and vitro data point towards a previously unknown role for IL-4 and IL-13 having a protective role in entheseal induction of IL23/17 axis cytokines. These findings point towards a novel explanation for IL-13 pathway SNPs in PsA and also a molecular explanation for why anti-IL4/13 therapy may induce entheseal pathology.References:[1]BOWES, J., S. EYRE, E. FLYNN, P. HO, S. SALAH, R.B. WARREN, H. MARZO-ORTEGA, L. COATES, R. MCMANUS, A.W. RYAN, D. KANE, E. KORENDOWYCH, N. MCHUGH, O. FITZGERALD, J. PACKHAM, A.W. MORGAN, C.E. GRIFFITHS, I.N. BRUCE, J. WORTHINGTON and A. BARTON. Evidence to support IL-13 as a risk locus for psoriatic arthritis but not psoriasis vulgaris.Ann Rheum Dis, 2011,70(6), pp.1016-9.[2]WILLSMORE, Z.N., R.T. WOOLF, C. HUGHES, B. MENON, B. KIRKHAM, C. SMITH and A. PINK. Development of inflammatory arthritis and enthesitis in patients on dupilumab: a case series.British Journal of Dermatology, 2019,181(5), pp.1068-1070.Disclosure of Interests:Charlie Bridgewood: None declared, Kassem Sharif: None declared, Hannah Rowe Grant/research support from: Novartis UK Investigator Initiated non-clinical research funding support, Tobias Russell Grant/research support from: Novartis UK Investigator Initiated non-clinical research funding support, Dennis McGonagle Grant/research support from: Janssen Research & Development, LLC

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Background:Bimekizumab (BKZ), a monoclonal antibody inhibitor of interleukin (IL)-17A and IL-17F, demonstrated clinical improvements in joint and skin outcomes up to 108 weeks (wks) in patients (pts) with active psoriatic arthritis (PsA).1,2Objectives:To report up to 3-year safety and efficacy of BKZ in pts with active PsA from a 48-week phase 2b dose-ranging study (BE ACTIVE; NCT02969525) and its open-label extension (OLE; NCT03347110).Methods:BE ACTIVE and OLE study design has been described previously.1 All OLE pts received BKZ 160 mg Q4W, irrespective of prior dosing regimen. Treatment-emergent adverse events (TEAEs) are reported for the safety set (SS; pts who received ≥1 dose BKZ in the dose-ranging study). Data are presented from dose-ranging study baseline (BL) to Wk 152. Efficacy outcomes are reported for the full analysis set (FAS): ACR50, minimal or very low disease activity (MDA/VLDA), Psoriasis Area and Severity Index (PASI) 90/100, body surface area affected by psoriasis (BSA) 0% and dactylitis/enthesitis resolution.Results:Over 152 wks, the exposure-adjusted incidence rate (EAIR) per 100 patient-years (PY) was 126.4 for all TEAEs, 4.1 for serious TEAEs, 0.7 for serious infections and 4.6 for Candida infections (Table 1). One event was adjudicated by an independent committee as inflammatory bowel disease (microscopic colitis). All Candida infections were localised, mild/moderate, and resolved with appropriate anti-fungal therapy. Overall, the proportions of patients with ACR50 response were sustained through Wk 152 (52.9%, non-responder imputation [NRI]; Figure 1). Response rates were also sustained through Wk 152 for MDA (51.5%), VLDA (30.1%), PASI90 (64.2%), PASI100 (57.7%) and resolution of dactylitis (71.2%) and enthesitis (62.6%) (NRI; Table 1).Table 1.Safety and efficacy outcomes up to 3 yearsSafety (SS)n (%) [EAIR/100 PY]BKZ160 mg [a](n=126)BKZ320 mg [b](n=78)Total(N=206)Any TEAE114 (90.5) [136.1]70 (89.7) [113.3]184 (89.3) [126.4]Serious TEAEs17 (13.5) [5.2]5 (6.4) [2.3]22 (10.7) [4.1]Key TEAEs of special monitoringSerious infections3 (2.4) [0.9]1 (1.3) [0.5]4 (1.9) [0.7]Candida infections15 (11.9) [4.7]9 (11.5) [4.4]24 (11.7) [4.6]Inflammatory bowel disease [c]1 (0.8) [0.3]01 (0.5) [0.2]Malignancies [d]1 (0.8) [0.3]01 (0.5) [0.2]Injection site reactions03 (3.8) [1.4]3 (1.5) [0.5]Suicidal ideation1 (0.8) [0.3]01 (0.5) [0.2]Liver function analyses13 (10.3) [4.1]11 (14.1) [5.3]24 (11.7) [4.6]Study discontinuation due to TEAEs12 (9.5) [3.5]4 (5.1) [1.8]16 (7.8) [2.8]Efficacy (FAS)n (%)BKZ160 mg [a](n=124)BKZ320 mg [b](n=82)Total(N=206)OCNRI, %OCNRI, %OCNRI, %MDA, Wk 15264/95 (67.4)51.642/62 (67.7)51.2106/157 (67.5)51.5VLDA, Wk 15241/95 (43.2)33.121/62 (33.9)25.662/157 (39.5)30.1PASI90 [e] Wk 15251/61 (83.6)64.637/46 (80.4)63.888/107 (82.2)64.2PASI100 [e] Wk 15247/61 (77.0)59.532/46 (69.6)55.279/107 (73.8)57.7BSA 0% [e] Wk 4848/72 (66.7)60.838/55 (69.1)65.586/127 (67.7)62.8Wk 15246/61 (75.4)58.231/45 (68.9)53.477/106 (72.6)56.2Dactylitis [f]/Enthesitis [g] resolution, Wk 48–70.6/56.9–84.0/57.1–76.3/57.0Wk 152–67.6/63.1–76.0/61.9–71.2/62.6No anaphylactic reactions or major adverse cardiac events were reported. [a] Includes pts within the indicated analysis set originally assigned to all arms who were subsequently re-randomized to 160 mg, or [b] 320 mg, after double-blind period; [c] Microscopic colitis; [d] Malignant melanoma in situ; [e] Pts with BL BSA ≥3%, NRI: n=79, 58, 137 respectively; [f] Pts with BL LDI >0, NRI: n=34, 25, 59 respectively; [g] Pts with BL MASES >0, NRI: n=65, 42, 107 respectively. LDI: Leeds Dactylitis Index; MASES: Maastricht AS Enthesitis Score; OC: observed case.Conclusion:The safety profile of BKZ in pts with PsA reflects previous observations1,2 for up to 3 years. High threshold disease control was achieved by >50% of BKZ-treated pts up to 3 years, reflected in long-term improvements in joint and skin outcomes.References:[1]Ritchlin CT. Lancet 2020;395:427–40;[2]McInnes I. Ann Rheum Dis 2020;79:1153–4.Acknowledgements:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Laura C Coates Speakers bureau: AbbVie, Amgen, Biogen, Celgene, Gilead, GSK, Janssen, Lilly, Medac, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Domain, Gilead, Janssen, Lilly, Grant/research support from: AbbVie, Amgen, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB Pharma, Richard B. Warren Consultant of: AbbVie, Almirall, Amgen, Arena, Avillion, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, UCB Pharma, Grant/research support from: AbbVie, Almirall, Amgen, Janssen, LEO Pharma, Novartis, UCB Pharma, Christopher T. Ritchlin Consultant of: Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, UCB Pharma, Grant/research support from: AbbVie, Amgen, UCB Pharma, Laure Gossec Speakers bureau: AbbVie, Amgen, Biogen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, Samsung, Sanofi, UCB Pharma, Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, Samsung, Sanofi, UCB Pharma, Grant/research support from: Eli Lilly, Pfizer, Sandoz, Joseph F. Merola Consultant of: AbbVie, Amgen, Bayer, Biogen, BMS, Celgene, Eli Lilly, Janssen, Novartis, Sanofi-Regeneron, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Amgen, Bayer, Biogen, BMS, Celgene, Eli Lilly, Janssen, Novartis, Sanofi-Regeneron, Pfizer, UCB Pharma, Principal investigator for Dermavant, LEO Pharma, UCB Pharma, Deepak Assudani Employee of: UCB Pharma, Jason Coarse Employee of: UCB Pharma, Jason Eells Shareholder of: UCB Pharma, Employee of: UCB Pharma, Barbara Ink Shareholder of: GSK, UCB Pharma, Employee of: UCB Pharma, Iain McInnes Consultant of: AbbVie, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Novartis, UCB Pharma, Grant/research support from: BMS, Boehringer Ingelheim, Celgene, Janssen, UCB Pharma.

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Abstract Severe aplastic anemia can be successfully treated with immunosuppressive therapies (IST) or hematopoietic stem cell transplantation (HSCT). Response rates with horse anti-thymocyte globulin (ATG) plus cyclosporine (CsA) are about 60–70%, and robust responders have excellent long term survival (Rosenfeld, Follmann et al. 2003). Relapse require reinstitution of IST and does not negatively affect survival. We introduced a third immunosuppressive agent to standard horse ATG/CsA, mycophenolate mofetil, in an attempt to improve response rate, survival and to decrease the relapse rate and clonal evolutions to myelodysplasia or leukemia. MMF blocks the proliferation of active lymphocytes by the inhibition of the enzyme inosine monophosphate dehydrogenase, an important step in purine and therefore DNA synthesis. MMF immunosuppression is due to direct inhibition of T cell proliferation and therefore, would be anticipated to favor the induction of tolerance by selective depletion of active lymphocytes. MMF has been employed as a “kidney-sparing” adjunct to CSA in renal and other solid organ transplantations, post-HSCT, and in certain autoimmune diseases with a favorable toxicity profile. A total of 104 consecutive patients with SAA were treated with horse ATG/CsA/MMF from May 1999 to June 2003 at the Warren Grant Magnuson Clinical Center at the National Institutes of Health in Bethesda, MD. Response was defined by blood counts no longer satisfying criteria for severe AA. The overall response rate at 6 months was 62%, with 24 (37% of responders) patients relapsing at a median of 389 days from ATG. Fifteen relapses occurred after CsA was discontinued at 6 months but before 18 months, while patients were still on MMF. Nine patients showed evidence of clonal evolution following ATG, five responders and 4 nonresponders. The median survival among responders was not reached and among nonresponders was 1,759 days. There was no difference in overall survival among patients who relapsed and those who did not relapse. Over half of the relapses occurred during MMF administration (15 of 24), suggesting that this drug is not active in preventing relapses among responders. Evolution to clonal disorders did not change with the intensification of immunosuppression with MMF. Despite a strong theoretical rationale for its use, MMF did not result in improvement in response or relapse rates, and it cannot be routinely recommended as a CsA-sparing agent in responders with poor tolerability to CsA.

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Background:Tyrosine kinase 2 (TYK2) is an intracellular kinase that mediates interleukin (IL)-23, IL-12, and interferon (IFN)α/β signaling. Deucravacitinib is a novel, oral, selective inhibitor of TYK2 acting via binding to the TYK2 regulatory domain.1 Phase 2 results showed deucravacitinib was efficacious and well tolerated versus placebo in patients with moderate to severe plaque psoriasis or active psoriatic arthritis.2,3 No herpes zoster infections, opportunistic infections, thromboembolic events, or hematologic or lipid abnormalities characteristic of Janus kinase (JAK) 1−3 inhibitors were reported in the Phase 2 trials.2,3Objectives:To compare the efficacy and safety of deucravacitinib versus placebo and apremilast in plaque psoriasis.Methods:This Phase 3, double-blinded, 52-week study (NCT03624127) randomized patients with moderate to severe plaque psoriasis (BSA ≥10%, PASI ≥12, sPGA ≥3) to deucravacitinib 6 mg once daily, placebo, or apremilast 30 mg twice daily (2:1:1). Patients receiving placebo were switched to deucravacitinib at Week 16; apremilast-treated patients not achieving PASI 50 at Week 24 were switched to deucravacitinib. Coprimary endpoints were PASI 75 and sPGA 0/1 response versus placebo at Week 16. Key secondary endpoints included superiority versus apremilast, assessed via multiple measures.Results:666 patients were randomized. Demographic and baseline disease characteristics were balanced across groups; mean age was 46.1 years, mean disease duration was 17.3 years, 18.2% of patients had psoriatic arthritis at baseline, and 38.9% had previously used biologic therapy. Mean BSA involvement at baseline was 26.3%, mean PASI was 21.4, and the percentage with severe sPGA (score=4) at baseline was 21.2%. Significantly greater proportions of patients in the deucravacitinib versus placebo and apremilast arms achieved PASI 75 (58.7% vs 12.7% vs 35.1%, respectively; P<0.0001) and sPGA 0/1 (53.6% vs 7.2% vs 32.1%, respectively; P<0.0001) response at Week 16 (Figure 1). Deucravacitinib was also superior to apremilast at Week 24, with 69.0% versus 38.1% of patients achieving PASI 75 and 58.4% versus 31.0% achieving sPGA 0/1 (P<0.0001 for both). In addition, DLQI 0/1 responses at Week 16 were significantly higher with deucravacitinib versus placebo and apremilast, demonstrating improved quality of life (40.7% vs 10.6% vs 28.6%, respectively; Figure 1). During the 16-week, placebo-controlled period, the most common AEs (≥5% in any arm) were nasopharyngitis, upper respiratory tract infection, headache, diarrhea, and nausea (Table 1). Frequencies of SAEs and treatment discontinuations due to AEs were low (Table 1).Table 1.Summary of adverse events (AEs) through Week 16Patients, n (%)Deucravacitinibn=332Placebon=165Apremilastn=168Any AEs176 (53.0)70 (42.4)93 (55.4)Severe AEs5 (1.5)7 (4.2)5 (3.0)Serious AEs7 (2.1)9 (5.5)4 (2.4)AEs leading to treatment discontinuation6 (1.8)7 (4.2)10 (6.0)Most common AEs (≥5% in any arm) Nasopharyngitis21 (6.3)7 (4.2)14 (8.3) Upper respiratory tract infection21 (6.3)6 (3.6)3 (1.8) Headache16 (4.8)5 (3.0)17 (10.1) Diarrhea13 (3.9)6 (3.6)17 (10.1) Nausea7 (2.1)4 (2.4)19 (11.3)Conclusion:Deucravacitinib demonstrated superiority versus placebo and apremilast across multiple efficacy endpoints in patients with moderate to severe plaque psoriasis, and was generally well tolerated. Overall, the efficacy and safety profile of deucravacitinib was consistent with that observed in the Phase 2 plaque psoriasis and psoriatic arthritis trials.2,3References:[1]Burke JR et al. Sci Transl Med. 2019;11:1-16.[2]Papp K et al. N Engl J Med. 2018;379:1313-21.[3]Mease PJ et al. Presented at: Annual Scientific Meeting of the American College of Rheumatology; November 5-9, 2020; Virtual meeting.Acknowledgements:This study was sponsored by Bristol Myers Squibb. Professional medical writing assistance was provided by Peloton Advantage, LLC, an OPEN Health company, and funded by Bristol Myers Squibb.Disclosure of Interests:April Armstrong Consultant of: Grants and personal fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Leo Pharma, Novartis; Personal fees from Boehringer Ingelheim/Parexel, Celgene, Dermavant, Genentech, GlaxoSmithKline, Menlo Therapeutics, Merck, Modernizing Medicine, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, Science 37, Sun Pharma, Valeant, Grant/research support from: Grants: Dermira, Kyowa Hakko Kirin, and UCB, outside the submitted work; Grants and personal fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Leo Pharma, Novartis, Melinda Gooderham Shareholder of: Speakers bureau, consultant, investigator/advisor: AbbVie, Akros, Amgen, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa Hakko Kirin, Leo Pharma, Merck, MedImmune, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Valeant, Richard B. Warren Consultant of: AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen, Leo Pharma, Eli Lilly, Novartis, Pfizer, Sanofi, Xenoport, UCB, Grant/research support from: AbbVie, Almirall, Amgen, Celgene, Janssen, Eli Lilly, Leo Pharma, Novartis, Pfizer, UCB, Kim Papp Speakers bureau: AbbVie, Amgen, Astellas, Celgene, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, Leo Pharma, Merck Sharp & Dohme, Novartis, Pfizer, Valeant, Consultant of: Scientific officer/steering committee/advisory board: AbbVie, Akros, Amgen, Anacor, Astellas, Baxter, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dow Pharma, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Valeant, Grant/research support from: AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, AstraZeneca, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Leo Pharma, MedImmune, Meiji Seika Pharma, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant;Consultant: AbbVie, Akros, Amgen, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol Myers Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, Leo Pharma, Meiji Seika Pharma, Merck Sharp & Dohme, Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant; Honoraria: AbbVie, Akros, Amgen, Baxter, Boehringer Ingelheim, Celgene, Coherus, Eli Lilly, Forward Pharma, Galderma, GlaxoSmithKline, Janssen, Kyowa Hakko Kirin, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Takeda, UCB, Valeant, Bruce Strober Speakers bureau: AbbVie, Janssen, Eli Lilly, Ortho Dermatologics, Consultant of: Honoraria or consultation fees: AbbVie, Almirall, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, GSK, Janssen, Kyowa Hakko Kirin, Leo Pharma, Medac, Meiji Seika Pharma, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi-Genzyme, Sun Pharma, UCB; Scientific Director (consulting fee): Corrona Psoriasis Registry; Investigator: AbbVie, Corrona Psoriasis Registry, Dermavant, Dermira., Diamant Thaçi Paid instructor for: Lectures: AbbVie, Almirall, Amgen, DS-Pharma, Janssen, Leo Pharma, MSD, Novartis, Pfizer, Roche-Posay, Sandoz-Hexal, Sanofi, Target-Solution, UCB; Scientific advisory board: AbbVie, Amgen, Celgene, DS Pharma, Eli Lilly, Galapagos, Janssen-Cilag, Leo Pharma, Morphosis, MSD Novartis, Pfizer, Sandoz, Sanofi, UCB., Consultant of: Consultant: AbbVie, Almirall, Celgene, Dignity, Galapagos, Leo Pharma, Maruho, Mitsubishi, Novartis, Pfizer, Xenoport, Grant/research support from: Research support/principal investigator (clinical trials): AbbVie, Almirall, Amgen, Biogen Idec, Boehringer Ingelheim, Celgene, Chugai, Dermira, DS-Pharma, Eli Lilly, Galderma, GSK, Janssen-Cilag, Leo, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, UCB, Elizabeth Colston Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, John Throup Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Sudeep Kundu Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Subhashis Banerjee Shareholder of: Bristol Myers Squibb, Employee of: Bristol Myers Squibb, Andrew Blauvelt Consultant of: Scientific adviser and/or clinical study investigator for AbbVie, Aligos, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Evommune, Forte, Galderma, Incyte, Janssen, Leo Pharma, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, UCB Pharma.

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Background:We recently reported that the inhibitor of hyaluronan (HA) biosynthesis, 4-methylumbelliferone (4-MU) blocked IL-1β activation of MMP13 mRNA and protein expression in human osteoarthritic (OA), bovine as well as bovine or OA cartilage explants [1]. This was a somewhat counterintuitive observation because we have also demonstrated that the overexpression of HAS2 (HAS2-OE) exerted the same chondroprotective effects on human and bovine chondrocytes. Others [2] have reported that HAS2-OE in tumor cells generates a flux in intracellular UDP-sugar pools that resulted in changes in cell metabolism; switching from a dependence on glycolysis to aerobic respiration. HAS2-OE and 4-MU likely also cause dramatic fluxes in intracellular UDP-GlcUA pools. From these results, we hypothesized that the effect of HAS2-OE and 4-MU relate to changing metabolism and the possibility of inhibition of glycolysis induce chondroprotective effect. To determine that, we used the glycolysis inhibitor, 2-Deoxyglucose (2DG) as an alternative agent to change metabolism in chondrocytes.Objectives:The objective of this study was to investigate the mechanism of chondroprotective effects of 2DGMethods:Bovine and human chondrocyte were stimulated with IL-1β (2ng/ml) in the presence or absence of 4MU (1.0 mM), 2DG (0.2-20 mM). Bovine chondrocytes were tested using Seahorse Flux Analyzer (Agilent Tech) to determine rate changes in medium accumulation of +H protons (indicative of lactic acid accumulation: ECAR) and for O2 consumption (indicative of mitochondrial respiration: OCR). Accumulation of MMP13 and phosphor AMPK (pAMPK) protein was quantified with Western blotting. Human and Bovine cartilage explants were cultured with L-1β in the presence or absence of 2DG (20 mM) and d 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) to pharmacologically induce AMPK for 7 days and stained with Safranin O.Results:Reduced mitochondrial potential and enhanced dependence on glycolysis was observed in IL-1β stimulated chondrocytes. Co-treatment with 4-MU and 2DG returned the cell metabolism to levels at or below baseline (Fig 1A, B). The Seahorse ATP Rate Assay means the contributions of glycolysis and mitochondrial respiration to chondrocyte ATP production (Fig 1C). In control chondrocytes, the use of glycolysis contributes to the majority of ATP produced (grey bars) approximately 1/5th from the TCA cycle (red bars). IL1β-activated chondrocytes display increase in glycolysis and decrease in mitochondrial contributions. These changes are reversed by co-treatment with 4MU and 2DG. As shown in Figs 2A, 2DG reversed the IL1β-induced increases accumulation of MMP13 protein in human OA chondrocytes by Western blotting analysis. Although IL-1β lost safranin O staining in human and bovine samples, co-incubation with 2DG blocked in the loss of proteoglycan (Fig 2B). pAMPK is associate with energy homeostasis in chondrocytes. IL-1β treatment decreased accumulation of phosphor AMPK. Co-treatment with 4-MU and 2DG resulted in a rescue of the pAMPK status (Figure 3A). Co treatment with AICAR, which is inducer of AMPK, also blocked in the loss of proteoglycan (Fig 3B).Conclusion:4-MU and 2DG have chondroprotective effect by changing metabolism and upregulate AMPK. We propose that 4MU and 2DG become useful when these endogenous responses are not enough to rescue cells from a pro-catabolic phenotype.References:[1]J. Biol. Chem. 291:12087, 2016; [2] J. Biol. Chem. 291:24105, 2016Disclosure of Interests:KENYA TERABE: None declared, Nobunori Takahashi Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Ono, Pfizer, Takeda, and UCB Japan, Ohashi Yoshifumi: None declared, Maeda Masataka: None declared, Warren Knudson: None declared, Cheryl Knudson: None declared, Toshihisa Kojima Grant/research support from: Chugai, Eli Lilly, Astellas, Abbvie, and Novartis, Consultant of: AbbVie, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Janssen, Mitsubishi Tanabe, Pfizer, and Takeda, Naoki Ishiguro Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi-Sankyo, Eisai, Kaken, Mitsubishi Tanabe, Otsuka, Pfizer, Takeda, and Zimmer Biomet, Consultant of: Ono, Speakers bureau: Astellas, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, and Taisho Toyama

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Background:The features of the underlying immune-mediated disease can affect the efficacy, pharmaco*kinetics and immunogenicity of the biologic agents, which are among the important predictors of loss of response to TNF-α inhibitors (TNFi).Objectives:To compare the frequency of TNFi low trough levels and their immunogenicity in the treatment of rheumatic diseases (RD) (ankylosing spondylitis (AS) and rheumatoid arthritis (RA)) and inflammatory bowel diseases (IBD) (Crohn’s disease (CD) and ulcerative colitis (UC)).Methods:Among 120 patients (40 with AS (33.3%), 19 with RA (15.8%), 42 with CD (35%), and 19 with UC (15.8%)), trough level of infliximab (INX) (n=36, 30%), adalimumab (ADM) (n=45, 37.5%) and certolizumab pegol (CZP) (n=39, 32.5%) and the level of anti-drug antibodies (ADAb) were measured in the serum samples drawn directly before the planned drug administration.Results:Low drug level (below 0.5 μg/mL for INX1, 4.9 µg/ml for ADM2, and 20 µg/l for CZP3) was found in 54 (45%) patients: in 33 (55.9%) patients with RD and 21 (34.4%) patients with IBD. In the RD group, low drug trough level was observed more often than in IBD (55.9% vs 34.4%, OR 2.418, 95% CI 1.157 to 5.052, p=0.018). Only in UC was there a relationship between the received low dose of the drug (up to 200 mg of INX, 40 mg of ADM, and 200 mg of CZP) and its low level in the serum (p=0.026). Among the additional factors associated with a low TNFi level, lower dose of concomitant therapy at the time of a biologic initiation (66.7% vs 20.8%, OR 7.6, 95% CI 1.388 to 41.617, p=0.033) and the absence of pseudopolyps (78.9% vs 21.1%, p=0.045) were found in IBD, and in case of RD these factors included the age of 30 to 45 years (72.7% vs 41.9%, OR 3.692, 95 % CI 1.136 to 12.0, p=0.026), the absence of comorbidities (58.6% vs 41.4%, OR 3.44, 1.09 to 10.858, p=0.032) and male gender (78.8% vs 50% in women, OR 3.714, 95% CI 1.194 to 11.552, p=0.02).ADAb were detected in 29 (24.2%) patients (7 to INX (19.4%), 8 (17.8%) to ADM, 14 (35.9%) to CZP), 23 (79.3%) of which had also a concomitant low trough level of the drug. There were no significant differences in the frequency of ADAb formation between the pathologies. In the AS group, antibodies to CZP were detected in all patients with a low level of the biologic, while only in 25% of patients receiving ADM, a low level was associated with the formation of ADAb (p=0.019). In addition, among patients with AS, ADAb were detected only in those patients who did not take prednisone at the time of blood serum sampling (100% vs 37.9%, p=0.037).Conclusion:Low level of TNFi is more common in RD than in IBD. For each group, the factors associated with a low trough level of TNFi were identified. There were no significant differences in the frequency of ADAb formation between nosologies.References:[1]Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol 2011; 46: 310–318.[2]Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305:1460–1468. doi: 10.1001/jama.2011.406.[3]Gehin, J.E., Goll, G.L., Warren, D.J. et al. Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response in patients with inflammatory joint diseases: data from the NOR-DMARD study. Arthritis Res Ther 21, 256 (2019). https://doi.org/10.1186/s13075-019-2009-5Disclosure of Interests:Tatiana Nuriakhmetova Grant/research support from: A grant to purchase reagents for scientific research from Novartis Pharmaceuticals, Ildariya Khairullovna Valeeva: None declared., Jana Shevnina: None declared., Diana Abdulganieva: None declared.

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Abstract Abstract 1821 Lenalidomide is an oral immune-modulating agent that has been shown to have clinical activity in patients with treatment-naive and previously treated chronic lymphocytic leukemia (CLL). In CLL, a disease-specific phenomenon of drug-induced tumor flare is often observed that results in lymph node enlargement, rash, and cytokine release. We and others have attributed both lenalidomide-induced tumor flare and cytokine release in part to CLL cell activation, with concomitant increase in surface co-stimulatory molecules including CD154. The potential consequences of such activation by lenalidomide in CLL are multiple. In symptomatic, previously untreated CLL, activation of tumor cells by lenalidomide likely contributes to reversal of hypogammaglobulinemia in a subset of patients. Additionally, activation of CLL cells increases their capacity for antigen presentation, potentially facilitating a clinically beneficial development of tumor-specific antibodies toward antigens such as ROR1. In patients with previously treated CLL, lenalidomide therapy does not reverse hypogammaglobulinemia. However, treatment has been documented to increase serum b-FGF and VEGF levels, which correlates with lack of response. Previous work demonstrates that CLL cells predominately utilize the PI3K p110δ isoform for activation following CD154 signaling. Given our prior findings of prominent lenalidomide induction of CD40-CD154 signaling in vitro and in vivo, we focused initially on molecular interrogation of isoforms responsible for this in CLL cells. Utilizing primary CLL cells, we demonstrated that inhibition of PI3K-δ signaling by CAL-101, a clinically relevant PI3K-δ isoform-specific inhibitor, abrogated lenalidomide-induced activation of CLL cells by directly reducing PI3K enzymatic activity and also reducing phosphorylation of the downstream PI3K target AKT. Parallel studies with siRNA targeted to the p110δ isoform of PI3K demonstrated antagonism of lenalidomide-induced AKT phosphorylation. Furthermore, we found that inhibition of PI3K-δ by CAL-101 at therapeutically relevant concentrations (1 μM) prevented up-regulation of CD40, CD154, and CD86 by lenalidomide and also antagonized production of IgM by normal B-cells co-cultured with CLL cells. Collectively, these data demonstrate the importance of PI3K-δ signaling in modulating the pharmacological effects of lenalidomide in CLL cell activation including up-regulation of CD40, CD154, CD86 and active CLL cell co-stimulation of normal B-cells. Our findings suggest that clinical evaluation of combination strategies of lenalidomide and CAL-101 in treatment-naive patients with CLL should be performed with careful pharmacodynamic monitoring of immune modulation and signaling to best preserve the clinical benefits of both drugs. This work is supported by the Leukemia and Lymphoma Society, D. Warren Brown Foundation, and The OSU Leukemia SPORE grant funded by the NCI. CAL-101 was provided by Calistoga Pharmaceuticals, Inc. Disclosures: Jones: Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Byrd:Calistoga Pharmaceutical Inc.: Equity Ownership. Johnson:Calistoga Pharmaceutical Inc.: Research Funding.

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Background:A lack or loss of response to TNFα inhibitors (TNFi) has been associated with low serum drug levels and formation of anti-drug antibodies (ADAb). Therapeutic drug monitoring (TDM), an individualised treatment strategy based on regular assessments of serum drug levels, has been suggested to optimise efficacy of TNFi. It is still unclear if TDM improves clinical outcomes, and the value of TDM has recently been included in the research agenda across different specialities. This first randomised controlled trial on the effectiveness of TDM in a range of immune mediated inflammatory diseases including rheumatic diseases, the NORwegian DRUg Monitoring trial part A (NOR-DRUM (A)) focus on the induction period of infliximab (INX) treatment.Objectives:To assess if TDM is superior to standard treatment in order to achieve remission in patients starting INX.Methods:In the investigator-initiated, randomised, open-label, multicentre NOR-DRUM (A) study, adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), spondyloarthritis (SpA), ulcerative colitis (UC), Crohn’s disease (CD) and psoriasis (Ps) starting INX therapy were randomly assigned to administration of INX according to a treatment strategy based on TDM (TDM arm) or to standard administration of INX without TDM (control arm). Study visits were conducted at each infusion. The primary endpoint was remission at week 30. In the TDM arm, the dose and interval were adjusted according to INX trough levels to reach the therapeutic range (Figure 1). If the patient developed significant levels of ADAb, INX was terminated. To guide the investigators, the TDM strategy was integrated in an interactive eCRF. The primary endpoint was analysed by mixed effect logistic regression in the full analyses set (FAS), adjusting for diagnoses. Infections and infusion reactions were specified as adverse events (AEs) of special interest.Clinical trial.gov:NCT03074656Results:We enrolled 411 patients at 21 study centres between January 2017 and December 2018. 398 patients (RA 80, PsA 42, SpA 117, UC 80, CD 57, Ps 22) received the allocated strategy and were included in the FAS population. Demographic and baseline characteristics were comparable in both arms. TDM was not found to be superior to standard treatment with regard to the primary outcome. Remission at week 30 was reached in 100 (53%) and 106 (54%) of the patients in the TDM and control arm, respectively (adjusted difference, 1.5%; 95% confidence interval (CI), -8.2 to 11.1, p=0.78) (Figure 2). Consistent results were shown for all the secondary endpoints (Figure 3) and in the sensitivity analyses. Twenty patients (10%) in the TDM arm and 30 patients (15%) in the control arm developed significant levels of ADAb. The number of adverse events (AE) was similar in both groups, however infusion reactions were less frequent (5 patients (2.5%) vs 16 patients (8.0%)) in the TDM arm (difference 5.5% (95% CI 1.1, 9.8%))Conclusion:NOR-DRUM (A) is the first randomised trial to address effectiveness of TDM in the induction period of TNFi treatment, and the first trial to address TDM in rheumatic diseases. In this study, TDM was not superior to standard treatment in order to achieve remission. Although improved safety is indicated by a reduction in infusion reactions, implementation of TDM as a general strategy in the induction period of INX is not supported by the NOR-DRUM (A) study.Disclosure of Interests:Silje Watterdal Syversen Speakers bureau: Roche, Thermo Fisher, Guro Løvik Goll Consultant of: Novartis, Pfizer, Speakers bureau: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, Kristin Kaasen Jørgensen Consultant of: AOP Orphan, Celltrion, Sandoz, Speakers bureau: Norgine, Tillots, Øystein Sandanger: None declared, Joe Sexton: None declared, Inge Olsen: None declared, Johanna Gehin Speakers bureau: Roche, Marthe Kirksæther Brun: None declared, David Warren: None declared, Cato Mørk Consultant of: Abbot, Novartis, Celagene, Almiral, Galderma, ACO, Almiral, ACO, Speakers bureau: Novartis, Abbott, Abbvie, Celegene, LEO, Almiral, Galderma, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Jørgen Jahnsen Consultant of: AbbVie, Boerhinger Ingelheim, Celltrion, Ferring, Janssen, Meda, MSD, Norgine, Novartis, Orion Pharma, Pfizer, Pharmacosmos, Takeda, and Sandoz., Speakers bureau: AbbVie, Astro Pharma, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Hikma, Janssen, Meda, MSD, Napp Pharma, Orion Pharma, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts and Sandoz, Nils Bolstad Consultant of: Pfizer, Janssen, Speakers bureau: Orion Pharma, Napp Pharmaceuticals, Takeda, Roche, Novartis, Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD

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Background:Survival in ANCA-associated vasculitis (AAV) has improved substantially in the last fifty years, but Australian data and studies with a control population are scarce.Objectives:The aim of this study was to compare the all-cause mortality rate between patients with AAV and matched controls in Western Australia.Methods:A retrospective population-based cohort study conducted using the Western Australia Health Data Linkage System (WADLS) for patients with a diagnostic code for AAV (International Classification of Diseases (ICD)-10-AM M30.1, M31.3 and M31.7). We included 240 patients with AAV (mean age 57.37 ± 16.69, 48.8% males) who had a hospital admission or emergency department visit between 1 January 2000 and 31 December 2014 and 4406 controls matched for age and sex. Death details were obtained from the WA Death registry. Mortality rates per 1000 person-years (MR) for AAV patients and controls were compared by mortality rate ratios (MRRs) with 95% CI. Kaplan Meijer survival estimates were analyzed by log-rank test.Results:During a mean follow-up of 6.58 years (3.37, 11.25) 83 incident AAV patients (34.6%) died, giving a mortality rate of 48.13 per 1000 person-years (95% CI 38.33, 59.66). This was 82% higher overall than in controls (MRR 1.82, 95% CI 1.46, 2.26, P < 0.0001), while the MRR for males with AAV was 2.28 (95% CI 1.46, 2.26; P < 0.0001) and for females 1.43 (95% CI 1.01, 2.02; P = 0.0267). Survival estimates at one (90.5%) and five years (75%) were significantly lower in AAV patients than controls.Conclusion:Over the last fifteen years, the mortality risk for AAV patients remains significantly increased compared with matched controls and more so for male than female AAV patients. Together with the reduced one- and five-year survival rate, this indicates the need for further improvements in initial disease management in order to reduce the risk of death in AAV.TableMortality rates (MR) per 100 patient years and Mortality rate ratio (MRR) with 95% CI in patients with AAV and controlsAAVControlDeathsPersonyearsMR(95% CI)DeathsPersonyearsMR(95% CI)MRR(95% CI)All83172448.1(38.3, 59.6)12194606926.4(25.0, 27.9)1.82 (1.46, 2.26)Male4978962.1(45.9 82.0)6902529528.2(25.2, 29.3)2.28 (1.72, 3.02)Female3493536.3(25.1, 50.7)5292077325.4 (23.3, 27.7)1.43 (1.01, 2.02)Figure.Kaplan Meyer Survival curves for AAV patients and controlsAcknowledgments:The authors thank the Data Custodians of the Hospital Morbidity Data Collection (HMDC), Emergency Department Data Collection (EDDC), the State Registry of Births, Deaths and Marriages, the WA Electoral Commission, and the staff at Data Linkage Branch at the Western Australian Department of Health for their assistance in provision of data. This work was supported by an unrestricted grant from the Arthritis Foundation of Western Australia. Author WDR received a PhD Scholarship in Memory of John Donald Stewart from the Arthritis Foundation of Western AustraliaDisclosure of Interests:Wade Taylor: None declared, warren raymond: None declared, Helen Keen Speakers bureau: Pfizer Austrlaia, Abbvie Australia, Charles Inderjeeth Consultant of: Linear Research Perth, David Preen: None declared, Johannes (“Hans”) Nossent Speakers bureau: Janssen

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Narrow field-of-view sensors on satellites monitoring solar radiation measure the reflected radiance in a particular direction. For climatic studies of the Earth’s radiation budget, the albedo is needed, which is the integral of the upward radiance over all angles divided by the downward irradiance. In order to infer the albedo from a radiance measurement at only one angle, it is necessary to know a priori the distribution of reflected radiation with angle, i.e. the bi-directional reflectance-distribution function (BRDF). The BRDF is a function of four angles: solar zenith and azimuth, and satellite zenith and azimuth. For areal or temporal averages on many natural surfaces, only three angles are needed to describe the function, because only the difference between the two azimuths is important, not their individual values. This assumption was made when developing empirical BRDFs from Nimbus-satellite data for use in the Earth Radiation Budget Experiment (ERBE). However, in large areas of the polar regions, all four angles are needed, because the sastrugi are oriented parallel to a prevailing wind direction. The BRDF shows a forward peak when the solar beam is along the direction of the sastrugi, and an enhanced backward peak when it is perpendicular. Averaging over all solar azimuths (relative to the sastrugi azimuth) causes back-scattering to be averaged together with forward-scattering. The conclusion of the ERBE analysis, that snow is the most nearly isotropic of all Earth surfaces, is therefore at least partly a spurious result of this averaging.Measurements of the BRDF were carried out from a 23 m tower at the South Pole during January and February at 900 nm wavelength for varying azimuths between the Sun and the sastrugi fabric. The wavelength was selected near the midpoint of the solar-energy spectrum but where scattered sky radiation is negligible. Measurements were made with 10° field of view at 15° intervals in viewing zenith and azimuth angles throughout the day, at intervals of 1 h (15° of solar azimuth). For BRDF normalized such that its angular average is unity, the principal features of the results include a forward-scattering peak with a value of about five together with a side- and back-scattering lobe of 1.1 to 1.3. Variations in solar azimuth produced a skewness in BRDF which was approximately consistent with enhanced scattering at the specular angle with respect to the solar azimuth and the orientation of the principal fabric of the sastrugi pattern. The angularly averaged pattern was remarkably similar to the results of Taylor and Stowe even though their values were integrated over wavelength and were made through the atmosphere. Our studies thus suggest that, for mid- to late summer, the Taylor and Stowe results require only small corrections for sastrugi effects. This is not, however, expected to be true from sunrise through late November.Spectral albedos showed values at visible wavelengths of 0.97 to 0.99 which agree very well with the model calculations of Wiscombe and Warren using our observed mean snow grain-sizes. Albedos for wavelengths above 1400 nm were higher than model predictions, indicating that the depth dependence of grain-size must be included in the analysis.This research was supported by National Science Foundation grant DPP-83–16220.

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Narrow field-of-view sensors on satellites monitoring solar radiation measure the reflected radiance in a particular direction. For climatic studies of the Earth’s radiation budget, the albedo is needed, which is the integral of the upward radiance over all angles divided by the downward irradiance. In order to infer the albedo from a radiance measurement at only one angle, it is necessary to know a priori the distribution of reflected radiation with angle, i.e. the bi-directional reflectance-distribution function (BRDF). The BRDF is a function of four angles: solar zenith and azimuth, and satellite zenith and azimuth. For areal or temporal averages on many natural surfaces, only three angles are needed to describe the function, because only the difference between the two azimuths is important, not their individual values. This assumption was made when developing empirical BRDFs from Nimbus-satellite data for use in the Earth Radiation Budget Experiment (ERBE). However, in large areas of the polar regions, all four angles are needed, because the sastrugi are oriented parallel to a prevailing wind direction. The BRDF shows a forward peak when the solar beam is along the direction of the sastrugi, and an enhanced backward peak when it is perpendicular. Averaging over all solar azimuths (relative to the sastrugi azimuth) causes back-scattering to be averaged together with forward-scattering. The conclusion of the ERBE analysis, that snow is the most nearly isotropic of all Earth surfaces, is therefore at least partly a spurious result of this averaging. Measurements of the BRDF were carried out from a 23 m tower at the South Pole during January and February at 900 nm wavelength for varying azimuths between the Sun and the sastrugi fabric. The wavelength was selected near the midpoint of the solar-energy spectrum but where scattered sky radiation is negligible. Measurements were made with 10° field of view at 15° intervals in viewing zenith and azimuth angles throughout the day, at intervals of 1 h (15° of solar azimuth). For BRDF normalized such that its angular average is unity, the principal features of the results include a forward-scattering peak with a value of about five together with a side- and back-scattering lobe of 1.1 to 1.3. Variations in solar azimuth produced a skewness in BRDF which was approximately consistent with enhanced scattering at the specular angle with respect to the solar azimuth and the orientation of the principal fabric of the sastrugi pattern. The angularly averaged pattern was remarkably similar to the results of Taylor and Stowe even though their values were integrated over wavelength and were made through the atmosphere. Our studies thus suggest that, for mid- to late summer, the Taylor and Stowe results require only small corrections for sastrugi effects. This is not, however, expected to be true from sunrise through late November. Spectral albedos showed values at visible wavelengths of 0.97 to 0.99 which agree very well with the model calculations of Wiscombe and Warren using our observed mean snow grain-sizes. Albedos for wavelengths above 1400 nm were higher than model predictions, indicating that the depth dependence of grain-size must be included in the analysis. This research was supported by National Science Foundation grant DPP-83–16220.

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Background:There is sparse population-level data on outcome in patients with Immunoglobulin-A vasculitis (IgAV) and none from AustraliaObjectives:We compared long-term mortality for paediatric and adult IgAV patients with age- and gender-matched controls.Methods:Linked health data for pediatric (<20 years=473) and adult (20+ years, n=267) IgAV patients were obtained from state-wide hospital and deaths registries in Western Australia for the period 1980-2015. All-cause mortality rates (MR) (deaths/1000 person-years) were compared with controls using mortality rate ratios (MRR) and with the general population of Western Australia by standardised mortality rate ratios (SMRR) with Poisson derived 95% confidence intervals (CI). We used Kaplan-Meier survival estimates and multivariate Cox regression derived hazard ratios (HR) for time dependent analyses.Results:In pediatric patients (mean age 7.2 years, 60 % male) MRR was 1.27 (CI: 0.34-4.08, p=0.68) and SMRR was 2.31 (CI: 0.72-5.7, p=0.47) (Table 1) with a 20-year survival rate (>99%) similar to controls. Despite higher rates of renal failure (1.5% vs 0.2%, p=0.002) deaths in pediatric IgAV patients were mainly from unrelated causes. In adult IgAV patients (mean age 55.8 years, 48% males) MMR was 2.06 (CI 1.70-2.50, p<0.01) and SMRR 6.16 (3.04 -14.3, p<0.01) (Table) during a mean of 19.5 years follow-up with significantly reduced survival at five (72.7 vs. 89.7 %) and twenty years (45.2% vs. 65.6 %) (p<0.05). Renal disease (HR: 1.47, CI 1.04 - 2.06), the presence of any comorbidity (HR:1.30, CI 1.23 - 1.37) and male gender (HR:1.23; CI 1.04 - 1.47) were independent predictors of death. While cardiovascular events (34.2%) and malignancy (19.4%) were the most frequent causes of death, only death from infections (5.8 vs 1.8%, p=0.02) and renal disease (3.6 vs 1.8%, p=0.03) were more frequent in adult IgAV patients than controls.Mortality data for childhood and adult-onset IgAV patients and controls. Figures indicate mean (±SD), numbers (%) or rate/1000 patient months (95% CI)PediatricAdultIgAVControlsP valueIgAVControlsPMean follow-up (yrs)22.71 (±5.2)23.75 (±3.17)0.00111.9 (±9.04)15.94 (±8.30)0.001Non-survivors (%)<5 (0.8)9 (0.9)0.5137 (51.3)394 (33.4)<0.001Person-years1027529520317818815MR0.39 (0.1, 0.9)0.30 (0.1, 0.5)43.11 (36,1,50.9)20.94 (18.9, 23.1)MRR1.27 (0.34, 4.08)0.672.06 (1.70, 2.50)<0.001SMRR2.31 (0.71, 5.71)0.716.16 (3.04, 14.3)<0.001Conclusion:Compared to controls and general population, mortality risk was not increased in paediatric IgAV patients for at least 20 years following diagnosis despite a higher rate of end stage renal failure. However, in adult IgAV patients, all-cause mortality risk was six times higher than in the general population leading to significantly reduced five-year survival, especially for male patients with comorbidity including renal disease.Acknowledgments:The authors thank the Data Custodians of the Hospital Morbidity Data Collection (HMDC), Emergency Department Data Collection (EDDC), the Western Australian Cancer Registry (WACR), the State Registry of Births, Deaths and Marriages, the WA Electoral Commission, and the NCIS for use of the CODURF dataset, and the staff at Data Linkage Branch at the Western Australian Department of Health for their assistance in provision of data. This work was supported by an unrestricted grant from the Arthritis Foundation of Western Australia. Author WDR received a PhD Scholarship in Memory of John Donald Stewart from the Arthritis Foundation of Western Australia.Disclosure of Interests:Johannes (“Hans”) Nossent Speakers bureau: Janssen, Milica Ognjenovic: None declared, warren raymond: None declared, Helen Keen Speakers bureau: Pfizer Austrlaia, Abbvie Australia, Charles Inderjeeth Consultant of: Linear Research Perth, David Preen: None declared

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Gingival recession is defined as the apical migration of the gingival margin from its physiologic level which further causes pathologic exposure of root surfaces. Mucogingival esthetic surgery includes the treatment of mucogingival esthetic alterations. The Mucogingival problems may be caused by gingival recession which is often associated with non-carious cervical lesion or by root caries or by altered passive eruption. Root coverage is achieved by many procedures like free gingival autografts, pedicle graft and connective tissue grafts. Recession can be treated by surgical or non-surgical means. surgical procedure includes various methods of increasing the width of keratinized tissue such as frenectomy in case of high frenal attachment & root coverage procedures and nonsurgical approach include-restorations, crowns, veneers and gingival masks. Lateral displaced pedicle flap was first described by Grupe and Warren in 1956 which was indicated in area to cover isolated apical migration of gingiva, & denuded root surfaces that have adequate amount of donor tissue adjacent to the recipient site. In few clinical studies it is seen that the success rate with Lateral pedicle graft is 70%, it is preferred over free gingival autografts in narrow and shallow gingival defects. This case report present the predictability of root coverage by using Lateral pedicle grafts in single tooth narrow and shallow gingival recession. Keywords: Lateral pedicle graft, Gingival recession, Attachment loss, Graft.

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Kass Banning and Warren Crichlow provide a historical and theoretical assessment of renowned British artist and filmmaker Isaac Julien's ten-screen installation Lessons of the Hour: Frederick Douglass (2019). Lessons of the Hour is inspired by a combination of Douglass's own genre-breaking autobiographical writing, personal letters, and published lectures that mobilized tropes of visuality for his own unique rhetorical ends. With its sculptural multiscreen architecture, lush color palette, and immersive affordances and soundscape, Julien's Lessons is less concerned with rendering a hagiographic portrait of Douglass than in reactivating his visionary thought as a continued force for human rights in the twenty-first century. Lessons underscores that the nascent technology of photography and the renewed struggle for liberation from chattel slavery emerged simultaneously in the mid-nineteenth century; this confluence fosters Douglass's lifelong personal and theoretical inquiry into what both truth and sovereignty—and visuality—might entail.

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Background:Immunoassays are used to measure a range of analytes in clinical laboratories. Rheumatoid factor (RF) and other patient antibodies, such as heterophilic antibodies, can bind animal antibodies used in immunoassays and cause erroneous results, which may lead to misdiagnosis and incorrect treatment of patients.1Objectives:To assess RF reactivity to animal antibodies and to test if selected commercial immunoassays are vulnerable to interference from RF-positive sera.Methods:Samples from 124 patients with RF-positive rheumatoid arthritis (RA) included in the Norwegian Very Early Arthritis Clinic (NOR-VEAC)-cohort2were included in the study. Samples from patients with seronegative RA (n=51) and psoriatic arthritis (n=15) from the same cohort were included as controls. Reactivity to mouse IgG1, mouse IgG2a, rabbit IgG, bovine IgG, sheep/goat IgG and human IgG was analysed using in-house interference assays detecting antibodies able to cross-link the animal or human antibodies. RF-positive sera with strong reactivity to mouse IgG1 were selected for testing in three commercial immunoassays previously shown to be susceptible to interference from heterophilic antibodies; Abbott Architect Total β-hCG assay, BioRad 27-plex cytokine assays and Roche Elecsys Soluble Transferrin Receptor (sTfR).3Samples were tested before and after addition of blocking aggregated murine IgG1 (interference protection). Interference was defined as a discrepancy between the unblocked and blocked samples likely to influence clinical interpretation of the results and exceeding the reported assay imprecision with a considerable margin.Results:We found considerably stronger reactivity toward animal antibodies, particularly mouse IgG1 and rabbit IgG, in sera from RF-positive RA-patients compared to the control group (Fig. 1a-b). In the Abbott β-hCG assay, interference was shown in 6 out of the 30 tested sera (Fig. 2a). In the 27-plex cytokine assays, interference was demonstrated in 7 out of 10 tested sera (for 3-14 analytes). Furthermore, 17 out of the 27 cytokine assays were found to be susceptible to interference (Fig. 2b). Interference was shown in 2 out of 33 samples in the sTfR assay. In unblocked samples, sTfR values were 8.1 and 8.2 mg/L, vs. 4.2 mg/L and 6.0 mg/L in blocked samples, respectively. Additionally, 3 sera had >25% relative difference, but the results were within the reference range.Figure. 1(a-b)Figure. 2(a-b)Conclusion:Reactivity to animal antibodies used in immunoassays is common in sera from RF-positive RA patients and are associated with falsely elevated results in commercial immunoassays. In our cohort, interference was demonstrated in a considerable proportion of samples in the Abbott hCG and 27-plex cytokine assays. Physicians as well as researchers, laboratories and assay manufacturers must be alert to the risk of falsely elevated test results in RF positive RA patients, particularly when results are unexpected or discordant with clinical findings. False test results may interfere with research results, and also lead to potentially harmful diagnostic and therapeutic interventions if unrecognised.References:[1] Bolstad N, et al. Heterophilic antibody interference in immunometric assays.Best Pract Res Clin Endocrinol Metab2013;27(5):647-61.[2] Norli ES, et al. Diagnostic spectrum and 2-year outcome in a cohort of patients with very early arthritis.RMD Open2017;3(2):e000573.[3] Bolstad N, et al. Heterophilic antibody interference in commercial immunoassays; a screening study using paired native and pre-blocked sera.Clinical Chem Lab Med2011;49(12):2001-6.Disclosure of Interests:Johanna Elin Gehin Speakers bureau: Roche, Rolf Anton Klaasen: None declared, Ellen Sauar Norli: None declared, Silje Watterdal Syversen Speakers bureau: Roche, Thermo Fisher, Guro Løvik Goll Consultant of: Novartis, Pfizer, Speakers bureau: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCB, David J Warren: None declared, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Kjell Johannes Nustad: None declared, Maria D Mjaavatten Speakers bureau: Pfizer, Abbott, Nils Bolstad Consultant of: Pfizer, Janssen, Speakers bureau: Orion Pharma, Napp Pharmaceuticals, Takeda, Roche, Novartis

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Background:Lack or loss of response to TNFα-inhibitors can be caused by subtherapeutic drug levels and anti-drug antibodies (ADAb). Knowledge about associations between clinical efficacy and drug levels as well as occurrence of ADAb is limited in patients with inflammatory joint diseases (IJD) treated with golimumab.Objectives:To identify the therapeutic target concentration and assess the frequency of ADAb in golimumab-treated patients with IJD.Methods:91 patients from the NOR-DMARD study with a clinical diagnosis of axial spondyloarthritis (n=41), rheumatoid arthritis (n=20) or psoriatic arthritis (n=30) starting treatment with golimumab, with an available biobank sample at 3 months follow-up, were included. Treatment response was defined by ASDAS Clinically important improvement in axial spondyloarthritis, EWULAR good/moderate response in rheumatoid arthritis and improvement of ≥50% in modified DAPSA (using 28 swollen/tender joint counts) in psoriatic arthritis. Serum drug concentrations were analysed in non-trough samples collected 3 months after treatment initiation, using an automated in-house target-based immunofluorometric assay. ADAb was measured with an inhibition assay that measures neutralising antibodies. The association between drug levels and treatment response was assessed by multivariable logistic regression (adjusted for age, sex and prior bDMARD (Y/N)). Drug-survival was assessed by Kaplan-Meier curves and Cox proportional hazard regression analysis.Results:Golimumab serum concentrations varied considerably between patients on standard dose (range 0.0-8.2 mg/L) with a median of 2.2 (IQR 1.0-3.5) mg/L. The proportions of responders after 3 months among patients with golimumab concentration <1.0, 1.0-3.9 and ≥4.0 mg/L, were 19%, 49% and 74%, respectively (Fig.1). The likelihood of response after 3 months of treatment was significantly higher among patients with serum golimumab concentration ≥1.0 mg/L compared to those with golimumab <1.0 mg/L (OR 5.8 (95% CI 1.7-19.7), P =0.005). The proportion of responders was highest among patients with golimumab concentrations ≥4.0 mg/L, but the difference in response between patients with concentrations ≥4.0 mg/L compared to 1.0-4.0 mg/L was not statistically significant (OR 2.1 (95% CI 0.6-7.1), P=0.24). We also found a higher rate of treatment discontinuation in patients with serum golimumab concentration <1.0 mg/L compared to ≥1.0 mg/L (HR 3.6 (95% CI 1.9-6.9), P <0.001) (Fig.2). ADAb were detected in 5 of 91 samples and were associated with lower drug concentrations. Only 1 out of 5 ADAb-positive patients was a responder at 3 months, and all 5 ADAb positive patients discontinued treatment within the first 14 months.Conclusion:Golimumab concentrations ≥1.0 mg/L were associated with improved treatment response and better drug survival, but our results also indicate that some patients might benefit from higher concentrations. ADAb were associated with lower drug concentrations and both reduced treatment response and drug survival. These findings suggest a rationale for personalised dosing guided by measurements of drug concentration and ADAb in golimumab-treated patients with IJD, which should be addressed in future randomised strategy trials.Disclosure of Interests:Johanna Elin Gehin Speakers bureau: Roche, David J Warren: None declared, Silje Watterdal Syversen Speakers bureau: Roche, Thermo Fisher, Elisabeth Lie: None declared, Joe Sexton: None declared, Liz Loli: None declared, Ada Wierød: None declared, Trine Bjøro: None declared, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Nils Bolstad Consultant of: Pfizer, Janssen, Speakers bureau: Orion Pharma, Napp Pharmaceuticals, Takeda, Roche, Novartis, Guro Løvik Goll Consultant of: Novartis, Pfizer, Speakers bureau: Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche, UCBTable 1.Change in FVC(ml) and DLCO% in the 6–12 months before and after different treatmentTreatment groupPre-TxPost-TxpR9.8% (11)FVCDLCO2015±74672.4±17.22024±80360.7±27.90.780.43CYC25.0% (28)FVCDLCO1853±58561.2±23.81796±57861.4±23.90.740.79R+CYC17.9% (20)FVCDLCO1901±66758.2±14.51922±67246.7±18.80.900.90Non-R, CYC47.3% (53)FVCDLCO2177±65746.7±18.82286±70445.8±19.60.470.69SubgroupUIP31.3% (35)FVCDLCO2053±72158.9±22.71949±72749.3±25.10.570.15Non-UIP68.8% (77)FVCDLCO(%)1908±60859.0±18.71961±65460.5±1850.530.46Table 2.Secondary outcome and multivariable Cox model for overall survival

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Abstract Abstract 1385 Bruton tyrosine kinase (Btk), a member of the Tec family kinases, has a well-characterized role in B-cell antigen receptor (BCR) signaling and B-cell activation. Btk is activate by Src family kinases which lead to downstream activation of essential cell survival pathways such as NF-κB and MAP kinase. Although Btk is expressed in multiple hematopoietic cells, the primary defect in Btk knockout mice is B-cell specific, suggesting a more selective B-cell function consistent with its role in the BCR signaling pathway. Btk was identified in an unbiased screen as an essential signaling kinase for survival of certain lymphomas including diffuse large B-cell lymphoma, but no information is available about its role in CLL cell survival. Inhibition of Btk by PCI-32765, a selective irreversible Btk inhibitor, has demonstrated promising clinical activity in an ongoing phase 1 study in B-cell non-Hodgkin lymphoma. We therefore hypothesized that inhibition of Btk would induce cytotoxicity in B-CLL cells. BTK protein expression was observed in CLL cells, but not NK or T-cells as previously reported. Surprisingly, significant variability in BTK expression was noted among different CLL patient samples. Treatment of primary CLL cells with PCI-32765 at concentrations ranging from 0.1–10μM resulted in significant cell killing compared to untreated control. At a 10μM concentration, PCI-32765 resulted in a median 73% viable cells at 48 hours as detected by annexin V/propidium iodide flow cytometry (n=55). Although again, considerable variability was observed among patient samples (range 93.5–5.5%). We found no correlation between response to PCI-32765 and prognostic factors such as interphase cytogenetics or IgVH gene mutational status, suggesting a potential clinical benefit to even high-risk CLL patients. To determine the selectivity of PCI-32765, we evaluated cytotoxicity of lymphocytes derived from healthy volunteers. At 10μM, PCI-32765 resulted in a median 90% viable normal B-cells with little variability (n=5), showing substantially lower cytotoxicity in normal B-cells relative to CLL tumor cells. The cytotoxicity observed with PCI-32765 in CLL cells was accompanied by PARP cleavage and the induction of caspase 3 activity, and PCI-32765-mediated cell death was blocked by the pan-caspase inhibitor z-VAD-fmk (n=3). These results indicate that PCI-32765 is dependent on caspase activation for its ability to induce apoptosis in CLL cells. Further studies to determine the apoptotic mechanism showed that PCI-32765 treatment (10μM) partially reversed CD40L- or CpG-induced phosphorylation of ERK1/2 and also caused an increase in endoplasmic reticulum-derived intracellular calcium flux in CLL cells (n=8). Microenvironmental factors such as CD40L, TNF-α, IL-6 and BAFF can induce activation of CLL and/or decrease spontaneous apoptosis. Treatment of CLL cells with PCI-32765 prevented the protective anti-apoptotic effect promoted by these cytokines, suggesting that this agent can overcome the protection induced by microenvironmental stimuli. Similarly, co-culture of CLL cells on the human stromal cell line HS-5 significantly decreases the spontaneous apoptosis of CLL cells. PCI-32765 treatment was able to overcome this stromal protection, and induced apoptosis comparable to cells cultured in suspension (median cytotoxicity 86% vs. 84%, respectively; 10μM PCI-32765 at 48 hr, n=5). This suggests that the cytotoxic effect elicited by PCI-32765 will not be significantly diminished by the presence of an in vivo microenvironment. Taken together, our results suggest that PCI-32765 acts directly on CLL cells to induce apoptosis and helps to block microenvironment-derived protection. These investigations demonstrate the efficacy of targeting Btk in CLL and provide preclinical validation for ongoing Phase 1/2 clinical trials for the treatment of this disease. This work is supported by the Leukemia and Lymphoma Society, D. Warren Brown Foundation and The OSU Leukemia SPORE grant funded by the NCI. Disclosures: Buggy: Pharmacyclics, Inc.: Employment. Hamdy:Pharmacyclics, Inc.: Employment.

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The article presents the efforts of Krzysztof Zawisza the warden of Minsk to receive the money promised to him by August II. It was a gift from the king to reward the loyalty and service that Zawisza gave to the monarch. It took over 20 years to get the money because Michal Kociell the Lithuanian treasurer was the personal enemy of Zawisza. Nevertheless some part of the promised sum went to his hands. The purpose of the article is to show the conflict over the payment of money, and in this example to show the specificity of political relations in the Grand Duchy of Lithuania and the Polish-Lithuanian Commonwealth at the turn of the 17th and 18th centuries. The article is based on archival materials and raises an important topic for the history of the former lands of the Grand Duchy of Lithuania.

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<p>The analysis of a 6-year patient’s medical history after correction of congenital heart disease (partial anomalous drainage of the right superior pulmonary vein into the superior vena cava) complicated by obstruction of the anastomosis between the SVC and the appendage right atrium is presented. The article discusses the stages of diagnosis and patient management features, as well as the choice of treatment.</p><p>Received 12 December 2016. Accepted 14 February 2017.</p><p><strong>Financing:</strong> The study did not have sponsorship.</p><p><strong>Conflict of interest:</strong> The authors declare no conflict of interest.</p><p>Svyazov E.A.: data analysis, article writing and editing. Podoksenov A.U.: article editing. Varvarenko V.I.: implantation of the stent-graft in superior vena cava.Martsinkevich G.I.: echocardiographic examination of the patient before and after endograft implantation, article editing. Krivoshchyokov E.V.: organizational work and referral of the patient to endovascular treatment, article editing.</p>

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Abstract Abstract 38 Introduction: During storage, red blood cells (RBC) undergo progressive deleterious functional, biochemical and structural changes, producing a “storage lesion”. The storage lesion includes reversible and irreversible changes that begin within hours of storage, progress during storage, release free hemoglobin (Hb) and Hb-containing microvesicles, and impair RBC function and lifespan after transfusion. Our recent studies in mice with endothelial dysfunction revealed an enhanced systemic vasoconstrictor response to infusion of tetrameric Hb or Hb-based oxygen carriers. Therefore, we sought to test the hypothesis that endothelial dysfunction would predispose mice to the vasoconstrictor effects of infusion of fresh and stored murine blood. Methods: Murine leukoreduced RBC from C57BL/6 mice were prepared with 14% CPDA-1 anticoagulant and stored at 4°C for either ≤24 h (fresh red blood cells, FRBC) or 2 weeks (stored red blood cells, SRBC). RBC morphology, as well as ATP levels, 2,3-diphosphoglycerate (2,3-DPG) levels, and P50 were measured in FRBC and SRBC before transfusion. We also prepared murine RBC storage components, i.e. supernatant from FRBC or SRBC, oxidized supernatant from SRBC, and washed SRBC. We studied three groups of mice, awake wild-type mice (WT, C57BL/6) fed a standard diet, WT mice fed a high-fat diet (HFD) for 4–6 weeks (to induce endothelial dysfunction), and diabetic (db/db, C57BL/6 background) mice. Each group was transfused with FRBC, SRBC, and db/db mice also received RBC components (10% of total blood volume). Systolic blood pressure (SBP) was measured every 10 min in awake mice before and 2 h after transfusion with FRBC, SRBC or RBC components. A subgroup of mice transfused with SRBC also breathed air (FiO2=0.21) supplement with nitric oxide (NO, 80 parts per million (ppm)). Invasive hemodynamic measurements were performed in anesthetized mice in order to obtain mean arterial blood pressure, heart rate, and cardiac output. Blood and tissue samples were collected 2 h after FRBC or SRBC transfusion for determination of plasma Hb and iron levels, and measurement of lung and liver levels of mRNA encoding inflammatory cytokines. In addition, heme oxygenase-1 (HO-1) in lung and liver was measured 2 h after FRBC or SRBC transfusion. Results: SRBC were characterized by altered RBC morphology, decreased ATP and 2,3-DPG levels, and a reduced P50. Transfusion of SRBC into awake WT mice fed a standard diet or HFD produced no systemic hemodynamic changes. In contrast, transfusion of SRBC or supernatant from SRBC into db/db mice induced systemic hypertension that was prevented by concurrent inhalation of NO. Infusion of washed SRBC or oxidized SRBC supernatant into db/db mice did not induce systemic vasoconstriction or hypertension. Invasive hemodynamic studies confirmed that transfusion of SRBC and SRBC supernatant induced systemic vasoconstriction and hypertension, but transfusion of washed SRBC did not. Plasma Hb levels were greater in all mouse groups at 2 h after transfusion of SRBC but not after FRBC transfusion. Two hours after transfusion of SRBC, plasma interleukin-6 and iron levels, as well as hepatic HO-1 mRNA levels, were increased in all mouse groups. Conclusions: Syngeneic transfusion of SRBC or only the supernatant from SRBC but not washed SRBC produces systemic hypertension and vasoconstriction in db/db mice, which is prevented by oxidizing the supernatant of SRBC or breathing NO during SRBC transfusion. Infusion of SRBC induced a mild systemic inflammatory response in WT fed a standard diet or HFD, and db/db mice. Transfused cell-free oxyHb in the supernatant released from RBC during storage appears to be responsible for the vasoconstriction produced in db/db mice, since it is prevented by oxidizing the supernatant. Our current data support examining the link between the RBC storage lesion and cardiovascular and immunological perturbations in highly susceptible recipients with endothelial dysfunction. Disclosures: Yu: Massachusetts General Hospital: patents on inhaled nitric oxide and blood transfusion. Bloch:MGH has received sponsored research grant funding from Ikaria LLC, the maker of nitric oxide gas for inhalation in the US, in support of Dr. Bloch's research program.: Research Funding. Zapol:Dr. Warren Zapol receives royalties from patents on inhaled nitric oxide licensed by Massachusetts General Hospital to Linde Corp, Munich, Germany, and Ikaria Corp, Clinton, New Jersey. Dr. Zapol has applied for patents on inhaled nitric oxide and blood t: Patents & Royalties.

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The transcript of a panel discussion marking three decades of the real business cycle approach to macroeconomic analysis as manifested in Kydland and Prescott's “Time to Build” (Econometrica, 1982) and Long and Plosser's “Real Business Cycles” (Journal of Political Economy, 1983). The panel consists of Edward Prescott, Finn Kydland, Charles Plosser, John Long, Thomas Cooley, and Gary Hansen. The discussion is moderated by Sumru Altug and Warren Young. The panel touches on a wide variety of issues related to real business cycle models, including their history and methodology, starting with the work of Prescott and Kydland at Carnegie Tech and Plosser and Long at Rochester; their applications to policy; and their role in the recent financial crisis and likely future.The panel discussion was held in a session sponsored by the History of Economics Society at the Allied Social Sciences Association (ASSA) meetings in the Randle A Room of the Manchester Grand Hyatt Hotel in San Diego, California.

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In this essay, I provide evidence that a new generation of prochoice advocates wishes to move away from defending abortion rights via the view that fetal life has little or no value (for example, as Mary Anne Warren does in her “On the Moral and Legal Status of Abortion”) and toward a more complex view of abortion rights. This newer view simultaneously grants that fetuses are more than simply “clumps of cells,” that they are, to some extent, entities that possess some degree of value, and also that women still have the right to decide whether they wish to continue a pregnancy (for example, as can be found in the writings of Rosalind Hursthouse, Judith Jarvis Thomson, and Margaret Olivia Little). Prima facie, this may sound like an impossible task—an instance of “having your cake and eating it too”—but I will show throughout my paper that, and how, such a task can indeed be accomplished.

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Abstract Abstract 39 Introduction: During extended storage, red blood cells (RBCs) undergo biochemical, mechanical, and functional changes. These changes reduce the viability of RBCs, resulting in elevated levels of the potent nitric oxide (NO) scavenger oxyhemoglobin in plasma. Recent studies have shown enhanced systemic vasoconstriction after challenge with tetrameric hemoglobin in murine endothelial dysfunction models. Based on human blood storage techniques, we developed and validated a new model for autologous transfusion of stored RBCs in lambs. We hypothesized that autologous transfusion of leukoreduced ovine RBCs stored for prolonged periods of time would increase plasma hemoglobin levels and induce pulmonary hypertension. We further hypothesized that inhalation of NO would prevent, and endothelial dysfunction would augment the pulmonary vasoconstriction induced by transfusing blood stored for prolonged periods. Methods: We studied three- to four-month-old Polypay lambs weighing 32±2 kg. Similar to current blood bank practices, leukoreduced ovine RBCs were stored in Adsol solution (additive solution-1, AS-1) for either 2 days (fresh red blood cells, FRBCs) or 40 days (stored red blood cells, SRBCs). Post-transfusion recovery of circulating biotinylated FRBCs (n=4) and SRBCs (n=4) was determined by flow cytometry. In separate experiments, 300 ml of autologous FRBCs (n=5) or SRBCs (n=6) were transfused over 30 min into awake lambs, which had been instrumented with carotid artery and pulmonary artery catheters under isoflurane anesthesia. Systemic and pulmonary hemodynamic parameters were measured continuously during and for 4 h after the transfusion. An additional group of animals receiving SRBCs concurrently inhaled 80 parts per million NO (n=4) at FiO2 0.25. We also studied the effects of transfusing FRBCs (n=4) or SRBCs (n=5) in lambs after acutely inducing endothelial dysfunction by IV injection of 25 mg·kg−1 of NG-nitro-L-arginine methyl-ester (L-NAME). An infusion of 5 mg·kg−1·h−1 L-NAME was continued throughout the experiment. Plasma hemoglobin and IL-6 levels were determined before and after transfusion. Tissue samples from the lung and liver were harvested 4 h after transfusion. Relative mRNA levels of inflammatory markers (IL-6, TNF-alpha, and myeloperoxidase) were measured by qPCR. All data are expressed as mean ± SEM. Results: Hemoglobin (41±6 vs. 148±8 mg/dl), potassium (3.7±0.4 vs. 7.9±0.9 mmol/l), and lactate levels (1.7±0.2 vs. 5.9±0.9 mmol/l) were higher in the supernatants of SRBCs than in those of FRBCs. Recovery of circulating biotinylated RBCs 24 h after autologous transfusion was 96±2% in FRBCs and 76±3% in SRBCs. Pulmonary arterial pressure (PAP) transiently increased from 13±0.3 to 18±1 mmHg (p<0.01) and pulmonary vascular resistance index (PVRI) from 108±8 to 156±14 dyne·sec·cm−5·m−2 (p<0.05) during the transfusion of SRBCs, but not FRBCs. This increase of PAP was temporally associated with an increase in plasma concentrations of hemoglobin. Transfusion of SRBCs did not produce systemic vasoconstriction. Concurrent inhalation of NO prevented the pulmonary vasoconstrictor effect induced by transfusing SRBCs, whereas the infusion of L-NAME potentiated the increase in PAP (16±0.3 to 26±2 mmHg, p<0.01) and PVRI (170±15 to 312±38 dyne·sec·cm−5·m−2, p<0.05) associated with transfusion of SRBCs. Plasma IL-6 levels did not change after transfusion of FRBCs or SRBCs. Lung and liver levels of mRNAs encoding inflammatory markers (IL-6, TNF-alpha, and myeloperoxidase) measured 4 h after transfusion did not differ in lambs receiving FRBCs or SRBCs. Conclusions: Ovine RBCs stored for 40 days have many in vitro storage properties and a post-transfusion recovery percentage similar to stored human RBCs. Autologous transfusion of leukoreduced SRBCs induces transient pulmonary hypertension associated with increased cell-free hemoglobin levels. This vasoconstrictor effect is increased in a model of L-NAME-induced endothelial dysfunction. Therefore, patients with disorders associated with pulmonary endothelial dysfunction might be more sensitive to pulmonary vasoconstriction associated with transfusion of SRBCs. Disclosures: Yu: Massachusetts General Hospital: Patents & Royalties. Bloch:MGH has received sponsored research grant funding from Ikaria LCC, the producer of NO gas in the US, in support of Dr. Bloch's research program: Research Funding. Zapol:Dr. Warren Zapol receives royalties from patents on inhaled nitric oxide licensed by Massachusetts General Hospital to Linde Corp, Munich, Germany, and Ikaria Corp, Clinton, New Jersey. Dr. Zapol has applied for patents on inhaled nitric oxide and blood t: Patents & Royalties.

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Background:Immunogenicity is related to loss of efficacy and safety to TNFα inhibitors and is frequently observed early in the treatment course. The highest rate of anti-drug antibody (ADAb) formation has been reported for infliximab (IFX). 1 Knowledge about risk factors for immunogenicity might contribute to better handling of this problem in clinical practice.Objectives:To identify risk factors for ADAb formation during the early phase of IFX treatment.Methods:411 patients with immune-mediated inflammatory diseases (84 rheumatoid arthritis (RA), 119 spondyloarthritis (SpA), 45 psoriatic arthritis, 83 ulcerative colitis, 58 Crohn’s disease and 22 psoriasis) initiating IFX treatment were included in the 38-week NOR-DRUM A trial and randomised 1:1 to therapeutic drug monitoring or standard IFX therapy.2 The primary endpoint was clinical remission at week 30. Serum (s) IFX levels and ADAb were measured at each infusion by in-house assays; time-resolved fluorometric assay for sIFX and inhibition assay for ADAb.2 In this sub-study, possible risk factors for ADAb formation including demographic variables, diagnosis, comedication, disease activity, IFX dose, sIFX and drug holidays, were assessed using logistic regression. Variables with a p-value <0.25 in univariate analyses were further examined in multivariate analyses adjusting for potential confounders (diagnosis, disease activity, age and gender).Results:410 of 411 patients had at least one measurement of sIFX and were included in the present analyses. 76% of patients were biologic-naive and 45% (18% of RA patients) used IFX as monotherapy. Patients received a mean IFX dose of 3.2-5.9 mg/kg (RA 3.2 mg/kg). ADAb were detected in 78 (19%) patients. The Table 1 shows variables with a significant association to ADAb development. Analyses revealed an increased risk of ADAb development in patients with RA (Odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-3.9), while SpA had a lower risk (OR 0.5, CI 0.2-0.9) compared to the other diagnoses. These findings were consistent in both univariate- and multivariate analyses (Table 1). Figure 1 shows the cumulative hazard for ADAb development according to diagnosis. Other risk factors for ADAb (Table 1) were smoking (OR 1.8, CI 1.0-3.3) and drug holidays of more than 12 weeks (OR 4.7, CI 1.2-18.3). Additionally, the risk of ADAb increased with higher disease activity (OR 1.5, CI 1.0-2.3) and lower sIFX levels (0.7, 0.6-0.8). Patients co-treated with methotrexate (OR 0.4, CI 0.2-0.9) or thiopurines (OR 0.3, CI 0.1-0.8), or having one or more IFX dose increments (OR 0.4, CI 0.3-0.8), had a reduced risk of immunogenicity.Table 1.Risk factors for ADAb. Results from logistic regression analysesUnivariate analysesMultivariate analyses (Adjusted for diagnosis, disease activity, age and gender)ORCIORCIRA2.2**[1.3,3.8]2.1*[1.1,3.9]SpA0.4**[0.2,0.8]0.5*[0.2,0.9]Methotrexate1.1[0.7,1.9]0.4*[0.2,0.9]Thiopurine0.3*[0.1,0.9]0.3*[0.1,0.8]Current or former smoking2.2**[1.3,3.8]1.8*[1.0,3.3]Mean sIFX0.7***[0.6,0.8]0.7***[0.6,0.8]>12 weeks between infusions4.5*[1.3,16.0]4.7*[1.2,18.3]IFX dose increment0.5*[0.3,0.9]0.4**[0.3,0.8]Mean DAS28 (RA and PsA)1.5*[1.0,2.1]1.5*[1.0,2.3]Mean ESR1.1***[1.0,1.1]1.1***[1.0,1.1]Mean CRP1.1**[1.0,1.1]1.1**[1.0,1.1]* p<0.05, ** p<0.01, *** p<0.001Only variables with a p-value <0.05 are shown. Non-significant variables include other demographic variables and IFX dose.Conclusion:This study identified smoking, drug holidays, high disease activity, IFX monotherapy and low sIFX levels as risk factors for ADAb development. Of particular interest, we found that RA patients had significantly increased risk of ADAb compared to the other immune-mediated inflammatory diseases. Whether this novel finding reflects different underlying disease mechanisms or the fact that RA patients receive a lower IFX dose, is not known and needs to be further explored.References:[1]Thomas SS et al. BioDrugs 2015;29(4):241-58 2 Syversen SW et al. Trials 2020 6;21(1):13Disclosure of Interests:Marthe Kirksæther Brun: None declared, Guro Løvik Goll Speakers bureau: Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion pharma, Sandoz and Novartis, Kristin Kaasen Jørgensen Speakers bureau: Celltrion, AOP Orphan Pharmaceuticals and Norgine, Joe Sexton: None declared, Johanna Elin Gehin Speakers bureau: Roche, Øystein Sandanger: None declared, Inge Olsen: None declared, Rolf Anton Klaasen: None declared, David J Warren: None declared, Cato Mørk Speakers bureau: Novartis Norge AS, LEO Pharma AS, ACO Hud Norge AS, Cellgene AS, Abbvie, Galderma Nordic and UCB, Tore K. Kvien Speakers bureau: TAmgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz and Sanofi, Consultant of: AbbVie, Amgen, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz and Sanofi, Grant/research support from: Research funding to Diakonhjemmet Hospital from AbbVie, Amgen, BMS, MSD, Pfizer and UCB, Jørgen Jahnsen: None declared, Nils Bolstad Speakers bureau: Roche Pharmaceuticals and Novartis, Consultant of: Janssen, Espen A Haavardsholm Speakers bureau: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly and UCB, Silje Watterdal Syversen Speakers bureau: Thermo Fisher.

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Abstract Autologous peripheral blood stem cell (PBSC)–supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.

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Our National Parks house some of North America's most undisturbed habitat and offer a benchmark for comparing ecosystem dynamics with areas more influenced by human related perturbations. Dam construction has altered water flow patterns on many of our country's rivers resulting in species composition changes of aquatic plants, invertebrates and fish. Semi-aquatic mammals such as otters and beaver are also profoundly influenced by the irregular seasonal flow patterns resulting from reservoir release schedules. For example, Jackson Lake dam was constructed in 1910 resulting in the impoundment of an additional 625,000 cubic feet of water. Since its construction and the establishment of Grand Teton National Park (GTNP), this water has been released during mid- to late summer months causing unpredictable fluctuations of river levels after the normal spring run off. This unpredictability is illustrated by the trend in water flow on the Snake River at Moran for the period 1904-2000 (Figure 1). A species that has received little attention in terms of population numbers and resistance to abnormal water fluctuations resulting from Jackson Dam is the beaver (Castor canadensis). In GTNP, only the work of Collins (1976) has provided any significant knowledge of the distribution and habitat of the beaver in the Park. In fact, the beaver has been generally overlooked in the Greater Yellowstone Area with only a few studies conducted in Yellowstone (Warren, 1926; Jonas, 1955; Consolo-Murphy and Hanson, 1993 ).

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Nanoparticles of Pt–Rh were studied by means of lattice-based Monte Carlo simulations with respect to the stability of ordered D022- and 40-phases as a function of particle size and composition. By thermodynamic integration in the semi-grand canonical ensemble, phase diagrams for particles with a diameter of 7.8 nm, 4.3 nm and 3.1 nm were obtained. Size-dependent trends such as the lowering of the critical ordering temperature, the broadening of the compositional stability range of the ordered phases, and the narrowing of the two-phase regions were observed and discussed in the context of complete size-dependent nanoparticle phase diagrams. In addition, an ordered surface phase emerges at low temperatures and low platinum concentration. A decrease of platinum surface segregation with increasing global platinum concentration was observed, when a second, ordered phase is formed inside the core of the particle. The order–disorder transitions were analyzed in terms of the Warren–Cowley short-range order parameters. Concentration-averaged short-range order parameters were used to remove the surface segregation bias of the conventional short-range order parameters. Using this procedure, it was shown that the short-range order in the particles at high temperatures is bulk-like.

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Dry bean (Phaseolus vulgaris L.) is grown under an extensive range of agro-climatic conditions and is an essential source of protein and income globally. This study aimed to evaluate yield performance, stability, and bacterial brown spot (BBS) disease resistance of fourteen dark red kidney genotypes across environments in South Africa namely Carolina, Clarens, Cedara, Middelburg, Potchefstroom, and Warden. Analysis of variance (ANOVA), additive main effects and multiplicative interaction (AMMI) and the genotype plus genotype by environment interaction (GGE-biplot) analysis were used to evaluate grain yield performance, stability, and BBS disease resistance. The AMMI ANOVA revealed that mean squares for grain yield and BBS severity for the environment, genotype, and genotype by environment interaction were highly significant (P<0.001). Four interaction principal components (IPCA1 - 4) for grain yield and IPCA1 for BBS severity were highly significant (P<0.001, P<0.01). Genotype G12 showed broad adaptation for both high grain yield and low BBS severity across the six environments, while genotypes G08, G06, G03, G02, G05, and G04 had specific adaption for high grain yield and low BBS severity. These genotypes recorded grain yield above the grand mean and the best check cultivar, both with 1.43 t ha-1 , and BBS severity below the grand mean (31.90%) and the best check (48.89%). The genotypes identified with either broad or specific adaptation can be released in the environments they are adapted to, or used as parents in breeding programmes aiming to improve grain yield and BBS disease resistance of dry bean for farmers in South Africa.

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AbstractFor geologists and antiquaries of the late 1850s debates over ancient stone tools were frustrated by a lack of accepted criteria. The artefacts were hard to interpret. It was not self-evident how to judge whether they were ancient or modern, natural or man-made; or indeed whether stone tools could pre-date the use of metal tools at all. Antiquary and papermaker John Evans provided a system that offered to resolve these issues. His criteria and his use of re-enactment, making his own stone implements, gained acceptance among flint experts across fluid disciplinary boundaries and enabled authoritative interpretations of the underdetermined objects. This paper explores how Evans drew on the concerns of his industrial culture to make sense of prehistoric artefacts and support his claim to access the past through his own actions. Situated industrial concerns provided the resources for his flint work: from a patent dispute with astronomer and fellow industrialist Warren de la Rue, through his role in the Victorian arms trade, to the struggle to displace skilled manual labour in his factories. Evans is remembered for pioneering the techniques and classificatory system of modern Palaeolithic archaeology and as one of the founders of the re-enactment science of experimental flint knapping. His work played a significant role in helping reconceive the antiquity of man, yet the system of proof for this grand claim was deeply situated in his industrial culture. This paper explores how the industrial resources of a Victorian papermaker made human history.

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Bacterial brown spot (BBS) disease caused by Pseudomonas syringae pv. syringae is an important disease of dry bean (Phaseolus vulgaris L.), with grain yield losses of 55% reported in South Africa. This study aimed to identify BBS disease-resistant genotypes from 415 Andean Diversity Panel (ADP) dry bean lines and 5 check cultivars under field conditions across three sites in South Africa: Warden and Middelburg under natural infestation and Potchefstroom under artificial inoculation. Plants at Potchefstroom were inoculated with P. syringae pv. syringae using three isolates at 21, 28, and 36 days after planting, and disease scoring was done at 7, 14, and 21 days after inoculation following a modified 1 to 9 International Centre for Tropical Agriculture (CIAT) scale. The BBS severity percentage and the area under the disease progress curve (AUDPC) were applied to quantify the reaction of bean genotypes to BBS disease. The study identified 17.2% of evaluated germplasm as resistant and 45.3% as moderately resistant. Genotypes ADP-0592, ADP-0790, ADP-0120, and ADP-0008 were selected for both resistance and high seed yield across the three environments. Genotypes ADP-0546, ADP-0630, ADP-0120, and ADP-0279 were selected for both high yield and resistance at Warden, whereas ADP-0038, ADP-0721, and ADP-0790 were selected for both traits at Middelburg, and lastly, ADP-0120 and ADP-0079 were selected for both traits at Potchefstroom. The best genotypes selected for both high yield and BBS resistance had grain yield >1.45 t ha−1 across sites and >1.85 t ha−1 at individual sites, and they out yielded the best-performing check cultivar (1.13 t ha−1) and the grand mean yield (0.87 t ha−1) across sites. The AUDPC had a strong negative correlation (r = −0.55, P < 0.001) with grain yield at Potchefstroom. Medium-seeded genotypes showed a lower AUDPC than the large-seeded genotypes, and indeterminate genotypes showed a lower AUDPC than determinate genotypes. The genotypes selected for resistance and yield can be utilized in future dry bean improvement efforts for the South African bean market.

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ZusammenfassungGefäß(endo)protheseninfektionen (GEPI) nach offener Chirurgie oder nach interventioneller Behandlung sind gefürchtete Komplikationen mit weitreichenden Konsequenzen für die betroffenen Patienten. Die Morbiditäts- und Mortalitätsraten des heute immer noch weitgehend gültigen Goldstandards, nämlich die radikale Prothesenentfernung mit in-situ oder extraanatomischer Rekonstruktion, teilweise kombiniert mit plastisch-chirurgischer Deckung, sind generell hoch. 2013 initiierten wir am Universitätsspital Zürich (USZ) deshalb die prospektive Vascular-Graft-(VASGRA)-Kohortenstudie mit dem Ziel, generell vorhandene Unsicherheiten und Unklarheiten bezüglich GEPI zu erforschen und einen allgemeingültigen Managementpfad für GEPI Szilagyi Grad 3 bzw. Samson Grad 3–5 zu entwickeln. Der neue Ansatz bestand darin, extra- und intrakavitäre GEPI mit einem möglichst minimal-invasiven, die Prothese erhaltenden oder teilerhaltenden Konzept unter lokaler NPWT multidisziplinär zu behandeln und zu erforschen. Zum gegenwärtigen Zeitpunkt haben wir umfassende Informationen zu 180 prospektiven Patienten mit GEPI in der Datenbank. Die Indexoperationen bei diesen Patienten mit nachgewiesenem GEPI waren Operationen der thorakalen Aorta (55), Operationen der abdominalen Aorta und/oder Iliakalarterien (92) und infrainguinale Gefäßoperationen (33). Die zensurierte 2‑Jahresmortalität der intrakavitären GEPI beträgt 25 %, diejenige der extrakavitären GEPI ist, nicht signifikant, leicht darunter. Die durch einen GEPI direkt bedingte Langzeit-Mortalität in der VASGRA-Kohortenstudie beträgt 8 %. Zur niedrigen Kurz- und Langzeitmortalität beigetragen haben unserer Ansicht nach das von Beginn weg gelebte multidisziplinäre Gesamtkonzept und neu gewonnene Erkenntnisse der Bildgebung und mikrobiologischen Diagnostik.

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For almost six and a half centuries, the wardens (and later the Deans) of St George's Chapel have been lodged in the extreme north-east corner of the Lower Ward at Windsor Castle. From fairly modest beginnings, the house developed into a much grander building, after the construction of a huge new chapel in the late fifteenth century. After the Elizabethan settlement it developed further and was a childhood home of Sir Christopher Wren, before being vandalized in the Commonwealth period. Following the Reformation, it was reconstructed and then given a grand new front in 1710 for the first of a series of aristocratic Deans. The final major rebuilding was carried out in 1831 immediately after the demise of George IV, and the house was used by Queen Victoria as a sort of ‘confessional’ and very private access to the royal pew after her widowhood. Today it is still a fine house after being reduced in size for twentieth-century Deans who do not have large families and many servants. Its rendered south front can still be seen immediately behind the buttressed east end of the Albert Memorial Chapel (fig. 1).

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For almost six and a half centuries, the wardens (and later the Deans) of St George's Chapel have been lodged in the extreme north-east corner of the Lower Ward at Windsor Castle. From fairly modest beginnings, the house developed into a much grander building, after the construction of a huge new chapel in the late fifteenth century. After the Elizabethan settlement it developed further and was a childhood home of Sir Christopher Wren, before being vandalized in the Commonwealth period. Following the Reformation, it was reconstructed and then given a grand new front in 1710 for the first of a series of aristocratic Deans. The final major rebuilding was carried out in 1831 immediately after the demise of George IV, and the house was used by Queen Victoria as a sort of ‘confessional’ and very private access to the royal pew after her widowhood. Today it is still a fine house after being reduced in size for twentieth-century Deans who do not have large families and many servants. Its rendered south front can still be seen immediately behind the buttressed east end of the Albert Memorial Chapel (fig. 1).

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Zusammenfassung Nach 1815 wurde in vielen deutschen Staaten die allgemeine Wehrpflicht eingeführt. Diese war nötig geworden, um die Vergrößerung der Armeen möglich zu machen. Die allgemeine Verpflichtung zum Wehrdienst enthielt allerdings die Möglichkeit, sich von einem Ersatzmann vertreten zu lassen. Der Aufsatz analysiert den Austausch der Rekruten durch Stellvertreter sowie die damit verbundenen Ausgaben im Großherzogtum Hessen. Dabei wird besonders auf den Anspruch der Regierung fokussiert, die Rekruten, die für die Armee von großer funktioneller Bedeutung waren, in ihrem Sinne zu beeinflussen. Das politische Ziel war es, ihre Loyalität zu stärken, da die meisten Unteroffiziere aus den Rängen der Wehrpflichtigen stammten. Sie mussten die militärische Ordnungs aufrecht erhalten und sie den neuen Rekruten beibringen. Daher war eine Auswahl unter den Rekruten durch die Regierung zweckdienlich und wurde trotz liberaler Gegenwehr in den 1830er Jahren durchgeführt. Das Kriegsministerium gründete zu diesem Zweck das Einstandbüro, das für den Austausch der Rekruten durch Ersatzmänner verantwortlich war. Ein Versicherungsunternehmen, die Assekuranzanstalt, unterstützte das Büro mit den notwendigen Geldern, wodurch die Regierung die kommerziellen Rekrutieranstalten um ihre Geschäftsgrundlage brachte und diese Form der Armeevergrößerung monopolisierte. Dass es möglich war, eine derartige Versicherung gegen den Militärdienst abzuschließen, war Gegenstand der Kritik. Jedoch gab es auch in anderen deutschen Staaten die Möglichkeit, durch den Ersatz eines Rekruten Geld zu verdienen, was die hessische Praxis, Geld gegen Freiheit einzutauschen, in einen strukturellen Kontext stellt.

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District commissariats and wójtostwa in Wielkopolska 1919–1935. Some remarks about their practical operationsThe Distriktsämter which functioned in the Grand Duchy of Poznań were renamed district commissariats after Wielkopolska was incorporated into Poland in 1919. They were headed by district commissars, whose scope of responsibilities was virtually the same as in the partition period. First of all, they performed police and administrative functions on the basis of a number of laws and regulations from the partition period adapted to the new Polish reality. In 1928 district commissariats in Wielkopolska were renamed district wójtostwa; each was headed by a wójt. A wójt was responsible for the finances of his wójtostwo and the various communes within it. District commissars and then wójtowie helped starosts with their administrative duties. In addition, they performed functions entrusted to them by other official bodies.Die Kommissariate und Bezirksvogteien in Großpolen 1919–1935. Einige Bemerkungen über ihre praktische TätigkeitDie im Großherzogtum Posen tätigen Distriktämter wurden nach dem Anschluss Großpolens an Polen in Bezirkskommissariate umbenannt. An ihrer Spitze standen die Bezirkskommissare, die grundsätzlich den selben Tätigkeitsbereich hatten, wie in der Besatzungszeit. Sie übten vor allem polizeiliche und administrative Funktionen aus und basierten dabei auf zahlreichen, an die polnischen Gegebenheiten angepassten Gesetzen und Vorschriften aus der Besatzungszeit.Im Jahre 1928 wurden die Bezirkskommissariate zu Bezirksvogteien mit Vögten an ihrer Spitze. Sie waren für die Finanzwirtschaft der Vogteien verantwortlich und beaufsichtigten die Finanzwirtschaft der einzelnen Gemeinden.Die Bezirkskommissare, und dann die Vögte unterstützten den Starost bei der Ausübung der administrativen Gewalt. Sie erfüllten auch Funktionen, die ihnen durch andere Ämter übertragen wurden.

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Zusammenfassung Einleitung Eine Stentprotheseninfektion nach endovaskulärer Versorgung ist eine seltene, jedoch schwere Komplikation mit hoher Mortalität. Aufgrund der steigenden Anzahl von endovaskulären Eingriffen ist mit einer Zunahme von Stentprotheseninfektionen zu rechnen. Eine einheitliche Leitlinie zu Diagnostik und Therapie dieses Krankheitsbilds existiert nicht. Die Datenlage beruht auf Fallberichten, retrospektiven Untersuchungen und Metaanalysen, oft aus der offenen Aortenchirurgie. Die Diagnosestellung kann mitunter schwierig sein. Die Klinik des Patienten, die Bildgebung und der kulturelle Erregernachweis sind entscheidend. Wenn möglich sollte eine Sanierung des Infektfokus mit Ausbau der infizierten Prothese erfolgen. Verschiedene Verfahren und Materialien kommen hierbei zum Einsatz. Zusätzlich sollte eine Langzeitantibiose unter engmaschiger Kontrolle der Entzündungsparameter gegeben werden. Methodik Es wurde eine retrospektive Analyse aller Patienten, die zwischen Januar 2008 und Mai 2017 an unserer Klinik aufgrund einer Stentprotheseninfektion behandelt wurden, durchgeführt. Die Studienendpunkte waren Infektfreiheit, Überleben und primäre Offenheit der Rekonstruktion. Zusätzlich wurde elektronisch nach gefäßchirurgischer Literatur gesucht, die sich mit der Therapie von Stentprotheseninfektionen nach EVAR (Endovascular aortic repair) und TEVAR (Thoracic endovascular aortic repair) befasst. Ergebnisse Insgesamt wurde bei 3 Patienten (100% Männer, Durchschnittsalter 77 Jahre) eine Stentprotheseninfektion diagnostiziert. In allen Fällen handelte es sich um eine Stentinfektion nach EVAR. Bei allen Patienten wurde der Stent-Graft entfernt und eine anatomische Rekonstruktion mit hom*ograft oder xenogenem Material durchgeführt. Ein Erregernachweis gelang in 2 von 3 Fällen. Alle Patienten erhielten eine Langzeitantibiose über 12 Wochen. Die 30-Tages-Mortalität lag bei 0%, im Nachbeobachtungszeitraum kam es zu keinem Re-Infekt. Ein Patient verstarb 2 Monate postoperativ an einer Darmperforation mit Peritonitis, ein weiterer Patient 92 Monate postoperativ an einem kleinzelligen Bronchialkarzinom. Die primäre Offenheit der Rekonstruktionen lag bei 100%. In der Literatur weist die konservative Therapie einer Stentprotheseninfektion eine sehr hohe Mortalität auf, wobei sie bei Patienten mit aortoenteraler oder aortobronchialer Fistel und konservativer Therapie am höchsten ist. Bei operativer Therapie der Stentprotheseninfektion ist diese deutlich niedriger. Zusammenfassung Die chirurgische Herdsanierung, der Prothesenersatz und die begleitende antibiotische Therapie sind entscheidend für das Langzeitergebnis nach Endostentinfektion. Eine konservative Therapie sollte nur bei chirurgisch nicht sanierbarem Fokus oder inoperablen Patienten durchgeführt werden.