An application of Mobley's intermediate linkages turnover model to a full-time employee group typology

2014 ◽  
Vol 87 (4) ◽  
pp. 806-812
Author(s):  
Jenell L. S. Wittmer ◽  
Agnieszka Shepard ◽  
James E. Martin
2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1094.2-1095
Author(s):  
A. S. Siebuhr ◽  
S. F. Madsen ◽  
M. Karsdal ◽  
A. C. Bay-Jensen ◽  
P. Juhl

Background:Systemic sclerosis has vascular, inflammatory and fibrotic components, which may be associated with different growth factors and cytokines. Platelet derived growth factor (PDGF) is associated with the vasculature, whereas tumor necrosis factor beta (TGFβ) is associated with inflammation and fibrosis. We have developed a fibroblast model system of dermal fibrosis for anti-fibrotic drugs testing, but the effect of the fibroblasts mechanistic properties are unknown.Objectives:We investigated different mechanical capacities of PDGF and TGFβ treated human healthy dermal fibroblasts in the SiaJ setting.Methods:Primary human healthy dermal fibroblasts were grown in DMEM medium containing 0.4% fetal calf serum, ficoll (to produce a crowded environment) and ascorbic acid for up to 17 days. A wound was induced by scratching the cells at 0, 1, 3 or 7 days after treatment initiation. Wound closure was followed for 3 days. Contraction capacity was tested by creating gels of human fibroblasts produced collagens containing dermal fibroblasts and contraction was assessed at day 2 by calculating the percentage of gel size to total well size. Collagen type I, III and VI formation (PRO-C1, PRO-C3 and PRO-C6) and fibronectin (FBN-C) were evaluated by validated ELISAs (Nordic Bioscience). Gene expression was analyzed after 2 days in culture. Statistical analyses included One-way ANOVA and student’s t-test.Results:Generally, PDGF closed the wound in half the time of w/o and TGFβ, when treatment and cells are added concurrently or scratched one day after treatment initiation. When treatments were added 3 or 7 days prior to scratch, the cells treated with PDGF had proliferated to a higher degree than w/o and TGFβ. A consequence of this, was that when cells were scratch the sheet of cells produced was lifted from the bottom and fold over itself, leaving a much greater scratch than in the other treatments. However, despite this increased gap the PDGF treated cells closed the wound at the same time as w/o and TGFβ, confirming the results of the cells scratched at day 0 and 1.Inhibition of contraction by ML-7 of otherwise untreated cells inhibited contraction significantly compared to untreated cells alone (p=0.0009). Contraction was increased in both TGFβ and PDGF treated cells compared to untreated cells (both p<0.0001). TGFβ+ ML-7 inhibited the contraction to the level of w/o (p=0.0024), which was only 35% of ML-7 alone. In the contraction study the cells were terminated after 2 days of culture, thus prior to when biomarker of ECM remodeling is usually assessed. However, FBN-C was detectable and a significant release of fibronectin by TGFβ and PDGF compared to w/o was found in the supernatant (both p<0.0001). The gene expression of FBN was only increased with TGFβ (p<0.05) and not PDGF. ML-7 alone tended to decrease FBN-C and in combination with TGFβ the FBN level was significantly decreased compared to TGFβ alone (p<0.0001). However, the level of TGFβ+ML-7 was significantly higher than ML-7 alone (p=0.038).TGFβ increased the gene expression of most genes assessed, except Col6a1. PDGF increased the gene expression of Col3a1, Col5a1 and Col6a1 above the critical fold change of 2, but only significantly in Col5a1 and Col6a1 (both p<0.05).Conclusion:This study demonstrates that TGFβ and PDGF have different mechanical capacities in human healthy dermal fibroblasts; TGFβ increased gene expression of ECM related genes, such as collagens and have increased FBN release in the supernatant already 2 days after initial treatment. PDGF has increased contraction, proliferation and migratory capacities and less expression of ECM related genes and proteins.Disclosure of Interests:Anne Sofie Siebuhr Employee of: Nordic Bioscience, Sofie Falkenløve Madsen: None declared, Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Pernille Juhl Employee of: Nordic Bioscience


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 159.1-159
Author(s):  
R. Dobrota ◽  
S. Jordan ◽  
P. Juhl ◽  
B. Maurer ◽  
M. O. Becker ◽  
...  

Background:Timely diagnosis of patients with very early systemic sclerosis (veSSc) is essential for their personalized and optimal management. We hypothesise that changes in serum-based extracellular matrix (ECM) turnover biomarkers are already detectable in patients with veSSc, even before occurrence of specific clinical signs.Objectives:To investigate circulating ECM turnover markers as potential biomarkers for veSSc.Methods:Patients with veSSc, n=42, defined as presence of Raynaud’s syndrome and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, who did not meet any classification criteria for SSc, were compared to healthy controls (HC, n=29). Longitudinal assessment, data and sera collection were conducted by EUSTAR standards. ECM-degradation (BGM, C3M, C4M, C6M) and ECM-formation biomarkers (PRO-C3, PRO-C4, PRO-C5) were measured in serum using ELISA assays. The statistical analyses included Mann-Whitney U, Spearman correlation and ROC analysis. Using Kaplan-Meier plots and univariable Cox regression, we explored if biomarkers can predict progression towards definite SSc (fulfillment of ACR/EULAR criteria or minimum two points increase in the criteria score) during the longitudinal follow-up.Results:Compared to HC, veSSc patients showed a deregulated turnover of type III and IV collagen, with higher degradation (higher C3M, C4M, both p<0.0001 and PRO-C3, p=0.004, Figure 1a, resulting in lower turnover ratios PRO-C3/C3M and PRO-C4/C4M, both p<0.0001). The biglycan degradation biomarker BGM was also higher in veSSc (p=0.006), whereas the degradation biomarker for type VI collagen, C6M, was lower than in HC (p=0.002). In the ROC analysis, biomarkers of type III and IV collagen distinguished between veSSc and HC: C3M, AUC=0.95, p<0.0001; C4M, AUC=0.97, p<0.0001; turnover ratios PRO-C3/C3M, AUC=0.80, p<0.0001; PRO-C4/C4M, AUC=0.97; p<0.0001 (Figure 1b).Median follow up was 4.5 years (range 0.5-7.9 years), mean age was 50±2.2 years, 88% female gender, 24% with puffy fingers, 92% were ANA positive, 64% had an abnormal capillaroscopy, none had organ involvement or skin fibrosis. 14/42 veSSc patients fulfilled the ACR/EULAR classification criteria at follow-up (time to fulfilment of criteria ranged between 0.5 and 6.8 years from inclusion) and in addition, 18/42 veSSc patients gained at least two classification criteria-points. This resulted in 14, respectively 18 progressors for the longitudinal analysis. However, in univariable Cox regression, the baseline levels of the markers did not predict progression over time.Conclusion:ECM turnover is already altered in veSSc patients compared to HC. Biomarkes of type III and IV collagen distinguished between veSSc patients and HC, which may indicate them as potential biomarkers for the detection of veSSc in addition to the established immunological and capillaroscopic criteria.Disclosure of Interests:Rucsandra Dobrota: None declared, Suzana Jordan: None declared, Pernille Juhl Employee of: Nordic Bioscience, Britta Maurer Grant/research support from: AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, Speakers bureau: Novartis, Mike O. Becker: None declared, Carina Mihai: None declared, Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Anne Sofie Siebuhr Employee of: Nordic Bioscience, Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kevin T Ousdigian ◽  
Sarah Rosemas ◽  
Jodi L Koehler ◽  
Ya-Jian Cheng ◽  
Esteban M Kloosterman

Introduction: Insertable Cardiac Monitors (ICM) aid in the diagnosis and monitoring of arrhythmias, however, reviewing the data is labor intensive and time consuming. Hypothesis: We hypothesized that new algorithms (ALG) and indication tailored programming (ITP) could reduce device-based alerts and clinician review time. Methods: Baseline data was obtained from a real-world de-identified Reveal LINQ TruRhythm ICMs database. The arrhythmia alerts and manual transmissions per patient/month was queried in this Control Group of patients with ≥3 months of follow-up. The effect of ALG and ITP was computed and applied to the Control Group. For practical purposes, the results were extrapolated to a 200 ICM clinic. Annualized clinic review time was estimated by assuming the staff time per transmission was 12.9 min., based on prior study. ALG improvements included: 1) Reject noise, loss of contact, and small R-waves for Pauses, 2) Require rapid onset for Tachy, 3) Limit nighttime episodes for Brady, and 4) Eliminate manual patient transmissions. ITP changes included: 1) Patients without Syncope: Pause ≥ 5 sec., Brady ≥ 12 beats and not during night, 2) Patients for AF Monitoring: AF ≥ 6 min. Results: The dataset consisted of 248,603 ICMs inserted for Syncope (36%), AF Diagnosis (35%), AF Monitoring (17%), and Other (12%) with an avg. of 1.1 years of follow-up (total 265,938 yrs). Applied to a 200 ICM clinic size, ALG and ITP reduced arrhythmia alerts by 32% (Control: 2,445 to ALG and ITP: 1,655 per clinic/yr). Using the new data transmission scheme eliminated 360 manual transmissions per clinic/yr.(Panel A) In total, the projected annual transmission volume (alerts + manuals in Panel A) and corresponding clinic review time (Panel B) dropped by 41% (247 hrs/yr = 13.1% full-time employee). Conclusion: Improved ALG and ITP can significantly reduce the volume of ICM alerts and consequently clinician review time impacting the management efficiency of this patient population.


Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Christopher J Edwards ◽  
Andrew J Bradley ◽  
Mani H Nassab ◽  
Burkhard Möller ◽  
Klaus P Machold ◽  
...  

Abstract Background With multiple biologic disease-modifying anti-rheumatic drugs (bDMARDs) available, comparisons are important for treatment decisions. At week 24 of the SPIRIT H2H study in patients with active PSA, IXE showed superiority to ADA for the simultaneous achievement of ACR50 and PASI100. Here we report the 52-week efficacy outcomes including individual ACR components and in subgroups +/- concomitant methotrexate (MTX). Methods SPIRIT H2H (NCT03151551) was a 52-week, multicentre, open-label, blinded-assessor study of bDMARD naïve patients with active PSA (defined as swollen joint count ≥3/68, and tender joint count ≥3/66), with a body surface area (BSA) ≥3% and inadequate response to conventional synthetic (cs)-DMARDs. Patients were randomised 1:1 to IXE or ADA stratified by concomitant csDMARD use and the presence of moderate-to-severe psoriasis (defined as Psoriasis Area and Severity Index [PASI] ≥12 combined with a static Physician Global Assessment ≥3 and BSA ≥10%). Patients received approved label dosing of assigned treatment dependent on presence/absence of moderate-to-severe psoriasis. Primary outcome was achievement of simultaneous ACR50 + PASI100; secondary outcomes were achievement of PASI100, ACR20/50/70 and changes in individual ACR component scores. Data were analysed using logistic regression with non-responder imputation for missing data. Results Baseline characteristics were balanced across treatment groups. At week 52, a significantly larger percentage of IXE- vs. ADA-treated patients achieved simultaneous ACR50 + PASI100 and PASI100, consistent with 24-week results (table). IXE performed at least as well as ADA at week 52 for all other outcomes (table). With/without MTX, IXE efficacy was consistent at week 52 across ACR20/50/70 with a significantly greater achievement of simultaneous ACR50 + PASI100 and ACR70 (table). IXE- versus ADA-treatment resulted in comparable changes from baseline for each individual ACR component at week 52. Safety was consistent with previous reports. Conclusion In patients with PSA, treatment with IXE versus ADA resulted in a significantly greater achievement of simultaneous skin and joint improvement at week 52, consistent with week 24 results. At week 52 consistent efficacy was shown for IXE when used with/without MTX. Disclosures C.J. Edwards: Consultancies; Celltrion, Abbvie, Samsung. Honoraria; Abbvie, BMS, Biogen, Chugai, Fresenius, Gilead, Janssen, Lilly, Pfizer, Roche, Samsung, UCB. Member of speakers’ bureau; Abbvie, BMS, Biogen, Chugai, Fresenius, Gilead, Janssen, Lilly, Pfizer, Roche, Samsung, UCB. Grants/research support; Pfizer, Biogen, Abbvie. A.J. Bradley: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. M.H. Nassab: Other; Full time employee of Eli Lilly. B. Möller: None. K.P. Machold: Honoraria; Arsanis, Astro, Baxter, BMS, Celgene, Eli-Lilly, MSD, Pfizer, Roche, Novartis, Sandoz. Member of speakers’ bureau; MSD, Pfizer, BMS, Janssen-Cilag, Sandoz, Novartis, Eli-Lilly. Grants/research support; AbbVie, BMS, Eli-Lilly, Novartis, MSD, Pfizer, Sanofi-Aventis, UCB. C. Sapin: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. R. Ranza: Consultancies; Abbvie, Novartis, Lilly, Pfizer, Janssen. Member of speakers’ bureau; Abbvie, Novartis, Lilly, Pfizer, Janssen. Grants/research support; Abbvie, Novartis, Pfizer, Janssen. S.L. Leage: Other; Full time employee of Eli Lilly.


Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Bruce Kirkham ◽  
Elena Nikiphorou ◽  
Pedro López-Romero ◽  
Ilias Kouris ◽  
Thorsten Holzkaemper ◽  
...  

Abstract Background In RA, disease activity correlates with physical function and there is a link between joint damage and functional disability. In many countries, RA patients with inadequate response (IR) to MTX or other conventional DMARDs (cDMARDs) are not eligible for potentially more effective treatments, such as biologic or targeted synthetic DMARDs (tsDMARDs), unless they have high disease activity (HDA). Thus, managing RA patients with persistent moderate disease activity (MDA) despite cDMARD treatment poses a problem. Baricitinib (BARI) is a tsDMARD approved for the treatment of moderate to severe RA in adults. This post-hoc analysis assessed if RA patients with MDA benefit from improved physical function with BARI treatment to the same extent as patients with HDA. Methods Patients analysed were from the modified intention-to-treat populations in the BARI phase 3 studies RA-BEAM (MTX-IR) and RA-BUILD (cDMARD-IR) with moderate to severe disability (HAQ-Disability Index [HAQ-DI] score ≥1), MDA (Simplified Disease Activity Index [SDAI] score 11.1-26.0) or HDA (SDAI score&gt;26.0) and non-missing SDAI data at baseline. All patients fulfilled ACR criteria for RA. Patients from RA-BEAM received BARI 4 mg + MTX once daily (n = 396), adalimumab 40 mg every 2 weeks + MTX (n = 270) or placebo (PBO) + MTX (n = 390); patients from RA-BUILD received BARI 4 mg (n = 189) or 2 mg (n = 186) or PBO (n = 185). Multivariable linear regression (MLR) models were used to estimate mean HAQ-DI scores at baseline and week 24 (W24) for the treatment arms stratified by baseline disease activity (MDA or HDA SDAI). Age, RA duration, BMI, high-sensitivity CRP, baseline SDAI disease activity (MDA/HDA), treatment and treatment-by-baseline SDAI interaction were included as covariates. The MLR model for HAQ-DI at (W24) was further adjusted by baseline HAQ-DI. Results In patients from RA-BEAM with MDA at baseline, the mean adjusted HAQ-DI score at W24 was greater in PBO (1.314) than in BARI 4 mg (0.843) patients (Δ = 0.472; p = 0.001). A similar pattern of improved physical function with BARI was seen in RA-BUILD, but the adjusted mean difference in HAQ-DI score between PBO (1.376) and BARI 4 mg (1.113) was not statistically significant (Δ = 0.263; p = 0.109). In patients with HDA at baseline, the W24 mean adjusted HAQ-DI score was 0.443 points greater (p &lt; 0.001) with PBO (1.387) than with BARI 4 mg (0.944) in RA-BEAM, and 0.257 points greater (p &lt; 0.001) in RA-BUILD. Conclusion MTX-IR and/or cDMARD-IR RA patients with MDA and moderate to severe disability at baseline treated with BARI showed a similar pattern of improvement in physical function vs. PBO-treated patients to that seen in patients with HDA, supporting early use of BARI in MDA patients. As for those with HDA, patients with persistent MDA despite MTX and/or other cDMARD treatment could benefit from access to biologic and tsDMARDs to prevent disability progression. Disclosures B. Kirkham: Consultancies; AbbVie, Eli Lilly, Gilead, Janssen, Novartis, Pfizer. Grants/research support; Eli Lilly, Novartis. E. Nikiphorou: Honoraria; Pfizer, Sanofi, Gilead, Celltrion, Eli Lilly. P. López-Romero: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. I. Kouris: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. T. Holzkaemper: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. L. Zaremba-Pechmann: Other; contractor for Eli Lilly and Company. I. de la Torre: Shareholder/stock ownership; Eli Lilly. Other; Full time employee of Eli Lilly. P.C. Taylor: Consultancies; AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Roche, Sanofi, Nordic Pharma, Fresenius, UCB. Grants/research support; Celgene, Galapagos, Janssen, Eli Lilly.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 240-240
Author(s):  
S. S. Groen ◽  
D. Sinkeviciute ◽  
C. Thudium ◽  
P. Önnerfjord ◽  
M. Karsdal ◽  
...  

Background:Altered extracellular matrix (ECM) remodelling is an important part of the pathology seen in joint degenerative diseases. Type II collagen is the most abundant ECM protein in the cartilage and provides the tissue with essential tensile strength in order to withstand high compressive loading. During cartilage erosion, type II collagen is cleaved by matrix metallopeptidases (MMPs) which generates new protein fragments called neo-epitopes. These fragments are released into circulation and may potentially serve as biomarkers by indicating the degree of cartilage destruction.Objectives:The aim of this study is to develop a highly specific immunoassay targeting a neo-epitope fragment of type II collagen cleaved, named T2CM. Moreover, we investigated the assays potential to evaluate type II collagen degradation in anex vivobovine full-depth cartilage explants model (BEX) with catabolic treatment and in healthy controls and osteoarthritis (OA) patients.Methods:A monoclonal antibody was raised in mouse against the C-terminus from protease cleavage site of type II collagen and a direct competitive ELISA was developed and technically validated. The assay specificity was evaluated for the standard peptide excluding cross-reactivity with elongated and truncated peptides, and a non-sense coating peptide. Human OA cartilage was cleaved with MMP-1, -2, -9 and -13 and measured with the T2CM-assay to investigate which MMPs generated the neo-epitope. T2CM levels were measured in supernatant from BEX explants cultured for 21 days in serum free DMEM/F12 medium with six different doses of OSM+TNF-α (O+T) treatment (20/10, 20/20, 20/40, 10/10, 10/20, 10/40 ng/mL) including a control group without (w/o) treatment. The supernatant was harvested 3 times weekly and replaced with new culture medium with O+T treatment. Biomarker results were confirmed by western blot, where T2CM was measured in supernatant from explants with O+T treatment 20/20 ng/mL and 20/40 ng/mL harvested on day 14 and day 21. To confirm the preclinical data, serum samples from 23 healthy controls (age range from 44-59 years with mean 51.4 ± SD 5.1, gender distribution was 56% female and 44% male, and 100% Caucasian) and 23 OA patients (age range from 41-77 years with mean 57.7 ± SD 13.7, gender distribution was 61% female and 39% male, and 100% Caucasian) were measured by T2CM.Results:A technically robust and T2CM-specific assay was developed. The assay linearity and spike-recovery were accepted with percentage of 99.69% and 93.15%. The assay showed no cross-reaction with the elongated, truncated or non-sense coating peptide. In addition, it was demonstrated that the T2CM neo-epitope was derived from MMP-1 and MMP-13 cleavage of type II collagen. O+T treatment induced the T2CM release in BEX compared to the untreated (Figure 1-2). Moreover, the western blot confirmed the T2CM results by the presence of two T2CM bands on day 21 from O+T treated explant compared to day 14 where no bands appeared. T2CM showed to be significantly elevated in patients with OA compared to controls (p=0.036; mean 3.262 ng/mL ± SD 1.065 vs 2.698 ng/mL ± SD 1.118).Conclusion:The newly developed assay was specific for the T2CM neo-epitope and was determined to be generated by MMP-1 and MMP-13. Additionally, the assay detected elevated levels of T2CM in supernatant from explants treated with O+T after 19 days of treatment compared to untreated. This was further confirmed in human OA patients, where the level of T2CM was elevated compared to healthy controls. This suggests that T2CM may have potential as biomarker for type II collagen degradation. Future preclinical and clinical studies are needed to validate these findings.Figure 1-2.T2CM measurements in BEX model. OSM + TNF-a (O+T) ng/mL.Disclosure of Interests:Solveig Skovlund Groen Employee of: Nordic Bioscience, Dovile Sinkeviciute Grant/research support from: Industrial PhD Student, Employee of: Industrial PhD Student, Christian Thudium Employee of: Employee at Nordic Bioscience A/S., Patrik Önnerfjord: None declared, Morten Karsdal Shareholder of: Nordic Bioscience A/S., Employee of: Full time employee at Nordic Bioscience A/S., Anne-Christine Bay-Jensen Shareholder of: Nordic Bioscience A/S, Employee of: Full time employee at Nordic Bioscience A/S., Signe Holm Nielsen Employee of: Full time employee at Nordic Bioscience


Author(s):  
Calvin Monroe

This chapter is concerned with acknowledging the mental health issues that Black men face in higher education. Research is presented and blended with lived experiences of being a full-time employee and doctoral student on a primarily white campus. This chapter focuses on the emotional trauma of Black men, imposter phenomenon traits, and offers strategies for healing from critical race theorist. Strategies to keep higher education institutions accountable for the hiring and retaining of Black men are also discussed.


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