Competitive bidding for outcome based contracts – price to win?

The suppliers of long-life assets such as submarines and airplanes no longer simply sell these assets but provide advanced engineering services. In other words companies that traditionally designed and manufactured long-life products now compete through the provision of a service, such as asset availability. These companies face a high level of uncertainty due to the novelty of the process and the long-term nature of services. However, regardless of these uncertainties the service provider needs to estimate the cost and expected profits for such provision. The pricing decision of these service contracts is influenced by multiple factors and considerations and as a minimum the supplying contractor needs to yield suitable profit to sustain their business. From current research it is known that the estimated company profit is often optimistic. This places pressure on both the customer and the service provider. From our research we found examples of reductions in profits for those providing services. For example a company, which moved to performance-based road maintenance contracts, only yielded less than 50% of their expected profit. So, how can providers of long-life, high-value assets estimate the costs for delivering an expected outcome and account for the uncertainties? One of the challenges is measuring such uncertainties and taking account of them in the pricing decision. In this paper we present our research to date on the provision of a framework and a five-step process for modelling the influencing uncertainties and the impact of these uncertainties on the price bid. We will present the background need for such analysis and then provide an overview of our approach and findings to date. Finally, using an exemplar service we will demonstrate how using our approach highlights the probability of winning the contract, the probability of making a profit and the expected profit value for particular price bids

AB0370 UTILITY OF CRP AND ESR IN THE DIAGNOSIS OF GIANT CELL ARTERITIS RELAPSE IN A PHASE 2 TRIAL OF MAVRILIMUMAB

Background:No universally accepted definition of flare currently exists in giant cell arteritis (GCA). Although relapses are defined mostly on clinical grounds (recurrence of GCA-related signs/symptoms), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) help clinicians assess disease activity. In fact, >70% of patients on glucocorticoids (GCs) alone have increased CRP or ESR when the disease is active. In contrast, tocilizumab, given its IL-6-blockade effect in the liver, rapidly reduces CRP and ESR levels, rendering them unreliable for disease activity monitoring. Mavrilimumab – a GM-CSF receptor α inhibitor with demonstrated efficacy in a Phase 2 GCA trial1 – downregulates inflammation upstream of IL-6. We hypothesized that mavrilimumab would not interfere with the utility of CRP and ESR in monitoring disease activity and in identifying GCA relapse.Objectives:To analyze the relationship between CRP/ESR and clinical disease activity in GCA patients treated with mavrilimumab.Methods:New-onset and relapsing GCA patients with active disease were recruited. GC-induced remission (no GCA symptoms and CRP <1 mg/dL or ESR <20 mm/hr) was required by baseline. Patients were randomized 3:2 to mavrilimumab 150 mg or placebo subcutaneously every 2 weeks plus a protocol-defined 26-week prednisone taper. The primary efficacy endpoint was time to relapse by Week 26. Relapse (adjudicated) was defined as recurrent GCA-related signs/symptoms, including new/worsening vasculitis on imaging, concurrent with CRP ≥1 mg/dL and/or ESR ≥30 mm/hr. CRP and ESR were also measured periodically during the trial.This post hoc analysis assessed the association of recurrent GCA-related signs/symptoms with concurrent CRP or ESR elevation post-randomization by treatment arm. We also assessed the proportion of patients with CRP or ESR elevation without GCA-related signs/symptoms up to Week 26.Results:Seventy patients were enrolled (mavrilimumab, N=42; placebo, N=28). The association of CRP or ESR elevation with unequivocal GCA-related signs/symptoms post-randomization was consistent regardless of treatment arm: 8/8 in the mavrilimumab group and 13/13 in the placebo group (Table 1). During relapse, median (range) CRP was 1.8 (1.4 – 8.4) mg/dL (mavrilimumab group) and 1.8 (1.1 – 9.0) mg/dL (placebo group). Corresponding ESR values were 39.5 (30 – 102) mm/hr (mavrilimumab group) and 49 (31 – 101) mm/hr (placebo group). Four mavrilimumab recipients had self-limited, equivocal GCA-related signs/symptoms without concurrent CRP or ESR elevation; all 4 completed the prespecified GC taper by Week 26 without need for rescue GCs, so relapse was not confirmed. At least 1 elevated CRP or ESR value in the absence of GCA-related signs/symptoms was observed in 58.8% of mavrilimumab recipients and 93.3% of placebo recipients by Week 26.Conclusion:The observed association of CRP or ESR elevation with GCA-related signs/symptoms is consistent with the upstream mechanism and supports the utility of the stringent protocol definition of relapse. The frequency and magnitude of CRP and ESR elevations at relapse were similar in both treatment groups, suggesting that CRP and ESR remain useful in assessments of disease activity in mavrilimumab-treated patients. CRP and ESR elevations without GCA-related signs/symptoms occurred more often in placebo recipients.References:[1]Cid, Unizony et al. Arthritis Rheumatol. 2020; 72 (suppl 10)Table 1.CRP and ESR levels in patients with or without GCA relapseAssessment§MavrilimumabPlaceboMavrilimumabPlaceboN=42N=28N=42N=28With RelapseWithout Relapse# of patients8 (19.1)13 (46.4)34 (81.0)15 (53.6) Elevated CRP* or ESR†8 (100.0)13 (100.0)20 (58.8)14 (93.3)  Elevated CRP*7 (87.5)10 (76.9)10 (29.4)11 (73.3)   Median (range) mg/dL1.8 (1.4 - 8.4)1.8 (1.1 - 9.0)2.6 (1.3 – 7.0)2.0 (1.0 – 6.6) Elevated ESR†6 (75.0)9 (69.2)16 (47.1)10 (66.7)  Median (range) mm/hr39.5 (30 - 102)49.0 (31 - 101)41.5 (30 - 110)53.5 (30 - 82)§# (%), except where indicated otherwise.*CRP ≥ 1 mg/dL†ESR ≥ 30 mm/hrDisclosure of Interests:Sebastian Unizony Consultant of: Janssen and Kiniksa, Grant/research support from: Genentech, Maria C. Cid Speakers bureau: Roche and Kiniksa, Paid instructor for: GSK and Vifor, Consultant of: Janssen, GSK, and Abbvie, Grant/research support from: Kiniksa, Elisabeth Brouwer Speakers bureau: Dr. E.Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017 2018 which were paid to the UMCG., Consultant of: Dr. E.Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche in 2017 2018 which were paid to the UMCG., Lorenzo Dagna Speakers bureau: Abbvie, Amgen, Biogen, BMS, Celltrion, Galapagos, Glaxo SmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Galapagos, Glaxo SmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI; clinical trial for Kiniksa, Grant/research support from: Abbvie, Amgen, BMS, Celltrion, Galapagos, Novartis, Pfizer, Roche, Sanofi-Genzyme, SOBI, Merk Sharp &Dohme, Janssen, Kiniksa, Bhaskar Dasgupta Paid instructor for: Educational grant symposium/workshop for Roche-chugai, Sanofi, and Abbvie, Consultant of: CI UK for the Kiniksa trial, Grant/research support from: Educational grant symposium/workshop for Roche-chugai, Sanofi, and Abbvie, Bernhard Hellmich Consultant of: Honoraria paid to the institution for participation in the clinical trial, Eamonn Molloy: None declared, Carlo Salvarani: None declared, Bruce C. Trapnell Consultant of: Consultant member of DSMB for Kiniksa., Kenneth J Warrington Consultant of: Clinical trial support from Eli Lilly and Kiniksa, Ian Wicks: None declared, Manoj Samant Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Teresa Zhou Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, Lara Pupim Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceuticals, John F. Paolini Shareholder of: Kiniksa Pharmaceuticals, Employee of: Kiniksa Pharmaceutical

Using quantile regression to understand visitor spending

A common approach to assessing visitor expenditures is to use least-squares regression analysis to determine statistically significant variables upon which key market segments are identified for marketing purposes. This was done by Wang (2004) for survey data based on expenditures by Mainland Chinese visitors to Hong Kong. In this research note we use this same dataset to demonstrate the benefits of using quantile regression analysis to better identify tourist spending patterns and market segments. The quantile regression method measures tourist spending in different categories against a fixed range of dependent variables, which distinguishes between lower, medium, and higher spenders. The results show that quantile regression is less susceptible to influence by outlier values and is better able to target finer tourist spending market segments

MIIT: International in-situ testing of nuclear-waste glasses: Performance of SRS simulated waste glass after five years of burial at the Waste Isolation Pilot Plant (WIPP)

In July of 1986, the first in-situ test involving burial of simulated high-level waste (HLW) forms conducted in the United States was started. This program, called the Materials Interface Interactions Test or MIIT, comprises the largest, most cooperative field-testing venture in the international waste management community. In July of 1991, the experimental portion of the 5-year MIIT study was completed on schedule. During this time interval, many in-situ measurements were performed, thousands of brine analyses conducted, and hundreds of waste glass and package components exhumed and evaluated after 6 mo., 1 yr., 2 yr. and 5 yr. burial periods. Although analyses are still in progress, the performance of SRS waste glass based on all data currently available has been seen to be excellent thus far. Initial analyses and assessment of Savannah River (SR) waste glass after burial in WIPP at 90{degrees}C for 5 years are presented in this document

Novel insights into diminished cardiac reserve in non-obstructive hypertrophic cardiomyopathy from four-dimensional flow cardiac magnetic resonance component analysis

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by hypercontractility and diastolic dysfunction, which alter blood flow haemodynamics and are linked with increased risk of adverse clinical events. Four-dimensional flow cardiac magnetic resonance (4D-flow CMR) enables comprehensive characterization of ventricular blood flow patterns. We characterized flow component changes in non-obstructive HCM and assessed their relationship with phenotypic severity and sudden cardiac death (SCD) risk. Methods and results: Fifty-one participants (37 non-obstructive HCM and 14 matched controls) underwent 4D-flow CMR. Left-ventricular (LV) end-diastolic volume was separated into four components: direct flow (blood transiting the ventricle within one cycle), retained inflow (blood entering the ventricle and retained for one cycle), delayed ejection flow (retained ventricular blood ejected during systole), and residual volume (ventricular blood retained for >two cycles). Flow component distribution and component end-diastolic kinetic energy/mL were estimated. HCM patients demonstrated greater direct flow proportions compared with controls (47.9 ± 9% vs. 39.4 ± 6%, P = 0.002), with reduction in other components. Direct flow proportions correlated with LV mass index (r = 0.40, P = 0.004), end-diastolic volume index (r = −0.40, P = 0.017), and SCD risk (r = 0.34, P = 0.039). In contrast to controls, in HCM, stroke volume decreased with increasing direct flow proportions, indicating diminished volumetric reserve. There was no difference in component end-diastolic kinetic energy/mL. Conclusion: Non-obstructive HCM possesses a distinctive flow component distribution pattern characterised by greater direct flow proportions, and direct flow-stroke volume uncoupling indicative of diminished cardiac reserve. The correlation of direct flow proportion with phenotypic severity and SCD risk highlight its potential as a novel and sensitive haemodynamic measure of cardiovascular risk in HCM

Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

OBJECTIVES: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is implicated in pathogenesis of giant cell arteritis. We evaluated the efficacy of the GM-CSF receptor antagonist mavrilimumab in maintaining disease remission. METHODS: This phase 2, double-blind, placebo-controlled trial enrolled patients with biopsy-confirmed or imaging-confirmed giant cell arteritis in 50 centres (North America, Europe, Australia). Active disease within 6 weeks of baseline was required for inclusion. Patients in glucocorticoid-induced remission were randomly assigned (3:2 ratio) to mavrilimumab 150 mg or placebo injected subcutaneously every 2 weeks. Both groups received a 26-week prednisone taper. The primary outcome was time to adjudicated flare by week 26. A prespecified secondary efficacy outcome was sustained remission at week 26 by Kaplan-Meier estimation. Safety was also assessed. RESULTS: Of 42 mavrilimumab recipients, flare occurred in 19% (n=8). Of 28 placebo recipients, flare occurred in 46% (n=13). Median time to flare (primary outcome) was 25.1 weeks in the placebo group, but the median was not reached in the mavrilimumab group (HR 0.38; 95% CI 0.15 to 0.92; p=0.026). Sustained remission at week 26 was 83% for mavrilimumab and 50% for placebo recipients (p=0.0038). Adverse events occurred in 78.6% (n=33) of mavrilimumab and 89.3% (n=25) of placebo recipients. No deaths or vision loss occurred in either group. CONCLUSIONS: Mavrilimumab plus 26 weeks of prednisone was superior to placebo plus 26 weeks of prednisone for time to flare by week 26 and sustained remission in patients with giant cell arteritis. Longer treatment is needed to determine response durability and quantify the glucocorticoid-sparing potential of mavrilimumab. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT03827018, Europe (EUdraCT number: 2018-001003-36), and Australia (CT-2018-CTN-01 865-1)

Non-Equilibrium in Adsorbed Polymer Layers

High molecular weight polymer solutions have a powerful tendency to deposit adsorbed layers when exposed to even mildly attractive surfaces. The equilibrium properties of these dense interfacial layers have been extensively studied theoretically. A large body of experimental evidence, however, indicates that non-equilibrium effects are dominant whenever monomer-surface sticking energies are somewhat larger than kT, a common case. Polymer relaxation kinetics within the layer are then severely retarded, leading to non-equilibrium layers whose structure and dynamics depend on adsorption kinetics and layer ageing. Here we review experimental and theoretical work exploring these non-equilibrium effects, with emphasis on recent developments. The discussion addresses the structure and dynamics in non-equilibrium polymer layers adsorbed from dilute polymer solutions and from polymer melts and more concentrated solutions. Two distinct classes of behaviour arise, depending on whether physisorption or chemisorption is involved. A given adsorbed chain belonging to the layer has a certain fraction of its monomers bound to the surface, f, and the remainder belonging to loops making bulk excursions. A natural classification scheme for layers adsorbed from solution is the distribution of single chain f values, P(f), which may hold the key to quantifying the degree of irreversibility in adsorbed polymer layers. Here we calculate P(f) for equilibrium layers; we find its form is very different to the theoretical P(f) for non-equilibrium layers which are predicted to have infinitely many statistical classes of chain. Experimental measurements of P(f) are compared to these theoretical predictions.Comment: 29 pages, Submitted to J. Phys.: Condens. Matte

Digital orphans: Data closure and openness in patient- powered networks

This is the author accepted manuscript. The final version is available from Palgrave Macmillan via the DOI in this record.In this paper, we discuss an issue linked to data-sharing regimes in patient-powered, social-media-based networks, namely that most of the data that patient users share are not used to research scientific issues or the patient voice. This is not a trivial issue, as participation in these networks is linked to openness in data sharing, which would benefits fellow patients and contributes to the public good more generally. Patient-powered research networks are often framed as disrupting research agendas and the industry. However, when data that patients share are not accessible for research, their epistemic potential is denied. The problem is linked to the business models of the organisations managing these networks: models centred on controlling patient data tend to close networks with regard to data use. The constraint on research is at odds with the ideals of a sharing, open and supportive epistemic community that networks’ own narratives evoke. This kind of failure can create peculiar scenarios, such as the emergence of the ‘digital orphans’ of Internet research. By pointing out the issue of data use, this paper informs the discussion about the capacity of patient-powered networks to support research participation and the patient voice.We are indebted to the anonymous reviewers and the editor, who with their supportive and constructive comments helped us to better clarify and highlight the argument of the article. We would like to also thank friends and colleagues who have offered valuable comments and suggestions on early drafts of this paper. We would like to especially thank Barbara Prainsack, Sabina Leonelli, Alena Buyx, and David Teira. This research is funded by the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement number 335925, and the German Federal Ministry of Education and Research (grant number 01GP1311

Jet Quenching in Heavy Ion Collisions

This review article was prepared for the Landolt-Boernstein volume on Relativisitc Heavy Ion Physics.Comment: Review articel accepted for publication in the Landolt-Boernstein Handbook of Physics, ed. R. Stock. 41 pages LaTex, 7 eps-figure

Mach Cones in Quark Gluon Plasma

The experimental azimuthal dihadron distributions at RHIC show a double peak structure in the away side ($\Delta \phi = \pi \pm 1.2$ rad.) for intermediate $p_t$ particles. A variety of models have appeared trying to describe this modification. We will review most of them, with special emphasis in the Conical Flow scenario in which the observed shape is a consequence of the emission of sound by a supersonic high momentum particle propagating in the Quark Gluon Plasma.Comment: 8 pages, 3 figures, Invited plenary talk given at the 19th International Conference on Ultrarelativistic Nucleus-Nucleus Collisions: Quark Matter 2006 (QM 2006), Shanghai, China, 14-20 Nov 200