Mathematical Explanation: A Contextual Approach

PurposeIn this article, we aim to present and defend a contextual approach to mathematical explanation.MethodTo do this, we introduce an epistemic reading of mathematical explanation.ResultsThe epistemic reading not only clarifies the link between mathematical explanation and mathematical understanding, but also allows us to explicate some contextual factors governing explanation. We then show how several accounts of mathematical explanation can be read in this approach.ConclusionThe contextual approach defended here clears up the notion of explanation and pushes us towards a pluralist vision on mathematical explanation

Mathematical proofs in practice: revisiting the reliability of published mathematical proofs

Mathematics seems to have a special status when compared to other areas of human knowledge. This special status is linked with the role of proof. Mathematicians often believe that this type of argumentation leaves no room for errors and unclarity. Philosophers of mathematics have differentiated between absolutist and fallibilist views on mathematical knowledge, and argued that these views are related to whether one looks at mathematics-in-the-making or finished mathematics. In this paper we take a closer look at mathematical practice, more precisely at the publication process in mathematics. We argue that the apparent view that mathematical literature, given the special status of mathematics, is highly reliable is too naive. We will discuss several problems in the publication process that threaten this view, and give several suggestions on how this could be countered

Varicellovirus UL 49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer

Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0–3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2–16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2–18.8) for CPE and 10.3 months (95% CI 7.1–15.5; hazard ratio (HR) 0.62, 95% CI 0.25–1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07–0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8–61.9 months) for CPE compared to 17.2 months (95% CI 11.5–45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22–1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity

ELSMOR – towards European Licensing of Small Modular Reactors: Methodology recommendations for light-water small modular reactors safety assessment

Decarbonization of energy production is key in today’s societies and nuclear energy holds an essential place in this prospect. Besides heavy-duty electricity production, other industrial and communal needs could be served by integrating novel nuclear energy production systems, among which are low-power nuclear devices, like small modular reactors (SMRs). The ELSMOR (towards European Licensing of Small Modular Reactors) European project addresses this topic as an answer to the Horizon 2020 Euratom NFRP-2018-3 call. The consortium includes 15 partners from eight European countries, involving research institutes, major European nuclear companies and technical support organizations. The 3.5-year project, launched in September 2019, investigates selected safety features of light-water (LW) SMRs with focus on licensing aspects. Providing a comprehensive compliance framework that regulators can adopt and operate, the licensing process of such SMRs could be optimized, helping their deployment. In this prospect, as a result of ELSMOR’s work, this article gives an overview of the specific issues that LW-SMRs may bring about in the different domains of nuclear safety, in terms of: Methodological standpoints: safety goals, safety requirements, safety principles (defence-in-depth implementation); Main safety functions of reactivity control, decay heat removal and confinement management; Severe accident management; Other safety issues particular to SMRs: use of shared systems; performing of multi-unit probabilistic safety assessment (PSA); refuelling, spent fuel management, transport and disposal management. In this article, adequate methodologies are developed to deal with these issues and to help assess the safety of LW-SMRs. This work gives a precious synthesis of the safety assessment issues of LW-SMRs and of the associated methodologies developed in the context of the ELSMOR European project. The removal of fossil fuels in energy production is very important in today’s societies and nuclear energy plays an essential role in this. Besides large-scale electricity production, other industrial and communal needs could be solved by using new nuclear energy production systems, among which are low-power nuclear devices, like small modular reactors (SMRs). The ELSMOR (towards European Licensing of Small Modular Reactors) European project looks at this topic as an answer to the Horizon 2020 Euratom NFRP-2018-3 initiative. This project includes 15 partners from eight European countries, involving research institutes, major European nuclear companies and technical support organizations. The 3.5-year project, started in September 2019, investigates selected safety features of light-water (LW) SMRs with a focus on the licensing aspects. Providing a comprehensive compliance framework that regulators can use and operate, the licensing process of such SMRs could be optimized, helping their deployment. With this prospect, this article gives an overview of the specific subjects that LW-SMRs may bring in the different areas of nuclear safety (in particular: safety goals, safety requirements, nuclear safety functions: reactivity control, decay heat removal and confinement management, etc..). In this article, methods are developed to deal with these new subjects and to help assess the safety of LW-SMRs. This work gives an overview of the safety assessment issues of LW-SMRs and of the associated methods developed in the context of the ELSMOR European project

Semiautomatic Assessment of the Terminal Ileum and Colon in Patients with Crohn Disease Using MRI (the VIGOR++ Project)

Rationale and Objectives: The objective of this study was to develop and validate a predictive magnetic resonance imaging (MRI) activity score for ileocolonic Crohn disease activity based on both subjective and semiautomatic MRI features. Materials and Methods: An MRI activity score (the “virtual gastrointestinal tract [VIGOR]” score) was developed from 27 validated magnetic resonance enterography datasets, including subjective radiologist observation of mural T2 signal and semiautomatic measurements of bowel wall thickness, excess volume, and dynamic contrast enhancement (initial slope of increase). A second subjective score was developed based on only radiologist observations. For validation, two observers applied both scores and three existing scores to a prospective dataset of 106 patients (59 women, median age 33) with known Crohn disease, using the endoscopic Crohn's Disease Endoscopic Index of Severity (CDEIS) as a reference standard. Results: The VIGOR score (17.1 × initial slope of increase + 0.2 × excess volume + 2.3 × mural T2) and other activity scores all had comparable correlation to the CDEIS scores (observer 1: r = 0.58 and 0.59, and observer 2: r = 0.34–0.40 and 0.43–0.51, respectively). The VIGOR score, however, improved interobserver agreement compared to the other activity scores (intraclass correlation coefficient = 0.81 vs 0.44–0.59). A diagnostic accuracy of 80%–81% was seen for the VIGOR score, similar to the other scores. Conclusions: The VIGOR score achieves comparable accuracy to conventional MRI activity scores, but with significantly improved reproducibility, favoring its use for disease monitoring and therapy evaluation

Cross-Border Dissemination of Methicillin-Resistant Staphylococcus aureus, Euregio Meuse-Rhin Region

MRSA clones were associated with hospital-associated clonal complexes and with Panton-Valentine leukocidin–positive community-associated MRSA

Dropout from exercise trials among cancer survivors—An individual patient data meta-analysis from the POLARIS study

Introduction: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. Methods: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. Results: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI &gt;28.4 kg/m2, performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI &gt;28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. Conclusions: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.</p