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Despite the surging interest in introducing lottery mechanisms into decision-making procedures for science funding bodies, the discourse on funding-by-lottery remains underdeveloped and, at times, misleading. Funding-by-lottery is sometimes presented as if it were a single mechanism when, in reality, there are many funding-by-lottery mechanisms with important distinguishing features. Moreover, funding-by-lottery is sometimes portrayed as an alternative to traditional methods of peer review when peer review is still used within funding-by-lottery approaches. This obscures a proper analysis of the (hypothetical and actual) variants of funding-by-lottery and important differences amongst them. The goal of this article is to provide a preliminary taxonomy of funding-by-lottery variants and evaluate how the existing evidence on peer review might lend differentiated support for variants of funding-by-lottery. Moreover, I point to gaps in the literature on peer review that must be addressed in future research. I conclude by building off of the work of Avin in moving toward a more holistic evaluation of funding-by-lottery. Specifically, I consider implications funding-by-lottery variants may have regarding trust and social responsibility.

There has been a resurgence between two closely related discussions concerning modern science funding policy. The first revolves around the coherence and usefulness of the distinction between basic and applied science and the second concerns whether science should be free to pursue research according to its own internal standards or pursue socially responsible research agendas that are held accountable to moral or political standards. In this paper, I argue that the distinction between basic and applied science, and the concomitant debate about freedom and social responsibility, require revision. I contend that the distinction can only be maintained in cases of urgent science. I go on to elucidate the notion of urgent science using a case study from research of the climate refugee crisis., Author(s): Jamie Shaw [sup.1] Author Affiliations: (1) Institute for History and Philosophy of Science and Technology, SSHRC Postdoctoral Fellow, , Toronto, Canada Preamble Whether scientists should be free to set [...]

Enpatoran is a novel, highly selective, and potent dual toll‐like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently recruiting. To support development of WILLOW as an Asia‐inclusive multiregional clinical trial (MRCT) according to International Conference on Harmonisation E5 and E17 principles, we have evaluated ethnic sensitivity to enpatoran based on clinical pharmacokinetic (PK), pharmacodynamic (PD), and safety data from an ethno‐bridging study (NCT04880213), supplemented by relevant quantitative PK, PD, and disease trajectory modeling (DTM) results, and drug metabolism/disease knowledge. A single‐center, open‐label, sequential dose group study in White and Japanese subjects matched by body weight, height, and sex demonstrated comparable PK and PD properties for enpatoran in Asian vs. non‐Asian (White and other) subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for Asian vs. non‐Asian individuals. Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach. [ABSTRACT FROM AUTHOR]

Background: Evobrutinib – an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor – has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS. Objective: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study. Methods: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily. Results: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05–0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population (Z -scores); T1 gadolinium-enhancing lesion numbers remained low. No new safety signals were identified. In the OLE, evobrutinib was detected in the CSF of all sub-study patients. Conclusion: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma. [ABSTRACT FROM AUTHOR]

This paper analyses three key components of a career development curriculum for business majors that has generated superior results, supporting undergraduates’ transition from higher education to professional employment while teaching students career advancement skills that will be used throughout their lives. Students have expressed strong satisfaction with opportunities for coaching and mentoring, coursework facilitating experiential learning, and mandatory internships in their major. Analyses of qualitative data drawn from student assignments and course evaluations suggest these three elements of the program have positively impacted students’ career-readiness, career aspirations and career achievements. Quantitative data shows increased student success in achieving their career goals. [ABSTRACT FROM AUTHOR]

Recent science funding policy scholars and practitioners have advocated for the use of lotteries, or elements of random chance, as supplementations of traditional peer review for evaluating grant applications. One of the primary motivations for lotteries is their purported openness to innovative research. The purpose of this article is to argue that current proponents of funding science by lottery overestimate the viability of peer review and thus unduly restrict the scope of lotteries in science funding practice. I further show how this analysis suggests a different way of introducing lotteries into science funding policy. [ABSTRACT FROM AUTHOR]

Enpatoran is a selective inhibitor of toll‐like receptors 7 and 8 (TLR7/8) that potentially targets pro‐inflammatory pathways induced by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). A phase II study conducted in Brazil, the Philippines, and the USA during the early pandemic phase assessed the safety and efficacy of enpatoran in patients hospitalized with COVID‐19 pneumonia (NCT04448756). A total of 149 patients, who scored 4 on the World Health Organization's (WHO) 9‐point ordinal severity scale, were randomized 1:1:1 and received enpatoran 50 mg (n = 54) or 100 mg (n = 46), or placebo (n = 49) twice daily (b.i.d.) for 14 days plus standard of care. The primary objectives were safety and time to recovery (WHO 9‐point scale ≤3). Clinical deterioration (WHO 9‐point scale ≥ 5) was a key secondary objective. Treatment‐emergent adverse events (TEAEs) were comparable across groups (56.5%–63.0%). Treatment‐related TEAEs were numerically higher with enpatoran 50 mg (14.8%) than 100 mg (10.9%) or placebo (8.2%). Serious TEAEs were numerically lower with enpatoran (50 mg 9.3%, 100 mg 2.2%) than placebo (18.4%). The primary efficacy objective was not met; median time to recovery was 3.4–3.9 days across groups, with placebo‐treated patients recovering on average faster than anticipated. Clinical deterioration event‐free rates up to Day 7 were 90.6%, 95.6%, and 81.6% with enpatoran 50 mg, 100 mg, and placebo, respectively. Enpatoran was well tolerated by patients acutely ill and hospitalized with COVID‐19 pneumonia. Positive signals in some secondary end points suggested potential beneficial effects, supporting further evaluation of enpatoran in patients with hyperinflammation due to infection or autoimmunity. [ABSTRACT FROM AUTHOR]

When a small, Midwestern business school launched a required, four-year career development curriculum, robust practicum courses, and a dynamic, co-curricular program, it proved itself to be in the vanguard of career development practices. Due to the extensive experiential learning this program provides, greater numbers of business and accounting majors are graduating with raised employment aspirations and the knowledge, skills, and confidence to begin their professional lives. Using quantitative measures, the results suggest the positive impact of these career development activities on students' certainty about career direction, assessment of the quality of their resumes and LinkedIn profiles, and confidence in interviewing. [ABSTRACT FROM AUTHOR]

Dual toll‐like receptor (TLR) 7 and TLR8 inhibitor enpatoran is under investigation as a treatment for lupus and coronavirus disease 2019 (COVID‐19) pneumonia. Population pharmacokinetic/pharmacodynamic (PopPK/PD) model‐based simulations, using PK and PD (inhibition of ex vivo‐stimulated interleukin‐6 (IL‐6) and interferon‐α (IFN‐α) secretion) data from a phase I study of enpatoran in healthy participants, were leveraged to inform dose selection for lupus and repurposed for accelerated development in COVID‐19. A two‐compartment PK model was linked to sigmoidal maximum effect (Emax) models with proportional decrease from baseline characterizing the PD responses across the investigated single and multiple doses, up to 200 mg daily for 14 days (n = 72). Concentrations that maintain 50/60/90% inhibition (IC50/60/90) of cytokine secretion (IL‐6/IFN‐α) over 24 hours were estimated and stochastic simulations performed to assess target coverage under different dosing regimens. Simulations suggested investigating 25, 50, and 100 mg enpatoran twice daily (b.i.d.) to explore the anticipated therapeutic dose range for lupus. With 25 mg b.i.d., > 50% of subjects are expected to achieve 60% inhibition of IL‐6. With 100 mg b.i.d., most subjects are expected to maintain almost complete target coverage for 24 hours (> 80% subjects IC90,IL‐6 = 15.5 ng/mL; > 60% subjects IC90,IFN‐α = 22.1 ng/mL). For COVID‐19, 50 and 100 mg enpatoran b.i.d. were recommended; 50 mg b.i.d. provides shorter IFN‐α inhibition (median time above IC90 = 13 hours/day), which may be beneficial to avoid interference with the antiviral immune response. Utilization of PopPK/PD models initially developed for lupus enabled informed dose selection for the accelerated development of enpatoran in COVID‐19. [ABSTRACT FROM AUTHOR]

BACKGROUND: The new type of virus (SARS-CoV-2 or COVID-19) from Coronaviridae family, discovered in 2019, caused a global pandemic with several massive lock-downs around the globe. Science and politicians became the center of world attention, receiving many questions without having clear answers. The hopes of many rested on vaccine development, which was done fast, facing novel challenges such as the massive production and distribution for several billions of people. OBJECTIVE: In this paper, the global reaction to the pandemic is reviewed along with some critical comments. METHOD: Different groups, including nations, took part in global lockdowns, while vaccine development was running in parallel without having enough capacity for some of the biggest medical demands in history. This review will bring together views from all interested groups in this pandemic crisis. RESULTS: The Western world waited too long (4 months), after the first case was confirmed in China, to introduce lock-down and safety measures. On the other side, vaccine development was done too fast to give clear long-term safety profiles of the medications developed. Due to the focus on development, it was overlooked that production and distribution of sterile products such as vaccines might have limitations globally. Usually when such limitations occur, power comes to the surface. Therefore, buyers who had power will get the vaccines they need first. However, we should recognize the economic impact that directly influenced healthcare funding. All of this will lead to post-crisis challenges, including depression, violence, suicide, migration, and many other social problems. CONCLUSIONS: The COVID-19 pandemic is a test for all of us, which many governments, industries and non-state actors are failing. It is a perfect "general probe" to detect some of the weaknesses of the current structure of global health. If politics and science do not work together to make a global production plan for vaccines and learn from this pandemic, then all of the lives lost were for nothing. [ABSTRACT FROM AUTHOR]

BACKGROUND: The pharmaceutical industry is believed to receive considerable support through research and development (R&D) tax credits. OBJECTIVE: The objectives of this paper are (a) to show that many of the pharmaceutical industry's apparent R&D activities are entangled with marketing efforts, and (b) to argue that supporting these activities through tax credits does not serve public interests in health. METHODS: The bulk of this paper summarizes the author's extended qualitative mixed-methods approach to following connections between pharmaceutical research and marketing. RESULTS: The pharmaceutical industry's R&D should be understood as broadly entangled with marketing, and so generally should be understood as integrated research, development and marketing (RD&M). CONCLUSIONS: R&D tax credits to the pharmaceutical industry largely do not serve public interests. [ABSTRACT FROM AUTHOR]

BACKGROUND: The COVID-19 pandemic has shocked society worldwide. Multiple efforts went immediately into developing treatments for managing and vaccines for preventing the disease. National and international initiatives emerged to deal with the deep economic and social inequalities in our world today. OBJECTIVE: To show that the global inequalities that have become salient during the COVID-19 pandemic and specially with the global vaccination campaign, are the result of a highly privatized system of research and development (R&D), which is first and foremost profit-driven, and where epistemic and social concerns are not prioritized. METHODS: Philosophical analysis. RESULTS: After exploring the current organization of scientific research, as well as its impact in the development of research at a global scale, the paper shows the way in which this highly privatized organization of research has permeated scientific research on COVID-19, identifying who is currently benefiting from pandemic science, and who on the contrary is suffering the consequences of this organization. Using the COVAX mechanism as an example, the paper argues that international efforts to counteract the power of commercially-driven science has not rendered the expected results. CONCLUSIONS: The current organization of science ought to be shaken and restructured if we aim to be better prepared to address the global challenges of the future with the relevant scientific and technological development. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has shown us that there are numerous research questions—empirical, political, and philosophical—that need addressing both prior to, during, and after a pandemic. The current organisation of medical research has hindered our ability to efficiently answer these questions. This in turn suggests that there ought to be changes to how the medical research agenda is set. [ABSTRACT FROM AUTHOR]

In a reference letter for Feyerabend's application to UC Berkeley, Carl Hempel writes that 'Mr. Feyerabend combines a forceful and penetrating analytic mind with a remarkably thorough training and high competence in theoretical physics and mathematics' (Collodel and Oberheim, [2], 80). The hope is to better understand Feyerabend's philosophy of physics, its historical impact and reception, and discern what fruits Feyerabend's philosophy of physics may still bear. Del Santo shows how Feyerabend's growing "resentment" toward his authoritarian father-figure and Popper's growing frustration with Feyerabend centred on disagreements concerning quantum mechanics: how to interpret it, how to criticize it, and how to teach it. [Extracted from the article]

This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of enpatoran (formerly named M5049), a new toll-like receptor (TLR) 7 and 8 dual antagonist, and the effect of food on a single dose in healthy participants. In this single phase 1, randomized (3:1), doubleblind, placebo-controlled study, 96 participants received single and multiple ascending oral doses of enpatoran. Participants in single-dose cohorts received one dose of enpatoran (1, 3, 9, 25, 50, 100, or 200 mg) or placebo using a sentinel dosing strategy. Multiple-dose cohorts received enpatoran (9, 25, or 200 mg once daily, or 25 or 50 mg twice daily) or placebo for 14 days. Safety, tolerability, PK, and PD (ex vivo-stimulated cytokine secretion) were assessed in both parts. The effect of food was assessed in an open-label, one-way crossover study in the 25 mg single-dose cohort. Single- and multiple-oral doses of enpatoran up to 200 mg were well tolerated and no significant dose-limiting adverse events or safety signals were observed under fasting or fed conditions. PK parameters were linear and dose-proportional across the dose range evaluated, with a slightly delayed absorption and lower peak concentration observed at 25 mg with food. Exposure-dependent inhibition of ex vivo-stimulated interleukin6 secretion was observed, with maximum inhibition at 200 mg. Enpatoran was well tolerated at doses up to 200 mg. Further investigation of enpatoran is warranted as a potential treatment for diseases driven by TLR7/8 overactivation, such as systemic lupus erythematosus and COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 global pandemic has produced widespread shortages of certified air-filtering personal protection equipment and an acute need for rapid evaluation of breathability and filtration efficiency of proposed alternative solutions. Here, we describe experimental efforts to nondestructively quantify three vital characteristics of mask approaches: breathability, material filtration effectiveness, and sensitivity to fit. We focus on protection against aqueous aerosols >0.3 μmusing off-the-shelf particle, flow, and pressure sensors, permitting rapid comparative evaluation of these three properties. We present and discuss both the pressure drop and the particle penetration as a function of flow to permit comparison of relative protection for a set of proposed filter and mask designs. The design considerations of the testing apparatus can be reproduced by university laboratories and medical facilities and used for rapid local quality control of respirator masks that are of uncertified origin, monitoring the long-term effects of various disinfection schemes and evaluating improvised products not designed or marketed for filtration. [ABSTRACT FROM AUTHOR]

The problem of the empirical basis is one of the most prominent difficulties within the Popperian tradition. Some claim that Popper's anti-inductivism and antipsychologism lead to the concession that science has no empirical basis. Recent commentators have focused on this problem in Popper's methodology. However, the problem also arises in a peculiar way in the thought of two underdiscussed members of the Popperian tradition: William Bartley and Paul Feyerabend. In this article, I aim to accomplish three primary goals. First, I argue that defenses of Popper's solution to the problem of the empirical basis fail to address the deeper issues that have been pointed out by Popper's critics. Second, I show how, despite Bartley's efforts, he also succumbs to a modified version of the problem of the empirical basis. However, Bartley's later work in evolutionary epistemology provides a more sensible response to the problem. Finally, I show how the problem arises in two distinct senses within Feyerabend's methodology. I show how Feyerabend accidentally dissolves one sense of the problem and then provide a proposal for remedying the second version of the problem. [ABSTRACT FROM AUTHOR]

The emerging consensus in the secondary literature on Duhem is that his notion of 'good sense' is a virtue of individual scientists that guides them choosie between empirically equal rival theories (Stump 2007. "Pierre Duhem's Virtue Epistemology." Studies in History and Philosophy of Science Part A 38 (1): 149–159; Ivanova 2010. "Pierre Duhem's Good Sense as a Guide to Theory Choice." Studies in History and Philosophy of Science Part A 41 (1): 58–64; Fairweather 2011. "The Epistemic Value of Good Sense." Studies in History and Philosophy of Science Part A 43 (1): 139–146; Bhakthavatsalam (2017). "Duhemian Good Sense and Agent Reliabilism." Studies in History and Philosophy of Science Part A 64: 22–29). In this paper, I argue that good sense is irrelevant for theory choice within Duhem's conception of scientific methodology. Theory choice, for Duhem, is either a pseudo-problem or addressed purely by empirical and formal desiderata depending on how it is understood. I go on to provide a positive interpretation of good sense as a feature of scientific communities that undergo particular forms of education that allow scientists to abandon theory pursuit. I conclude by suggesting that this interpretation entails that virtue epistemological readings of Duhem are insufficient for understanding good sense; we must employ a social epistemological perspective. [ABSTRACT FROM AUTHOR]

Bernard Williams notes how Aristotle's doctrine of the mean, or the view that one should always pursue the mean between excess and deficiency, is an implicit endorsement of a depressingly conservative approach to life. As such, the ‘good life' in Aristotle's thought is bereft of existential vibrancy and colour leaving it as an unattractive theory of how we ought to live. This paper aims to show how this characterization is a misrepresentation and demonstrate how such existential concerns can be addressed within an Aristotelian framework. I will accomplish this by demonstrating how Friedrich Nietzsche's notion of the ‘Dionysian spirit', understood as a state of spiritual intoxication, can be reconciled with Aristotle's framework. While the Dionysian spirit is prima facie incompatible with this framework, since it explicitly values irrational self-experimentation through the expression of instincts as opposed to rational reflection, I will argue that it can be accommodated in Aristotle's account by analyzing the common role of ‘health' in both accounts. This reconciliation not only enriches Aristotle's ethics, but also clarifies interpretive difficulties with what the doctrine of the mean entails. [ABSTRACT FROM AUTHOR]

Background: Bruton's tyrosine kinase (BTK) plays an important role in proinflammatory pathways potentially involved in multiple sclerosis (MS). Consequently, BTK inhibition is being investigated as a potential therapeutic approach for MS. Evobrutinib, a highly selective BTK inhibitor (BTKi), has a dual mechanism of action, affecting both B cells and macrophages through inhibition of B-cell receptor, Fc receptor, and granulocyte--macrophage colony-stimulating factor receptor signaling, and has demonstrated clinical efficacy in MS in a phase 2 study (trial registration: NCT02975349; Montalban et al, ECTRIMS 2018 [P322]). Objectives: To examine the effect of evobrutinib on immune cells and immunoglobulins (Igs) over 48 weeks. Methods: Patients aged 18-65 years with active relapsing--remitting MS or secondary progressive MS and superimposed relapses were randomized to receive either doubleblind evobrutinib (25 mg once daily [qd], 75 mg qd, or 75 mg twice daily), placebo, or open-label dimethyl fumarate 240 mg (reference arm). After 24 weeks, placebo-treated patients were switched to evobrutinib 25 mg qd; other treatment arms continued under original allocation. Safety of evobrutinib, including assessment of B-cell count and Ig level, was a key secondary end point; investigations of the effects of evobrutinib on B-cell subsets, T-cell subsets, and natural killer cells in peripheral blood over 48 weeks were exploratory. Results: Of 267 patients randomized to treatment, 227 patients completed 48 weeks of treatment. No clinically relevant changes in the number of total B cells, or of memory B, mature naive B, total T, helper T, cytotoxic T, or natural killer cells, were observed in any evobrutinib treatment group over 48 weeks. No changes in IgG or IgG subtype levels were observed over 48 weeks in any treatment group. At week 48, there were slight increases from baseline in IgA and reductions in IgM for all evobrutinib groups, which were numerically greater than those with placebo at week 24. Conclusions: Patients with MS treated with the BTKi evobrutinib showed no evidence of B-cell depletion or change in mature vs naive B-cell subsets over 48 weeks. IgG levels remained stable and slight elevations in IgA levels were observed. These findings demonstrate that, in contrast to genetic deletion of BTK, continued pharmacologic BTK inhibition does not lead to B-cell depletion or signifi- cant reductions in circulating Igs. [ABSTRACT FROM AUTHOR]

Although ductal carcinoma in situ (DCIS) does not require axillary evaluation, controversy exists regarding the use of sentinel lymph node biopsy (SLNB) in patients with DCIS diagnosed by core needle biopsy (CNB). Advocates of concomitant SLNB and lumpectomy cite the low morbidity of SLNB, the high rate of invasive ductal carcinoma in resected specimens, and the positive nodes found in 1 to 2 per cent of patients with resected DCIS despite finding no invasive component. Opponents of this practice cite the complication risk and the improbability of clinically significant axillary recurrence. We therefore proposed to determine our rate of invasive cancer in DCIS diagnosed by CNB and to determine whether SLNB at first operation would decrease return to the operating room. We retrospectively reviewed patients diagnosed with DCIS by CNB from 2003 to 2008. Standard clinicopathological data were collected and analyzed. In 110 patients, the prevalence of invasive cancer on final resection pathology was 13.6 per cent (15 of 110). Of those patients with invasive cancer, 93 per cent (14 of 15) had high-grade DCIS (P = 0.077) by CNB. Seventeen percent (14 of 82) of patients with high-grade DCIS had invasive cancer. Of 34 patients with SLNB, three (9%) had positive nodes. Fifteen patients required re-excision to obtain negative margins, including 13 patients with invasive cancer. Five patients (4.5%) were spared additional operative intervention by initially performing SLNB. We suggest using concomitant SLNB when a high clinical suspicion of invasive cancer exists, in the presence of a palpable mass, or when mastectomy precludes future SLNB. Intraoperative margin assessment is needed to avoid return to the operating room. [ABSTRACT FROM AUTHOR]