A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements (...) must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework—a dynamic knowledge repository—wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline. (shrink)

Selected response items and constructed response items are often found in the same test. Conventional psychometric models for these two types of items typically focus on using the scores for correctness of the responses. Recent research suggests, however, that more information may be available from the CR items than just scores for correctness. In this study, we describe an approach in which a statistical topic model along with a diagnostic classification model was applied to a mixed item format formative test (...) of English and Language Arts. The DCM was used to estimate students’ mastery status of reading skills. These mastery statuses were then included in a topic model as covariates to predict students’ use of each of the latent topics in their written answers to a CR item. This approach enabled investigation of the effects of mastery status of reading skills on writing patterns. Results indicated that one of the skills, Integration of Knowledge and Ideas, helped detect and explain students’ writing patterns with respect to students’ use of individual topics. (shrink)

The language $L_A(\Finv)$ is formed by adding the quantifier $\Finv x$ , "few x", to the infinitary logic L A on an admissible set A. A complete axiomatization is obtained for models whose universe is the set of ordinals of A and where $\Finv x$ is interpreted as there exist A-finitely many x. For well-behaved A, every consistent sentence has a model with an A-recursive diagram. A principal tool is forcing for $L_A(\Finv)$.

The language $L_A$ is formed by adding the quantifier $\Finv x$ , "few x", to the infinitary logic L A on an admissible set A. A complete axiomatization is obtained for models whose universe is the set of ordinals of A and where $\Finv x$ is interpreted as there exist A-finitely many x. For well-behaved A, every consistent sentence has a model with an A-recursive diagram. A principal tool is forcing for $L_A$.

Objective: To determine whether a moral reasoning exercise can improve response quality to surveys of healthcare priorities Methods: A randomised internet survey focussing on patient age in healthcare allocation was repeated twice. From 2574 internet panel members from the USA and Canada, 2020 (79%) completed the baseline survey and 1247 (62%) completed the follow-up. We elicited respondent preferences for age via five allocation scenarios. In each scenario, a hypothetical health planner made a decision to fund one of two programmes identical (...) except for average patient age (35 vs 65 years). Half of the respondents (intervention group) were randomly assigned to receive an additional moral reasoning exercise. Responses were elicited again 7 weeks later. Numerical scores ranging from –5 (strongest preference for younger patients) to +5 (strongest preference for older patients); 0 indicates no age preference. Response quality was assessed by propensity to choose extreme or neutral values, internal consistency, temporal stability and appeal to prejudicial factors. Results: With the exception of a scenario offering palliative care, respondents preferred offering scarce resources to younger patients in all clinical contexts. This preference for younger patients was weaker in the intervention group. Indicators of response quality favoured the intervention group. Conclusions: Although people generally prefer allocating scarce resources to young patients over older ones, these preferences are significantly reduced when participants are encouraged to reflect carefully on a wide range of moral principles. A moral reasoning exercise is a promising strategy to improve response quality to surveys of healthcare priorities. (shrink)

The ways in which people conceptualize the human–nature relationship have significant implications for proenvironmental values and attitudes, sustainable behavior, and environmental policy measures. Human exceptionalism (HE) is one such conceptual framework, involving the belief that humans and human societies exist independently of the ecosystems in which they are embedded, promoting a sharp ontological boundary between humans and the rest of the natural world. In this paper, we introduce HE in more depth, exploring the impact of HE on perceptions of the (...) human–nature relationship, the role of culture in HE, and speculating on the origins of HE. We consider potential implications for environmental decision-making, conservation and environmental science, and promoting proenvironmental behavior. We present empirical evidence on the pervasiveness and consequences of HE in WEIRD (Western, Educated, Industrialized, Rich and Democratic) populations, and potential interventions. Finally, we close with implications of human-exceptionalist thinking on other sustainability-related fields, including conservation practices, nature management, climate change adaptation, and environmental science. Understanding the cognitive and social drivers of this disconnect is vital on a planet now dominated by environmental change, as not only are humans increasingly impacted by natural disasters, but the choices they make can have ever more dire consequences for the sustainability of ecosystems. (shrink)

The spatial dynamics of the optical emission from an array of 50 times 50 individual microcavity plasma devices is investigated. The array is operated in argon and argon-neon mixtures close to atmospheric pressure with an ac voltage. The optical emission is analysed with phase and space resolution. It has been found that the emission is not continuous over the entire ac period, but occurs once per half period. Each of the observed emission phases shows a self-pulsing of the discharge, with (...) several bursts of emission of fixed width and repetition rate. The number of emission bursts depends on applied voltage and frequency. Spatially resolved measurements prove that the emission bursts are formed by overlapping emission pulses from single discharge cavities. Intensity differences between positive and negative half-wave can be interpreted through spatially resolved measurements of single discharge cavities. (shrink)

While stigmatisation is universal, stigma research in low- and middle-income countries (LMIC) is limited. LMIC stigma research predominantly concerns health-related stigma, primarily regarding HIV/AIDS or mental illness from an adult perspective. While there are commonalities in stigmatisation, there are also contextual differences. The aim of this study in DR Congo (DRC), as a formative part in the development of a common stigma reduction intervention, was to gain insight into the commonalities and differences of stigma drivers (triggers of stigmatisation), facilitators (factors (...) positively or negatively influencing stigmatisation), and manifestations (practices and experiences of stigmatisation) with regard to three populations: unmarried mothers, children formerly associated with armed forces and groups (CAAFAG), and an indigenous population. Group exercises, in which participants reacted to statements and substantiated their reactions, were held with the ‘general population’ (15 exercises, n = 70) and ‘populations experiencing stigma’ (10 exercises, n = 48). Data was transcribed and translated, and coded in Nvivo12. We conducted framework analysis. There were two drivers mentioned across the three populations: perceived danger was the most prominent driver, followed by perceived low value of the population experiencing stigma. There were five shared facilitators, with livelihood and personal benefit the most comparable across the populations. Connection to family or leaders received mixed reactions. If unmarried mothers and CAAFAG were perceived to have taken advice from the general population and changed their stereotyped behaviour this also featured as a facilitator. Stigma manifested itself for the three populations at family, community, leaders and services level, with participation restrictions, differential treatment, anticipated stigma and feelings of scapegoating. Stereotyping was common, with different stereotypes regarding the three populations. Although stigmatisation was persistent, positive interactions between the general population and populations experiencing stigma were shared as well. This study demonstrated utility of a health-related stigma and discrimination framework and a participatory exercise for understanding non-health related stigmatisation. Results are consistent with other studies regarding these populations in other contexts. This study identified commonalities between drivers, facilitators and manifestations—albeit with population-specific factors. Contextual information seems helpful in proposing strategy components for stigma reduction. (shrink)

Early executive function skills reliably predict school readiness and future academic success. While children’s skills undergo rapid development during the transition to formal schooling, it remains unclear the extent to which schooling exerts a unique influence on the accelerated development of EF and academic skills during the early years of schooling. In the present study, a quasi-experimental technique known as the school cutoff design was used to examine whether same-aged children who made vs. missed the age cutoff for school entry (...) significantly differed on EF, reading, and math outcomes. Data from 166 pre-k, kindergarten, and first grade children from a longitudinal study of literacy development were analyzed. Children were assessed on EF, reading, and math skills in fall and spring. Results revealed unique effects of kindergarten, but not first grade, on growth in EF and reading over and above the effect of age. Schooling was unrelated to growth in math. Because kindergarten represents the first year of elementary school and children’s first exposure to a formal schooling environment, kindergarten schooling may be uniquely positioned to produce greater gains in academic and behavioral outcomes compared to other grades. (shrink)

While the bioethics literature demonstrates that the field has spent substantial time and thought over the last four decades on the goals, methods, and desired outcomes for service and training in bioethics, there has been less progress defining the nature and goals of bioethics research and scholarship. This gap makes it difficult both to describe the breadth and depth of these areas of bioethics and, importantly, to gauge their success. However, the gap also presents us with an opportunity to define (...) this scope of work for ourselves and to help shape the broader conversation about the impact of academic research. Because of growing constraints on academic funding, researchers and scholars in many fields are being asked to demonstrate and also forecast the value and impact of their work. To do that, and also to satisfy ourselves that our work has meaningful effect, we must understand how our work can motivate change and how that change can be meaningfully measured. In a field as diverse as bioethics, the pathways to and metrics of change will likewise be diverse. It is therefore critical that any assessment of the impact of bioethics research and scholarship be informed by an understanding of the nature of the work, its goals, and how those goals can and ought to be furthered. In this paper, we propose a conceptual model that connects individual bioethics projects to the broader goals of scholarship, describing the translation of research and scholarly output into changes in thinking, practice, and policy. One of the key implications of the model is that impact in bioethics is generally the result of a collection of projects rather than of any single piece of research or scholarship. Our goal is to lay the groundwork for a thoroughgoing conversation about bioethics research and scholarship that will advance and shape the important conversation about their impact. (shrink)

REMARKS ON EVOLUTION AND TIME-SCALES, Graham Cairns-Smith; HODGSON'S BLACK BOX, Thomas Clark; DO HODGSON'S PROPOSITIONS UNIQUELY CHARACTERIZE FREE WILL?, Ravi Gomatam; WHAT SHOULD WE RETAIN FROM A PLAIN PERSON'S CONCEPT OF FREE WILL?, Gilberto Gomes; ISOLATING DISPARATE CHALLENGES TO HODGSON'S ACCOUNT OF FREE WILL, Liberty Jaswal; FREE AGENCY AND LAWS OF NATURE, Robert Kane; SCIENCE VERSUS REALIZATION OF VALUE, NOT DETERMINISM VERSUS CHOICE, Nicholas Maxwell; COMMENTS ON HODGSON, J.J.C. Smart; THE VIEW FROM WITHIN, Sean Spence; COMMENTARY ON HODGSON, Henry (...) Stapp. (shrink)

Both fairness and efficiency are important considerations in market design and regulation, yet many regulators have neither defined nor measured these concepts. We develop an evidencebased policy framework in which these are both defined and measured using a series of empirical proxies. We then build a systems estimation model to examine the 2003–2011 explosive growth in algorithmic trading on the London Stock Exchange and NYSE Euronext Paris. Our results show that greater AT is associated with increased transactional efficiency and reduced (...) information leakage in top quintile stocks. For less liquid stocks, manipulation at the close declines. We also document the tradeoff between reduced spreads and increased manipulation or information leakage following the introduction of MiFID1. (shrink)

Both fairness and efficiency are important considerations in market design and regulation, yet many regulators have neither defined nor measured these concepts. We develop an evidencebased policy framework in which these are both defined and measured using a series of empirical proxies. We then build a systems estimation model to examine the 2003–2011 explosive growth in algorithmic trading on the London Stock Exchange and NYSE Euronext Paris. Our results show that greater AT is associated with increased transactional efficiency and reduced (...) information leakage in top quintile stocks. For less liquid stocks, manipulation at the close declines. We also document the tradeoff between reduced spreads and increased manipulation or information leakage following the introduction of MiFID1. (shrink)

Ample research links mothers’ postpartum depression (PPD) to adverse interactions with their infants. However, most studies relied on general population samples, whereas a substantial number of women are at elevated depression risk. The purpose of this study was to describe mothers’ interactions with their 6- and 12-month-old infants among women at elevated risk, although with a range of symptom severity. We also identified higher-order factors that best characterized the interactions and tested longitudinal consistency of these factors from 6 to 12 (...) months of infant age. We leveraged data from eight projects across the United States (n = 647), using standardized depression measures and an adaptation of the NICHD Mother-Infant Interaction Scales. Overall, these depression-vulnerable mothers showed high levels of sensitivity and positive regard and low levels of intrusiveness, detachment, and negative regard with their infants. Factor analyses of maternal behaviors identified two overarching factors—“positive engagement” and “negative intrusiveness” that were comparable at 6 and 12 months of infant age. Mothers’ ability to regulate depressed mood was a key behavior that defined “positive engagement” in factor loadings. An exceptionally strong loading of intrusiveness on the second factor suggested its central importance for women at elevated depression risk. Mothers with severe depressive symptoms had significantly more “negative intrusiveness” and less “positive engagement” with their 6-month-old infants than women with moderate or fewer depressive symptoms, suggesting a potential tipping point at which symptoms may interfere with the quality of care. Results provide the foundation for further research into predictors and moderators of women’s interactions with their infant among women at elevated risk for PPD. They also indicate a need for evidence-based interventions that can support more severely depressed women in providing optimal care. (shrink)

The development of a defensible and fecund notion of emergence has been dogged by a number of threshold issues neatly highlighted in a recent paper by Jaegwon Kim. We argue that physicalist assumptions confuse and vitiate the whole project. In particular, his contention that emergence entails supervenience is contradicted by his own argument that the ‘microstructure’ of an object belongs to the whole object, not to its constituents. And his argument against the possibility of downward causation is question-begging and makes (...) false assumptions about causal sufficiency. We argue, on the contrary, for a rejection of the deeply entrenched assumption, shared by physicalists and Cartesians alike, that what basically exists are things (entities, substances). Our best physics tells us that there are no basic particulars, only fields in process. We need an ontology which gives priority to organization, which is inherently relational. Reflection upon the fact that all biological creatures are far-from-equilibrium systems, whose very persistence depend upon their interactions with their environment, reveals incoherence in the notion of an ‘emergence base’. (shrink)

Background The use of lengthy, detailed, and complex informed consent forms is of paramount concern in biomedical research as it may not truly promote the rights and interests of research participants. The extent of information in ICFs has been the subject of debates for decades; however, no clear guidance is given. Thus, the objective of this study was to determine the perspectives of research participants about the type and extent of information they need when they are invited to participate in (...) biomedical research. Methods This multi-center, cross-sectional, descriptive survey was conducted at 54 study sites in seven Asia-Pacific countries. A modified Likert-scale questionnaire was used to determine the importance of each element in the ICF among research participants of a biomedical study, with an anchored rating scale from 1 to 5. Results Of the 2484 questionnaires distributed, 2113 were returned. The majority of respondents considered most elements required in the ICF to be ‘moderately important’ to ‘very important’ for their decision making. Major foreseeable risk, direct benefit, and common adverse effects of the intervention were considered to be of most concerned elements in the ICF. Conclusions Research participants would like to be informed of the ICF elements required by ethical guidelines and regulations; however, the importance of each element varied, e.g., risk and benefit associated with research participants were considered to be more important than the general nature or technical details of research. Using a participant-oriented approach by providing more details of the participant-interested elements while avoiding unnecessarily lengthy details of other less important elements would enhance the quality of the ICF. (shrink)

BackgroundBiobanks are considered to be key infrastructures for research development and have generated a lot of debate about their ethical, legal and social implications. While the focus has been on human genomic research, rapid advances in human microbiome research further complicate the debate.DiscussionWe draw on two cystic fibrosis biobanks in Toronto, Canada, to illustrate our points. The biobanks have been established to facilitate sample and data sharing for research into the link between disease progression and microbial dynamics in the lungs (...) of pediatric and adult patients. We begin by providing an overview of some of the ELSI associated with human microbiome research, particularly on the implications for the broader society. We then discuss ethical considerations regarding the identifiability of samples biobanked for human microbiome research, and examine the issue of return of results and incidental findings. We argue that, for the purposes of research ethics oversight, human microbiome research samples should be treated with the same privacy considerations as human tissues samples. We also suggest that returning individual microbiome-related findings could provide a powerful clinical tool for care management, but highlight the need for a more grounded understanding of contextual factors that may be unique to human microbiome research.ConclusionsWe revisit the ELSI of biobanking and consider the impact that human microbiome research might have. Our discussion focuses on identifiability of human microbiome research samples, and return of research results and incidental findings for clinical management. (shrink)

BackgroundKinarm Standard Tests is a suite of upper limb tasks to assess sensory, motor, and cognitive functions, which produces granular performance data that reflect spatial and temporal aspects of behavior. We have previously used principal component analysis to reduce the dimensionality of multivariate data using the Kinarm End-Point Lab. Here, we performed PCA using data from the Kinarm Exoskeleton Lab, and determined agreement of PCA results across EP and EXO platforms in healthy participants. We additionally examined whether further dimensionality reduction (...) was possible by using PCA across behavioral tasks.MethodsHealthy participants were assessed using the Kinarm EXO and EP. Four behavioral tasks were performed that quantified arm sensory and motor function, including position sense [Arm Position Matching ] and three motor tasks [Visually Guided Reaching, Object Hit, and Object Hit and Avoid ]. The number of components to include per task was determined from scree plots and parallel analysis, and rotation type was decided on a per-task basis. To assess agreement, we compared principal components across platforms using distance correlation. We additionally considered inter-task interactions in EXO data by performing PCA across all six behavioral assessments.ResultsBy applying PCA on a per task basis to data collected using the EXO, the number of behavioral parameters were substantially reduced by 58–75% while accounting for 76–87% of the variance. These results compared well to the EP analysis, and we found good-to-excellent agreement values between PCs from the EXO and those from the EP. Finally, we were able to reduce the dimensionality of the EXO data across tasks down to 16 components out of a total of 76 behavioral parameters, which represents a reduction of 79% while accounting for 73% of the total variance.ConclusionPCA of Kinarm robotic assessment appears to capture similar relationships between kinematic features in healthy individuals and is agnostic to the robotic platform used for collection. Further work is needed to investigate the use of PCA-based data reduction for the characterization of neurological deficits in clinical populations. (shrink)

Little is known about how ethical organizational contexts influence employees’ perceived stress levels and well-being. This study used two theoretical lenses, ethical impact theory (Promislo et al. in Handbook of Unethical Work Behavior, M.E. Sharpe, Armonk, 2013) and ethical decision-making theory (Schwartz in J Bus Ethics 139(4): 755–776, 2016), to investigate the relationships among perceived organizational ethics (comprised of ethical climate, leader/manager ethics, and corporate social responsibility), work-related stress, and employee well-being (comprised of vitality, life satisfaction, personal growth initiative, flourishing, (...) positive mental health, and self-actualization). Findings across two studies indicated that organizational ethics was negatively related to work-related stress, and that work-related stress was negatively related to employee well-being. Perceived organizational ethics is positively related to employee well-being, with post hoc mediation tests indicating that work-related stress partially mediates this relationship. Our findings suggest that organizations should be proactive in improving their ethical climate, such as choosing ethical leaders, developing a robust and well-communicated code of ethics, and actively practicing CSR. These measures should reduce excessive work-related stress and improve employee well-being. (shrink)

A total of 1918 loci, detected by the hybridization of 938 expressed sequence tag unigenes from 26 Triticeae cDNA libraries, were mapped to wheat homoeologous group 4 chromosomes using a set of deletion, ditelosomic, and nulli-tetrasomic lines. The 1918 EST loci were not distributed uniformly among the three group 4 chromosomes; 41, 28, and 31% mapped to chromosomes 4A, 4B, and 4D, respectively. This pattern is in contrast to the cumulative results of EST mapping in all homoeologous groups, as reported (...) elsewhere, that found the highest proportion of loci mapped to the B genome. Sixty-five percent of these 1918 loci mapped to the long arms of homoeologous group 4 chromosomes, while 35% mapped to the short arms. The distal regions of chromosome arms showed higher numbers of loci than the proximal regions, with the exception of 4DL. This study confirmed the complex structure of chromosome 4A that contains two reciprocal translocations and two inversions, previously identified. An additional inversion in the centromeric region of 4A was revealed. A consensus map for homoeologous group 4 was developed from 119 ESTs unique to group 4. Forty-nine percent of these ESTs were found to be homoologous to sequences on rice chromosome 3, 12% had matches with sequences on other rice chromosomes, and 39% had no matches with rice sequences at all. Limited homology was found between wheat ESTs on homoeologous group 4 and the Arabidopsis genome. Forty-two percent of the homoeologous group 4 ESTs could be classified into functional categories on the basis of blastX searches against all protein databases. (shrink)