Prion removal capacity of plasma protein manufacturing processes

BACKGROUND The variant Creutzfeldt-Jakob disease incidence peaked a decade ago and has since declined. Based on epidemiologic evidence, the causative agent, pathogenic prion, has not constituted a tangible contamination threat to large-scale manufacturing of human plasma-derived proteins. Nonetheless, manufacturers have studied the prion removal capabilities of various manufacturing steps to better understand product safety. Collectively analyzing the results could reveal experimental reproducibility and detect trends and mechanisms driving prion removal. STUDY DESIGN AND METHODS Plasma Protein Therapeutics Association member companies collected more than 200 prion removal studies on plasma protein manufacturing steps, including precipitation, adsorption, chromatography, and filtration, as well as combined steps. The studies used a range of model spiking agents and bench-scale process replicas. The results were grouped based on key manufacturing variables to identify factors impacting removal. The log reduction values of a group are presented for comparison. RESULTS Overall prion removal capacities evaluated by independent groups were in good agreement. The removal capacity evaluated using biochemical assays was consistent with prion infectivity removal measured by animal bioassays. Similar reduction values were observed for a given step using various spiking agents, except highly purified prion protein in some circumstances. Comparison between combined and single-step studies revealed complementary or overlapping removal mechanisms. Steps with high removal capacities represent the conditions where the physiochemical differences between prions and therapeutic proteins are most significant. CONCLUSION The results support the intrinsic ability of certain plasma protein manufacturing steps to remove prions in case of an unlikely contamination, providing a safeguard to products.

Io volcano observer (IVO) integrated approach to optimizing system design for radiation challenges

One of the major challenges for a mission to the Jovian system is the radiation tolerance of the spacecraft (S/C) and the payload. Moreover, being able to achieve science observations with high signal to noise ratios (SNR), while passing through the high flux radiation zones, requires additional ingenuity on the part of the instrument provider. Consequently, the radiation mitigation is closely intertwined with the payload, spacecraft and trajectory design, and requires a systems-level approach. This paper presents a design for the Io Volcano Observer (IVO), a Discovery mission concept that makes multiple close encounters with Io while orbiting Jupiter. The mission aims to answer key outstanding questions about Io, especially the nature of its intense active volcanism and the internal processes that drive it. The payload includes narrow-angle and wide-angle cameras (NAC and WAC), dual fluxgate magnetometers (FGM), a thermal mapper (ThM), dual ion and neutral mass spectrometers (INMS), and dual plasma ion analyzers (PIA). The radiation mitigation is implemented by drawing upon experiences from designs and studies for missions such as the Radiation Belt Storm Probes (RBSP) and Jupiter Europa Orbiter (JEO). At the core of the radiation mitigation is IVO's inclined and highly elliptical orbit, which leads to rapid passes through the most intense radiation near Io, minimizing the total ionizing dose (177 krads behind 100 mils of Aluminum with radiation design margin (RDM) of 2 after 7 encounters). The payload and the spacecraft are designed specifically to accommodate the fast flyby velocities (e.g. the spacecraft is radioisotope powered, remaining small and agile without any flexible appendages). The science instruments, which collect the majority of the high-priority data when close to Io and thus near the peak flux, also have to mitigate transient noise in their detectors. The cameras use a combination of shielding and CMOS detectors with extremely fast readout to mi- imize noise. INMS microchannel plate detectors and PIA channel electron multipliers require additional shielding. The FGM is not sensitive to noise induced by energetic particles and the ThM microbolometer detector is nearly insensitive. Detailed SNR calculations are presented. To facilitate targeting agility, all of the spacecraft components are shielded separately since this approach is more mass efficient than using a radiation vault. IVO uses proven radiation-hardened parts (rated at 100 krad behind equivalent shielding of 280 mils of Aluminum with RDM of 2) and is expected to have ample mass margin to increase shielding if needed.

Adjudication-related processes are underreported and lack standardization in clinical trials of venous thromboembolism: a systematic review

OBJECTIVES Although the use of an adjudication committee (AC) for outcomes is recommended in randomized controlled trials, there are limited data on the process of adjudication. We therefore aimed to assess whether the reporting of the adjudication process in venous thromboembolism (VTE) trials meets existing quality standards and which characteristics of trials influence the use of an AC. STUDY DESIGN AND SETTING We systematically searched MEDLINE and the Cochrane Library from January 1, 2003, to June 1, 2012, for randomized controlled trials on VTE. We abstracted information about characteristics and quality of trials and reporting of adjudication processes. We used stepwise backward logistic regression model to identify trial characteristics independently associated with the use of an AC. RESULTS We included 161 trials. Of these, 68.9% (111 of 161) reported the use of an AC. Overall, 99.1% (110 of 111) of trials with an AC used independent or blinded ACs, 14.4% (16 of 111) reported how the adjudication decision was reached within the AC, and 4.5% (5 of 111) reported on whether the reliability of adjudication was assessed. In multivariate analyses, multicenter trials [odds ratio (OR), 8.6; 95% confidence interval (CI): 2.7, 27.8], use of a data safety-monitoring board (OR, 3.7; 95% CI: 1.2, 11.6), and VTE as the primary outcome (OR, 5.7; 95% CI: 1.7, 19.4) were associated with the use of an AC. Trials without random allocation concealment (OR, 0.3; 95% CI: 0.1, 0.8) and open-label trials (OR, 0.3; 95% CI: 0.1, 1.0) were less likely to report an AC. CONCLUSION Recommended processes of adjudication are underreported and lack standardization in VTE-related clinical trials. The use of an AC varies substantially by trial characteristics.

Recommendations for sex/gender neuroimaging research: Key principles and implications for research design, analysis and interpretation

Neuroimaging (NI) technologies are having increasing impact in the study of complex cognitive and social processes. In this emerging field of social cognitive neuroscience, a central goal should be to increase the understanding of the interaction between the neurobiology of the individual and the environment in which humans develop and function. The study of sex/gender is often a focus for NI research, and may be motivated by a desire to better understand general developmental principles, mental health problems that show female-male disparities, and gendered differences in society. In order to ensure the maximum possible contribution of NI research to these goals, we draw attention to four key principles—overlap, mosaicism, contingency and entanglement—that have emerged from sex/gender research and that should inform NI research design, analysis and interpretation. We discuss the implications of these principles in the form of constructive guidelines and suggestions for researchers, editors, reviewers and science communicators.

Essays on behavioral aspects of the design and disclosure of compensation contracts

This thesis consists of four essays on the design and disclosure of compensation contracts. Essays 1, 2 and 3 focus on behavioral aspects of mandatory compensation disclosure rules and of contract negotiations in agency relationships. The three experimental studies develop psychology- based theory and present results that deviate from standard economic predictions. Furthermore, the results of Essay 1 and 2 also have implications for firms’ discretion in how to communicate their top management’s incentives to the capital market. Essay 4 analyzes the role of fairness perceptions for the evaluation of executive compensation. For this purpose, two surveys targeting representative eligible voters as well as investment professionals were conducted. Essay 1 investigates the role of the detailed ‘Compensation Discussion and Analysis’, which is part of the Security and Exchange Commission’s 2006 regulation, on investors’ evaluations of executive performance. Compensation disclosure complying with this regulation clarifies the relationship between realized reported compensation and the underlying performance measures and their target achievement levels. The experimental findings suggest that the salient presentation of executives’ incentives inherent in the ‘Compensation Discussion and Analysis’ makes investors’ performance evaluations less outcome dependent. Therefore, investors’ judgment and investment decisions might be less affected by noisy environmental factors that drive financial performance. The results also suggest that fairness perceptions of compensation contracts are essential for investors’ performance evaluations in that more transparent disclosure increases the perceived fairness of compensation and the performance evaluation of managers who are not responsible for a bad financial performance. These results have important practical implications as firms might choose to communicate their top management’s incentive compensation more transparently in order to benefit from less volatile expectations about their future performance. Similar to the first experiment, the experiment described in Essay 2 addresses the question of more transparent compensation disclosure. However, other than the first experiment, the second experiment does not analyze the effect of a more salient presentation of contract information but the informational effect of contract information itself. For this purpose, the experiment tests two conditions in which the assessment of the compensation contracts’ incentive compatibility, which determines executive effort, is either possible or not. On the one hand, the results suggest that the quality of investors’ expectations about executive effort is improved, but on the other hand investors might over-adjust their prior expectations about executive effort if being confronted with an unexpected financial performance and under-adjust if the financial performance confirms their prior expectations. Therefore, in the experiment, more transparent compensation disclosure does not lead to more correct overall judgments of executive effort and to even lower processing quality of outcome information. These results add to the literature on disclosure which predominantly advocates more transparency. The findings of the experiment however, identify decreased information processing quality as a relevant disclosure cost category. Firms might therefore carefully evaluate the additional costs and benefits of more transparent compensation disclosure. Together with the results from the experiment in Essay 1, the two experiments on compensation disclosure imply that firms should rather focus on their discretion how to present their compensation disclosure to benefit from investors’ improved fairness perceptions and their spill-over on performance evaluation. Essay 3 studies the behavioral effects of contextual factors in recruitment processes that do not affect the employer’s or the applicant’s bargaining power from a standard economic perspective. In particular, the experiment studies two common characteristics of recruitment processes: Pre-contractual competition among job applicants and job applicants’ non-binding effort announcements as they might be made during job interviews. Despite the standard economic irrelevance of these factors, the experiment develops theory regarding the behavioral effects on employees’ subsequent effort provision and the employers’ contract design choices. The experimental findings largely support the predictions. More specifically, the results suggest that firms can benefit from increased effort and, therefore, may generate higher profits. Further, firms may seize a larger share of the employment relationship’s profit by highlighting the competitive aspects of the recruitment process and by requiring applicants to make announcements about their future effort. Finally, Essay 4 studies the role of fairness perceptions for the public evaluation of executive compensation. Although economic criteria for the design of incentive compensation generally do not make restrictive recommendations with regard to the amount of compensation, fairness perceptions might be relevant from the perspective of firms and standard setters. This is because behavioral theory has identified fairness as an important determinant of individuals’ judgment and decisions. However, although fairness concerns about executive compensation are often stated in the popular media and even in the literature, evidence on the meaning of fairness in the context of executive compensation is scarce and ambiguous. In order to inform practitioners and standard setters whether fairness concerns are exclusive to non-professionals or relevant for investment professionals as well, the two surveys presented in Essay 4 aim to find commonalities in the opinions of representative eligible voters and investments professionals. The results suggest that fairness is an important criterion for both groups. Especially, exposure to risk in the form of the variable compensation share is an important criterion shared by both groups. The higher the assumed variable share, the higher is the compensation amount to be perceived as fair. However, to a large extent, opinions on executive compensation depend on personality characteristics, and to some extent, investment professionals’ perceptions deviate systematically from those of non-professionals. The findings imply that firms might benefit from emphasizing the riskiness of their managers’ variable pay components and, therefore, the findings are also in line with those of Essay 1.

Descriptive/Inferential Cognitive Processes and Evaluative Cognitive Processes: Relationships Among Each Other and with Emotional Distress

We aimed to delineate key constructs from two forms of cognitive-behavioral therapy: cognitive therapy and rational-emotive behavior therapy. Furthermore, we aimed to investigate the interrelations among each other and with emotional distress. The key constructs of the underlying theories of these therapies (i.e., descriptive/inferential beliefs, evaluative beliefs) are often treated together as distorted cognitions and included as such in various scales. We used a cross-sectional design. Seventy-four undergraduate students (mean age = 24.68) completed measures of automatic thoughts and emotional distress. Three therapists trained in cognitive-behavioral therapy divided automatic thoughts into descriptive/inferential beliefs and evaluative beliefs by consensus. Correlation and mediation analyses were performed. These constructs showed medium to high associations to each other and to distress. The relationship between descriptive/inferential beliefs and distress was mediated by evaluative beliefs. Descriptive and inferential cognitions may not produce emotions without first being appraised in terms of personal relevance.

Differentiating the Multipoint Expected Improvement for Optimal Batch Design

This work deals with parallel optimization of expensive objective functions which are modelled as sample realizations of Gaussian processes. The study is formalized as a Bayesian optimization problem, or continuous multi-armed bandit problem, where a batch of q > 0 arms is pulled in parallel at each iteration. Several algorithms have been developed for choosing batches by trading off exploitation and exploration. As of today, the maximum Expected Improvement (EI) and Upper Confidence Bound (UCB) selection rules appear as the most prominent approaches for batch selection. Here, we build upon recent work on the multipoint Expected Improvement criterion, for which an analytic expansion relying on Tallis’ formula was recently established. The computational burden of this selection rule being still an issue in application, we derive a closed-form expression for the gradient of the multipoint Expected Improvement, which aims at facilitating its maximization using gradient-based ascent algorithms. Substantial computational savings are shown in application. In addition, our algorithms are tested numerically and compared to state-of-the-art UCB-based batchsequential algorithms. Combining starting designs relying on UCB with gradient-based EI local optimization finally appears as a sound option for batch design in distributed Gaussian Process optimization.