Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

OBJECTIVES/GOALS: Active surveillance (AS) is a recognized strategy to manage low-risk prostate cancer (PCa) in the absence of cancer progression. Little prospective data exists on the decisional factors associated with selecting and adhering to AS in the absence of cancer progression. We developed a survey instrument to predict AS uptake and adherence. METHODS/STUDY POPULATION: We utilized a three-step process to develop and refine a survey instrument designed to predict AS uptake and adherence among men with low-risk PCa: 1) We identified relevant conceptual domains based on prior research and a literature review. 2) We conducted 21 semi-structured concept elicitation interviews to identify patient-perceived barriers and facilitators to AS uptake and adherence among men with a low-risk PCa who had been on AS for ≥1 year. The identified concepts became the basis of our draft survey instrument. 3) We conducted two rounds of cognitive interviews with men with low-risk PCa (n = 12; n = 6) to refine and initially validate the instrument. RESULTS/ANTICIPATED RESULTS: Relevant concepts identified from the initial interviews included the importance of patient: knowledge of their PCa risk, value in delaying treatment, trust in urologist and the AS surveillance protocol, and perceived social support. Initially, the survey was drafted as a single instrument to be administered after a patient had selected AS comprising sections on patient health, AS selection, and AS adherence. Based on the first round of cognitive interviews, we revised the single instrument into two surveys to track shifts in patient preference and experience. The first, administered at diagnosis, focuses on selection, and the second, a 6-month follow up, focuses on adherence. Following revisions, participants indicated the revised 2-part instrument was clear and not burdensome to complete. DISCUSSION/SIGNIFICANCE OF IMPACT: The instrument’s content validity was evaluated through cognitive interviews, which supported that the survey items’ intended and understood meanings were isomorphic. In the next phase, we plan to conduct a large-scale prospective cohort study to evaluate the predictive validity, after which it will be available for public research use.

Micronutrient deficiencies contribute to many age-related disorders. One group at particular risk of micronutrient deficiencies is the elderly. Many elderly, such as the frail and those living in institutions, rely on ready meals of variable, often poor, nutritional quality for a significant part of their daily nutritional needs. New policies are needed to ensure that micronutrients (vitamins and minerals) and phytochemicals of known nutritional value are retained during the manufacture of ready meals. This together with increased awareness of the importance of micronutrients for health, and simple, clear labelling of the micronutrient content of ready meals would help in the choice of healthier products. Professionally prepared ready meals monitored by nutritionists and dietitians can help achieve these goals so that ready meals become part of the solution to poor nutrition in the elderly, rather than being viewed as part of the problem.

Objectives: The aim of this study was to assess the association between personality factors and age-related longitudinal cognitive performance, and explore interactions of stress-proneness with apolipoprotein E (APOE) ɛ4, a prevalent risk factor for Alzheimer’s disease (AD). Methods: A total of 510 neuropsychiatrically healthy residents of Maricopa County recruited through media ads (mean age 57.6±10.6 years; 70% women; mean education 15.8±2.4 years; 213 APOE ɛ4 carriers) had neuropsychological testing every 2 years (mean duration follow-up 9.1±4.4 years), and the complete Neuroticism Extraversion Openness Personality Inventory-Revised. Several tests were administered within each of the following cognitive domains: memory, executive skills, language, visuospatial skills, and general cognition. Primary effects on cognitive trajectories and APOE ɛ4 interactions were ascertained with quadratic models. Results: With personality factors treated as continuous variables, Neuroticism was associated with greater decline, and Conscientiousness associated with reduced decline consistently across tests in memory and executive domains. With personality factors trichotomized, the associations of Neuroticism and Conscientiousness were again highly consistent across tests within memory and to a lesser degree executive domains. While age-related memory decline was greater in APOE ɛ4 carriers as a group than ɛ4 noncarriers, verbal memory decline was mitigated in ɛ4 carriers with higher Conscientiousness, and visuospatial perception and memory decline was mitigated in ɛ4 carriers with higher Openness. Conclusions: Neuroticism and Conscientiousness were associated with changes in longitudinal performances on tests sensitive to memory and executive skills. APOE interactions were less consistent. Our findings are consistent with previous studies that have suggested that personality factors, particularly Neuroticism and Conscientiousness are associated with cognitive aging patterns. (JINS, 2016, 22, 765–776)

Under high burnup UO2 fuel pellets can experience high burnup structure (HBS) at the rim also known as rim effect. The HBS is exceptionally porous with fine grain sizes. HBS increases the swelling further than it would have achieved at a larger grain size. A theoretical swelling model is used in conjunction with a grain subdivision simulation to calculate the swelling of UO2. In UO2 the nucleation sites are at vacancies and the bubbles are concentrated at grain boundaries. Vacancies are created due to irradiation and gas diffusion is dependent on vacancy migration. In addition to intragranular bubbles, there are intergranular bubbles at the grain boundaries. Over time as intragranular bubbles and gas atoms accumulate on the grain boundaries, the intergranular bubbles grow and cover the grain faces. Eventually they grow into voids and interconnect along the grain boundaries, which can lead to fission gas release when the interconnection reaches the surface. This is known as the saturation point. While the swelling model used does not originally incorporate a changing grain size, the simulation allows for more accurate swelling calculations by introducing a fractional HBS based on the temperature and burnup of the pellet. The fractional HBS is introduced with a varying grain size. Our simulations determine the level of swelling and saturation as a function of burnup by combining an independent model and simulation to obtain a more comprehensive model.

A Kinetic Monte Carlo simulation, using a modified version of the SPPARKS code, of simple defects and complex vacancy clusters was run on a bcc lattice. In this simulation the complexity of void formation was varied by introducing a detachment rate for individual vacancies leaving the void and either treating this value as constant for all size voids or having this value be dependent on the size of the void. Molecular Dynamics simulations were used to determine the binding energies of vacancies for voids of varying size. The simulation was then run over long time periods to determine the number of defects in the simulation under irradiation conditions. It was found that the additional complexity of size dependent void detachment rates had little effect on the defect concentrations and thus a constant barrier should be sufficient for simulations of voids in bcc metals.

The Mediterranean diet (MD) emerged as a healthy food regimen long before it could be recognised which nutrients or foods were responsible for its observed benefits, and it was only in the middle of the last century that the first scientific approach ‘The Seven Countries Study’ appeared. Epidemiological and anthropological studies of the MD converged, first by investigating at single nutrients or foods, then by adopting the more holistic approach of dietary patterns (DP), and now with a molecular approach. These studies resulted in convincing evidence that a MD decreases the risk of all-cause mortality and cardiovascular mortality and incidence. A risk reduction of developing type 2 diabetes is probable. Evidence is less stringent for other metabolic diseases and all cancers but from possible to probable for some cancer sites. Although DP showed that the MD has to be considered in its totality, olive oil could have a specific role. Lifestyle factors such as physical activity for energy balance, outdoor life for vitamin D synthesis and conviviality are also probably partly responsible for the health benefits. The MD is a lifestyle well suited for coping not only with personal health but also with wider societal concerns in relation to environment, public health and economy.

We expected that the commentary process would provide valuable feedback to improve our ideas and identify potential obstacles, and we were not disappointed. The commentaries were generally in agreement that synthetic validity is a good idea, although we also received a fair amount of suggestions for improvements, conditional or tempered praise, and explicitly critical comments. We address the concerns that were raised and conclude that we should move forward with developing a large-scale synthetic validity database, incorporating the suggestions of some of the commentators.

Although synthetic validation has long been suggested as a practical and defensible approach to establishing validity evidence, synthetic validation techniques are infrequently used and not well understood by the practitioners and researchers they could most benefit. Therefore, we describe the assumptions, origins, and methods for establishing validity evidence of the two primary types of synthetic validation techniques: (a) job component validity and (b) job requirements matrix. We then present the case for synthetic validation as the best approach for many situations and address the potential limitations of synthetic validation. We conclude by proposing the development of a comprehensive database to build prediction equations for use in synthetic validation of jobs across the U.S. economy and reviewing potential obstacles to the creation of such a database. We maintain that synthetic validation is a practically useful methodology that has great potential to advance the science and practice of industrial and organizational psychology.

Excessive pain during medical procedures, such as burn wound dressing changes, is a widespread medical problem and is especially challenging for children. This article describes the rationale behind virtual reality (VR) pain distraction, a new non-pharmacologic adjunctive analgesia, and gives a brief summary of empirical studies exploring whether VR reduces clinical procedural pain. Results indicate that patients using VR during painful medical procedures report large reductions in subjective pain. A neuroimaging study measuring the neural correlates of VR analgesia is described in detail. This functional magnetic resonance imaging pain study in healthy volunteers shows that the large drops in subjective pain ratings during VR are accompanied by large drops in pain-related brain activity. Together the clinical and laboratory studies provide converging evidence that VR distraction is a promising new non-pharmacologic pain control technique.

The present narrative review compares evidence from experimental, epidemiological and clinical studies of the health benefits of rapeseed oil (RO) (known as canola oil) and olive oil (OO) in order to assess whether rapeseed oil is suitable as a sustainable alternative to OO as part of a Mediterranean-style diet in countries where olive trees do not grow. From epidemiological studies, the evidence for cardiovascular protection afforded by extra-virgin OO is ‘convincing’, and for cancers ‘limited-suggestive’, especially oestrogen receptor-negative breast cancer, but more studies are required in relation to cognitive impairment. Evidence for RO is limited to short-term studies on the biomarkers of risk factors for CVD. Any benefits of RO are likely to be due to α-linolenic acid; however, it is prone to oxidation during frying. We conclude that due to a lack of evidence from observational or intervention studies indicating that RO has comparable health benefits to extra-virgin OO, RO cannot currently be recommended as a suitable substitute for extra-virgin OO as part of a Mediterranean-style diet.

According to many experts, a public health emergency arising from an influenza pandemic, bioterrorism attack, or natural disaster is likely to develop in the next few years. Meeting the public health and medical response needs created by such an emergency will likely involve volunteers, health care professionals, public and private hospitals and clinics, vaccine manufacturers, governmental authorities, and many others. Conducting response activities in emergency circumstances may give rise to numerous issues of liability, and medical professionals and other potential responders have expressed concern about liability exposure. Providers may face inadequate resources, an insufficient number of qualified personnel, overwhelming demand for services, and other barriers to providing optimal treatment, which could lead to injury or even death in some cases. This article describes the different theories of liability that may be used by plaintiffs and the sources of immunity that are available to public health emergency responders in the public sector, private sector, and as volunteers. It synthesizes the existing immunity landscape and analyzes its gaps. Finally, the authors suggest consideration of the option of a comprehensive immunity provision that addresses liability protection for all health care providers during public health emergencies and that, consequently, assists in improving community emergency response efforts. (Disaster Med Public Health Preparedness. 2009;3:117–125)