BackgroundRandomized controlled trials (RCTs) are often complex and expensive to perform. Less than one third achieve planned recruitment targets, follow-up can be labor-intensive, and many have limited real-world generalizability. Designs for RCTs conducted using cohorts and routinely collected health data, including registries, electronic health records, and administrative databases, have been proposed to address these challenges and are being rapidly adopted. These designs, however, are relatively recent innovations, and published RCT reports often do not describe important aspects of their methodology in (...) a standardized way. Our objective is to extend the Consolidated Standards of Reporting Trials (CONSORT) statement with a consensus-driven reporting guideline for RCTs using cohorts and routinely collected health data.MethodsThe development of this CONSORT extension will consist of five phases. Phase 1 (completed) consisted of the project launch, including fundraising, the establishment of a research team, and development of a conceptual framework. In phase 2, a systematic review will be performed to identify publications (1) that describe methods or reporting considerations for RCTs conducted using cohorts and routinely collected health data or (2) that are protocols or report results from such RCTs. An initial “long list” of possible modifications to CONSORT checklist items and possible new items for the reporting guideline will be generated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statements. Additional possible modifications and new items will be identified based on the results of the systematic review. Phase 3 will consist of a three-round Delphi exercise with methods and content experts to evaluate the “long list” and generate a “short list” of key items. In phase 4, these items will serve as the basis for an in-person consensus meeting to finalize a core set of items to be included in the reporting guideline and checklist. Phase 5 will involve drafting the checklist and elaboration-explanation documents, and dissemination and implementation of the guideline.DiscussionDevelopment of this CONSORT extension will contribute to more transparent reporting of RCTs conducted using cohorts and routinely collected health data. (shrink)

We tested the hypothesis that choices determined by Type 1 processes are compelling because they are fluent, and for this reason they are less subject to analytic thinking than other answers. A total of 104 participants completed a modified version of Wason's selection task wherein they made decisions about one card at a time using a two-response paradigm. In this paradigm participants gave a fast, intuitive response, rated their feeling of rightness for that response, and were then allowed free time (...) to reconsider their answers. As we predicted, answers consistent with a matching heuristic were made more quickly than other answers, were given higher FOR ratings, and received less subsequent analysis as measured by rethinking time and the probability of changing answers. These data suggest that reasoning biases may be compelling because they are fluently generated; this is turn creates a strong FOR, which acts as a signal that further analysis is not necessary. (shrink)

This case describes an adolescent in a crisis of a chronic medical condition whose situation is complicated by substance abuse and mental illness. D. Micah Hester provides an analytic approach, teasing apart the multiple layers of medical, developmental, and moral issues at hand and describing possible responses and outcomes. Amy T. Campbell examines existing legal guidelines for adolescent decision making, arguing that greater space exists for clinical discretion in these matters than commonly thought. Cheryl D. Lew discusses the development (...) of agency in adolescent patients, the ideal of autonomous decision making in the context of impairment and chronic illness, and the obligation of healthcare teams to examine an adolescent patient’s decisions in relation to her identity. (shrink)

Background The rise in genomic and biobanking research worldwide has led to the development of different informed consent models for use in such research. This study analyses consent documents used by investigators in the H3Africa (Human Heredity and Health in Africa) Consortium. Methods A qualitative method for text analysis was used to analyse consent documents used in the collection of samples and data in H3Africa projects. Thematic domains included type of consent model, explanations of genetics/genomics, data sharing and feedback of (...) test results. Results Informed consent documents for 13 of the 19 H3Africa projects were analysed. Seven projects used broad consent, five projects used tiered consent and one used specific consent. Genetics was mostly explained in terms of inherited characteristics, heredity and health, genes and disease causation, or disease susceptibility. Only one project made provisions for the feedback of individual genetic results. Conclusion H3Africa research makes use of three consent models—specific, tiered and broad consent. We outlined different strategies used by H3Africa investigators to explain concepts in genomics to potential research participants. To further ensure that the decision to participate in genomic research is informed and meaningful, we recommend that innovative approaches to the informed consent process be developed, preferably in consultation with research participants, research ethics committees and researchers in Africa. (shrink)

Nanomedicine is yielding new and improved treatments and diagnostics for a range of diseases and disorders. Nanomedicine applications incorporate materials and components with nanoscale dimensions where novel physiochemical properties emerge as a result of size-dependent phenomena and high surface-to-mass ratio. Nanotherapeutics and in vivo nanodiagnostics are a subset of nanomedicine products that enter the human body. These include drugs, biological products, implantable medical devices, and combination products that are designed to function in the body in ways unachievable at larger scales. (...) Nanotherapeutics andin vivonanodiagnostics incorporate materials that are engineered at the nanoscale to express novel properties that are medicinally useful. These nanomedicine applications can also contain nanomaterials that are biologically active, producing interactions that depend on biological triggers. Examples include nanoscale formulations of insoluble drugs to improve bioavailability and pharmacokinetics, drugs encapsulated in hollow nanoparticles with the ability to target and cross cellular and tissue membranes and to release their payload at a specific time or location, imaging agents that demonstrate novel optical properties to aid in locating micrometastases, and antimicrobial and drug-eluting components or coatings of implantable medical devices such as stents. (shrink)

Randomized controlled trial trial designs exist on an explanatory-pragmatic spectrum, depending on the degree to which a study aims to address a question of efficacy or effectiveness. As conceptualized by Schwartz and Lellouch in 1967, an explanatory approach to trial design emphasizes hypothesis testing about the mechanisms of action of treatments under ideal conditions, whereas a pragmatic approach emphasizes testing effectiveness of two or more available treatments in real-world conditions. Interest in, and the number of, pragmatic trials has grown substantially (...) in recent years, with increased recognition by funders and stakeholders worldwide of the need for credible evidence to inform clinical decision-making. This increase has been accompanied by the onset of learning healthcare systems, as well as an increasing focus on patient-oriented research. However, pragmatic trials have ethical challenges that have not yet been identified or adequately characterized. The present study aims to explore the views of key stakeholders with respect to ethical issues raised by the design and conduct of pragmatic trials. It is embedded within a large, four-year project that seeks to develop guidance for the ethical design and conduct of pragmatic trials. As a first step, this study will address important gaps in the current empirical literature with respect to identifying a comprehensive range of ethical issues arising from the design and conduct of pragmatic trials. By opening up a broad range of topics for consideration within our parallel ethical analysis, we will extend the current debate, which has largely emphasized issues of consent, to the range of ethical considerations that may flow from specific design choices. Semi-structured interviews with key stakeholders, across multiple jurisdictions, identified based on their known experience and/or expertise with pragmatic trials. We expect that the study outputs will be of interest to a wide range of knowledge users including trialists, ethicists, research ethics committees, journal editors, regulators, healthcare policymakers, research funders and patient groups. All publications will adhere to the Tri-Agency Open Access Policy on Publications. (shrink)

1 Evidence-based policy requires researchers to provide the answers to ecological questions that are of interest to policy makers. To find out what those questions are in the UK, representatives from 28 organizations involved in policy, together with scientists from 10 academic institutions, were asked to generate a list of questions from their organizations. 2 During a 2-day workshop the initial list of 1003 questions generated from consulting at least 654 policy makers and academics was used as a basis for (...) generating a short list of 100 questions of significant policy relevance. Short-listing was decided on the basis of the preferences of the representatives from the policy-led organizations. 3 The areas covered included most major issues of environmental concern in the UK, including agriculture, marine fisheries, climate change, ecosystem function and land management. 4 The most striking outcome was the preference for general questions rather than narrow ones. The reason is that policy is driven by broad issues rather than specific ones. In contrast, scientists are frequently best equipped to answer specific questions. This means that it may be necessary to extract the underpinning specific question before researchers can proceed. 5 Synthesis and applications. Greater communication between policy makers and scientists is required in order to ensure that applied ecologists are dealing with issues in a way that can feed into policy. It is particularly important that applied ecologists emphasize the generic value of their work wherever possible. (shrink)

Using a longitudinal case study design, we have tracked the recovery of motor function following severe traumatic brain injury (TBI) through a multimodal neuroimaging approach. In 2006, Canadian Soldier Captain (retired) Trevor Greene (TG) was attacked with an axe to the head while on tour in Afghanistan. TG continues intensive daily rehabilitation, which recently included the integration of physical therapy (PT) with neuromodulation using translingual neurostimulation (TLNS) to facilitate neuroplasticity. Recent findings with PT+TLNS demonstrated that recovery of motor function occurred (...) beyond conventional time limits, currently extending past 14-years post-injury. To investigate whether PT+TLNS similarly resulted in associated cognitive function improvements, we examined event-related potentials (ERPs) with the brain vital signs framework. In parallel with motor function improvements, brain vital signs detected significant increases in basic attention (as measured by P300 response amplitude) and cognitive processing (as measured by contextual N400 response amplitude). These objective cognitive improvements corresponded with TG’s self-reported improvements, including a noteworthy and consistent reduction in ongoing symptoms of post-traumatic stress disorder (PTSD). The findings provide valuable insight into the potential importance of non-invasive neuromodulation in cognitive rehabilitation, in addition to initial indications for physical rehabilitation. (shrink)

Imaginative resistance refers to cases in which one’s otherwise flexible imaginative capacity is constrained by an unwillingness or inability to imaginatively engage with a given claim. In three studies, we explored which specific imaginative demands engender resistance when imagining morally deviant worlds and whether individual differences in emotion predict the degree of this resistance. In Study 1 (N = 176), participants resisted the notion that harmful actions could be morally acceptable in the world of a narrative regardless of the author’s (...) claims about these actions but did not resist imagining that a perpetrator of harm could believe their actions to be morally acceptable. In Study 2 (N = 167) we replicated the findings of Study 1 and showed that imaginative resistance is greatest among participants who experience more negative affect in response to imagining harm and are lower in either trait anxiety or trait psychopathy. In Study 3 (N = 210) we show that this is the case even when the harms assessed include both low-severity (i.e., emotional harm) and high-severity (i.e., killing) cases. Thus, people’s moral beliefs constrain their ability to imagine hypothetical moral alternatives, although this ability systematically varies on the basis of stable individual differences in emotion. (shrink)

This article reviews the effects of malnutrition on early brain development using data generated from animal experiments and human clinical studies. Three related processes, each with their own functional consequences, are implicated in the alteration of brain development. (1) Maternal undernutrition at the start of pregnancy results in reduced transfer of nutrients across the placenta, allowing the conservation of effort for future reproductive episodes. (2) Differential allocation to growing organs by the fetus in response to nutritional stress spares the brain (...) to a large though still limited degree, reflecting the organ’s relative contribution to survival and reproductive success. (3) Prenatal malnutrition disrupts developing neurotransmitter systems, which results in the expression of specific cognitive and affective traits. It is argued that the increasing size and therefore cost of the brain, in conjunction with increasing ecological instability and marginality, reinforced selection for maternally controlled growth suppression of offspring, reallocation of organ growth rates by offspring, and behavioral changes related to development of neurotransmitter systems. (shrink)

Book reviewed in this article: In That Case: Medical Ethics in Everyday Practice. By Alastair Campbell and Roger Higgs. Medical Genetics Casebook: A Clinical Introduction to Medical Ethics Systems Theory. By Colleen D. Clements. Cases in Bioethics from the Hastings Center Report. Edited by Carol Levine and Robert M. Veatch. Hastings‐on‐Hudson.

BackgroundAlthough patient advocates have developed templates for standard consent forms, evaluating patient preferences for first in human (FIH) and window of opportunity (Window) trial consent forms is critical due to their unique risks. FIH trials are the initial use of a novel compound in study participants. In contrast, Window trials give an investigational agent over a fixed duration to treatment naïve patients in the time between diagnosis and standard of care (SOC) surgery. Our goal was to determine the patient-preferred presentation (...) of important information in consent forms for these trials.MethodsThe study consisted of two phases: (1) analyses of oncology FIH and Window consents; (2) interviews of trial participants. FIH consent forms were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH information); Window consents were analyzed for the location(s) of information stating the trial may delay SOC surgery (delay information). Participants were asked about their preferred placement of the information in their own trial’s consent form. The location of information in the consent forms was compared to the participants’ suggestions for placement. Results34 [17 FIH; 17 Window] of 42(81%) cancer patients approached participated. 25 consents [20 FIH; 5 Window] were analyzed. 19/20 FIH consent forms included FIH information, and 4/5 Window consent forms included delay information. 19/20(95%) FIH consent forms contained FIH information in the risks section 12/17(71%) patients preferred the same. Fourteen (82%) patients wanted FIH information in the purpose, but only 5(25%) consents mentioned it there. 9/17(53%) Window patients preferred delay information to be located early in the consent, before the “Risks” section. 3/5(60%) consents did this.ConclusionsDesigning consents that reflect patient preferences more accurately is essential for ethical informed consent; however, a one-size fits all approach will not accurately capture patient preferences. We found that preferences differed for FIH and Window trial consents, though for both, patients preferred key risk information early in the consent. Next steps include determining if FIH and Window consent templates improve understanding. (shrink)

Editors of Pliny's Naturalis Historia have not had to deplore the paucity of the MS. tradition, but rather its value; while MSS. belonging to the ordo recentiorum are numerous and fairly complete, those of the ordo uetustiorum are very few, and never contain more than a few books, often with considerable gaps. They are A ii 196–vi 51, M xi–xv, P and H parts of xviii, I xxiii, xxv, B xxxii–xxxvii . There are also some scattered fragments. Detlefsen indeed claimed (...) that the restoration of the original text of the N.H. is more difficult than that of any other Latin author owing to the mutilated and defective transmission of considerable parts. (shrink)

Editors of Pliny's Naturalis Historia have not had to deplore the paucity of the MS. tradition, but rather its value; while MSS. belonging to the ordo recentiorum are numerous and fairly complete, those of the ordo uetustiorum are very few, and never contain more than a few books, often with considerable gaps. They are A ii 196–vi 51, M xi–xv, P and H parts of xviii, I xxiii, xxv, B xxxii–xxxvii. There are also some scattered fragments. Detlefsen indeed claimed that (...) the restoration of the original text of the N.H. is more difficult than that of any other Latin author owing to the mutilated and defective transmission of considerable parts. (shrink)

As fundamental researchers in the neuroethology of efference copy, we were stimulated by Grush's bold and original synthesis. In the following critique, we draw attention to ways in which it might be tested in the future, we point out an avoidable conceptual error concerning emulation that Grush seems to share with other workers in the field, and we raise questions about the neural correlates of Grush's schemata that might be probed by neurophysiologists.