There is growing interest in tissue procurement for cancer research through autopsy. Establishing an autopsy/tissue donation programme for breast cancer research within an academic medical centre i...

BackgroundIn the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort, participants underwent magnetic resonance imaging (MRI) of the brain, heart, and abdomen, that generated incidental findings (IFs). The approach to managing these unexpected results remain a complex issue. Our objectives were to describe the CAHHM policy for the management of IFs, to understand the impact of disclosing IFs to healthy research participants, and to reflect on the ethical obligations of researchers in future MRI studies.MethodsBetween 2013 and 2019, 8252 participants (...) (mean age 58 ± 9 years, 54% women) were recruited with a follow-up questionnaire administered to 909 participants (40% response rate) at 1-year. The CAHHM policy followed a restricted approach, whereby routine feedback on IFs was not provided. Only IFs of severe structural abnormalities were reported.ResultsSevere structural abnormalities occurred in 8.3% (95% confidence interval 7.7–8.9%) of participants, with the highest proportions found in the brain (4.2%) and abdomen (3.1%). The majority of participants (97%) informed of an IF reported no change in quality of life, with 3% of participants reporting that the knowledge of an IF negatively impacted their quality of life. Furthermore, 50% reported increased stress in learning about an IF, and in 95%, the discovery of an IF did not adversely impact his/her life insurance policy. Most participants (90%) would enrol in the study again and perceived the MRI scan to be beneficial, regardless of whether they were informed of IFs. While the implications of a restricted approach to IF management was perceived to be mostly positive, a degree of diagnostic misconception was present amongst participants, indicating the importance of a more thorough consent process to support participant autonomy.ConclusionThe management of IFs from research MRI scans remain a challenging issue, as participants may experience stress and a reduced quality of life when IFs are disclosed. The restricted approach to IF management in CAHHM demonstrated a fair fulfillment of the overarching ethical principles of respect for autonomy, concern for wellbeing, and justice. The approach outlined in the CAHHM policy may serve as a framework for future research studies.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/nct02220582. (shrink)

This report describes the rationale, approaches, organization, and resource development leading to a large-scale deletion bin map of the hexaploid wheat genome. Accompanying reports in this issue detail results from chromosome bin-mapping of expressed sequence tags representing genes onto the seven homoeologous chromosome groups and a global analysis of the entire mapped wheat EST data set. Among the resources developed were the first extensive public wheat EST collection. Described are protocols for sequencing, sequence processing, EST nomenclature, and the assembly of (...) ESTs into contigs. These contigs plus singletons were used for selection of distinct sequence motif unigenes. Selected ESTs were rearrayed, validated by 5′ and 3′ sequencing, and amplified for probing a series of wheat aneuploid and deletion stocks. Images and data for all Southern hybridizations were deposited in databases and were used by the coordinators for each of the seven homoeologous chromosome groups to validate the mapping results. Results from this project have established the foundation for future developments in wheat genomics. (shrink)

While every health care system stakeholder would seem to be concerned with obtaining the greatest value from a given technology, there is often a disconnect in the perception of value between a technology’s promoters and those responsible for the ultimate decision as to whether or not to pay for it. Adopting an empirical ethics approach, this paper examines how five Canadian medical device manufacturers, via their websites, frame the corporate “value proposition” of their innovation and seek to respond to what (...) they consider the key expectations of their customers. Our analysis shows that the manufacturers’ framing strategies combine claims that relate to valuable socio-technical goals and features such as prevention, efficiency, sense of security, real-time feedback, ease of use and flexibility, all elements that likely resonate with a large spectrum of health care system stakeholders. The websites do not describe, however, how the innovations may impact health care delivery and tend to obfuscate the decisional trade-offs these innovations represent from a health care system perspective. Such framing strategies, we argue, tend to bolster physicians’ and patients’ expectations and provide a large set of stakeholders with powerful rhetorical tools that may influence the health policy arena. Because these strategies are difficult to counter given the paucity of evidence and its limited use in policymaking, establishing sound collective health care priorities will require solid critiques of how certain kinds of medical devices may provide a better (i.e., more valuable) response to health care needs when compared to others. (shrink)

It has been demonstrated that death certificates do not accurately record the actual cause of death in up to one-fourth of cases, as determined from subsequent autopsy findings. The purpose of this study was to explore the use of natural language autopsy data bases as an automated quality assurance mechanism. We translated the account of the major process leading to death, or the primary diagnosis, from all 45,564 narrative autopsy reports obtained at The Johns Hopkins Hospital between May 28, 1889, (...) and June 30, 1987, into the hierarchical system of Medical Subject Heading (MeSH) titles. We obtained a total of 125,772 MeSH title translations, 1,563 of them distinct (average 2.8 per case), ranging in frequency from 6,029 occurrences of LUNG to 1 occurrence apiece of 357 MeSH titles. The natural-language-to-MeSH translations showed expected trends over the past century: fewer infectious diseases; more cardiovascular and neoplastic disease among adults; and more respiratory diseases and congenital malformations in the pediatric age group. The greater availability of autopsy documents in electronic form should increase the value of this resource for quality assurance. (shrink)

BackgroundThe U.S. Food and Drug Administration traditionally has kept confidential significant amounts of information relevant to the approval or non-approval of specific drugs, devices, and biologics and about the regulatory status of such medical products in FDA’s pipeline.ObjectiveTo develop practical recommendations for FDA to improve its transparency to the public that FDA could implement by rulemaking or other regulatory processes without further congressional authorization. These recommendations would build on the work of FDA’s Transparency Task Force in 2010.MethodsIn 2016-2017, we convened (...) a team of academic faculty from Harvard Medical School, Brigham and Women’s Hospital, Yale Medical School, Yale Law School, and Johns Hopkins Bloomberg School of Public Health to develop recommendations through an iterative process of reviewing FDA’s practices, considering the legal and policy constraints on FDA in expanding transparency, and obtaining insights from independent observers of FDA.ResultsThe team developed 18 specific recommendations for improving FDA’s transparency to the public. FDA could adopt all these recommendations without further congressional action.FundingThe development of the Blueprint for Transparency at the U.S. Food and Drug Administration was funded by the Laura and John Arnold Foundation. (shrink)

Initial responses to questionnaires used to assess participants' understanding of informed consent for malaria vaccine trials conducted in the United States and Mali were tallied. Total scores were analyzed by age, sex, literacy (if known), and location. Ninety-two percent (92%) of answers by United States participants and 85% of answers by Malian participants were correct. Questions more likely to be answered incorrectly in Mali related to risk, and to the type of vaccine. For adult participants, independent predictors of higher scores (...) were younger age and female sex in the United States, and male sex in Mali. Scores in the United States were higher than in Mali (P = 0.005). Despite this difference participants at both sites were well informed overall. Although interpretation must be qualified because questionnaires were not intended as research tools and were not standardized among sites, these results do not support concerns about systematic low understanding among research participants in developing versus developed countries. (shrink)

In this paper, I will examine John Smeaton’s contribution to the vis viva controversy in Britain, focusing on how the hybridization of science, technology, and industry helped to establish vis viva, or mechanic power, as a measure of motive force. Smeaton, embodying the ‘hybrid expert’ who combined theoretical knowledge and practical knowhow, demonstrated that the notion of vis viva possessed a greater explanatory power than momentum, because it could be used to explain the difference in efficiency between overshot and undershot (...) waterwheels. Smeaton’s conclusions were correct since waterwheel efficiency was already measured in terms that were proportional to vis viva, not momentum, as a result of the industrial applications of waterwheel technology, which favored measuring efficiency by the product of mass and vertical displacement. Toward the end of the eighteenth century, the loss of motive force in the inelastic collision driving the undershot wheel began to be seen as equivalent to the expenditure of labor in the manufacture of commodities, further underlining how strictly scientific conclusions about motive force could have their origin in industrial practices. (shrink)

We use a result due to Rolin, Speissegger, and Wilkie to show that definable sets in certain o-minimal structures admit definable parameterizations by mild maps. We then use this parameterization to prove a result on the density of rational points on curves defined by restricted Pfaffian functions.

Subjective feelings of familiarity associated with a stimulus tend to be strongest when specific information about the previous encounter with the stimulus is difficult to retrieve . Recognizing: The judgment of previous occurrence. Psychological Review, 87, 252–271.]). When a stimulus has been encountered previously and the circumstances of the encounter cannot be recollected, additional cognitive resources may be directed toward recollection processes; this resource allocation is accompanied by autonomic arousal [Dawson, M. E., Filion, D. L., & Schell, A. M. . (...) Is elicitation of the autonomic orienting response associated with allocation of processing resources?. Psychophysiology, 26, 560–572]. One easily measurable index of autonomic arousal is the skin conductance response . In the present study, participants studied lists of words and then gave recognition ratings to briefly displayed and masked studied and nonstudied test words while their SCRs were monitored. Results revealed a relationship between recognition ratings and the temporal characteristics of the SCR, supporting the idea that feelings of familiarity are indeed “feelings” in that they stem from autonomic arousal associated with cognitive resource allocation. (shrink)

Recruiting research participants based on genetic information generated about them in a prior study is a potentially powerful way to study the functional significance of human genetic variation, but it also presents ethical challenges. To inform policy development on this issue, we conducted a survey of U.S. institutional review board chairs concerning the acceptability of recontacting genetic research participants about additional research and their views on the disclosure of individual genetic results as part of recruitment. Our findings suggest there is (...) unlikely to be a “one-size-fits-all” solution, but rather several ethically acceptable approaches to genotype-driven recruitment, depending on context. Disclosures made during the consent process for the original study and the clinical validity of the results are key considerations. Researchers must be prepared to communicate and answer questions in clear lay language about what is known and not known regarding the role of genetics in their proposed area of research. (shrink)

Primary progressive aphasia is a clinical syndrome in which patients progressively lose speech and language abilities. Three variants are recognized: logopenic, associated with phonology and/or short-term verbal memory deficits accompanied by left temporo-parietal atrophy; semantic, associated with semantic deficits and anterior temporal lobe atrophy; non-fluent associated with grammar and/or speech-motor deficits and inferior frontal gyrus atrophy. Here, we set out to investigate whether the three variants of PPA can be dissociated based on error patterns in a single language task. We (...) recruited 21 lvPPA, 28 svPPA, and 24 nfvPPA patients, together with 31 healthy controls, and analyzed their performance on an auditory noun-to-verb generation task, which requires auditory analysis of the input, access to and selection of relevant lexical and semantic knowledge, as well as preparation and execution of speech. Task accuracy differed across the three variants and controls, with lvPPA and nfvPPA having the lowest and highest accuracy, respectively. Critically, machine learning analysis of the different error types yielded above-chance classification of patients into their corresponding group. An analysis of the error types revealed clear variant-specific effects: lvPPA patients produced the highest percentage of “not-a-verb” responses and the highest number of semantically related nouns ; in contrast, svPPA patients produced the highest percentage of “unrelated verb” responses and the highest number of light verbs. Taken together, our findings indicate that error patterns in an auditory verb generation task are associated with the breakdown of different neurocognitive mechanisms across PPA variants. Specifically, they corroborate the link between temporo-parietal regions with lexical processing, as well as ATL with semantic processes. These findings illustrate how the analysis of pattern of responses can help PPA phenotyping and heighten diagnostic sensitivity, while providing insights on the neural correlates of different components of language. (shrink)

Rare copy number variants have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large CNVs at several loci, including microdeletions at 1q21.1, 3q29, 15q13.3 and 22q11.2 and microduplication at 16p11.2. However, these CNVs collectively account for a small fraction of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy (...) number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 patients versus 2 of 7,431 controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. © 2011 Macmillan Publishers Limited. All rights reserved. (shrink)

lecting statistics about missing bindings and macros, and other errors. This guides debugging and development efforts, leading to iterative improvements in both the tools and the quality of the converted corpus. The build system thus serves as both a production conversion engine and software test harness. We have now processed the complete arχiv collection through 2006 consisting of more than 400,000 documents (a complete run is a processor-yearsize undertaking), continuously improving our success rate. We are now able to convert more (...) than 90% of these documents to XHTML+MathML. We consider over 60% to be successes, converted with no or minor warnings. While the remaining 30% can also be converted, their quality is doubtful, due to unsupported macros or conversion errors. (shrink)

Many research ethics guidelines now oblige researchers to offer research participants the results of research in which they participated. This practice is intended to uphold respect for persons and ensure that participants are not treated as mere means to an end. Yet some scholars have begun to question a generalised duty to disclose research results, highlighting the potential harms arising from disclosure and questioning the ethical justification for a duty to disclose, especially with respect to individual results. In support of (...) this view, we argue that current rationales for a duty of disclosure do not form an adequate basis for an ethical imperative. We review policy guidance and scholarly commentary regarding the duty to communicate the results of biomedical, epidemiological and genetic research to research participants and show that there is wide variation in opinion regarding what should be disclosed and under what circumstance. Moreover, we argue that there is fundamental confusion about the notion of “research results,” specifically regarding three core concepts: the distinction between aggregate and individual results, amongst different types of research, and across different degrees of result veracity. Even where policy guidance and scholarly commentary have been most forceful in support of an ethical imperative to disclose research results, ambiguity regarding what is to be disclosed confounds ethical action. (shrink)

In Alabaster v. Barclays Bank plc and Secretary of State for Social Security (No. 2: [2005] E.W.C.A Civ. 508, [2005] I.R.L.R. 576.) Michelle Alabaster won a grand total of £204.53 (plus £65.86 interest) after eight years of litigation, which included two visits to the Court of Appeal and one to the European Court of Justice. This marathon resulted from the sex discrimination which Alabaster had alleged in relation to the calculation of her Statutory Maternity Pay (S.M.P.) whilst she was pregnant (...) 10 years earlier. The technicalities of the statutory schemes involved should not be allowed to disguise the important principle which finally emerges in the Court of Appeal and which underlines one of the longstanding criticisms of the equality legislation, namely the requirement that a woman must compare herself with a man in order to establish unlawful sex discrimination. (shrink)

Importance Informed consent is essential to ethical, rigorous research and is important to recruitment and retention in cancer trials.Objective To examine cancer clinical trial (CCT) participants’ perceptions of informed consent processes and variations in perceptions by cancer type.Design and Setting and Participants Cross-sectional survey from mixed-methods study at National Cancer Institute–designated Northeast comprehensive cancer center. Open-ended and forced-choice items addressed: (1) enrollment and informed consent experiences and (2) decision-making processes, including risk-benefit assessment. Eligibility: CCT participant with gastro-intestinal or genitourinary, hematologic-lymphatic (...) malignancies, lung cancer, and breast or gynecological cancer (N = 334).Main Outcome Measures Percentages satisfied with consent process and information provided; and assessing participation’s perceptions of risks/benefits. Multivariable logistic or ordinal regression examined differences by cancer type.Results Most patient-participants felt well informed by the consent process (more than 90% overall and by cancer type) and. most (87.4%) reported that the consent form provided all the information they wanted, although nearly half (44.8%) reported that they read the form somewhat carefully or less. More than half (57.9%) said that talking to research staff (i.e., the consent process) had a greater impact on participation decisions than reading the consent form (2.1%). A third (31.1%) were very sure of joining in research studies before the informed consent process (almost half of lung cancer patients did—47.1%). Most patients personally assessed the risks and benefits before consenting. However, trust in physicians played an important role in the decision to enroll in CCT.Conclusions and Relevance Cancer patients rely less on written features of the informed consent process than on information obtained from the research staff and their own physicians. Research should focus on information and communication strategies that support informed consent from referring physicians, researchers, and others to improve patient risk-benefit assessment and decision-making. (shrink)

What is the temporal course of gratitude and indebtedness and how do these feelings influence helping in the context of reciprocity? In an online-game tapping real-life behaviour, Study 1 (N = 106) finds that while gratitude towards a benefactor remains elevated after an opportunity to reciprocate, indebtedness declines along with helping. Yet, indebtedness rather than gratitude better predicts real-life helping of a benefactor. Using a vignette-based experiment, Study 2 (N = 217) finds that after reciprocation indebtedness and likelihood of helping (...) a benefactor reset to a baseline level while gratitude endures. Furthermore, the decrease in helping after reciprocation is better explained by indebtedness than by gratitude. Study 3 (N = 217) assessed the unique influences of gratitude and indebtedness on helping by comparing contexts in which gratitude is at a baseline level but indebtedness is elevated (e.g. before a monetary payment for a service received) to contexts in which indebtedness is at a baseline level but gratitude is elevated (e.g. after reciprocation of benefits freely given by a friend). People are more likely to help in the former compared to latter context, and this difference is better explained by indebtedness rather than by gratitude. We discuss the interrelated and understudied relationships between gratitude, indebtedness, and reciprocity. (shrink)

There is a growing literature on the concept of e-trust and on the feasibility and advisability of “trusting” artificial agents. In this paper we present an object-oriented model for thinking about trust in both face-to-face and digitally mediated environments. We review important recent contributions to this literature regarding e-trust in conjunction with presenting our model. We identify three important types of trust interactions and examine trust from the perspective of a software developer. Too often, the primary focus of research in (...) this area has been on the artificial agents and the humans they may encounter after they are deployed. We contend that the humans who design, implement, and deploy the artificial agents are crucial to any discussion of e-trust and to understanding the distinctions among the concepts of trust, e-trust and face-to-face trust. (shrink)

This paper addresses the ontological status of the ontological categories as defended within E.J. Lowe’s four-category ontology (kinds, objects, properties/relations, and modes). I consider the arguments in Griffith (2015. “Do Ontological Categories Exist?” Metaphysica 16 (1):25–35) against Lowe’s claim that ontological categories do not exist, and argue that Griffith’s objections to Lowe do not work once we fully take advantage of ontological resources available within Lowe’s four-category ontology. I then argue that the claim that ontological categories do not exist has (...) no undesirable consequences for Lowe’s brand of realism. (shrink)