The Declaration of Helsinki and the Council of the International Organization of Medical Sciences provide guidance on standards of care and prevention in clinical trials. In the current and increasingly challenging research environment, the ethical status of a trial design depends not only on protection of participants, but also on social value, feasibility, and scientific validity. Using the example of a study assessing efficacy of a vaccine to prevent human papilloma virus in HIV-1 infected adolescent girls in low resource countries (...) without access to the vaccine, we compare several trial designs which rank lower on some criteria and higher on others, giving rise to difficult trade-offs. This case demonstrates the need for developing more nuanced guidance documents to help researchers balance these often conflicting criteria. (shrink)

Transcriptional silencing may not necessarily depend on the continuous residence of a sequence‐specific repressor at a control element and may act via a “hit and run” mechanism. Due to limitations in assays that detect transcription factor (TF) binding, such as chromatin immunoprecipitation followed by high‐throughput sequencing (ChIP‐seq), this phenomenon may be challenging to detect and therefore its prevalence may be underappreciated. To explore this possibility, erythroid gene promoters that are regulated directly by GATA1 in an inducible system are analyzed. It (...) is found that many regulated genes are bound immediately after induction of GATA1 but the residency of GATA1 decreases over time, particularly at repressed genes. Furthermore, it is shown that the repressive mark H3K27me3 is seldom associated with bound repressors, whereas, in contrast, the active (H3K4me3) histone mark is overwhelmingly associated with TF binding. It is hypothesized that during cellular differentiation and development, certain genes are silenced by repressive TFs that subsequently vacate the region. Catching such repressor TFs in the act of silencing via assays such as ChIP‐seq is thus a temporally challenging prospect. The use of inducible systems, epitope tags, and alternative techniques may provide opportunities for detecting elusive “hit and run” transcriptional silencing. Also see the video abstract here https://youtu.be/vgrsoP_HF3g. (shrink)

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)

Background: Healthcare providers who are accountable for patient care safety and quality but who are not empowered to actualize them experience moral distress. Interventions to mitigate moral distress in the healthcare organization are needed. Objective: To evaluate the effect on moral distress and clinician empowerment of an established, health-system-wide intervention, Moral Distress Consultation. Methods: A quasi-experimental, mixed methods study using pre/post surveys, structured interviews, and evaluation of consult themes was used. Consults were requested by staff when moral distress was present. (...) The purpose of consultation is to identify the causes of moral distress, barriers to action, and strategies to improve the situation. Intervention participants were those who attended a moral distress consult. Control participants were staff surveyed prior to the consult. Interviews were conducted after the consult with willing participants and unit managers. Moral distress was measured using the Moral Distress Thermometer. Empowerment was measured using the Global Empowerment Scale. Results: Twenty-one consults were conducted. Analysis included 116 intervention and 30 control surveys, and 11 interviews. A small but significant decrease was found among intervention participants, especially intensive care staff. Empowerment was unchanged. Interview themes support the consult service as an effective mode for open discussion of difficult circumstances and an important aspect of a healthy work environment. Conclusions: Moral distress consultation is an organization-wide mechanism for addressing moral distress. Consultation does not resolve moral distress but helps staff identify strategies to improve the situation. Further studies including follow up may elucidate consultation effectiveness. (shrink)

Cicero's philosophical works are now exciting renewed interest, in part because he provides vital evidence of the views of the Greek philosophers of the Hellenistic age, and partly because of the light he casts on the intellectual life of first century Rome. This edition uses the 1997 Clarendon text by the acclaimed translator P.G. Walsh.

Starting from a connected, partially ordered set of events, it is shown that results of the measurement of time are elements of a partially ordered and filtering field, as used in a previous paper. Moreover, some relations between physical formulas and properties of the field are proved. Finally, some open problems and suggestions are pointed out. For the convenience of the reader not acquainted with elementary algebraic methods, proofs are given in detail.

A neurosurgical view of consciousness is presented. It is biased by our need to deal with coma. The concept of primary or neurosurgical consciousness is discussed, and the anatomy, physiology, pathology and clinical features described in a simple a way. It is suggested that the dynamic interaction between the reticular activating system and the cerebral cortex is the anatomic and physiologic basis for primary consciousness. It is emphasised that this in no way diminishes the role of the cortex in either (...) primary or higher-order consciousness. In essence, a presentation is made of the neurosurgical view of cortex-brainstem inter- relationships, and the importance of this interrelationship to consciousness. (shrink)

In its original form Dirac's equations have been expressed by use of the γ-matrices γμ, μ=0, 1, 2, 3. They are elements of the matrix algebra M 4 (ℂ). As emphasized by Hestenes several times, the γ-matrices are merely a (faithful) matrix representation of an orthonormal basis of the orthogonal spaceℝ 1,3, generating the real Clifford algebra Cl 1,3 . This orthonormal basis is also denoted by γμ, μ=0, 1, 2, 3. The use of the matrix algebra M 4 (ℂ) (...) to represent Cl 1,3 has some unsatisfactory aspects. The γ-matrices contain imaginary numbers as entries whereas Cl 1,3 is real. Moreover, as a matrix algebra Cl 1,3 is M 2 (ℍ) but only a part of M 4 (ℂ). For that reason we investigate in this paper several forms of Dirac's equations in terms of M 2 (ℍ) instead of M 4 (ℂ). In Section1 we survey Dirac's equations describing the interaction of matter with electromagnetic, electroweak, and strong fields. Section2 deals with electromagnetic/weak interactions employing M 2 (ℍ). Finally, in Section3 we deal with Dirac's equations for strong interactions between quarks. In contrast to su(2) ⊕ u(1), the Lie algebra su(3) is not isomorphic to any subalgebra of Cl 1,3 . Therefore we do not give a description of strong interactions by use of M 2 (ℍ). Instead of such an approach we describe these interactions using the space of quadruples of bivector fields in Cl 1,3 . The thus obtained description has remarkable formal resemblance to the original Dirac equations using wave functions with values in the linear spaceℂ 4. (shrink)

‘Menander has set up a confrontation between this law [the law about epikleroi] and love… He wants the audience to regard the law as stupid and wrong… Surely one of Menander's purposes in writing this play was to make the Athenians consider seriously whether the law ought to be changed.’ Thus Professor D. M. MacDowell in the concluding paragraph of his article ‘Love versus the Law: an Essay on Menander's Aspis’. A similar view was already implicit in E. Karabelias' treatment (...) of the play as indicative of the general attitude to this law in Athens in Menander's day: ‘A n'en point douter, l'épiclérat est ressenti, á l'epoque de Ménandre, comme une anomalie intolérable pour les mceurs de la societe athénienne à la fin du ive s.av.n.è L'épiclérat est odieux et ridicule… L'hostilité envers l'épiclérat est done un signe des temps’. And Professor E. G. Turner has written: ‘it is hard to imagine that the institution of the epiclerate emerged in good standing from this derisory treatment’. (shrink)