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)

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)

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)

The text of Euripides' Troades depends mainly upon the versions preserved in two manuscripts, viz. Palatinus 287 and Vaticanus 909 . Both these manuscripts are well known and have been several times collated. Their importance in relation to one another and to the other existing manuscripts for the study of the text of Euripides in general has been frequently discussed and is no longer a subject of major controversy. The notes which follow are designed to put on record a number (...) of corrections to the readings ascribed to P and V for the Troades in the apparatus criticus of Prinz-Wecklein and later editors; and to correct and amplify the general descriptions of P and to call attention to certain difficulties in the current views of its relationship to Laurentianus xxxii. (shrink)

Psychiatric polypharmacy refers to the prescription of two or more psychiatric medications concurrently to a patient. It can be categorised as same-class, multi-class, adjunctive, augmentation and total polypharmacy. Despite advances in psychopharmacology and a better understanding of the principles of therapeutics, its practice is increasing rapidly. The prevalence of polypharmacy in psychiatry varies between 13%-90%. There are various clinical and pharmaco-economic factors associated with it. Dealing with polypharmacy requires an understanding of its associated factors. Education, guidelines and algorithms for the (...) appropriate management of various conditions are effective ways to avoid irrational polypharmacy. (shrink)

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.