Drug-induced stress granule formation protects sensory hair cells in mouse cochlear explants during ototoxicity

Stress granules regulate RNA translation during cellular stress, a mechanism that is generally presumed to be protective, since stress granule dysregulation caused by mutation or ageing is associated with neurodegenerative disease. Here, we investigate whether pharmacological manipulation of the stress granule pathway in the auditory organ, the cochlea, affects the survival of sensory hair cells during aminoglycoside ototoxicity, a common cause of acquired hearing loss. We show that hydroxamate (-)-9, a silvestrol analogue that inhibits eIF4A, induces stress granule formation in both an auditory cell line and ex-vivo cochlear cultures and that it prevents ototoxin-induced hair-cell death. In contrast, preventing stress granule formation using the small molecule inhibitor ISRIB increases hair-cell death. Furthermore, we provide the first evidence of stress granule formation in mammalian hair cells in-vivo triggered by aminoglycoside treatment. Our results demonstrate that pharmacological induction of stress granules enhances cell survival in native-tissue, in a clinically-relevant context. This establishes stress granules as a viable therapeutic target not only for hearing loss but also other neurodegenerative diseases.EI:595 - Action on Hearing Loss; 091092/Z/09/Z - Wellcome Trust (Wellcome); MR/N004329/1 - RCUK | Medical Research Council (MRC)Published versio

Pacific Northwest GridWise™ Testbed Demonstration Projects; Part I. Olympic Peninsula Project

This report describes the implementation and results of a field demonstration wherein residential electric water heaters and thermostats, commercial building space conditioning, municipal water pump loads, and several distributed generators were coordinated to manage constrained feeder electrical distribution through the two-way communication of load status and electric price signals. The field demonstration took place in Washington and Oregon and was paid for by the U.S. Department of Energy and several northwest utilities. Price is found to be an effective control signal for managing transmission or distribution congestion. Real-time signals at 5-minute intervals are shown to shift controlled load in time. The behaviors of customers and their responses under fixed, time-of-use, and real-time price contracts are compared. Peak loads are effectively reduced on the experimental feeder. A novel application of portfolio theory is applied to the selection of an optimal mix of customer contract types

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Research and Practice: A Reflexive and Recursive Relationship- Three Narratives, Five Voices

In this multiply-authored account, five academicians discuss the connections between their work as clinicians and their clinical qualitative research. Each saw connections between practice and research, and each in her or his own domain of interest has found that practice informs research and research informs practice. This article also introduces three major types of qualitative clinical family research: conversational analysis, recursive frame analysis, and hermeneutic phenomenology

It\u27s Nothing Serious, but... : Parents\u27 Interpretations of Referral to Pediatric Cardiologists

Differences in parents\u27 interpretations of their child\u27s referral for a heart murmur to pediatric cardiologists were investigated. Interviews with 32 families making their initial visits to a heart specialist were studied through the use of discourse analysis. Among the study\u27s areas of investigation were: parents\u27 concerns over being told that the heart murmur was not cause for worry, but the physician still felt the need to refer the child to a pediatric cardiologist; parents\u27 doubts whether the referring physician had the expertise necessary to know when a murmur was inconsequential; and parents\u27 uneasiness as to whether they should or should not be concerned over their chid\u27s condition. A transcript of an actual referral to a pediatric cardiologist was used to illustrate to physicians how to conduct future referrals for heart murmurs