4 results
68 Metformin prevents the diagnosis of Long Covid in phase 3 trial of early treatment.
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- Carolyn Bramante, Esteban Wirtz, John Buse, David Boulware, Jacinda Nicklas, David Odde, Ken Cohen, Michael Puskarich, Christopher Tignanelli, Nichole Klatt, David Leibovitz, Hrishikesh Belani
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue s1 / April 2023
- Published online by Cambridge University Press:
- 24 April 2023, pp. 18-19
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- Article
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OBJECTIVES/GOALS: Chronic or new symptoms after infection with severe-acute-respiratory-coronavirus-2 (SARS-CoV-2) has been termed post-acute sequelae of Covid-19 (PASC) or Long Covid. Our objective is to present results from COVID-OUT, a phase 3 double-blind, randomized controlled trial of early outpatient treatment of Covid-19 with repurposed medications. METHODS/STUDY POPULATION: COVID-OUT enrolled adults age 30 to 85 with overweight or obesity who had proof of SARS-CoV-2 infection and fewer than 7 days of symptoms. In this 2 by 3 factorial design trial of metformin, ivermectin, fluvoxamine, or exact-matching placebo of each medication, participants were randomized 1:1:1:1:1:1 to the 6 treatment allocations. This abstract focuses on whether early treatment with metformin prevented Long Covid. Immediate release metformin was titrated to 1500mg daily over the first 6 days. We assessed the incidence of clinician-diagnosed Long Covid with follow up through 10 months after enrollment. We also assessed where participants were diagnosed with Long Covid, and where they received Long Covid treatment. RESULTS/ANTICIPATED RESULTS: Of 1124 participants, 98 (8.7%) report having a healthcare provider make a diagnosis of long covid. By arm, 6.9% (39/564) of metformin participants report having a diagnosis for long covid as compared with 10.5% (59/560) of matched placebo controls. The absolute reduction attributable to metformin was 3.6% (95%CI, 0.3% to 7.0%; P=0.031) with a relative risk reduction of 34% (95%CI, 3% to 55%). The metformin cost per long covid case averted was $28 (95%CI, $15 to $306). 10-month follow-up data will be available at the time of presentation as well as an analysis of baseline factors associated with the development of Long-Covid, independent of treatment allocation in the trial. DISCUSSION/SIGNIFICANCE: Metformin reduced the incidence of clinician-diagnosed long covid by 34% in a double-blind randomized placebo-controlled trial, and previous research published in-vitro activity by metformin against SARS-CoV-2 and other RNA viruses. Further investigation of metformin as early treatment for SARS-CoV-2 is warranted.
Contributors
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- By Sofya Abazyan, Saskia S. Arndt, Jonathon C. Arnold, Sandra Beeské, Odd-Geir Berge, Valerie J. Bolivar, David Borchelt, Marie-Françoise Chesselet, Yoon H. Cho, Angelo Contarino, John C. Crabbe, Wim E. Crusio, Bianca De Filippis, Mara Dierssen, Stephanie C. Dulawa, Emily C. Eastwood, Haim Einat, Raul R. Gainetdinov, David Gordon, Guy Griebel, F. Scott Hall, John H. Harkness, Christopher Janus, Zhengping Jia, Nirit Kara, Tim Karl, Martien J. H. Kas, Federica Klaus, Robert Lalonde, Glenda Lassi, Giovanni Laviola, Iddo Magen, Stephen C. Maxson, Douglas Ashley Monks, Rebecca E. Nordquist, Lucy R. Osborne, Tamara J. Phillips, Alisdair R. Philp, Marina R. Picciotto, Susanna Pietropaolo, Mikhail V. Pletnikov, Christopher R. Pryce, James L. Resnick, Laura Ricceri, Frans Sluyter, Emily Y. Smith, Ichiro Sora, Tatyana D. Sotnikova, Rebecca C. Steiner, Ortrud K. Steinlein, Catherine Strazielle, Enejda Subashi, Ashlyn Swift-Gallant, Aki Takahashi, Kevin Talbot, Stewart Thompson, Valter Tucci, F. Josef van der Staay, Gertjan van Dijk, Nancy S. Woehrle
- Edited by Susanna Pietropaolo, Centre National de la Recherche Scientifique (CNRS), Paris, Frans Sluyter, University of Portsmouth, Wim E. Crusio, Centre National de la Recherche Scientifique (CNRS), Paris
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- Book:
- Behavioral Genetics of the Mouse
- Published online:
- 05 October 2014
- Print publication:
- 25 September 2014, pp ix-xii
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1 - Neurological outcome after perinatal asphyxia at term
- from Section 1 - Scientific background
- Edited by A. David Edwards, Denis V. Azzopardi, Alistair J. Gunn
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- Book:
- Neonatal Neural Rescue
- Published online:
- 05 March 2013
- Print publication:
- 04 April 2013, pp 1-15
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Summary
Introduction
It was nearly 150 years ago that an association between perinatal events and brain injury was first reported, claiming that “the act of birth does occasionally imprint upon the nervous and muscular systems of the infantile organism very serious and peculiar evils” [1]. While a great deal is now known about this association and the pathophysiology behind it, the quantification of these “evils” is still uncertain. While the World Health Organisation estimates that 25% of neonatal and 8% of all deaths under 5 years in low-income countries are due to birth asphyxia [2], there remains no agreed definition; therefore, the reported prevalence varies. Consequently, the number of infants exposed is unknown, although approximately 7% of term infants require resuscitation after birth [3]. It is well recognized that only a small proportion of these infants will go on to develop neurological signs in the neonatal period and an estimated 2 per 1000 births in the developed world [4] will develop neonatal encephalopathy.
While encephalopathy is, therefore, relatively uncommon, the outcome can be devastating to the infant and family and it remains a major cause of death and long-term disability with a substantial burden on the community as a whole. It is estimated that each infant with complex neurological sequelae will cost the state over 1 million US dollars (800,000 Euros) in health care, social support and lost productivity throughout their lifetime [5]. In addition, unmeasured impacts on behaviour, school failure and psychiatric disease are likely all to have additive effects. As well as the direct costs, other population impacts are also likely. Increasingly literature suggests a causal link between IQ and lifespan [6] and the true cost to society of perinatal asphyxia is likely to be extensive.
10 - Microtubule Bending and Breaking in Cellular Mechanotransduction
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- By Andrew D. Bicek, University of Minnesota, Dominique Seetapun, University of Minnesota, David J. Odde, University of Minnesota
- Edited by Mohammad R. K. Mofrad, University of California, Berkeley, Roger D. Kamm, Massachusetts Institute of Technology
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- Book:
- Cellular Mechanotransduction
- Published online:
- 05 July 2014
- Print publication:
- 23 November 2009, pp 234-249
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Summary
Introduction
Cellular mechanotransduction is the mechanism by which living cells respond to mechanical signals from their environment. As early as 1892, Julius Wolff described the ability of bone to be deposited and resorbed in accordance with the mechanical stresses placed upon it, implying that the bone must have some internal mechanical stress or strain sensors (Huiskes and Verdonschot, 1997; Roesler, 1987; Wolff, 1892). More recently, investigating the precise biochemical mechanisms by which a direct mechanical stimulus is converted into a cellular response has become an area of interest, and the macro-scale effects of mechanotransduction, such as the alignment of load-bearing components, are now widely recognized. For example, the extracellular matrix protein, collagen, is organized into a hierarchy of fibrillar structures by tenocytes to form a tendon that functionally transmits mechanical tension (Kastelic et al., 1978). Additionally, vascular endothelial cells have been observed to align and alter their morphology in response to an applied fluid shear stress (Levesque and Nerem, 1985). In another example of cells sensing a mechanical stimulus, neuronal cells are capable of responding directly to a tensile force through neurite initiation and extension, a phenomenon termed “towed growth” (Bray, 1984; Fass and Odde, 2003; Fischer et al., 2005; Heidemann and Buxbaum, 1990; Pfister et al., 2004). Since individual cells are capable of responding directly to an applied force via secreting, organizing, and remodeling the extracellular matrix, or through morphological and gene expression changes, mechanotransduction is presumably controlled and integrated into a response at the cellular level.
Perhaps the best documentation of cellular mechanotransduction is the role of mechanically gated ion channels in hearing (Hudspeth, 1989). The stereocilia of the auditory hair cells vibrate and bend with incoming sound waves. As the stereocilia bend, a linker protein filament is tensed between two adjacent cilia and the tension generated opens a mechanically gated ion channel. Opening of the ion channel causes an influx of positive charges that depolarize the hair cell and lead to an electrical signal that the brain interprets as sound. While this is a clear example of a mechanotransduction event, it is also clear that mechanically gated ion channels are not the sole mechanism for mechanotransduction in every cell. Other structures within the cell therefore need to be identified and investigated for their mechanosensory features, with the cytoskeleton being a leading candidate.