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BACKGROUND: Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. METHODS: In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60. RESULTS: Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. CONCLUSIONS: Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment. CLINICAL TRIALS REGISTRATION: EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351.

The northern North American Cordilleran margin has been active for >200 million years, as recorded by punctuated phases of crustal growth and deformation. Accretion of the exotic Wrangellia Composite Terrane (Insular Belt) is considered the largest addition of juvenile crust to the Cordilleran margin, though margin-parallel translation during the Cenozoic has obscured much of the accretionary history. Three zones of inverted metamorphism spatially correspond to the Insular-North American suture zone from north to south: (1) Clearwater Mountains; (2) Kluane Lake; and (3) Coast Mountains, each preserving kinematics indicative of thrusting of North American-derived rocks over Insular-derived assemblages. We performed in situ monazite petrochronology on samples collected across strike in both the Clearwater and Coast Mountain regions. New and recently published data from these three metamorphic belts indicate that thrust-sense deformation accompanied the formation of inverted metamorphic isograds from 72 to 56 Ma. We leverage recent estimates of Denali fault offset to reconstruct a >1000-km-long zone of inverted metamorphism and interpret it as the Insular-North America terminal suture. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) affects millions of people each year. Previous studies using the central fluid percussion injury (CFPI) model in adult male rats indicated that elevated intracranial pressure (ICP) was associated with long-term effects, including neuronal cell loss and increased sensory sensitivity post-injury and secondary ICP elevation, which were not seen following injury alone. Investigations also indicated that cathepsin B (Cath B), a lysosomal cysteine protease, may play a role in the pathological progression of neuronal membrane disruption; however, the specific impact of Cath B inhibition following CFPI remained unknown. Thus, the focus of this study was to evaluate the effects of Cath B inhibition via the intracerebroventricular infusion of the Cath B inhibitor to the CA-074 methyl ester (CA-074Me) 2w following injury with or without secondary ICP elevation. This was accomplished using adult male rats continuously infused with CA-074Me or 10% DMSO as a vehicle control for 2w following either sham injury, CFPI only, or CFPI with subsequent ICP elevation to 20 mmHg. We assessed Cath B activity and evaluated the protein levels of Cath B and Cath B-binding partners AIF, Bcl-XL, and Bak. We also conducted histological analyses of the total cell counts to assess for cell loss, membrane disruption, and Cath B localization. Finally, we investigated somatosensory changes with the whisker nuisance task. Overall, this study demonstrated that Cath B is not a direct driver of membrane disruption; however, the administration of CA-074Me alters Cath B localization and reduces hypersensitivity, emphasizing Cath B as an important component in late secondary pathologies. [ABSTRACT FROM AUTHOR]

In order to accurately probe high energy density matter states, it is vital to create powerful x-ray backlighters. One approach to create such x-ray sources is based on the usage of short-pulse, high-energy lasers, which greatly benefits from an optimization of the laser target coupling. Here, the spectral and temporal x-ray emission profiles of structured silicon targets with micron-sized spikes on the front surface are studied at laser intensities of 1017 W cm−2. The laser pulse length is varied between 1 and 20 ps with an energy of up to 1 kJ. The structured targets show an up to 13× enhancement of silicon Heα emission compared to flat foils with a well-defined, sharp emission pulse profile. Furthermore, the performance of the microstructured targets is compared to targets with a CH shield as well as foils irradiated with a UV prepulse. [ABSTRACT FROM AUTHOR]

Geochemical and Nd isotopic data from mafic and newly discovered ultramafic rocks in the Adirondack Lowlands suggest widespread enrichment of the lithospheric mantle under the Grenville Province. Incompatible element abundances and previously published Hf [T.sub.DM (zircon)] (depleted mantle model age) and Nd [T.sub.DM] ages from rocks of the anorthosite-mangeritecharnockite-granite suite in the Adirondack Highlands document similar enrichment in the lower crust and its strong influence on subsequent magmatic events throughout the Ontario-Quebec-Adirondack segment of the Grenville Province. Likely the consequence of long-lived (ca. 1.4-1.2 Ga) northwest-directed subduction along the southeast edge of Laurentia (previously proposed Andean margin), this enrichment is similar to that associated with the vast (>240,000 [km.sup.2]) ultrapotassic province of the western Churchill Province. Enrichment of the lithospheric mantle beneath orogenic belts is a predictable and important differentiation process that has operated on Earth for at least the past 3 b.y. doi: 10.1130/G30342.1

Sydney, UNSW Press, 2002 The cover shows a dog sniffing another dog's bum. While one gets the marketing point, it does not quite capture the overarching themes of the collection, [...]