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

Data from: Noninvasive sampling reveals short-term genetic rescue in an insular red fox population

Genetic factors in the decline of small populations are extremely difficult to study in nature. We leveraged a natural experiment to investigate evidence of inbreeding depression and genetic rescue in a remnant population of subalpine-specialized Sierra Nevada red foxes (Vulpes vulpes necator) using noninvasive genetic monitoring during 2010–2017. Only 7 individuals were detected in the first 2 years. These individuals assigned genetically to the historical population and exhibited genetic hallmarks of inbreeding and no evidence of reproduction. Two years into the study, we detected 2 first-generation immigrant males from a recently expanding population of red foxes in the Great Basin Desert. Through annual resampling of individuals (634 red fox DNA samples, 41 individuals) and molecular reconstruction of pedigrees, we documented 1–3 litters/yr for 5 years, all descended directly or indirectly from matings involving immigrant foxes. The observed heterozygosity and allelic richness of the population nearly doubled in 2 years. Abundance increased, indicative of a rapidly expanding population. Throughout the study, adult survival was high. Restoration of gene flow apparently improved the demographic trajectory of this population in the short term. Whether these benefits continue in the longer-term could depend on numerous factors, such as maintenance of any locally adapted alleles. This study highlights the value of noninvasive genetic monitoring to assess rapidly shifting conditions in small populations. Uncertainties about the longer-term trajectory of this population underscore the need to continue monitoring and to research potential for both negative and positive aspects of continued genetic infusion

Pattern and timing of mitochondrial divergence of island spotted skunks on the California Channel Islands

Island spotted skunks (Spilogale gracilis amphiala) are a rare subspecies endemic to the California Channel Islands, currently extant on Santa Cruz and Santa Rosa islands. How and when skunks arrived on the islands is unknown, hindering decision-making about their taxonomic status and conservation priority. We investigated these questions by sequencing the complete mitochondrial genomes of 55 skunks from the two islands and mainland (California and Arizona) and examining phylogenetic patterns and estimations of isolation times among populations. Island spotted skunks grouped in a single monophyletic clade distinct from mainland spotted skunks. A haplotype network analysis had the most recent common ancestral haplotype sampled from an individual on Santa Rosa, suggesting both islands were colonized by a single matriline. Additionally, no haplotypes were shared between skunk populations on the two islands. These patterns imply that both island populations were derived from a common ancestral population shortly after establishment and have remained isolated from each other ever since. Together with divergence estimates from three methods, this topology is consistent with colonization of the super-island, Santarosae, by a single ancestral population of spotted skunks in the early Holocene, followed by divergence as the sea level rose and split Santarosae into Santa Cruz and Santa Rosa islands 9,400-9,700 years ago. Such a scenario of colonization could be explained either by rafting or one-time transport by Native Americans. Given their distinct evolutionary history, high levels of endemism, and current population status, island spotted skunks may warrant management as distinct evolutionarily significant units

Contrasting genetic trajectories of endangered and expanding red fox populations in the western U.S.

As anthropogenic disturbances continue to drive habitat loss and range contractions, the maintenance of evolutionary processes will increasingly require targeting measures to the population level, even for common and widespread species. Doing so requires detailed knowledge of population genetic structure, both to identify populations of conservation need and value, as well as to evaluate suitability of potential donor populations. We conducted a range-wide analysis of the genetic structure of red foxes in the contiguous western U.S., including a federally endangered distinct population segment of the Sierra Nevada subspecies, with the objectives of contextualizing field observations of relative scarcity in the Pacific mountains and increasing abundance in the cold desert basins of the Intermountain West. Using 31 autosomal microsatellites, along with mitochondrial and Y-chromosome markers, we found that populations of the Pacific mountains were isolated from one another and genetically depauperate (e.g., estimated Ne range = 3-9). In contrast, red foxes in the Intermountain regions showed relatively high connectivity and genetic diversity. Although most Intermountain red foxes carried indigenous western matrilines (78%) and patrilines (85%), the presence of nonindigenous haplotypes at lower elevations indicated admixture with fur-farm foxes and possibly expanding midcontinent populations as well. Our findings suggest that some Pacific mountain populations could likely benefit from increased connectivity (i.e., genetic rescue) but that nonnative admixture makes expanding populations in the Intermountain basins a non-ideal source. However, our results also suggest contact between Pacific mountain and Intermountain basin populations is likely to increase regardless, warranting consideration of risks and benefits of proactive measures to mitigate against unwanted effects of Intermountain gene flow

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

AAA?DDD Triple Hydrogen Bond Complexes

Experiment and theory both suggest that the AAA?DDD pattern of hydrogen bond acceptors (A) and donors (D) is the arrangement of three contiguous hydrogen bonding centers that results in the strongest association between two species. Murray and Zimmerman prepared the first example of such a system (complex 3•2) and determined the lower limit of its association constant (Ka) in CDCl3 to be 105 M?1 by 1H NMR spectroscopy (Murray, T. J. and Zimmerman, S. C. J. Am. Chem. Soc. 1992, 114, 4010?4011). The first cationic AAA?DDD pair (3•4+) was described by Bell and Anslyn (Bell, D. A. and Anslyn, E. A. Tetrahedron 1995, 51, 7161?7172), with a Ka > 5 × 105 M?1 in CH2Cl2 as determined by UV?vis spectroscopy. We were recently able to quantify the strength of a neutral AAA?DDD arrangement using a more chemically stable AAA?DDD system, 6•2, which has an association constant of 2 × 107 M?1 in CH2Cl2 (Djurdjevic, S., Leigh, D. A., McNab, H., Parsons, S., Teobaldi, G., and Zerbetto, F. J. Am. Chem. Soc. 2007, 129, 476?477). Here we report on further AA(A) and DDD partners, together with the first precise measurement of the association constant of a cationic AAA?DDD species. Complex 6•10+[B(3,5-(CF3)2C6H3)4?] has a Ka = 3 × 1010 M?1 at RT in CH2Cl2, by far the most strongly bound triple hydrogen bonded system measured to date. The X-ray crystal structure of 6•10+ with a BPh4? counteranion shows a planar array of three short (NH···N distances 1.95?2.15 Å), parallel (but staggered rather than strictly linear; N?H···N angles 165.4?168.8°), primary hydrogen bonds. These are apparently reinforced, as theory predicts, by close electrostatic interactions (NH?·?N distances 2.78?3.29 Å) between each proton and the acceptor atoms of the adjacent primary hydrogen bonds