Caribou, Petroleum, and the Limits of Locality in the Canada–US Borderlands

his article discusses Karsten Heuer’s 2006 book Being Caribou in light of debates in ecocriticism and border studies about how to define the local in the context of environmental problems of vast range and uncertain temporality. It explores how Heuer’s book about following the Porcupine Caribou herd’s migration engages in multiple forms of boundary crossing—between countries, between hemispheric locations, and between species—and shows how insights from Indigenous storytelling complicate the book’s appeal to environmentalist readers by asserting a prior, transnational Indigenous presence in the transboundary landscapes of present-day Alaska and the Yukon

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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Metformin and a DPP-4-inhibitor differentially modulate the microbiome and metabolome of Metabolic Syndrome mice

This study assessed the impact of 2 anti-diabetic therapies on the gut microbiome and markers of cardiometabolic disease risk in mice. We employed a metabolic syndrome model in which C57BL/6 mice were fed a high-fat diet for 25 weeks while receiving 1 of 2 antidiabetic therapeutics—metformin or a DPP-4 inhibitor (PKF-275- 055)—for the final 12 weeks. Animals were monitored for weight gain, as well as glucose/cholesterol metabolism. In addition, adiposity was investigated at dissection, cecal microbiome was analyzed by 16S compositional sequencing and serum was analyzed by liquid chromatography-tandem mass spectrometry. Both therapeutics significantly improved glucose/cholesterol metabolism, attenuated weight gain and mesenteric adipose accumulation. However, multivariate analyses of microbiome and metabolomics data revealed clear profile separation of the therapeutic groups. While both metformin (0.78; p<0.05) and PKF-275-055 (1.00; p<0.05) mice displayed significantly decreased Firmicutes/Bacteroidetes ratios, only metformin animals harboured metabolic health-promoting Akkermansia (3.4%; p<0.0001). Intriguingly, PKF-275-055 mice displayed elevated levels of the butyrate-producing Rumminococcus (2.0%; p<0.05) and the acetogen Dorea (0.95%; p<0.05). We identified reduced levels of certain sphingomyelin, phosphatidylcholine and lysophosphatidylcholine entities within serum of the PKF-275- 055 group when compared to metformin and control. Conversely, metformin mice presented primarily with reduced levels of acylcarnitines, a functional group that has correlated with obesity, insulin resistance and systemic metabolic dysfunction in humans. This study adds weight to the hypothesis that some anti-diabetic therapeutics act in part through manipulation of the gut microbiome. Additionally, we identify several metabolites that may be of central importance in the mechanisms of metformin and PKF-275-055

Metformin and DPP-4 inhibitor differentially modulate the intestinal microbiota and plasma metabolome of metabolically dysfunctional mice

Background Recent evidence indicates that the gut microbiota is altered considerably by a variety of commonly prescribed medications. This study assessed the impact of two antidiabetic therapeutics on the gut microbiota and markers of cardiometabolic disease in metabolically dysfunctional mice. Materials & Methods C57BL/6 mice were fed a high-fat diet for 24-weeks while receiving one of two antidiabetic therapeutics - metformin or DPP-4 inhibitor, PKF-275-055 - for the final 12 weeks. Mice were assessed for weight gain, glucose and cholesterol metabolism, and adiposity. In addition, caecal microbiota was analysed by 16S compositional sequencing and plasma metabolome was analysed by LC-MS/MS. Results Both therapeutics had similar metabolic effects, attenuating mesenteric adiposity, improving cholesterol metabolism and insulin sensitivity. However, multivariate analyses of microbiota and metabolomics data revealed clear divergence of the therapeutic groups. While both metformin and PKF-275-055 mice displayed significantly decreased Firmicutes/Bacteroidetes ratios, only metformin harboured metabolic health-associated Akkermansia, Parabacteroides and Christensenella. Paradoxically, metformin also reduced α-diversity, a metric frequently associated with host metabolic fitness. PKF-275-055 mice displayed elevated levels of butyrate-producing Ruminococcus and acetogen Dorea, with reduced levels of certain plasma sphingomyelin, phosphatidylcholine and lysophosphatidylcholine entities. In turn, metformin reduced levels of acylcarnitines, a functional group associated with systemic metabolic dysfunction. Finally, several associations were identified between metabolites and altered taxa. Conclusions This study represents the first direct comparison of the microbiota-modifying effects of metformin and a DPP-4 inhibitor, and proposes several putative microbial targets both in terms of novel therapeutic development and adverse effect prevention