Leaf litter identity alters the timing of lotic nutrient dynamics

1. The effects of resource quality on ecosystems can shift through time based on preferential use and elemental needs of biotic consumers. For example, leaf litter decomposition rates are strongly controlled by initial litter quality, where labile litter is processed and depleted more quickly than recalcitrant litters. 2. We examined the effect of this processing continuum on stream nutrient dynamics.We added one of four different litter compositions differing in litter quality (cot ‐tonwood [Populus deltoides], labile; sycamore [Platanus occidentalis], recalcitrant; bur oak [Quercus macrocarpa], recalcitrant; and mixed [equivalent mixture of pre ‐vious three species]) to 12 large (c. 20 m long, with riffle, glide and pool sections) outdoor stream mesocosms to assess the effect of litter species composition on whole‐stream nutrient uptake. Nutrients were dosed once weekly for 8 weeks to measure uptake of NH4–N, NO3–N, and PO4–P. We also measured changes in lit ‐ter C, N, and P content on days 28 and 56 of the study. 3. Nutrient uptake rates were highly variable, but occasionally very different among litter treatments (c. 5× between highest and lowest uptake rates by species). Uptake rates were generally greatest in cottonwood (labile) streams early in the study. However, during the last 4 weeks of the study, bur oak streams (recalci ‐trant) took up more nutrients than cottonwood streams, resulting in more cumu‐lative NO3–N uptake in bur oak than in cottonwood streams. Cumulative NO3–N uptake was greater in mixed streams than expected (non‐additive) on two dates of measurement, but was generally additive. 4. Changes in litter nutrient content largely corroborated nutrient uptake patterns, suggesting strong N immobilisation early in the study and some N mineralisation later in the study. P was strongly retained by most litters, but especially bur oak. Nutrient content of litter also largely changed additively, suggesting minimal evi ‐dence for non‐additive diversity effects on nutrient source/sink status. 5. Our results demonstrate that litter species identity can have whole‐ecosystem effects on stream nutrient dynamics, with important implications for the for fate of nutrients exported downstream. Further, diverse litter assemblages may serve as temporal stabilisers of ecosystem processes, such as nutrient sequestra‐tion, due to microbial nutrient requirements and differential decomposition rates, or the classic litter processing continuum.NSF, Grant/Award Number: DEB‐144259

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

Background Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Biological trait responses of river macroinvertebrate assemblages to a phosphorus gradient.

Phosphorus is the most important nutrient driving anthropogenic eutrophication of inland fresh waters. Several river basins in the Ozark Highlands and Boston Mountains ecoregions of central North America have elevated concentrations of total phosphorus, due to both point-source discharges and nonpoint source runoff in their catchments. Benthic macroinvertebrate responses, expressed as density and biomass of biological trait groups (functional feeding group, voltinism), were modeled across a steep phosphorus gradient spanning 35 river locations. Biomass and density increased across the gradient, and communities shifted from diverse, insect-dominated communities to communities dominated by small, multivoltine taxa (such as Chironomidae) and benthic algal grazers, particularly pleurocerid snails. These shifts are likely related to increased benthic primary production and supply of phosphorus to small-bodied consumers with high phosphorus demand (under the growth rate hypothesis). These results imply that phosphorus enrichment can have significant effects at multiple trophic levels in river ecosystems

Biological trait responses of river macroinvertebrate assemblages to a phosphorus gradient.

Phosphorus is the most important nutrient driving anthropogenic eutrophication of inland fresh waters. Several river basins in the Ozark Highlands and Boston Mountains ecoregions of central North America have elevated concentrations of total phosphorus, due to both point-source discharges and nonpoint source runoff in their catchments. Benthic macroinvertebrate responses, expressed as density and biomass of biological trait groups (functional feeding group, voltinism), were modeled across a steep phosphorus gradient spanning 35 river locations. Biomass and density increased across the gradient, and communities shifted from diverse, insect-dominated communities to communities dominated by small, multivoltine taxa (such as Chironomidae) and benthic algal grazers, particularly pleurocerid snails. These shifts are likely related to increased benthic primary production and supply of phosphorus to small-bodied consumers with high phosphorus demand (under the growth rate hypothesis). These results imply that phosphorus enrichment can have significant effects at multiple trophic levels in river ecosystems

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway