Sediment entrainment and depletion from patches of fine material in a gravel-bed river

This paper presents the results of experiments in which a portable flume was used to manipulate hydraulic conditions and create bed load transport in a gravel bed river. Flume data are coupled with those from Helley‐Smith samples to assess bed load characteristics at shear stresses ranging from 5 to 60 N/m2. Experiments demonstrate that patches of fine sediment control both the intensity and duration of bed load under hydraulic conditions characteristic of the early stages of floods. The experiments allow quantifying bed load at the entrainment threshold, providing the first empirical evidence that marginal bed load transport can be attributed to the mobilization of sediments from patches. Bed load transport was recorded consistently once shear stress exceeded 5 N/m2. The experiments produced low bed load rates (<6 g/sm). Depletion of material in the patches occurred rapidly, with bed load rates and particle sizes decreasing after only 5 minutes. Combining flume and Helley‐Smith data for the study reach, a breakpoint in the relation between shear stress and bed load rate was calculated to be around 30 N/m2. This represents the transition between bed load transport phases: below the breakpoint, transport occurs at a low rate and is composed predominantly of fine sediment from patches, but above it, much higher rates occur from across the reach as a whole. Hydraulic conditions at the threshold are those which occur during small, frequent floods (25% bankfull, flow equaled or exceeded 15% of time). This indicates that sediment entrainment from patches of fine material is a frequent process and the threshold change between bed load phases occurs regularlyWe gratefully acknowledge the Leverhulme Trust for funding the work described in this paper. Damia Vericat was employed on this project with grants from the Catalan Foundation for Research and Innovation and the Leverhulme Trust

The importance of a small ephemeral tributary for fine sediment dynamics in a main‐stem river

Studies of ephemeral streams have focused mainly in arid and semi‐arid regions. Such streams also occur widely in temperate regions, but much less is known about their influence on fluvial processes in main‐stem rivers here. In this paper, we present evidence of the importance of a small ephemeral temperate stream for main‐stem fine sediment dynamics. The paper focuses on a restoration project (River Ehen, North West England) which involved the reconnection of a headwater tributary to the main‐stem river. We present data on suspended sediment transport 2 years prior to and 2 years following the reconnection. Despite the small size and non‐perennial flow of the tributary, its reconnection resulted in an increase of 65% in the main‐stem sediment yield. During both the pre‐reconnection and post‐reconnection periods, a higher proportion of the annual yield was conveyed during short events with relatively high suspended sediment concentrations. Following the reconnection, the magnitude and frequency of such events increased, primarily due to sediment being delivered from the tributary at times when main‐stem flows were not elevated. Overall, the main‐stem remains supply limited and so is highly dependent on sediment delivered from the tributary. The study helps stress that even non‐perennial tributaries yielding only a small increase in catchment size (+1.2% in this case) can have a major influence on main‐stem fluvial dynamics. Their role as sediment sources may be especially important where, as in the case of the Ehen, the main‐stem is regulated and the system is otherwise starved of sediment.Damià Vericat is funded by a Ramon y Cajal Fellowship (RYC‐2010‐06264). Authors acknowledge the support from the Economy and Knowledge Department of the Catalan Government through the Consolidated Research Group “Fluvial Dynamics Research Group”—RIUS (2014 SGR 645), and the additional support provided by the CERCA Programme, also from the Catalan Government

Discovery of novel GPVI receptor antagonists by structure-based repurposing.

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Nova tècnica per a l'estudi de la relació entre la deriva de macroinvertebrats i el transport de sediments

En aquesta nota tècnica es presenten els resultats obtinguts amb un canal d'assaigs portàtil que permet l'estudi de la interacció entre els paràmetres hidràulics del flux, el transport de sediments i la mobilitat de macroinvertebrats en sistemes fluvials. Els resultats obtinguts en els experiments realitzats a la conca de la ribera Salada posen de manifest que la mobilitat involuntària de macroinvertebrats (anomenada deriva catastròfica) és un fenomen relativament freqüent i que està directament relacionat amb l'inici de moviment de les partícules del llit del riu.This technical communication describes the results obtained using a novel portable flume that allows the study of the interactions among channel hydraulics, sediment transport and macroinvertebrate drift. First results obtained in the experimental Ribera Salada basin show as involuntary drift (so-called catastrophic drift) is a relatively frequent process and it is directly related to the sediment entrainment threshold conditions.En esta nota técnica se presentan los resultados obtenidos con un canal de ensayos portátil que permite el estudio de la interacción entre los parámetros hidráulicos del flujo, el transporte de sedimentos y la movilidad de macroinvertebrados en sistemas fluviales. Los resultados obtenidos en los experimentos realizados a la cuenca de la Ribera Salada ponen de manifiesto que la movilidad involuntaria de macroinvertebrados (denominada deriva catastrófica) es un fenómeno relativamente frecuente y que está directamente relacionado con el inicio de movimiento de las partículas del lecho del río