Determining constraints imposed by salt fabrics on the morphology of solution-mined energy storage cavities, through dissolution experiments using brine and seawater in halite

Large-scale compressed air energy storage facilities offer one solution to the UK's energy demands, using solution-mined caverns in salt lithologies. For optimum gas storage efficiency, cavern geometry should ideally be smooth: spherical to cylindrical with a circular cross-section. However, such caverns are often irregular with marked asymmetry or ellipticity, and although the reasons for non-circular cross-sections developing during solution mining in some caverns can be related to, for example, the presence of interbedded lithologies, in other instances they are not fully understood. Cavities from dissolution experiments using five main end-member salt facies fabrics from the Triassic Preesall and Northwich Halite formations have been assessed to determine factors affecting cavity geometry, formation and variability in dissolution behaviour. Identical sets of experiments were performed on each fabric type, using two solution concentration strengths: brine and synthetic seawater. Comparison of experimental results using a combination of analytical and imaging techniques shows the extent to which the salt fabric and enhancement of features within the salt influence the resulting dissolution cavity. Observations show a visible increase in micropores within the adjacent halite matrix following dissolution. Smaller-scale features provide further insights into the dissolution processes, and salt fabric behaviour under different dissolution conditions. Supplementary material: A detailed description of methods is available at https://doi.org/10.6084/m9.figshare.c.428245

Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here, we report a systematic investigation of the structure–activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics

Lithium-isotope evidence for enhanced silicate weathering during OAE 1a (Early Aptian Selli event)

An abrupt rise in temperature, forced by a massive input of CO2 into the atmosphere, is commonly invoked as the main trigger for Oceanic Anoxic Events (OAEs). Global warming initiated a cascade of palaeoenvironmental perturbations starting with increased continental weathering and an accelerated hydrological cycle that delivered higher loads of nutrients to coastal areas, stimulating biological productivity. The end-result was widespread anoxia and deposition of black shales: the hallmarks of OAEs. In order to assess the role of weathering as both an OAE initiator and terminator (via CO2 sequestration) during the Early Aptian OAE 1a (Selli Event, ∼120 Ma) the isotopic ratio of lithium isotopes was analysed in three sections of shallow-marine carbonates from the Pacific and Tethyan realms and one basinal pelagic section from the Tethyan domain. Because the isotopic composition of lithium in seawater is largely controlled by continental silicate weathering and high- and low-temperature alteration of basaltic material, a shift to lighter δ7Li values is expected to characterize OAEs. The studied sections illustrate this phenomenon: δ7Li values decrease to a minimum coincident with the negative carbon-isotope excursion that effectively records the onset of OAE 1a. A second negative δ7Li excursion occurs coeval with the minimum in strontium isotopes after the event. The striking similarity to the strontium-isotope record argues for a common driver. The formation and destruction (weathering) of an oceanic LIP could account for the parallel trend in both isotope systems. The double-spike in lithium isotopes is probably related to a change in weathering congruencies. Such a chemostratigraphy is consistent with the hypothesis that an increase in silicate weathering, in conjunction with organic-carbon burial, led to drawdown of atmospheric CO2 during the early Aptian OAE 1a

Assessing bulk carbonates as archives for seawater Li isotope ratios

Silicate weathering is a primary control on the carbon cycle and therefore long-term climate. Tracing silicate weathering in the geological record has been a challenge for decades, with a number of proxies proposed and their limits determined. Recently lithium isotopes in marine carbonates have emerged as a potential tracer. Bulk carbonates are increasingly being used as a Li isotope archive, though with limited tests thus far of the robustness of this approach in the modern ocean. As the bulk composition of marine pelagic carbonates has changed through time and geographically, assessing the fidelity of bulk carbonate as proxy carrier is fundamental. To address the impact of compositional variability in bulk carbonate on Li isotopes, we examine 27 Bahamian aragonitic bulk carbonates and 16 Atlantic largely calcitic core-top sediment samples. Two core-tops only have trace (<10 %) carbonate, and are analysed to test whether carbonates in such sections are still a viable archive. We selectively extract the exchangeable and carbonate fractions from the core-top samples. The exchangeable fraction contains ∼2 % of the total Li and has a fairly constant offset from seawater of 16.5 ± 0.8‰. When leaching silicate-containing carbonates, acetic acid buffered with sodium acetate appears a more robust method of solely attacking carbonates compared to dilute HCl, which may also liberate some silicate-bound Li. Carbonates from samples that do not contain aragonite have the isotopic fractionation of seawater of Δ7Liseawater-calcite = 6.1 ± 1.3‰ (2sd), which is not affected by latitude or the water depth the sample was deposited at. The pure aragonite bulk carbonates from the Bahamas have a fractionation of Δ7Liseawater-aragonite = 9.6 ± 0.6‰. A sediment sample from the Galician coast that mostly consists of quartz is highly offset from seawater by ∼20‰ and also has relatively high Li/Ca ratios. These high values are not due to leaching of silicate material directly (Al/Ca ratios are low). We interpret this addition via cation exchange of Li from silicate during recrystallisation. Overall bulk carbonates from the open ocean are a reliable archive of seawater δ7Li, but care must be taken with carbonate mineralogy and low-carbonate samples. Overall, therefore, any examination of the palaeo-seawater δ7Li record must be reproduced in different global settings (e.g. multiple global cores) before it can be considered robust

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy

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

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries