Exploring changing attitudes to non-invasive liver fibrosis tests in secondary care pathways: comparison of two national surveys

INTRODUCTION: The increasing availability of non-invasive tests (NITs) has created the opportunity to explore their use in improving risk stratification of advanced liver disease. The study aimed to determine the attitudes and practices among UK secondary care specialists, focusing primarily on attitudes to fibrosis assessment and the use of NITs. METHODS: Two web-based surveys were circulated, first between 2014 and 2015 (survey 1), and again in 2021 (survey 2). The surveys were promoted via the British Society of Gastroenterology, the British Association for the Study of the Liver and using Twitter. RESULTS: In survey 1, 215 healthcare professionals (HCPs) completed the online survey. 112 HCPs completed survey 2. 71 acute UK trusts were represented in survey 1 compared with 60 trusts in survey 2. Between the two surveys, the proportion of HCPs performing fibrosis assessment in all or nearly all cases rose from 45.1% to 74.1% (χ2=25.01; p<0.0001). 46.5% (n=33/71) respondents in acute services reported the use of NITs in clinical pathways in survey 1, rising to 70.0% (n=42/60) in survey 2 (χ2=7.35; p=0.007). Availability of tests has increased but is not universal. The proportion reporting availability as a barrier to uptake fell from 57.2% of responses in survey 1 to 38.4% in 2021 χ2=11.01; p=0.0009). CONCLUSION: Between 2014 and 2021, the role of NITs in fibrosis assessment has risen substantially, as has the proportion of clinicians using NITs in clinical pathways to assess risk of liver disease. Poor access to NITs remains the predominant barrier

The LSST DESC data challenge 1: Generation and analysis of synthetic images for next-generation surveys

Data Challenge 1 (DC1) is the first synthetic data set produced by the Rubin Observatory Legacy Survey of Space and Time (LSST) Dark Energy Science Collaboration (DESC). DC1 is designed to develop and validate data reduction and analysis and to study the impact of systematic effects that will affect the LSST data set. DC1 is comprised of r-band observations of 40 deg2 to 10 yr LSST depth. We present each stage of the simulation and analysis process: (a) generation, by synthesizing sources from cosmological N-body simulations in individual sensor-visit images with different observing conditions; (b) reduction using a development version of the LSST Science Pipelines; and (c) matching to the input cosmological catalogue for validation and testing. We verify that testable LSST requirements pass within the fidelity of DC1. We establish a selection procedure that produces a sufficiently clean extragalactic sample for clustering analyses and we discuss residual sample contamination, including contributions from inefficiency in star-galaxy separation and imperfect deblending. We compute the galaxy power spectrum on the simulated field and conclude that: (i) survey properties have an impact of 50 per cent of the statistical uncertainty for the scales and models used in DC1; (ii) a selection to eliminate artefacts in the catalogues is necessary to avoid biases in the measured clustering; and (iii) the presence of bright objects has a significant impact (2-6) in the estimated power spectra at small scales (> 1200), highlighting the impact of blending in studies at small angular scales in LSST

Leaching of copper and nickel in soil-water systems contaminated by bauxite residue (Red mud) from Ajka, Hungary: The importance of soil organic matter

Red mud is a highly alkaline (pH >12) waste product from bauxite ore processing. The red mud spill at Ajka, Hungary, in 2010 released 1 million m3 of caustic red mud into the surrounding area with devastating results. Aerobic and anaerobic batch experiments and solid phase extraction techniques were used to assess the impact of red mud addition on the mobility of Cu and Ni in soils from near the Ajka spill site. Red mud addition increases aqueous dissolved organic carbon (DOC) concentrations due to soil alkalisation, and this led to increased mobility of Cu and Ni complexed to organic matter. With Ajka soils, more Cu was mobilised by contact with red mud than Ni, despite a higher overall Ni concentration in the solid phase. This is most probably because Cu has a higher affinity to form complexes with organic matter than Ni. In aerobic experiments, contact with the atmosphere reduced soil pH via carbonation reactions, and this reduced organic matter dissolution and thereby lowered Cu/Ni mobility. These data show that the mixing of red mud into organic rich soils is an area of concern, as there is a potential to mobilise Cu and Ni as organically bound complexes, via soil alkalisation. This could be especially problematic in locations where anaerobic conditions can prevail, such as wetland areas contaminated by the spill

Legacy iron and steel wastes in the UK: Extent, resource potential, and management futures

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordThe iron and steel industry has a long tradition of bulk reuse of slags for a range of construction applications. Growing interest in recent years has seen slag resource recovery options extend to critical raw material recovery and atmospheric carbon capture. Full scale deployment of such technologies is currently limited in part by absent or partial inventories of slag deposit locations, data on composition, and volume estimates in many jurisdictions. This paper integrates a range of spatial information to compile a database of iron and steel slag deposits in mainland United Kingdom (UK) for the first time and evaluate the associated resource potential. Over 190 million tonnes of legacy iron and steel slag are present across current and former iron and steel working regions of the UK, with particular concentrations in the north west and north east of England, and central Scotland. While significant potential stockpiles of blast furnace and basic oxygen furnace slag could provide up to 0.9 million tonnes of vanadium and a cumulative carbon dioxide capture potential of 57–138 million tonnes, major management challenges for resource recovery are apparent. Over one third are located in close proximity to designated conservation areas which may limit resource recovery. Furthermore, land use analyses show that many of the sites have already been redeveloped for housing (nearly 30% urban cover). Deposits from recent decades in current or recently closed steel-working areas may have the greatest potential for resource recovery where such ambitions could be coupled with site restoration and regeneration efforts.Natural Environment Research Council (NERC)Engineering and Physical Sciences Research Council (EPSRC)Economic and Social Research Council (ESRC)UK Department for Business Energy and Industrial Strategy (BEIS

Information transmission in oscillatory neural activity

Periodic neural activity not locked to the stimulus or to motor responses is usually ignored. Here, we present new tools for modeling and quantifying the information transmission based on periodic neural activity that occurs with quasi-random phase relative to the stimulus. We propose a model to reproduce characteristic features of oscillatory spike trains, such as histograms of inter-spike intervals and phase locking of spikes to an oscillatory influence. The proposed model is based on an inhomogeneous Gamma process governed by a density function that is a product of the usual stimulus-dependent rate and a quasi-periodic function. Further, we present an analysis method generalizing the direct method (Rieke et al, 1999; Brenner et al, 2000) to assess the information content in such data. We demonstrate these tools on recordings from relay cells in the lateral geniculate nucleus of the cat.Comment: 18 pages, 8 figures, to appear in Biological Cybernetic

Depolarization-Evoked Secretion Requires Two Vicinal Transmembrane Cysteines of Syntaxin 1A

BACKGROUND: The interactions of the voltage-gated Ca(2+) channel (VGCC) with syntaxin 1A (Sx 1A), Synaptosome-associated protein of 25 kD (SNAP-25), and synaptotagmin, couple electrical excitation to evoked secretion. Two vicinal Cys residues, Cys 271 and Cys 272 in the Sx 1A transmembrane domain, are highly conserved and participate in modulating channel kinetics. Each of the Sx1A Cys mutants, differently modify the kinetics of Cav1.2, and neuronal Cav2.2 calcium channel. METHODOLOGY/PRINCIPLE FINDINGS: We examined the effects of various Sx1A Cys mutants and the syntaxin isoforms 2, 3, and 4 each of which lack vicinal Cys residues, on evoked secretion, monitoring capacitance transients in a functional release assay. Membrane capacitance in Xenopus oocytes co-expressing Cav1.2, Sx1A, SNAP-25 and synaptotagmin, which is Bot C- and Bot A-sensitive, was elicited by a double 500 ms depolarizing pulse to 0 mV. The evoked-release was obliterated when a single Cys Sx1A mutant or either one of the Sx isoforms were substituted for Sx 1A, demonstrating the essential role of vicinal Cys residues in the depolarization mediated process. Protein expression and confocal imaging established the level of the mutated proteins in the cell and their targeting to the plasma membrane. CONCLUSIONS/SIGNIFICANCE: We propose a model whereby the two adjacent transmembranal Cys residues of Sx 1A, lash two calcium channels. Consistent with the necessity of a minimal fusion complex termed the excitosome, each Sx1A is in a complex with SNAP-25, Syt1, and the Ca(2+) channel. A Hill coefficient >2 imply that at least three excitosome complexes are required for generating a secreting hetero-oligomer protein complex. This working model suggests that a fusion pore that opens during membrane depolarization could be lined by alternating transmembrane segments of Sx1A and VGCC. The functional coupling of distinct amino acids of Sx 1A with VGCC appears to be essential for depolarization-evoked secretion

Incorporating conceptual site models into national-scale environmental risk assessments for legacy waste in the coastal zone

Solid wastes deposited in the coastal zone that date from an era of lax environmental regulations continue to pose significant challenges for regulators and coastal managers worldwide. The increasing risk of contaminant release from these legacy disposal sites, due to a range of factors including rising sea levels, associated saline intrusion, and greater hydrological extremes, have been highlighted by many researchers. Given this widespread challenge, and the often-limited remedial funds available, there is a pressing need for the development of new advanced site prioritization protocols to limit potential pollution risks to sensitive ecological or human receptors. This paper presents a multi-criteria decision analysis that integrates the principles of Conceptual Site Models (Source-Pathway-Receptor) at a national scale in England and Wales to identify legacy waste sites where occurrence of pollutant linkages are most likely. A suite of spatial data has been integrated in order to score potential risks associated with waste type (Source), likelihood of pollutant release relating to current and future flood and erosion climate projections, alongside current management infrastructure (Pathway), and proximity to sensitive ecological features or proxies of human use in coastal areas (Receptors). Of the 30,281 legacy waste deposits identified in England and Wales, 3,219 were located within the coastal zone, with coastal areas containing a density of legacy wastes (by area) 10.5 times higher than inland areas. Of these, 669 were identified as priority sites in locations without existing coastal defences or flood management infrastructure, with 2550 sites identified in protected areas where contaminant transfer risks could still be apparent. The majority (63%) of the priority sites have either undefined source terms, or are classified as mixed wastes. Mining and industrial wastes were also notable waste categories, and displayed strong regional distributions in the former mining areas of north-east and south-west of England, south Wales, and post-industrial estuaries. The large-scale screening process presented here could be used by environmental managers as a foundation to direct more high-resolution site assessment and remedial work at priority sites, and can be used as a tool by governments for directing funding to problematic sites. List of Acronyms

Dibucaine Mitigates Spreading Depolarization in Human Neocortical Slices and Prevents Acute Dendritic Injury in the Ischemic Rodent Neocortex

Spreading depolarizations that occur in patients with malignant stroke, subarachnoid/intracranial hemorrhage, and traumatic brain injury are known to facilitate neuronal damage in metabolically compromised brain tissue. The dramatic failure of brain ion homeostasis caused by propagating spreading depolarizations results in neuronal and astroglial swelling. In essence, swelling is the initial response and a sign of the acute neuronal injury that follows if energy deprivation is maintained. Choosing spreading depolarizations as a target for therapeutic intervention, we have used human brain slices and in vivo real-time two-photon laser scanning microscopy in the mouse neocortex to study potentially useful therapeutics against spreading depolarization-induced injury.We have shown that anoxic or terminal depolarization, a spreading depolarization wave ignited in the ischemic core where neurons cannot repolarize, can be evoked in human slices from pediatric brains during simulated ischemia induced by oxygen/glucose deprivation or by exposure to ouabain. Changes in light transmittance (LT) tracked terminal depolarization in time and space. Though spreading depolarizations are notoriously difficult to block, terminal depolarization onset was delayed by dibucaine, a local amide anesthetic and sodium channel blocker. Remarkably, the occurrence of ouabain-induced terminal depolarization was delayed at a concentration of 1 µM that preserves synaptic function. Moreover, in vivo two-photon imaging in the penumbra revealed that, though spreading depolarizations did still occur, spreading depolarization-induced dendritic injury was inhibited by dibucaine administered intravenously at 2.5 mg/kg in a mouse stroke model.Dibucaine mitigated the effects of spreading depolarization at a concentration that could be well-tolerated therapeutically. Hence, dibucaine is a promising candidate to protect the brain from ischemic injury with an approach that does not rely on the complete abolishment of spreading depolarizations