21-cm signatures of residual HI inside cosmic HII regions during reionization

We investigate the impact of sinks of ionizing radiation on the reionization-era 21-cm signal, focusing on 1-point statistics. We consider sinks in both the intergalactic medium and inside galaxies. At a fixed filling factor of HII regions, sinks will have two main effects on the 21-cm morphology: (i) as inhomogeneous absorbers of ionizing photons they result in smaller and more widespread cosmic HII patches; and (ii) as reservoirs of neutral gas they contribute a non-zero 21-cm signal in otherwise ionized regions. Both effects damp the contrast between neutral and ionized patches during reionization, making detection of the epoch of reionization with 21-cm interferometry more challenging. Here we systematically investigate these effects using the latest semi-numerical simulations. We find that sinks dramatically suppress the peak in the redshift evolution of the variance, corresponding to the midpoint of reionization. As previously predicted, skewness changes sign at midpoint, but the fluctuations in the residual HI suppress a late-time rise. Furthermore, large levels of residual HI dramatically alter the evolution of the variance, skewness and power spectrum from that seen at lower levels. In general, the evolution of the large-scale modes provides a better, cleaner, higher signal-to-noise probe of reionization.Comment: Minor edits to agree with MNRAS published versio

Successfully initiating an escalation of care in acute ward settings—A qualitative observational study

Aims: To address knowledge gaps by (i) developing a theoretical understanding of escalation and (ii) identifying escalation success factors. Design: Non‐participant observations were used to examine deteriorating patient escalation events. Methods: Escalation event data were collected by a researcher who shadowed clinical staff, between February 16th 2021 and March 17th 2022 from two National Health Service Trusts. Events were analysed using Framework Analysis. Escalation tasks were mapped using a Hierarchical Task Analysis diagram and data presented as percentages, frequency and 95% CI. Results: A total of 38 observation sessions were conducted, totaling 105 h, during which 151 escalation events were captured. Half of these were not early warning score‐initiated and resulted from bleeding, infection, or chest pain. Four communication phenotypes were observed in the escalation events. The most common was Outcome Focused Escalation, where the referrer expected specific outcomes like blood cultures or antibiotic prescriptions. Informative Escalations were often used when a triggering patient's condition was of low clinical concern and ranked as the second most frequent escalation communication type. General Concern Escalations occurred when the referrer did not have predetermined expectations. Spontaneous Interaction Escalations were the least frequently observed, occurring opportunistically in communal workspaces. Conclusion: Half of the events were non‐triggering escalations and understanding these can inform the design of systems to support staff better to undertake them. Escalation is not homogenous and differing escalation communication phenotypes exist. Informative Escalations represent an organizational requirement to report triggering warning scores and a targeted reduction of these may be organizationally advantageous. Increasing the frequency of Spontaneous Escalations, through hospital designs, may also be beneficial. Impact Statement: Our work highlights that a significant proportion of escalation workload occurs without a triggering early warning score and there is scope to better support these with designed systems. Further examination of reducing Informative and increasing Spontaneous Escalations is also warranted. Patient and Public Contribution: Extensive PPIE was completed throughout the lifecycle of this study. PPIE members validated the research questions and overarching aims of the overall study. PPIE members contributed to the design of the study reviewed documents and the final data generated

Determining the probability of cyanobacterial blooms: the application of Bayesian networks in multiple lake systems

A Bayesian network model was developed to assess the combined influence of nutrient conditions and climate on the occurrence of cyanobacterial blooms within lakes of diverse hydrology and nutrient supply. Physicochemical, biological, and meteorological observations were collated from 20 lakes located at different latitudes and characterized by a range of sizes and trophic states. Using these data, we built a Bayesian network to (1) analyze the sensitivity of cyanobacterial bloom development to different environmental factors and (2) determine the probability that cyanobacterial blooms would occur. Blooms were classified in three categories of hazard (low, moderate, and high) based on cell abundances. The most important factors determining cyanobacterial bloom occurrence were water temperature, nutrient availability, and the ratio of mixing depth to euphotic depth. The probability of cyanobacterial blooms was evaluated under different combinations of total phosphorus and water temperature. The Bayesian network was then applied to quantify the probability of blooms under a future climate warming scenario. The probability of the "high hazardous" category of cyanobacterial blooms increased 5% in response to either an increase in water temperature of 0.8°C (initial water temperature above 24°C) or an increase in total phosphorus from 0.01 mg/L to 0.02 mg/L. Mesotrophic lakes were particularly vulnerable to warming. Reducing nutrient concentrations counteracts the increased cyanobacterial risk associated with higher temperatures

Improving escalation of deteriorating patients through cognitive task analysis: Understanding differences between work-as-prescribed and work-as-done

AbstractBackgroundAppropriate care escalation requires the detection and communication of in-hospital patient deterioration. Although deterioration in the ward environment is common, there continue to be patient deaths where problems escalating care have occurred. Learning from the everyday work of health care professionals (work-as-done) and identifying performance variability may provide a greater understanding of the escalation challenges and how they overcome these. The aims of this study were to i) develop a representative model detailing escalation of care ii) identify performance variability that may negatively or positively affect this process and iii) examine linkages between steps in the escalation process.MethodsThirty Applied Cognitive Task Analysis interviews were conducted with clinical experts (> 4 years' experience) including Ward Nurses (n = 7), Outreach or Sepsis Nurses (n = 8), Nurse Manager or Consultant (n = 6), Physiotherapists (n = 4), Advanced Practitioners (n = 4), and Doctor (n = 1) from two National Health Service hospitals and analysed using Framework Analysis. Task-related elements of care escalation were identified and represented in a Functional Resonance Analysis Model.FindingsThe NEWS2's clinical escalation response constitutes eight unique tasks and illustrates work-as-prescribed, but our interview data uncovered an additional 24 tasks (n = 32) pertaining to clinical judgement, decisions or processes reflecting work-as-done. Over a quarter of these tasks (9/32, 28 %) were identified by experts as cognitively challenging with a high likelihood of performance variability. Three out of the nine variable tasks were closely coupled and interdependent within the Functional Resonance Analysis Model (‘synthesising data points’, ‘making critical decision to escalate’ and ‘identifying interim actions’) so representing points of potential escalation failure. Data assimilation from different clinical information systems with poor usability was identified as a key cognitive challenge.ConclusionOur data support the emphasis on the need to retain clinical judgement and suggest that future escalation protocols and audit guidance require in-built flexibility, supporting staff to incorporate their expertise of the patient condition and the clinical environment. Improved information systems to synthesise the required data surrounding an unwell patient to reduce staff cognitive load, facilitate decision-making, support the referral process and identify actions are required. Fundamentally, reducing the cognitive load when assimilating core escalation data allows staff to provide better and more creative care.Study registration (ISRCTN 38850) and ethical approval (REC Ref 20/HRA/3828; CAG-20CAG0106)

Does designation as a UNESCO World Heritage Site influence tourist evaluation of a local destination?

The purpose of this study is to explore whether the UNESCO World Heritage Site (WHS) designation affects tourists’ evaluation of the local destination hosting the site, building on a large sample of about 0.8 million tourists who visited Italy over the period 1997-2015. We find that the inscription onto the UNESCO World Heritage List exerts surprisingly a negative effect on the overall evaluation of the destination and also on the evaluation of its artistic assets though the magnitude of the latter is lower. The effect is heterogeneous across visitors, depending on evaluation levels, as well as origin/destinations and demographics. Nonetheless, the presence of multiple WHSs in the same destination tends to increase evaluation suggesting that destination stakeholders with previous experience in dealing with WHS designations are better equipped to manage the complicated relationship between tourism and preservation. Managerial and policy-making implications are discussed

Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (Cmax; 335 ng/ml), time to Cmax (Tmax; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC0–24; 3,045 ng · h/ml), and concentration at 24 h (C24; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated Cmax (238 ng/ml), Tmax (3 h), AUC0–24 (3,036 ng · h/ml), and C24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies

Biofortification of UK food crops with selenium

Se is an essential element for animals. In man low dietary Se intakes are associated with health disorders including oxidative stress-related conditions, reduced fertility and immune functions and an increased risk of cancers. Although the reference nutrient intakes for adult females and males in the UK are 60 and 75 μg Se/d respectively, dietary Se intakes in the UK have declined from >60 μg Se/d in the 1970s to 35 μg Se/d in the 1990s, with a concomitant decline in human Se status. This decline in Se intake and status has been attributed primarily to the replacement of milling wheat having high levels of grain Se and grown on high-Se soils in North America with UK-sourced wheat having low levels of grain Se and grown on low-Se soils. An immediate solution to low dietary Se intake and status is to enrich UK-grown food crops using Se fertilisers (agronomic biofortification). Such a strategy has been adopted with success in Finland. It may also be possible to enrich food crops in the longer term by selecting or breeding crop varieties with enhanced Se-accumulation characteristics (genetic biofortification). The present paper will review the potential for biofortification of UK food crops with Se

Gridded and direct Epoch of Reionisation bispectrum estimates using the Murchison Widefield Array

We apply two methods to estimate the 21~cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly-spaced triangles of antenna tiles, as well as an estimate based on data gridded to the $uv$-plane. The direct and gridded bispectrum estimators are applied to 21 hours of high-band (167--197~MHz; $z$=6.2--7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 hours, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21~cm bispectrum may be accessible in less time than the 21~cm power spectrum for some wave modes, with detections in hundreds of hours.Comment: 19 pages, 10 figures, accepted for publication in PAS

Population overlap and habitat segregation in wintering Black-tailed Godwits Limosa limosa

Distinct breeding populations of migratory species may overlap both spatially and temporally, but differ in patterns of habitat use. This has important implications for population monitoring and conservation. To quantify the extent to which two distinct breeding populations of a migratory shorebird, the Black-tailed Godwit Limosa limosa, overlap spatially, temporally and in their use of different habitats during winter. We use mid-winter counts between 1990 and 2001 to identify the most important sites in Iberia for Black-tailed Godwits. Monthly surveys of estuarine mudflats and rice-fields at one major site, the Tejo estuary in Portugal in 2005-2007, together with detailed tracking of colour-ringed individuals, are used to explore patterns of habitat use and segregation of the Icelandic subspecies L. l. islandica and the nominate continental subspecies L. l. limosa. In the period 1990-2001, over 66 000 Black-tailed Godwits were counted on average in Iberia during mid-winter (January), of which 80% occurred at just four sites: Tejo and Sado lower basins in Portugal, and Coto Dontildeana and Ebro Delta in Spain. Icelandic Black-tailed Godwits are present throughout the winter and forage primarily in estuarine habitats. Continental Black-tailed Godwits are present from December to March and primarily use rice-fields. Iberia supports about 30% of the Icelandic population in winter and most of the continental population during spring passage. While the Icelandic population is currently increasing, the continental population is declining rapidly. Although the estuarine habitats used by Icelandic godwits are largely protected as Natura 2000 sites, the habitat segregation means that conservation actions for the decreasing numbers of continental godwits should focus on protection of rice-fields and re-establishment of freshwater wetlands

Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1

<p>Abstract</p> <p>Background</p> <p>Despite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.</p> <p>Methods</p> <p>We analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.</p> <p>Results</p> <p>We conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly <it>COL11A1 </it>and other genes, mainly <it>THBS2 </it>and <it>INHBA</it>. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.</p> <p>Conclusions</p> <p>Therefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.</p