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The polo-box domain (PBD) has critical roles in the mitotic functions of polo-like kinase 1 (PLK1). The replacement with partial ligand alternative through computational enrichment (REPLACE) strategy to develop inhibitors of protein–protein interactions has identified alternatives for the N-terminal tripeptide of a Cdc25C substrate. In addition, a peptide structure–activity relationship described key determinants and novel information useful for drug design. Fragment-ligated inhibitory peptides (FLIP) were generated with comparable affinity to peptide PBD inhibitors and possessed antiproliferative phenotypes in cells consistent with the observed decrease in PLK1 centrosomal localization. These FLIPs showed evidence of enhanced PLK1 inhibition in cells relative to peptides and induced monopolar and multipolar spindles, which stands in contrast to previously reported small-molecule PBD inhibitors that display phenotypes only partially representative of PLK1 knockdown. Progress obtained applying REPLACE validates this approach for identifying fragment alternatives for determinants of the Cdc25C-binding motif and extends its applicability of the strategy for discovering protein–protein interaction inhibitors. In addition, the described PBD inhibitors retain high specificity for PLK1 over PLK3 and therefore show promise as isotype selective, non-ATP competitive kinase inhibitors that provide new impetus for the development of PLK1-selective antitumor therapeutics. Mol Cancer Ther; 11(8); 1683–92. ©2012 AACR.

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Background There is no pharmacological treatment for the acute respiratory distress syndrome (ARDS). Platelets play an important role in the pathophysiology of ARDS. Pre-clinical, observational and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option. Research question Is enteral aspirin 75mg once daily safe and effective in improving surrogate outcomes in adult patients with ARDS? Study Design and Methods This randomised, double blind (patient and investigator), allocation concealed, placebo-controlled phase 2 trial was conducted in five UK intensive care units. Patients fulfilling the Berlin definition of ARDS were randomly assigned in a 1:1 ratio to receive enteral aspirin 75mg or placebo, for a maximum of 14 days, using a computer-generated randomisation schedule, with variable block size, stratified by vasopressor requirement. The primary endpoint was oxygenation index (OI) at day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat. Results The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. 24 patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI (unadjusted mean 54.4 [SD 26.8] in aspirin group, 42.4 [SD 25] in placebo group; mean difference 12.0, 95% CI -6.1 to 30.1, p= 0.19). Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each, odds ratio 1.04, 95% CI 0.56 to 1.94, p=0.56). Interpretation Aspirin was well tolerated but did not improve OI or other physiological outcomes, a larger trial is not feasible in its current design.

PURPOSE: Fluid overload is common in critical illness and is associated with mortality. This study investigated the feasibility of a randomised trial comparing conservative fluid administration and deresuscitation (active removal of accumulated fluid using diuretics or ultrafiltration) with usual care in critical illness.METHODS: Open-label, parallel-group, allocation-concealed randomised clinical feasibility trial. Mechanically ventilated adult patients expected to require critical care beyond the next calendar day were enrolled between 24 and 48 h following admission to the intensive care unit (ICU). Patients were randomised to either a 2-stage fluid strategy comprising conservative fluid administration and, if fluid overload was present, active deresuscitation, or usual care. The primary endpoint was fluid balance in the 24 h up to the start of study day 3. Secondary endpoints included cumulative fluid balance, mortality, and duration of mechanical ventilation.RESULTS: One hundred and eighty patients were randomised. After withdrawal of 1 patient, 89 patients assigned to the intervention were compared with 90 patients assigned to the usual care group. The mean plus standard deviation (SD) 24-h fluid balance up to study day 3 was lower in the intervention group (- 840 ± 1746 mL) than the usual care group (+ 130 ± 1401 mL; P CONCLUSIONS: A strategy of conservative fluid administration and active deresuscitation is feasible, reduces fluid balance compared with usual care, and may cause benefit or harm. In view of wide variations in contemporary clinical practice, large, adequately powered trials investigating the clinical effectiveness of conservative fluid strategies in critically ill patients are warranted.

Lowland karst aquifers can generate unique wetland ecosystems which are caused by groundwater fluctuations that result in extensive groundwater–surface water interactions (i.e. flooding). However, the complex hydrogeological attributes of these systems, linked to extremely fast aquifer recharge processes and flow through well-connected conduit networks, often present difficulty in predicting how they will respond to changing climatological conditions. This study investigates the predicted impacts of climate change on a lowland karst catchment by using a semi-distributed pipe network model of the karst aquifer populated with output from the high spatial resolution (4 km) Consortium for Small-scale Modelling Climate Lokalmodell (COSMO-CLM) regional climate model simulations for Ireland. An ensemble of projections for the future Irish climate were generated by downscaling from five different global climate models (GCMs), each based on four Representative Concentration Pathways (RCPs; RCP2.6, RCP4.5, RCP6.0 and RCP8.5) to account for the uncertainty in the estimation of future global emissions of greenhouse gases. The one-dimensional hydraulic/hydrologic karst model incorporates urban drainage software to simulate open channel and pressurised flow within the conduits, with flooding on the land surface represented by storage nodes with the same stage volume properties of the physical turlough basins. The lowland karst limestone catchment is located on the west coast of Ireland and is characterised by a well-developed conduit-dominated karst aquifer which discharges to the sea via intertidal and submarine springs. Annual above ground flooding associated with this complex karst system has led to the development of unique wetland ecosystems in the form of ephemeral lakes known as turloughs; however, extreme flooding of these features causes widespread damage and disruption in the catchment. This analysis has shown that mean, 95th and 99th percentile flood levels are expected to increase by significant proportions for all future emission scenarios. The frequency of events currently considered to be extreme is predicted to increase, indicating that more significant groundwater flooding events seem likely to become far more common. The depth and duration of flooding is of extreme importance, both from an ecological perspective in terms of wetland species distribution and for extreme flooding in terms of the disruption to homes, transport links and agricultural land inundated by flood waters. The seasonality of annual flooding is also predicted to shift later in the flooding season, which could have consequences in terms of ecology and land use in the catchment. The investigation of increasing mean sea levels, however, showed that anticipated rises would have very little impact on groundwater flooding due to the marginal impact on ebb tide outflow volumes. Overall, this study highlights the relative vulnerability of lowland karst systems to future changing climate conditions, mainly due to the extremely fast recharge which can occur in such systems. The study presents a novel and highly effective methodology for studying the impact of climate change in lowland karst systems by coupling karst hydrogeological models with the output from high-resolution climate simulations.

The paper considers doctoral supervision between a candidate grounded in practice and a practice sensitive supervisor. The paper presents five autoethnographies to embellish a. conceptual argument. The contribution made lies at the nexus between three literatures; doctoral supervision, engaged scholarship and performativity. The paper contributes to the performativity literature by adding a principle of performative co-creation to frameworks which consider the emergence of performativity after theory formation. A core contention is that by considering engaged scholarship, the potential for performative outcomes in doctoral programs can be enhanced. The paper enters the black box of the emergence of performative theory and asks whether the formation of a theory can affect its eventual performative effects. Taking the doctoral supervision process as a performance, a series of tensions in the supervision process are identified and four acts are proposed to unlock the potential of performative outcomes. It is suggested that doctoral candidates engaged in practice are more likely to identify practice based on anomalies and experiment with the subsequent theoryin a professional context due to their ongoing embeddedness in communities of practice. The authors suggest that this has particular relevance to industrial marketing scholars due to high levels of embeddedness in practice.

The “value” of university courses in the UK is increasingly\ud equated with their potential for employability enhancement.\ud Part 1 of this research utilized theory from the marketing\ud discipline to highlight the many other aspects of value that a\ud law degree in particular offers beyond lawyer qualification,\ud and Part 2 presented a theory of value for the UK legal\ud education market specifically, based upon the value\ud propositions articulated by UK providers in their online\ud prospectus pages. This third paper in the series explores\ud student perspectives on this theme, identified through six life\ud history interviews conducted with past and present LLB\ud students from a post-92 university in the UK. The findings\ud indicate that - whilst employability (and lawyer qualification\ud specifically) is unquestionably important - there is still much\ud untapped value potential that can be harnessed in order to\ud differentiate law programmes in an increasingly competitive\ud market. As the relevant regulatory body prepares to make\ud radical changes to the way that solicitors qualify in England\ud and Wales from 2021, the time for providers to develop\ud differentiated and distinctive value, is now.

Several different approaches have been developed to model the specific characteristics of karst aquifers, taking account of their inherent complex spatial and temporal heterogeneities. This paper sets out the development of a semidistributed modelling approach for applications in an Irish karst context using urban drainage software. The models have proven to be very useful for different studies, with examples given for the ecohydrology of ephemeral karst lakes, extreme groundwater-flood alleviation, karst network investigation, submarine groundwater discharge, and quantification of different recharge and flow components. The limitations of the approach are also highlighted, in particular not being able to simulate diffuse infiltration and flow paths explicitly across the groundwater catchment. Hence, a more distributed, finite-difference modelling approach using MODFLOW Unstructured Grid (USG) with the newly developed Connected Linear Network (CLN) process is then compared against the semidistributed approach on the same karst catchment. Whilst it has proven difficult to achieve the same levels of model performance in simulating the spring flows in the distributed model compared to the semidistributed model, the ability to interrogate the flow paths at any point on the three-dimensional aquifer is demonstrated, which can give new insights into flows (and potential contaminant transport) through such complex systems. The influence of the proximity of highly transmissive conduits on the flow dynamics through the much-lower transmissive matrix cells in which the network is embedded has been particularly investigated.Plusieurs approches différentes ont été développées pour modéliser les caractéristiques spécifiques des aquifères karstiques, prenant en compte leurs hétérogénéités spatiales et temporelles associées à leur complexité intrinsèque. Cet article présente le développement d’une approche de modélisation semi-distribuée appliquée à un contexte karstique irlandais en utilisant un logiciel de drainage urbain. Ces modèles se sont avérés très utiles pour différentes études, avec des exemples appliqués à l’écohydrologie de lacs karstiques éphémères, l’atténuation de crues extrêmes liées aux eaux souterraines, à l’étude du réseau karstique, à la décharge des sources sous-marines et à la quantification des différentes composantes aussi bien de la recharge que du débit. Les limites de cette approche sont aussi mises en évidence, avec en particulier l’incapacité de simuler l’infiltration diffuse et les voies d’écoulement de manière explicite au sein du bassin d’alimentation d’eaux souterraines. Par conséquent, une approche de modélisation plus distribuée aux différences finies utilisant le logiciel MODFLOW avec une grille non structurée (USG) intégrant le processus récemment développé de réseau linéaire connecté (CLN) est ensuite comparée à l’approche semi-distribuée appliquée au même bassin karstique. Alors qu’il s’est avéré difficile d’atteindre les mêmes niveaux de performance du modèle concernant la simulation du débit à la source à l’aide du modèle distribué en comparaison au modèle semi-distribué, la possibilité d’examiner les voies d’écoulement en tout point de l’aquifère en 3D est démontrée, ce qui peut donner de nouvelles connaissances sur les écoulements (et le transport potentiel de contaminants) au sein de tels systèmes complexes. L’influence de la proximité de conduits hautement transmissifs sur les écoulements dynamiques au travers des cellules de transmissivité plus faible de la matrice au sein de laquelle le réseau est intégré, a été particulièrement étudiée.Se han elaborado varios enfoques diferentes para modelar las características específicas de los acuíferos kársticos, teniendo en cuenta sus complejas y propias heterogeneidades espaciales y temporales. En el presente documento se expone la elaboración de un enfoque de modelización semidistribuido para aplicaciones en un contexto kárstico de Irlanda utilizando programas informáticos de drenaje urbano. Los modelos han demostrado ser muy útiles para diferentes estudios, y se dan ejemplos para la ecohidrología de los lagos kársticos efímeros, la mitigación de las inundaciones extremas de aguas subterráneas, la investigación de redes kársticas, la descarga submarina de aguas subterráneas y la cuantificación de diferentes componentes de la recarga y el flujo. También se ponen de relieve las limitaciones del enfoque, en particular el hecho de no poder simular explícitamente la infiltración difusa y las trayectorias de flujo a través de la cuenca de captación de aguas subterráneas. Por lo tanto, un enfoque de modelización de diferencias finitas distribuidas utilizando la red no estructurada (USG) de MODFLOW con el proceso de la Red Lineal Conectada (CLN) recientemente desarrollado se compara entonces con el enfoque semidistribuido en la misma cuenca kárstica. Si bien se ha demostrado que es difícil lograr los mismos niveles de rendimiento del modelo en la simulación de los flujos de manantiales en el modelo distribuido en comparación con el modelo semidistribuido, se demuestra la capacidad de interrogar las trayectorias de los flujos en cualquier punto del acuífero tridimensional, lo que puede dar nuevos conocimientos sobre los flujos (y el transporte de contaminantes potenciales) a través de sistemas tan complejos. Se ha investigado en particular la influencia de la proximidad de conductos altamente transmisivos en la dinámica de los flujos a través de las células de la matriz transmisiva, mucho más bajas, en las que está incorporada la red.鉴于岩溶含水层内在的复杂时空异质性, 已经开发出几种不同的方法来模拟岩溶含水层的特定性质。本文提出了基于城市排水软件的半分布式模型的开发方法, 并在爱尔兰喀斯特环境中应用。该模型已被证明对不同的研究非常有用, 并举例说明了季节性的喀斯特湖的生态水文学, 极端地下水洪涝减缓, 岩溶网络调查, 海底地下水排泄以及不同补给量和流动量的量化。还强调了该方法的局限性, 特别是不能明确模拟整个地下水盆地的扩散入渗和流动路径。因此, 然后将MODFLOW非结构化网格(USG)和新开发的连接线性网络(CLN)过程耦合的分布式有限差分方法与同一个喀斯特流域的半分布式方法进行了比较。尽管已证明分 布式模型模拟的泉流量难以达到与半分布式模型相比相同水平的模型性能, 但仍展示了在三维含水层上任意点处查询流路的能力, 这可以给出分析该类复杂系统流量(以及潜在的污染物传输)的新方法。特别研究了高传输管流的邻近度对通过嵌入网络的传导率低得多单元的流动动力学的影响。.Diversas abordagens diferentes foram desenvolvidas para modelar as características específicas dos aquíferos cársticos, levando em consideração suas complexas heterogeneidades espaciais e temporais inerentes. Este artigo apresenta o desenvolvimento de uma abordagem de modelagem semidistribuída para aplicações em um contexto cárstico irlandês usando software de drenagem urbana. Os modelos provaram ser muito úteis para diferentes estudos, com exemplos dados para a ecohidrologia de lagos cársticos efêmeros, alívio de inundações subterrâneas extremas, investigação de rede cárstica, descarga de água subterrânea submarina e quantificação de diferentes componentes de recarga e fluxo. As limitações da abordagem também são destacadas, em particular não ser capaz de simular infiltração difusa e caminhos de fluxo explicitamente através da captação de água subterrânea. Portanto, uma abordagem de modelagem de diferenças finitas, mais distribuída, usando MODFLOW Unstructured Grid (USG) com o processo de Rede Linear Conectada (RLC) recém-desenvolvido é então comparada com a abordagem semidistribuída na mesma bacia cárstica. Embora tenha se mostrado difícil alcançar os mesmos níveis de desempenho do modelo na simulação dos fluxos de nascente no modelo distribuído em comparação com o modelo semidistribuído, a capacidade de interrogar os caminhos de fluxo em qualquer ponto do aquífero tridimensional é demonstrada, o que pode dar novas percepções sobre os fluxos (e o transporte potencial de contaminantes) por meio de tais sistemas complexos. A influência da proximidade de condutos altamente transmissivos na dinâmica do fluxo através das células da matriz transmissiva muito inferior nas quais a rede está inserida foi investigada particularmente.

Karstified carbonate aquifers may receive significant recharge contributions from losing streams, hence, the knowledge about surface water‐groundwater (SW‐GW) interactions is crucial with regard to water management (e.g., source protection zone delineation). The dynamics of SW‐GW interactions may depend on factors such as the relative water levels between streams and aquifers, resulting in a temporal variation of exchange, which imposes complexity to the understanding of such dynamics. This study highlights the use of high‐resolution time series and multiresolution analysis to help to gain insights into such complex dynamics. Wavelet coherence is applied on hourly time series of rainfall, stream, and spring discharges of a low‐lying karstified spring catchment to yield a correlation in the time‐frequency domain. This analysis provides comprehensive information on the overall impact of the river on the spring, which is supported by the cross‐correlation function, as well as by more detailed information, including time‐variant influences such as a threshold level of influence. Field observations of turbidity sampling at the spring appear to support this interpretation. This innovative approach relies on basic hydrological parameters, water level, or discharge, and is therefore applicable to many other systems with such existing time series., Article impact statement: Wavelet coherence yields high‐resolution information on surface water‐groundwater interaction.

In September 2016, 36 spectrometers from 24 institutes measured a number of key atmospheric pollutants for a period of 17 d during the Second Cabauw Intercomparison campaign for Nitrogen Dioxide measuring Instruments (CINDI-2) that took place at Cabauw, the Netherlands (51.97∘ N, 4.93∘ E). We report on the outcome of the formal semi-blind intercomparison exercise, which was held under the umbrella of the Network for the Detection of Atmospheric Composition Change (NDACC) and the European Space Agency (ESA). The three major goals of CINDI-2 were (1) to characterise and better understand the differences between a large number of multi-axis differential optical absorption spectroscopy (MAX-DOAS) and zenith-sky DOAS instruments and analysis methods, (2) to define a robust methodology for performance assessment of all participating instruments, and (3) to contribute to a harmonisation of the measurement settings and retrieval methods. This, in turn, creates the capability to produce consistent high-quality ground-based data sets, which are an essential requirement to generate reliable long-term measurement time series suitable for trend analysis and satellite data validation. The data products investigated during the semi-blind intercomparison are slant columns of nitrogen dioxide (NO2), the oxygen collision complex (O4) and ozone (O3) measured in the UV and visible wavelength region, formaldehyde (HCHO) in the UV spectral region, and NO2 in an additional (smaller) wavelength range in the visible region. The campaign design and implementation processes are discussed in detail including the measurement protocol, calibration procedures and slant column retrieval settings. Strong emphasis was put on the careful alignment and synchronisation of the measurement systems, resulting in a unique set of measurements made under highly comparable air mass conditions. The CINDI-2 data sets were investigated using a regression analysis of the slant columns measured by each instrument and for each of the target data products. The slope and intercept of the regression analysis respectively quantify the mean systematic bias and offset of the individual data sets against the selected reference (which is obtained from the median of either all data sets or a subset), and the rms error provides an estimate of the measurement noise or dispersion. These three criteria are examined and for each of the parameters and each of the data products, performance thresholds are set and applied to all the measurements. The approach presented here has been developed based on heritage from previous intercomparison exercises. It introduces a quantitative assessment of the consistency between all the participating instruments for the MAX-DOAS and zenith-sky DOAS techniques.

This paper reports on ground-based validation of the atmospheric OClO data record produced in the framework of EUMETSAT’s Satellite Application Facility on Atmospheric Chemistry Monitoring (AC SAF) using the GOME2-A and -B instruments over the 2007–2016 and 2013–2016 periods, respectively. OClO slant column densities are compared to correlative measurements collected from 9 NDACC Zenith-Scattered-Light DOAS (ZSL-DOAS) instruments distributed in both the Arctic and Antarctic. Sensitivity tests are performed on the ground-based data to estimate the impact of the different OClO DOAS analysis settings. On this basis, we infer systematic uncertainties of about 25 % between the different ground-based data analysis, reaching total uncertainties ranging from about 26 % to 33 % for the different stations. Time-series at the different sites show good agreement between satellite and ground-based data, both for the inter-annual variability and the overall OClO seasonal behavior. GOME-2A results are found to be nosier than those of GOME-2B, especially after 2011, probably due to instrumental degradation effects. Daily linear regression analysis for OClO activated periods yield correlation coefficients of 0.8 for GOME-2A and 0.87 for GOME-2B, with slopes of 0.64 and 0.72, respectively. Biases are within 8 x 1013 molec/cm2 with some differences between GOME-2A and GOME-2B, depending on the station. Overall, considering all the stations, a median bias of about −2.2 x 1013 molec/cm2 is found for both GOME-2 instruments.

Deformation measurements from satellite-borne synthetic aperture radar interferometry (InSAR) are usually measured relative to an arbitrary reference point (RP) of assumed stability over time. For InSAR rates to be reliably interpreted as uplift or subsidence, they must be connected to a defined Earth-centred terrestrial reference frame (TRF), usually made through GNSS continuously operating reference stations (CORS). We adapt and compare three methods of TRF connection proposed by different studies which we term the single CORS RP (SCRP), plane-fit multiple CORS (PFMC), and the multiple CORS RP (MCRP). We generalise equations for these methods, and importantly, develop equations to propagate InSAR and GNSS uncertainties through the transformation process. This is significant, because it is important to not only estimate the InSAR uncertainties, but also to account for the uncertainties that are introduced when connecting to the CORS so as to better inform our interpretation of the deformation field and the limitation of the measurements. We then test these methods using Sentinel-1 data in the Latrobe Valley, Australia. These results indicate that differences among the three TRF connection methods may be greater than their estimated uncertainties. MCRP appears the most reliable method, although it may be limited in large study areas with sparse CORS due to long wavelength InSAR errors and that gaps and/or steps may appear at the spatial limit from the CORS. SCRP relies on the quality of the single CORS connection, but can be validated by unconnected CORS in the study area. The PFMC method is suited to larger areas undergoing slow, constant deformation covering large spatial extents where there are evenly distributed CORS across the study area. Selecting an optimal method of TRF connection is dependent on local site conditions, CORS network geometry and the characteristics of the deformation field. Hence, the choice of TRF connection method should be carefully considered, because different methods may result in significantly different transformed deformation rates. We confirm slow subsidence across the Latrobe Valley relative to the vertical component of the ITRF2014, with localised high subsidence rates near open cut mining activities. Subsidence of ~ -6 mm/year is observed in the adjacent coastal region which may exacerbate relative sea level rise along the coastline, increasing future risks of coastal inundation.

Field data of topography, water levels, and peat hydraulic conductivity collected over a 28‐year period have revealed the impacts of marginal drainage on uncut raised bog ecohydrology and its peat properties. Drainage of the regional groundwater body has induced changes in the hydraulic properties of deep peat, with peat compression decreasing hydraulic conductivity and storativity while simultaneously introducing localized secondary porosity and effective storage. Where peat has increased in hydraulic conductivity, there is a corresponding decline in vertical hydraulic gradients and significant localized increases in recharge to the underlying substrate. Repeated topographic surveys show intense localized areas of peat consolidation (>5%) where it is underlain by highly permeable (>10 m/day) glacial till deposits. More widely, continued subsidence (4–6 mm/year) of the bog surface has been measured over 900 m from the bog margin, resulting in the progressive loss of approximately 40% of actively growing raised bog since 1991. This loss has thus been shown to be attributable to changes in the underlying groundwater head due to deep‐cut drainage, rather than near‐surface peatland drainage. However, although reinstating regional hydrostatic pressures in order to restore this ombrotrophic peatland may control the rapid drainage through preferential flow pathways, this may not eliminate the ecological impacts resulting from changed surface morphology arising from subsidence. Hence, this longitudinal study provides new insights into the role that aquifer systems and groundwater bodies play in maintaining hydrogeological processes in ombrotrophic peatland systems, while highlighting the difficulty in ecological restoration where regional groundwater dependencies are significant.

Water samples from 29 small waterways located in 10 different countries in the European Union were screened for the presence of a large number of pesticides (275) and veterinary drugs (101). Solid phase extraction was combined with liquid chromatography coupled to Orbitrap high resolution tandem mass spectrometry to quantify the levels of pesticides in the samples and to detect the presence of veterinary drugs. All the sampled European rivers and canals included in this investigation were contaminated with mixtures of pesticides and, in most of the cases, with several veterinary drugs at the time of sampling, without a clear national or regional pattern. In total, 103 different pesticides, 24 of them banned in the EU, and 21 veterinary drugs were found in the analysed samples. Herbicides were the main contributor to the total amount of pesticides found in the samples, with terbuthylazine present in all the samples. The maximum individual concentration recorded was of dimethenamid at 59.85 μg L−1. The maximum combined pesticide concentration was found in a sample from the Wulfdambeek canal, Belgium, with 94.02 μg L−1 comprised of a mixture of 70 different pesticides. European regulatory standards defining acceptable concentration levels were exceeded for at least one pesticide in 13 of the 29 samples analysed, with the neonicotinoid insecticides imidacloprid and clothianidin most frequently present above such limits. The majority of the veterinary drugs detected were antimicrobials, most being antibiotics. The β-lactam antibiotic dicloxacillin was present in two thirds of the analysed samples. The application of this consistent research approach across Europe allowed the identification of a significant threat to the aquatic environment associated with pesticide contamination, and in some cases veterinary drugs, at the time of sampling in the water bodies tested.

Using earthen liners at the base of an integrated constructed wetland (ICW) maintains a hydraulic continuum between the ICW and the underlying groundwater body. This may enable migration of reactive carbon (dissolved organic and inorganic carbon (DOC, DIC)) and reactive nitrogen (Nr) across this liner to groundwater along this continuum to groundwater. Therefore, in terms of a holistic assessment of ICWs, quantification of these losses is important and indeed from an environmental perspective comparing such losses to other ICW dis-connected areas within the same groundwater body is critical. The main objective of the present study on an ICW site in SE Ireland was to compare reactive forms of C and N in groundwater (three piezometer nests) representing the continuum end point of ICW Cell 2 and 3 with that of groundwater dis-connected to the ICW system. For this purpose two control planes consisting of shallow and deep groundwater piezometer nests were installed and monitored at 1 and 4 m depths, respectively underneath the earthen liners at 0.2 m adjacent to the ICW cells. Fieldwork was conducted between Nov 2013 and Nov 2014 and results showed that groundwater beneath the ICW liner had a highly reduced signal with C and N concentrations being significantly higher to those of the disconnected up-gradient groundwater. The DOC, DIC and dissolved CO2 and CH4 concentrations in groundwater beneath the ICW cells were significantly higher than the up-gradient groundwater. All the reactive forms of C were higher in Cell 2 than in Cell 3. With respect to depth, all forms of reactive C were higher in deeper groundwater than the shallow equivalents except for DOC. Equally, Nr concentrations (NH4+, DON, NO3−-N and N2O) were higher in groundwater beneath the ICW cells than the up-gradient groundwater. They were higher in Cell 2 than in Cell 3 and higher in shallow rather than deep groundwater. The fate of the reactive C and N is unknown. Typically DOC delivery from groundwater to surface water drives many biogeochemical processes as an electron donor to microbes or can be converted to CO2 and CH4 emissions and the dissolved CO2 and CH4 can be indirectly exchanged to the atmosphere. The results suggest that nutrient delivery from the ICW cells to the underlying groundwater needs to be evaluated and the design of earthen-lined ICWs should consider this nutrient loss continuum across the liner.

There is no pharmacologic treatment for ARDS. Platelets play an important role in the pathophysiology of ARDS. Preclinical, observational, and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option.Is enteral aspirin (75 mg, once daily) safe and effective in improving surrogate outcomes in adult patients with ARDS?This randomized, double-blind (patient and investigator), allocation-concealed, placebo-controlled phase 2 trial was conducted in five UK ICUs. Patients fulfilling the Berlin definition of ARDS were randomly assigned at a 1:1 ratio to receive enteral aspirin (75 mg) or placebo, for a maximum of 14 days, using a computer-generated randomization schedule, with variable block size, stratified by vasopressor requirement. The primary end point was oxygenation index (OI) on day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat.The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. Twenty-four patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI [aspirin group: unadjusted mean, 54.4 (SD 26.8); placebo group: 42.4 (SD 25); mean difference, 12.0; 95% CI, -6.1 to 30.1; P = .19]. Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each; OR, 1.04; 95% CI, 0.56-1.94; P = .56).Aspirin was well tolerated but did not improve OI or other physiological outcomes; a larger trial is not feasible in its current design.ClinicalTrials.gov; No.: NCT02326350; URL: www.gov.

Despite ever-strengthening political rhetoric to the contrary, there can be little doubt that the holistic value of an undergraduate degree is far greater than merely its potential for employability enhancement. However, what is less clear is the extent to which fee-paying students perceive broader aspects of value, and how such value perceptions are formed. This paper outlines findings from an exploratory case study comprising six life history interviews in which past and present law students from a post-92 university in the UK were asked to explore how they perceive the value of their degree, specifically focusing on how and when such value perceptions might have been shaped by their life experiences. Through analysis of the resultant data, a wide range of possible ‘generative mechanisms’ were identified which may influence student value perceptions in this context. Generative mechanisms are not direct causes but things which have the potential to have a real-world impact given the right conditions. By understanding such mechanisms, legal education providers – and to a lesser extent also providers from other disciplines – can more effectively design and market their programmes to ensure that they deliver maximum value that is perceived within their markets.

Recent high-profile analyses of trajectories and prognoses of ecosystem decline around the world have called for a renewed focus on embedding the values of the natural world across all areas of public policy. This paper reports the results of a UK-based deliberative process involving experts from a wide range of policy domains and across societal sectors: government departments, associated agencies, national and international NGOs, professional institutions, academia and independent experts. A symposium, based on a collaborative learning approach, explored instances in which ecosystem values have successfully been embedded into public policy, identified challenges to their more widespread embedding despite commitments to do so over generational timescales, and took a backcasting approach to develop actionable outcomes required to deliver transformation change across state and civil society. Emergent themes were expressed in social, technological, environmental, economic and political terms. Recommendations for interventions in complex social-ecological systems are cross-sectoral in scope and will necessarily entail multiple agents of change, well beyond governmental leadership, within any given sphere of societal activity and interest. We identify strategic challenges for, and between, a spectrum of societal policy areas, many currently overlooking ecosystem dependencies, impacts and potential benefits. Reflections on the collaborative learning approach are also provided.

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.

Changes in streamflow within catchments can have a significant impact on agricultural production, as soil moisture loss, as well as frequent drying and wetting, may have an effect on the nutrient availability of many soils. In order to predict future changes and explore the impact of different scenarios, machine learning techniques have been used recently in the hydrological sector for simulation streamflow. This paper compares the use of four different models, namely artificial neural networks (ANNs), support vector machine regression (SVR), wavelet-ANN, and wavelet-SVR as surrogate models for a geophysical hydrological model to simulate the long-term daily water level and water flow in the River Shannon hydrological system in Ireland. The performance of the models has been tested for multi-lag values and for forecasting both short- and long-term time scales. For simulating the water flow of the catchment hydrological system, the SVR-based surrogate model performs best overall. Regarding modeling the water level on the catchment scale, the hybrid model wavelet-ANN performs the best among all the constructed models. It is shown that the data-driven methods are useful for exploring hydrological changes in a large multi-station catchment, with low computational cost.

Karstified carbonate aquifers are highly heterogeneous systems characterized by multiple recharge, flow, and discharge components. The quantification of the relative contribution of these components, as well as their numerical representation, remains a challenge. This paper identifies three recharge components in the time and frequency domain. While the analysis in the time domain follows traditional approaches, the analysis of the power spectrum allows frequencies associated with specific spectral coefficients and noise types to be distinguished more objectively. The analysis follows the presented hypothesis that the different frequency‐noise components are the result of aquifer heterogeneity transforming the random rainfall input into a sequence of non‐Gaussian signals. The distinct signals are then numerically represented in the context of a semidistributed pipe network model in order to simulate recharge, flow, and discharge of an Irish karst catchment more realistically. By linking the power spectra of the modeled recharge components with the spectra of the spring discharge, the information usually gained by classical performance indicators is significantly widened. The modeled spring discharge is well matched in the time and frequency domain, yet the different recharge dynamics explain the signal of the aquifer outlet in different noise domains across the spectrum. This study demonstrates the conjunctive use of frequency analysis in conceptualization of a hydrological system together with modeling and evaluation., Key Points Hydrograph analysis was coupled with frequency and noise analysis to identify recharge dynamics in a karst spring discharge time seriesRecharge, flow, and discharge were modeled in a semidistributed pipe network model considering aquifer heterogeneities and noise domainsA new model evaluation approach using noise analysis provided information on the individual contribution of the internal flows

Highlights • There is an increasing trend in incidence of and interest in zoonotic diseases. • Pervasive ecosystem degradation reduces the ecosystem service of disease regulation. • Decreasing barriers between humans and wildlife exacerbate zoonotic disease risks. • Ecosystem degradation degrades natural resources vital for managing transmission. • Policy responses addressing zoonotic threats should include ecosystem regeneration., There is rising international concern about the zoonotic origins of many global pandemics. Increasing human-animal interactions are perceived as driving factors in pathogen transfer, emphasising the close relationships between human, animal and environmental health. Contemporary livelihood and market patterns tend to degrade ecosystems and their services, driving a cycle of degradation in increasingly tightly linked socio-ecological systems. This contributes to reductions in the natural regulating capacities of ecosystem services to limit disease transfer from animals to humans. It also undermines natural resource availability, compromising measures such as washing and sanitation that may be key to managing subsequent human-to-human disease transmission. Human activities driving this degrading cycle tend to convert beneficial ecosystem services into disservices, exacerbating risks related to zoonotic diseases. Conversely, measures to protect or restore ecosystems constitute investment in foundational capital, enhancing their capacities to provide for greater human security and opportunity. We use the DPSIR (Drivers-Pressures-State change-Impact-Response) framework to explore three aspects of zoonotic diseases: (1) the significance of disease regulation ecosystem services and their degradation in the emergence of Covid-19 and other zoonotic diseases; and of the protection of natural resources as mitigating contributions to both (2) regulating human-to-human disease transfer; and (3) treatment of disease outbreaks. From this analysis, we identify a set of appropriate response options, recognising the foundational roles of ecosystems and the services they provide in risk management. Zoonotic disease risks are ultimately interlinked with biodiversity crises and water insecurity. The need to respond to the Covid-19 pandemic ongoing at the time of writing creates an opportunity for systemic policy change, placing scientific knowledge of the value and services of ecosystems at the heart of societal concerns as a key foundation for a more secure future. Rapid political responses and unprecedented economic stimuli reacting to the pandemic demonstrate that systemic change is achievable at scale and pace, and is also therefore transferrable to other existential, global-scale threats including climate change and the ‘biodiversity crisis’. This also highlights the need for concerted global action, and is also consistent with the duties, and ultimately the self-interests, of developed, donor nations.

Background: COVID-19 can result in a severe viral pneumonia, with high reported mortality rates in patients requiring mechanical ventilation. There is controversy as to whether established therapeutic approaches to acute respiratory distress syndrome are optimal in this condition, and numerous novel therapies have been used, often outside the context of randomised trials. In addition, longer term quality of life outcomes associated with COVID-19 are as yet unknown. The aim of this case series is to describe demographic, physiological and outcome data of patients with COVID-19 admitted to our intensive care units who were treated according to evidence-based guidelines for acute respiratory distress syndrome.Methods: We retrospectively reviewed the records of all patients admitted to intensive care units in our institution with COVID-19 between March and June, 2020. Physiological and laboratory data were recorded at baseline and daily until intensive care discharge or death. Quality of life was assessed at a virtual post-intensive care follow-up clinic around 10 weeks after ICU discharge.Results: 45 patients with COVID-19 were included, 37 (82.2%) of whom were male, with a mean age of 55 years. 42 (93.3%) of this cohort met criteria for acute respiratory distress syndrome at time of admission. Clinical management was consistent with evidence based institutional guidelines introduced for acute respiratory distress syndrome. Median length of intensive care stay was 14 days. The intensive care mortality rate was 8.9%. Functional and psychological morbidity post intensive care was significant: 45.2% of respondents had at least moderate impairment of mobility and 35.5% described at least moderate symptoms of anxiety or depression at the time of follow up.Conclusions : This case series demonstrates low mortality in a cohort of patients treated according to an established evidence-based approach for acute respiratory distress syndrome. However, COVID-19 survivors have a marked functional and psychological morbidity impacting quality of life following ICU admission. The therapeutic goal in the future will be to achieve similar survival outcomes while minimizing the significant morbidity associated with COVID-19 related critical care admission.