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Background: The dense stroma of pancreatic ductal adenocarcinoma (PDAC) is thought to impede tumour drug delivery. LSTA1, a novel cyclic tumour-penetrating peptide internalising arginylglycylaspartic acid, promotes tumour-specific drug delivery. In the phase Ib setting, LSTA1 3.2 mg/kg with gemcitabine and nab-paclitaxel showed a 92% disease control rate at 16 weeks and was well tolerated. Methods/design: This is a multicentre, phase II, double-blinded, placebo-controlled, randomised trial evaluating the activity and safety of LSTA1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Initially, participants were randomised 2 : 1 to receive gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 and LSTA1 3.2 mg/kg or placebo. The trial design was updated in a protocol amendment (v4.0) to include a second placebo-controlled cohort which receives a second dose of LSTA1/placebo 4 h following chemotherapy. Treatment is administered on days 1, 8, and 15 of each 28-day cycle until progression (progressive disease). The sample size is 155 based on a clinically worthwhile increase in 6-month progression-free survival (PFS) of 16%-63% with 80% power and 95% confidence to exclude the null hypothesis. The recruitment period is 22 months and follow-up 18 months. Study endpoints are: (1) PFS; (2) objective response rate (RECIST 1.1), safety (Common Terminology Criteria for Adverse Events v5.0), overall survival, participant-reported outcomes; (3) predictive/prognostic biomarkers via archival tissue, and to assess whether a second dose of LSTA1 warrants further evaluation.

Patient samples are often available in limited amounts, restricting the number of possible omics analyses. Here the authors present MONTE, a workflow that enables serial HLA-I and HLA-II immunopeptidome, ubiquitylome, proteome, phosphoproteome, and acetylome data collection from patient samples.

Groundwater-dominated catchments are often critical for nationally important water resources. Many conceptual rainfall–runoff models tend to degrade in their model performance in groundwater-dominated catchments, as they are rarely designed to simulate spatial groundwater behaviours or interactions with surface waters. Intercatchment groundwater flow is one such neglected variable. Efforts have been made to incorporate this process into existing models, but there is a need for improving our perceptual models of groundwater–surface water interactions prior to any model modifications. In this study, national meteorological, hydrological, hydrogeological, geological and artificial influence (characterising abstractions and return flows) datasets are used to infer a perceptual model of intercatchment groundwater flow (IGF) and how it varies across the river Thames, United Kingdom (UK). We characterise the water balance, presence of gaining/losing river reaches and intra-annual dynamics in 80 subcatchments of the river Thames, taking advantage of its wealth of data, densely gauged river network and geological variability. We show the prevalence of non-conservative river reaches across the study area, with heterogeneity both between, and within, geological units, giving rise to a complex distribution of recharge and discharge points along the river network. We infer where non-conservative reaches can be attributed to IGF and where other processes (e.g. surface water abstractions) are the likely cause. Through analysis of recorded reach length water balance data and hydrogeological perceptualisation, we conclude that outcrops of carbonate fractured aquifers (Chalk and Jurassic limestone) show evidence of IGF both from headwater to downstream reaches, and out-of-catchment via spring lines. We found variability across the study area, with more seasonality and variability in river catchments on Jurassic limestone outcrops compared to Chalk and Lower Greensand outcrops. Our results demonstrate the need for local investigation and hydrogeological perceptualisation within regional analysis, which we show to be achievable given relatively simple geological interpretation and data requirements. We support the inclusion of IGF fluxes within existing models to enable calibration improvements in groundwater-dominated catchments, but with geologically specific characteristics, and (when perceptually appropriate) connectivity between catchments.

Source functions for mechanically driven coarse-mode sea spray and dust aerosol particles span orders of magnitude owing to a combination of physical sensitivity in the system and large measurement uncertainty. Outside special idealized settings (such as wind tunnels), aerosol particle fluxes are largely inferred from a host of methods, including local eddy correlation, gradient methods, and dry deposition methods. In all of these methods, it is difficult to relate point measurements from towers, ships, or aircraft to a general representative flux of aerosol particles. This difficulty is from the particles' inhomogeneous distribution due to multiple spatiotemporal scales of an evolving marine environment. We hypothesize that the current representation of a point in situ measurement of sea spray or dust particles is a likely contributor to the unrealistic range of flux and concentration outcomes in the literature. This paper aims to help the interpretation of field data: we conduct a series of high-resolution, cloud-free large eddy simulations (LESs) with Lagrangian particles to better understand the temporal evolution and volumetric variability of coarse- to giant-mode marine aerosol particles and their relationship to turbulent transport. The study begins by describing the Lagrangian LES model framework and simulates flux measurements that were made using numerical analogs to field practices such as the eddy covariance method. Using these methods, turbulent flux sampling is quantified based on key features such as coherent structures within the marine atmospheric boundary layer (MABL) and aerosol particle size. We show that for an unstable atmospheric stability, the MABL exhibits large coherent eddy structures, and as a consequence, the flux measurement outcome becomes strongly tied to spatial length scales and relative sampling of crosswise and streamwise sampling. For example, through the use of ogive curves, a given sampling duration of a fixed numerical sampling instrument is found to capture 80 % of the aerosol flux given a sampling rate of zf/w∗∼ 0.2, whereas a spanwise moving instrument results in a 95 % capture. These coherent structures and other canonical features contribute to the lack of convergence to the true aerosol vertical flux at any height. As expected, sampling all of the flow features results in a statistically robust flux signal. Analysis of a neutral boundary layer configuration results in a lower predictive range due to weak or no vertical roll structures compared to the unstable boundary layer setting. Finally, we take the results of each approach and compare their surface flux variability: a baseline metric used in regional and global aerosol models.

Abstract Interventions that increase population physical activity are required to promote health and wellbeing. parkrun delivers community-based, 5 km events worldwide yet 43% who register never participate in a parkrun event. This research had two objectives; i) explore the demographics of people who register for parkrun in United Kingdom, Australia, Ireland, and don’t initiate or maintain participation ii) understand the barriers to participating in parkrun amongst these people. Mandatory data at parkrun registration provided demographic characteristics of parkrun registrants. A bespoke online survey distributed across the three countries captured the reasons for not participating or only participating once. Of 680,255 parkrun registrants between 2017 and 19, 293,542 (43%) did not participate in any parkrun events and 147,148 (22%) only participated in one parkrun event. Females, 16–34 years and physically inactive were more likely to not participate or not return to parkrun. Inconvenient start time was the most frequently reported barrier to participating, with females more likely than males to report the psychological barrier of feeling too unfit to participate. Co-creating strategies with and for people living with a chronic disease, women, young adults, and physically inactive people, could increase physical activity participation within parkrun.

The tradition of memorialising people and events through physical constructions such as statues and monuments like in many countries, has shaped the public space of a modern South Africa. Considering the colonial and apartheid history of South Africa, these physical markers, often uncontextualized, continue to maintain positions of prominence within the modern streetscape.Since the turn of the democratic era in South Africa, a pressing need has existed to assess the impact of the markers on the heritage landscape of the country. An endeavour made more difficult by a lack of a comprehensive inventory of these resources across the country.The National Audit of Monuments and Memorials (NAMM) was designed to address this gap through a full national survey of monuments and memorials, conducted under the auspices of a job creation stimulus package designed to create short term employment in the wake of the economic fallout from the Covid-19 pandemic. Undertaking this project under this funding mechanism required that all phases of the project be undertaken within a six-month period.The compressed timeframes associated with this project required an approach that could support a level of fluidity to address the challenges of undertaking a project of this nature, whilst ensuring that the data collected by field surveyors can be monitored and included in the inventory of the national estate in an effective manner.The aim of this paper is to discuss and showcase the tools and workflows used to roll out and manage the large-scale national audit of monuments and memorials across South Africa.

Introduction The coronavirus disease 19 (COVID-19) pandemic has prompted concerns regarding increased suicide rates and exacerbation of underlying mental illness symptoms. •There is evidence suggesting neurocognitive changes as well as immune response in COVID-19 infection may increase a patient’s propensity for suicidal ideation. • Patients who are diagnosed with COVID-19 may be affected by psychological factors of anxiety, stress related to having this novel virus as well as depression, post-traumatic stress disorder and sleep disorders throughout treatment and post-treatment of continued concerns. •The combination of psychiatric, neurological, and physical symptoms associated with COVID-19 may elevate suicide risk Objectives We present a case of a female with no prior psychiatric history who impulsively attempted suicide after a recent COVID-19 diagnosis and subsequent quarantine. Will explore possible link between increase of suicidal ideation and COVID-19 infection. Methods A case report. Results Link between increase of suicidal ideation and COVID-19 infection has not been clearly established but there have been reports, as in our case, of the possible vulnerability to mental illness and new onset suicidal ideation that COVID-19 survivors may experience. It may be useful to screen all patients for depressive symptoms after a COVID-19 infection. Early identification and treatment of depression in recovered COVID-19 patients will help to improve psychological impact on COVID-19 survivors and potentially reduce suicide rates. Conclusions As COVID-19 infection may trigger new onset mental illness, exacerbate symptoms of underlying mental illness, and may increase suicidal ideation, further research is needed to evaluate links between COVID-19 infection and depression with suicidal ideation Disclosure No significant relationships.

Abstract Background Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) has challenged public health agencies globally. In order to effectively target government responses, it is critical to identify the individuals most at risk of coronavirus disease-19 (COVID-19), developing severe clinical signs, and mortality. We undertook a systematic review of the literature to present the current status of scientific knowledge in these areas and describe the need for unified global approaches, moving forwards, as well as lessons learnt for future pandemics. Methods Medline, Embase and Global Health were searched to the end of April 2020, as well as the Web of Science. Search terms were specific to the SARS-CoV-2 virus and COVID-19. Comparative studies of risk factors from any setting, population group and in any language were included. Titles, abstracts and full texts were screened by two reviewers and extracted in duplicate into a standardised form. Data were extracted on risk factors for COVID-19 disease, severe disease, or death and were narratively and descriptively synthesised. Results One thousand two hundred and thirty-eight papers were identified post-deduplication. Thirty-three met our inclusion criteria, of which 26 were from China. Six assessed the risk of contracting the disease, 20 the risk of having severe disease and ten the risk of dying. Age, gender and co-morbidities were commonly assessed as risk factors. The weight of evidence showed increasing age to be associated with severe disease and mortality, and general comorbidities with mortality. Only seven studies presented multivariable analyses and power was generally limited. A wide range of definitions were used for disease severity. Conclusions The volume of literature generated in the short time since the appearance of SARS-CoV-2 has been considerable. Many studies have sought to document the risk factors for COVID-19 disease, disease severity and mortality; age was the only risk factor based on robust studies and with a consistent body of evidence. Mechanistic studies are required to understand why age is such an important risk factor. At the start of pandemics, large, standardised, studies that use multivariable analyses are urgently needed so that the populations most at risk can be rapidly protected. Registration This review was registered on PROSPERO as CRD42020177714 .

In Europe, it is estimated that around 65 % of drinking water is extracted from groundwater. Worryingly, groundwater drought events (defined as below normal groundwater levels) pose a threat to water security. Groundwater droughts are caused by seasonal to multi-seasonal or even multi-annual episodes of meteorological drought during which the drought propagates through the river catchment into the groundwater system by mechanisms of pooling, lagging, and lengthening of the drought signals. Recent European drought events in 2010–2012, 2015 and 2017–2018 exhibited spatial coherence across large areas, thus demonstrating the need for transboundary monitoring and analysis of groundwater level fluctuations. However, such monitoring and analysis of groundwater drought at a pan-European scale is currently lacking, and so represents a gap in drought research as well as in water management capability. To address this gap, the European Groundwater Drought Initiative (GDI), a pan-European collaboration, is undertaking a large-scale data synthesis of European groundwater level data. This is being facilitated by the establishment of a new network to co-ordinate groundwater drought research across Europe. This research will deliver the first assessment of spatio-temporal changes in groundwater drought status from ∼1960 to present, and a series of case studies on groundwater drought impacts in selected temperate and semi-arid environments across Europe. Here, we describe the methods used to undertake the continental-scale status assessment, which are more widely applicable to transboundary or large-scale groundwater level analyses also in regions beyond Europe, thereby enhancing groundwater management decisions and securing water supply.

Objectives: The aim of this study was to describe antibiotic prescribing patterns and antimicrobial resistance rates in hospitalised children with febrile and afebrile urinary tract infections (UTIs). Methods: Antibiotic prescriptions and antibiograms for neonates, infants and older children with UTI admitted to a general district hospital in Central Greece were evaluated. Data covering a 5-year period were collected retrospectively from the Paediatric Department’s Electronic Clinical Archive. Patients were included based on clinical and microbiological criteria. Antimicrobial susceptibility was determined by the Kirby–Bauer disk diffusion method. Results: A total of 230 patients were included in the study. Among 459 prescriptions identified, amikacin (31.2%) was the most common antibiotic prescribed in this population, followed by amoxicillin/clavulanic acid (17.4%) and ampicillin (13.5%). Children received prolonged intravenous (i.v.) treatments for febrile (mean ± S.D., 5.4 ± 1.45 days) and afebrile UTIs (mean ± S.D., 4.4 ± 1.64 days). A total of 236 pathogens were isolated. The main causative organism was Escherichia coli (79.2%) with high reported resistance rates to ampicillin (42.0%), trimethoprim/sulfamethoxazole (26.5%) and amoxicillin/clavulanic acid (12.2%); lower resistance rates were identified for third-generation cephalosporins (1.7%), nitrofurantoin (2.3%), ciprofloxacin (1.4%) and amikacin (0.9%). Klebsiella spp. isolates were highly resistant to cefaclor (27.3%). Conclusion: High prescribing rates for amikacin and penicillins (± β-lactamase inhibitors) and prolonged i.v. treatments were observed. Escherichia coli was highly resistant to ampicillin, whilst third-generation cephalosporins exhibited greater in vitro efficacy. Establishment of antimicrobial stewardship programmes and regular monitoring of antimicrobial resistance could help to minimise inappropriate prescribing for UTIs.

The management of heritage resources within the South African context is governed by the National Heritage Resources Act, act 25 of 1999 (NHRA). This legislation calls for an integrated system of heritage management that allows for the good governance of heritage across the three tiers of government. The South African Heritage Resources Agency (SAHRA), as the national body responsible for heritage management, is mandated to compile and maintain an inventory of the national estate. The South African Heritage Resources Information System (SAHRIS) was designed to facilitate this mandate as well as provide a management platform through which the three-tiers of governance can be integrated. This vision of integrated management is however predicated on the implementation of the three-tier system of heritage management, a system which to date has not been fully implemented, with financial and human resource constraints being present at all levels. In the absence of the full implementation of this system and the limited resources available to heritage authorities, we argue that a risk based approach to heritage management will allow under resourced heritage authorities in South Africa to prioritise management actions and ensure mitigations are in place for at risk heritage resources. The aim of this paper is to position the inventory of the national estate as the key driver in the production of risk analysis models for an informed approach to heritage management.

This paper will focus on the national inventory of South Africa and application in heritage management. The South African Heritage Resources Agency (SAHRA) is mandated to compile and maintain an inventory of the national estate, defined as heritage resources of cultural and other significance as per Sections 3 and 39 of the National Heritage Resources Act. No.25 of 1999. This inventory is presented in a form of a database facilitated through the South African Heritage Resources Information System (SAHRIS). SAHRA is also mandated to produce a summary and analysis of this inventory of the national estate at regular intervals as per Section 39(7) of the NHRA. This inventory and its subsequent publication facilitate accountability for the institution, access to the data by the public as well as public awareness. The national inventory is populated through numerous digitisation projects by various heritage institutions namely museums, galleries, Provincial Heritage Resources Authorities (PHRA’s) and the public at large.

Abstract Background Simvastatin therapy for patients with acute respiratory distress syndrome (ARDS) has been shown to be safe and associated with minimal adverse effects, but it does not improve clinical outcomes. The aim of this research was to report on mortality and cost-effectiveness of simvastatin in patients with ARDS at 12 months. Methods This was a cost-utility analysis alongside a multicentre, double-blind, randomised controlled trial carried out in the UK and Ireland. Five hundred and forty intubated and mechanically ventilated patients with ARDS were randomly assigned (1:1) to receive once-daily simvastatin (at a dose of 80 mg) or identical placebo tablets enterally for up to 28 days. Results Mortality was lower in the simvastatin group (31.8%, 95% confidence interval (CI) 26.1–37.5) compared to the placebo group (37.3%, 95% CI 31.6–43.0) at 12 months, although this was not significant. Simvastatin was associated with statistically significant quality-adjusted life year (QALY) gain (incremental QALYs 0.064, 95% CI 0.002–0.127) compared to placebo. Simvastatin was also less costly (incremental total costs –£3601, 95% CI –8061 to 859). At a willingness-to-pay threshold of £20,000 per QALY, the probability of simvastatin being cost-effective was 99%. Sensitivity analyses indicated that the results were robust to changes in methodological assumptions with the probability of cost-effectiveness never dropping below 90%. Conclusion Simvastatin was found to be cost-effective for the treatment of ARDS, being associated with both a significant QALY gain and a cost saving. There was no significant reduction in mortality at 12 months, Trial registration ISRCTN, 88244364. Registered 26 November 2010.

Land surface models (LSMs) are prospective starting points to develop a global hyper-resolution model of the terrestrial water, energy, and biogeochemical cycles. However, there are some fundamental limitations of LSMs related to how meaningfully hydrological fluxes and stores are represented. A diagnostic approach to model evaluation and improvement is taken here that exploits hydrological expert knowledge to detect LSM inadequacies through consideration of the major behavioural functions of a hydrological system: overall water balance, vertical water redistribution in the unsaturated zone, temporal water redistribution, and spatial water redistribution over the catchment's groundwater and surface-water systems. Three types of information are utilized to improve the model's hydrology: (a) observations, (b) information about expected response from regionalized data, and (c) information from an independent physics-based model. The study considers the JULES (Joint UK Land Environmental Simulator) LSM applied to a deep-groundwater chalk catchment in the UK. The diagnosed hydrological limitations and the proposed ways to address them are indicative of the challenges faced while transitioning to a global high resolution model of the water cycle.

This paper is composed of three elements: 3D modeling, web design, and heritage visualization. The aim is to use computer graphics design to inform and create an interest in historical visualization by rebuilding Fort Frontenac using 3D modeling and interactive design. The final model will be integr ated into an interactive website to learn more about the fort’s historic imp ortance. It is apparent that using computer graphics can save time and money when it comes to historical visualization. Visitors do not have to travel to the actual archaeological buildings. They can simply use the Web in their own home to learn about this information virtually. Meticulously following historical records to create a sophisticated restoration of archaeological buildings will draw viewers into visualizations, such as the historical world of Fort Frontenac. As a result, it allows the viewers to effectively understand the fort’s social sy stem, habits, and historical events.

The dataset Future Flows Hydrology was developed as part of the project "Future Flows and Groundwater Levels'' to provide a consistent set of transient daily river flow and monthly groundwater level projections across England, Wales and Scotland to enable the investigation of the role of climate variability on river flow and groundwater levels nationally and how this may change in the future. Future Flows Hydrology is derived from Future Flows Climate, a national ensemble projection derived from the Hadley Centre's ensemble projection HadRM3-PPE to provide a consistent set of climate change projections for the whole of Great Britain at both space and time resolutions appropriate for hydrological applications. Three hydrological models and one groundwater level model were used to derive Future Flows Hydrology, with 30 river sites simulated by two hydrological models to enable assessment of hydrological modelling uncertainty in studying the impact of climate change on the hydrology. Future Flows Hydrology contains an 11-member ensemble of transient projections from January 1951 to December 2098, each associated with a single realisation from a different variant of HadRM3 and a single hydrological model. Daily river flows are provided for 281 river catchments and monthly groundwater levels at 24 boreholes as .csv files containing all 11 ensemble members. When separate simulations are done with two hydrological models, two separate .csv files are provided. Because of potential biases in the climate–hydrology modelling chain, catchment fact sheets are associated with each ensemble. These contain information on the uncertainty associated with the hydrological modelling when driven using observed climate and Future Flows Climate for a period representative of the reference time slice 1961–1990 as described by key hydrological statistics. Graphs of projected changes for selected hydrological indicators are also provided for the 2050s time slice. Limitations associated with the dataset are provided, along with practical recommendation of use. Future Flows Hydrology is freely available for non-commercial use under certain licensing conditions. For each study site, catchment averages of daily precipitation and monthly potential evapotranspiration, used to drive the hydrological models, are made available, so that hydrological modelling uncertainty under climate change conditions can be explored further. doi:10.5285/f3723162-4fed-4d9d-92c6-dd17412fa37b

The piRNA pathway is a conserved germline-specific small RNA pathway that ensures genomic integrity and continued fertility. In C. elegans and other nematodes, Type-I piRNAs are expressed from >10,000 independently transcribed genes clustered within two discrete domains of 1.5 and 3.5 MB on Chromosome IV. Clustering of piRNA genes contributes to their germline-specific expression, but the underlying mechanisms are unclear. We analyze isolated germ nuclei to demonstrate that the piRNA genomic domains are located in a heterochromatin-like environment. USTC (Upstream Sequence Transcription Complex) promotes strong association of nucleosomes throughout piRNA clusters, yet organizes the local nucleosome environment to direct the exposure of individual piRNA genes. Localization of USTC to the piRNA domains depends upon the ATPase chromatin remodeler ISW-1, which maintains high nucleosome density across piRNA clusters and ongoing production of piRNA precursors. Overall, this work provides insight into how chromatin states coordinate transcriptional regulation over large genomic domains, with implications for global genome organization. Author summary: Here we address how gene expression is coordinated over long stretches of DNA that is embedded in a dense chromatin environment. We focus on a large DNA domain that contains thousands of tiny noncoding piRNA genes that are only expressed in germ cells. Our work demonstrates that a specific factor called USTC works with chromatin remodeling factors and with the core transcription complex to activate piRNA gene expression. The ISW-1 chromatin remodeler creates a dense environment that is favorable for USTC to be recruited to piRNA genes. USTC then clears the chromatin away from a space around each piRNA gene that allows for the factor TBP-1 to bind and presumably recruit the core transcriptional machinery to turn on the short piRNA. This work illuminates a mechanism by which both local and long-distance regulatory information can be integrated to coordinate gene expression. [ABSTRACT FROM AUTHOR]