Landscape distribution and abundance of animal-associated adult filth flies on commercial swine facilities in North Carolina, US.

Filth flies associated with animal production transmit pathogens to humans and animals, propagate antimicrobial resistance in microbial communities and provoke nuisance litigation. Although dispersal of flies from facilities is often responsible for these negative effects, filth fly research on swine facilities has been limited to within the barns. Filth fly adaptations in space and time, as well as influences of abiotic and biotic factors impact distribution and abundance of animal-associated filth flies on swine production facilities. In this study, fly surveillance was conducted around four swine facilities in Bladen County, North Carolina, U.S.A. from January 2019 to October 2019. Traps were replaced weekly and animal-associated filth flies were identified. Flies were grouped for comparison based on biology and differences in pest management strategies. There were distinct differences in abundance and spatial distribution of different filth fly groups on the swine facilities, which are likely linked to environmental factors like spatial relation to crop production and species phenology. The impact of the observed temporal and spatial distribution and abundance is discussed in the context of filth fly management.

Synthesis, analysis and biological evaluation of novel indolquinonecryptolepine analogues as potential anti-tumour agents.

A small library of cryptolepine analogues were synthesised incorporating halogens and/or nitrogen containing side chains to optimise their interaction with the sugar-phosphate backbone of DNA to give improved binding, interfering with topoisomerase II hence enhancing cytotoxicity. Cell viability, DNA binding and Topoisomerase II inhibition is discussed for these compounds. Fluorescence microscopy was used to investigate the uptake of the synthesised cryptolepines into the nucleus. We report the synthesis and anti-cancer biological evaluation of nine novel cryptolepine analogues, which have greater cytotoxicity than the parent compound and are important lead compounds in the development of novel potent and selective indoloquinone anti-neoplastic agents.

Temporal genetic stability of Stegomyia aegypti (= Aedes aegypti) populations.

The mosquito Stegomyia aegypti (= Aedes aegypti) (Diptera: Culicidae) is the primary vector of viruses that cause yellow fever, dengue and Chikungunya fever. In the absence of effective vaccines, the reduction of these diseases relies on vector control strategies. The success of these strategies is tightly linked to the population dynamics of target populations. In the present study, 14 collections from St. aegypti populations separated by periods of 1-13 years were analysed to determine their temporal genetic stability. Although temporal structure is discernible in most populations, the degree of temporal differentiation is dependent on the population and does not obscure the geographic structure of the various populations. The results suggest that performing detailed studies in the years prior to and after population reduction- or modification-based control interventions at each target field site may be useful in assessing the probability of success.

Acute 'limited' magnetic resonance imaging in childhood stroke--an illustrative case.

Paediatric stroke is a major cause of morbidity and death in children. There is often a delay in making the diagnosis because common differential diagnoses such as migraine and seizures need to be considered and quick access to imaging is difficult. Early recognition is increasingly important for early treatment and to improve outcomes. We present the case of a 4-year-old boy who presented to the Emergency Department with acute hemiparesis. To target the provisional diagnosis of an acute ischaemic stroke, we requested magnetic resonance imaging (MRI) limited to two sequences only: diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI). We were able to confirm the diagnosis of acute ischaemic stroke within 90 min of presentation to hospital.

Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.

BACKGROUND: Osteonecrosis of the jaw (ONJ) has been reported in patients receiving bisphosphonates for metastatic bone disease. ONJ incidence, risk factors, and outcomes were evaluated in a combined analysis of three phase III trials in patients with metastatic bone disease receiving antiresorptive therapies. PATIENTS AND METHODS: Patients with bone metastases secondary to solid tumors or myeloma were randomly assigned to receive either s.c. denosumab (120 mg) or i.v. zoledronic acid (4 mg) every 4 weeks. On-study oral examinations were conducted by investigators at baseline and every 6 months. Oral adverse events were adjudicated by an independent blinded committee of dental experts. RESULTS: Of 5723 patients enrolled, 89 (1.6%) patients were determined to have ONJ: 37 (1.3%) received zoledronic acid and 52 (1.8%) received denosumab (P = 0.13). Tooth extraction was reported for 61.8% of patients with ONJ. ONJ treatment was conservative in >95% of patients. As of October 2010, ONJ resolved in 36.0% of patients (29.7% for zoledronic acid and 40.4% for denosumab). CONCLUSIONS: In this combined analysis of three prospective trials, ONJ was infrequent, management was mostly conservative, and healing occurred in over one-third of the patients. Educating physicians about oral health before and during bone-targeted therapy may help reduce ONJ incidence and improve outcomes.

Validation of quantitative ELISAS for measuring anti-Yersinia pestis F1 and V antibody concentrations in nonhuman primate sera.

This study systematically validated two quantitative enzyme-linked immunosorbent assays (ELISAs) for determining Yersinia pestis anti-F1 or anti-V IgG concentration in cynomolgus macaque sera. The results demonstrated that these ELISAs are reliable, reproducible, and suitable for their intended use to measure both anti-F1 and anti-V IgG in monkey sera following vaccination with a heterologous recombinant fusion F1-V protein (rF1-V). Statistical analysis demonstrated assay precision, accuracy, specificity, linearity/dilutional linearity, and robustness for both assays. The quantitative ranges of standard curves were defined as 40-700 ng/mLfor both anti-F1 and anti-V IgG. Either serological assay could be used to determine potency of F1/V antigen-based vaccines in surrogate clinical studies or to define correlates of protective immunity against plague under the Food and Drug Administration's (FDA) two-animal rule.

Angiogenesis, Metabolism, Endothelial and Platelet Markers in Diabetes and Cardiovascular Disease.

Introduction: Diabetes is a leading risk factor for cardiovascular disease (CVD), the pathophysiology of both being linked to metabolic, endothelial, renal, angiogenic and platelet abnormalities. We hypothesised that abnormalities in these systems are more adverse in those whose CVD is compounded by diabetes, compared to those with diabetes or CVD alone. Materials and methods: Serum or plasma from 66 patients with diabetes alone, 76 with CVD alone, and 70 with both diabetes and CVD i.e. diabetic cardiovascular disease, was probed for markers of angiogenesis [angiopoietin 1 and 2, vascular endothelial growth factor (VEGF) and endoglin], metabolic [soluble receptor for advanced glycation products (sRAGE), leptin, lipocalin-2, interleukin-8, and cystatin-C], the endothelium (von Willebrand factor, endothelial microparticles and soluble E selectin)], and the platelet (platelet microparticles and soluble P selectin) by ELISA, Luminex or flow cytometry. Results: VEGF (p = 0.04), von Willebrand factor (p = 0.001) and endothelial microparticles (p = 0.042) were all higher in diabetic cardiovascular disease than in diabetes alone and cardiovascular disease alone. Soluble E selectin was higher in diabetic cardiovascular disease than in diabetes alone (p = 0.045), whilst cystatin-C (p = 0.004) and soluble P selectin (p < 0.001) were higher in diabetes and diabetic cardiovascular disease than in cardiovascular disease alone. There were no differences in angiopoietin 1 or 2, endoglin, sRAGE, leptin, lipocalin-2, or interleukin-8. Conclusion: Angiopoietin 1 or 2, endoglin, sRAGE, leptin, lipocalin-2, interleukin-8, and cystatin-c cannot differentiate diabetes from cardiovascular disease, or both conditions combined. Our data point to a more adverse endothelial (von Willebrand factor, endothelial microparticles), and angiogenic profile (VEGF) in those with diabetic cardiovascular disease, supporting the view that this group should be targeted more aggressively.

"The use of bisphosphonates to treat skeletal complications in solid tumours".

The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%-40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours. Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL. Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50 years ago and their introduction more than 30 years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs. Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.

Resistant Starch Production and Glucose Release from Pre-Prepared Chilled Food: The SPUD Project.

With an increasing prevalence of diabetes worldwide, effective dietary strategies for blood glucose control are crucial. As carbohydrates make up approximately 50% of the diet, it is neither practical nor advisable to avoid them altogether. Most of the carbohydrate in the diet is derived from starch, found in potatoes, pasta, rice and bread. These foods are often processed in some way before consumption, yet little is known about the effects processing, such as chilling and reheating, has on the glycaemic response, particularly when the food is consumed in the context of a mixed meal. This article introduces the SPUD project, a BBSRC DRINC-funded initiative. Taking the potato as the model carbohydrate, this project will investigate, via in vitro and in vivo studies, the effects of domestic food processing techniques on the glycaemic response. A final study, utilising intrinsically labelled potato and a dual stable isotope methodology, will model glucose flux data to determine the underlying mechanisms of action.

Consequences for Norway from a hypothetical accident at the Sellafield reprocessing plant: Atmospheric transport of radionuclides.

The potential consequences for Norway should a nuclear accident at the Sellafield nuclear site occur, have been of concern for Norwegian authorities for several decades. Meteorological data from a 33-year period and the dispersion model 'SNAP' were used to evaluate meteorological conditions for which atmospheric transport of radionuclides from Sellafield to Norway would lead to the most severe impacts. The worst-case meteorological scenario for Norway, was found on 25th June 1989 for a low elevation (0-800 m) release and on 29th June 2001 for a higher elevation (800-1600 m) release. In both cases the western part of Norway was most affected. In general, the probability for depositions (>10 Bq/m2 of 137Cs) increased about 40% during the autumn and winter compared to the spring and summer months. An influence of climate change on the depositions was analysed, but not verified. Results from a number of simulations were also compared to identify how factors such as radioactive particle characteristics and initial release conditions could affect the predicted radionuclide deposition. The impact on predicted total depositions as well as hot-spot depositions by varying particle density and size as well as release elevation in worst-case scenario simulations amounted to about 40%-50%.

Management of bone metastasis and cancer treatment-induced bone loss during the COVID-19 pandemic: An international perspective and recommendations.

Optimum management of patients with cancer during the COVID-19 pandemic has proved extremely challenging. Patients, clinicians and hospital authorities have had to balance the risks to patients of attending hospital, many of whom are especially vulnerable, with the risks of delaying or modifying cancer treatment. Those whose care has been significantly impacted include patients suffering from the effects of cancer on bone, where delivering the usual standard of care for bone support has often not been possible and clinicians have been forced to seek alternative options for adequate management. At a virtual meeting of the Cancer and Bone Society in July 2020, an expert group shared experiences and solutions to this challenge, following which a questionnaire was sent internationally to the symposium's participants, to explore the issues faced and solutions offered. 70 respondents, from 9 countries (majority USA, 39%, followed by UK, 19%) included 50 clinicians, spread across a diverse range of specialties (but with a high proportion, 64%, of medical oncologists) and 20 who classified themselves as non-clinical (solely lab-based). Spread of clinician specialty across tumour types was breast (65%), prostate (27%), followed by renal, myeloma and melanoma. Analysis showed that management of metastatic bone disease in all solid tumour types and myeloma, adjuvant bisphosphonate breast cancer therapy and cancer treatment induced bone loss, was substantially impacted. Respondents reported delays to routine CT scans (58%), standard bone scans (48%) and MRI scans (46%), though emergency scans were less affected. Delays in palliative radiotherapy for bone pain were reported by 31% of respondents with treatments often involving only a single dose without fractionation. Delays to, or cancellation of, prophylactic surgery for bone pain were reported by 35% of respondents. Access to treatments with intravenous bisphosphonates and subcutaneous denosumab was a major problem, mitigated by provision of drug administration at home or in a local clinic, reduced frequency of administration or switching to oral bisphosphonates taken at home. The questionnaire also revealed damaging delays or complete stopping of both clinical and laboratory research. In addition to an analysis of the questionnaire, this paper presents a rationale and recommendations for adaptation of the normal guidelines for protection of bone health during the pandemic.

Considerations for the integration of human and wildlife radiological assessments.

A number of tools and approaches have been developed recently to allow assessments of the environmental impact of radiation on wildlife to be undertaken. The International Commission on Radiological Protection (ICRP) has stated an intention to provide a more inclusive protection framework for humans and the environment. Using scenarios, which are loosely based on real or predicted discharge data, we investigate how radiological assessments of humans and wildlife can be integrated with special consideration given to the recent outputs of the ICRP. We highlight how assumptions about the location of the exposed population of humans and wildlife, and the selection of appropriate benchmarks for determining potential risks can influence the outcome of the assessments. A number of issues associated with the transfer component and numeric benchmarks were identified, which need to be addressed in order to fully integrate the assessment approaches. A particular issue was the lack of comparable benchmark values for humans and wildlife. In part this may be addressed via the ICRP's recommended derived consideration reference levels for their 12 Reference Animals and Plants.

Background dose-rates to reference animals and plants arising from exposure to naturally occurring radionuclides in aquatic environments.

In order to put dose-rates derived in environmental impact assessments into context, the International Commission on Radiological Protection (ICRP) has recommended the structuring of effects data according to background exposure levels. The ICRP has also recommended a suite of reference animals and plants (RAPs), including seven aquatic organisms, for use within their developing framework. In light of these propositions, the objective of this work was to collate information on activity concentrations of naturally occurring primordial radionuclides for marine and freshwater ecosystems and apply appropriate dosimetry models to derive absorbed dose-rates. Although coverage of activity concentration data is comprehensive for sediment and water, few, or in some cases no, data were found for some RAPs, e.g. for frogs (Ranidae) and freshwater grasses (Poaceae) for most radionuclides. The activity concentrations for individual radionuclides in both organisms and their habitat often exhibit standard deviations that are substantially greater than arithmetic mean values, reflecting large variability in activity concentrations. To take account of variability a probabilistic approach was adopted. The dominating radionuclides contributing to exposure in the RAPs are (40)K, (210)Po and (226)Ra. The mean unweighted and weighted dose-rates for aquatic RAPs are in the ranges 0.07-0.39 microGy h(-1) and 0.37-1.9 microGy h(-1) respectively.

Assessment of risk to wildlife from ionising radiation: can initial screening tiers be used with a high level of confidence?

A number of models are being used to assess the potential environmental impact of releases of radioactivity. These often use a tiered assessment structure whose first tier is designed to be highly conservative and simple to use. An aim of using this initial tier is to identify sites of negligible concern and to remove them from further consideration with a high degree of confidence. In this paper we compare the screening assessment outputs of three freely available models. The outputs of these models varied considerably in terms of estimated risk quotient (RQ) and the radionuclide-organism combinations identified as being the most limiting. A number of factors are identified as contributing to this variability: values of transfer parameters (concentration ratios and K(d)) used; organisms considered; different input options and how these are utilised in the assessment; assumptions as regards secular equilibrium; geometries and exposure scenarios. This large variation in RQ values between models means that the level of confidence required by users is not achieved. We recommend that the factors contributing to the variation in screening assessments be subjected to further investigation so that they can be more fully understood and assessors (and those reviewing assessment outputs) can better justify and evaluate the results obtained.

Protection of the environment from ionising radiation in a regulatory context--an overview of the PROTECT coordinated action project.

The outcome of the PROTECT project (Protection of the Environment from Ionising Radiation in a Regulatory Context) is summarised, focusing on the protection goal and derivation of dose rates which may detrimentally affect wildlife populations. To carry out an impact assessment for radioactive substances, the estimated dose rates produced by assessment tools need to be compared with some form of criteria to judge the level of risk. To do this, appropriate protection goals need to be defined and associated predefined dose rate values, or benchmarks, derived and agreed upon. Previous approaches used to estimate dose rates at which there may be observable changes in populations or individuals are described and discussed, as are more recent derivations of screening benchmarks for use in regulatory frameworks. We have adopted guidance and procedures used for assessment and regulation of other chemical stressors to derive benchmarks. On the basis of consultation with many relevant experts, PROTECT has derived a benchmark screening dose rate, using data on largely reproductive effects to derive species sensitivity distributions, of 10 microGy h(-1) which can be used to identify situations which are below regulatory concern with a high degree of confidence.

Predicting the radiation exposure of terrestrial wildlife in the Chernobyl exclusion zone: an international comparison of approaches.

There is now general acknowledgement that there is a requirement to demonstrate that species other than humans are protected from anthropogenic releases of radioactivity. A number of approaches have been developed for estimating the exposure of wildlife and some of these are being used to conduct regulatory assessments. There is a requirement to compare the outputs of such approaches against available data sets to ensure that they are robust and fit for purpose. In this paper we describe the application of seven approaches for predicting the whole-body ((90)Sr, (137)Cs, (241)Am and Pu isotope) activity concentrations and absorbed dose rates for a range of terrestrial species within the Chernobyl exclusion zone. Predictions are compared against available measurement data, including estimates of external dose rate recorded by thermoluminescent dosimeters attached to rodent species. Potential reasons for differences between predictions between the various approaches and the available data are explored.

An international model validation exercise on radionuclide transfer and doses to freshwater biota.

Under the International Atomic Energy Agency (IAEA)'s EMRAS (Environmental Modelling for Radiation Safety) programme, activity concentrations of (60)Co, (90)Sr, (137)Cs and (3)H in Perch Lake at Atomic Energy of Canada Limited's Chalk River Laboratories site were predicted, in freshwater primary producers, invertebrates, fishes, herpetofauna and mammals using eleven modelling approaches. Comparison of predicted radionuclide concentrations in the different species types with measured values highlighted a number of areas where additional work and understanding is required to improve the predictions of radionuclide transfer. For some species, the differences could be explained by ecological factors such as trophic level or the influence of stable analogues. Model predictions were relatively poor for mammalian species and herpetofauna compared with measured values, partly due to a lack of relevant data. In addition, concentration ratios are sometimes under-predicted when derived from experiments performed under controlled laboratory conditions representative of conditions in other water bodies.

Using a chain of models to predict health and environmental impacts in Norway from a hypothetical nuclear accident at the Sellafield site.

When a nuclear accident occurs, decision makers in the affected country/countries would need to act promptly to protect people, the environment and societal interests from harmful impacts of radioactive fallout. The decisions are usually based on a combination of model prognoses, measurements, and expert judgements within in an emergency decision support system (DSS). Large scale nuclear accidents would need predictive models for the atmospheric, terrestrial, freshwater, and marine ecosystems, for the connections between these in terms of radionuclide fluxes, and for the various exposure pathways to both humans and biota. Our study showed that eight different models and DSS modules could be linked to assess the total human and environmental consequences in Norway from a hypothetical nuclear accident, here chosen to be the Sellafield nuclear reprocessing plant. Activity concentrations and dose rates from 137Cs for both humans and the environment via various exposure routes were successfully modelled. The study showed that a release of 1% of the total inventory of 137Cs in the Highly Active Liquor Tanks at Sellafield Ltd is predicted to severely impact humans and the environment in Norway if strong winds are blowing towards the country at the time of an accidental atmospheric release. Furthermore, since the models did not have built-in uncertainty ranges when this Sellafield study was performed, investigations were conducted to identify the key factors contributing to uncertainty in various models and prioritise the ones to focus on in future research.

The drugs don't work: evaluation of educational theatre to gauge and influence public opinion on antimicrobial resistance.

Increased public awareness of antimicrobial resistance (AMR) is a key component of effective antimicrobial stewardship strategies. Educational theatre combined with an expert panel was used to engage the public about AMR through delivery of a play entitled 'The drugs don't work'. Audience knowledge and understanding of AMR were measured by pre- and post-play questionnaires. Performance of the play and discussion with the expert panel significantly improved audience knowledge and understanding of AMR, including antibiotic misuse and prescribing. Educational theatre provides a positive learning experience and is an innovative method of public engagement to disseminate important public health messages.

Endocytosis from coated pits of Shiga toxin: a glycolipid-binding protein from Shigella dysenteriae 1.

Evidence is presented that endocytosis is involved in the transport to the cytosol of the cytotoxin from Shigella dysenteriae 1, Shiga toxin, which acts by removal of a single adenine residue in 28-S ribosomal RNA. Inhibition of endocytosis by ATP depletion of the cells prevented toxin uptake. Exposure of HeLa S3 and Vero cells to toxin at low extracellular pH, where translocation to the cytosol, but not endocytosis is inhibited, allowed the toxin to accumulate in a compartment where it was protected against antibodies to the toxin. Upon transfer of the cells to normal medium endocytosed toxin entered the cytosol. Electron microscopical studies of cells exposed at 0 degrees C to a toxin-horseradish peroxidase (HRP) conjugate, or to unconjugated toxin followed by horse antitoxin antibodies and then protein G-gold, revealed that the Shiga toxin binding sites were randomly distributed on the cell surface, without any preference to, for example, coated pits. In contrast, when cells were exposed to toxin at 37 degrees C, the binding sites were preferentially localized in coated pits. The Shiga-HRP conjugate was also seen in endosomes, lysosomes, and in the Golgi region. Endocytosis by the coated pit/coated vesicle pathway was selectively inhibited by acidification of the cytosol. Under these conditions, both the uptake of toxin-HRP conjugates and intoxication of the cells were inhibited. Evidence from the literature as well as our own results suggest that Shiga toxin binding sites are glycolipids. Thus, Shiga toxin appears to be the first example of a lipid-binding ligand that is endocytosed from coated pits.