An audit of antimicrobial prescribing by dental practitioners in the north east of England and Cumbria

Background Inappropriate prescribing of antimicrobials is a significant threat to global public health. In England, approximately 5% of all antimicrobial items are prescribed by dentists, despite the limited indications for their use in the treatment of oral infections in published clinical guidelines. The objective of this study was to survey antimicrobial prescribing by dental practitioners in North East England and Cumbria, identify educational and training needs and develop a self-assessment tool that can be used for Continued Professional Development by individual practitioners. Methods During October 2016, 275 dental practitioners used a standardised form to record anonymous information about patients who had been prescribed antimicrobials. Clinical information and prescribing details were compared against clinical guidelines published by the Faculty of General Dental Practitioners UK. Results Dental practitioners provided data on 1893 antimicrobial prescriptions. There was documented evidence of systemic spread, such as pyrexia in 18% of patients. Dentists recorded patients’ pain (91.1% of patients), local lymph gland involvement (41.5%) gross diffuse swelling (55.5%) dysphagia (7.2%) and trismus (13.6%). Reasons for prescribing antimicrobials included patient expectations (25.8%), patient preference (24.8%), time pressures (10.9%), and patients uncooperative with other treatments (10.4%). The most commonly prescribed antimicrobials were amoxicillin, accounting for 61.2% of prescriptions, followed by metronidazole (29.9%). Most prescriptions for amoxicillin were for either 5 days (66.8%) or 7 days (29.6%) and most prescriptions for metronidazole were for a 5-day course (65.2%) or 7-day (18.6%) course. Conclusion In most cases, when an antimicrobial was prescribed, practitioners used the correct choice of agents and usually prescribed these at the correct dose. However, some evidence of suboptimal prescribing practices when compared to the Faculty of General Dental Practitioner guidelines were identified. The audit has identified training needs across the region and aided the development of Continued Professional Development sessions. Further work to identify barriers and facilitators for improving antimicrobial prescribing and determining appropriate methods to improve clinical practice are required

Statistical models for over-dispersion in the frequency of peaks over threshold data for a flow series.

In a peaks over threshold analysis of a series of river flows, a sufficiently high threshold is used to extract the peaks of independent flood events. This paper reviews existing, and proposes new, statistical models for both the annual counts of such events and the process of event peak times. The most common existing model for the process of event times is a homogeneous Poisson process. This model is motivated by asymptotic theory. However, empirical evidence suggests that it is not the most appropriate model, since it implies that the mean and variance of the annual counts are the same, whereas the counts appear to be overdispersed, i.e., have a larger variance than mean. This paper describes how the homogeneous Poisson process can be extended to incorporate time variation in the rate at which events occur and so help to account for overdispersion in annual counts through the use of regression and mixed models. The implications of these new models on the implied probability distribution of the annual maxima are also discussed. The models are illustrated using a historical flow series from the River Thames at Kingston

Systemic RALA/iNOS nanoparticles; a potent gene therapy for metastatic breast cancer coupled as a biomarker of treatment

This study aimed to determine the therapeutic benefit of a nanoparticular formulation for the delivery of inducible nitric oxide synthase (iNOS) gene therapy in a model of breast cancer metastasis. Nanoparticles comprising a cationic peptide vector, RALA, and plasmid DNA were formulated and characterized using a range of physiochemical analyses. Nanoparticles complexed using iNOS plasmids and RALA approximated 60 nm in diameter with a charge of 25 mV. A vector neutralization assay, performed to determine the immunogenicity of nanoparticles in immunocompetent C57BL/6 mice, revealed that no vector neutralization was evident. Nanoparticles harboring iNOS plasmids (constitutively active cytomegalovirus [CMV]-driven or transcriptionally regulated human osteocalcin [hOC]-driven) evoked iNOS protein expression and nitrite accumulation and impaired clonogenicity in the highly aggressive MDA-MB-231 human breast cancer model. Micrometastases of MDA-MB-231-luc-D3H1 cells were established in female BALB/c SCID mice by intracardiac delivery. Nanoparticulate RALA/CMV-iNOS or RALA/hOC-iNOS increased median survival in mice bearing micrometastases by 27% compared with controls and also provoked elevated blood nitrite levels. Additionally, iNOS gene therapy sensitized MDA-MB-231-luc-D3H1 tumors to docetaxel treatment. Studies demonstrated that systemically delivered RALA-iNOS nanoparticles have therapeutic potential for the treatment of metastatic breast cancer. Furthermore, detection of nitrite levels in the blood serves as a reliable biomarker of treatment. Keywords: nonviral gene therapy, nitric oxide, nanoparticle, breast cancer, metastasi

A novel HLA-B18 restricted CD8+ T cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen

NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8<sup>+</sup>T cell epitope, NY-ESO-1<sub>88–96</sub> (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1<sub>157–165</sub> epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1<sub>88–96</sub> is much more efficiently cross-presented from the soluble form, than NY-ESO-1<sub>157–165</sub>. On the other hand, NY-ESO-1<sub>157–165</sub> is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A<sub>26–35</sub>; whereas NY-ESO-1<sub>88–96</sub> was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1<sub>88–96</sub> is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18+ melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1<sub>88–96</sub> from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8<sup>+</sup>T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed

Modelling environmental changes and effects on wild-caught species in Queensland. Environmental drivers.

We report on the findings of a collaborative research project that was designed to identify and measure the effects of environmental drivers on the abundance and population dynamics of key Queensland fishery species. The project was co-funded by the Commonwealth Government’s Fisheries Research and Development Corporation (FRDC) and carried out by a multi-disciplinary team of scientists from the University of Queensland (UQ), the Queensland Department of Agriculture and Fisheries (DAF) and the Australian Institute of Marine Science (AIMS). The research team applied modern statistical, data science and modelling techniques in combination with biological insights into the life cycles of the three target species. Background With increasing evidence that environmental conditions in the marine environment are changing rapidly, it is becoming ever more important to understand how these changes may impact on the population dynamics and abundance of important fish stocks. Understanding the influence of environmental conditions can provide greater certainty that the risk of overfishing (under adverse environmental conditions) or under harvesting (under favourable conditions) are accounted for by resource managers. This project aimed to identify the environmental factors which may be influencing the recruitment, catchability or productivity of Snapper, Pearl Perch, and Spanner Crab stocks in Queensland. Results from this work will support sustainable management of Queensland’s fisheries by directly informing the assessment and management of these key species within Queensland waters

Exploring the impact of CMIP5 model biases on the simulation of North Atlantic decadal variability

Instrumental observations, palaeo-proxies, and climate models suggest significant decadal variability within the North Atlantic subpolar gyre (NASPG). However, a poorly sampled observational record and a diversity of model behaviours mean that the precise nature and mechanisms of this variability are unclear. Here, we analyse an exceptionally large multi-model ensemble of 42 present-generation climate models to test whether NASPG mean state biases systematically affect the representation of decadal variability. Temperature and salinity biases in the Labrador Sea co-vary and influence whether density variability is controlled by temperature or salinity variations. Ocean horizontal resolution is a good predictor of the biases and the location of the dominant dynamical feedbacks within the NASPG. However, we find no link to the spectral characteristics of the variability. Our results suggest that the mean state and mechanisms of variability within the NASPG are not independent. This represents an important caveat for decadal predictions using anomaly-assimilation methods

Ex Vivo Tracking of Endogenous CO with a Ruthenium(II) Complex

[EN] A two-photon fluorescent probe based on a ruthenium(II) vinyl complex is capable of selectively detecting carbon monoxide in cells and ex vivo using mice with a subcutaneous air pouch as a model for inflammation. This probe combines highly selective and sensitive ex vivo detection of endogenous CO in a realistic model with facile, inexpensive synthesis, and displays many advantages over the widely used palladium-based systems.The authors thank the Spanish government (Project MAT2015-64139-C4-1), the Generalitat Valencia (Project PROME-TEOII/2014/047), CIBER-BBN, IC Global Engagements fund, Santander Mobility Award. C.T. is grateful to the Spanish Ministry of Science and Innovation, A.T. thanks the Leverhulme Trust (RPG-2012-634) and J.A.R. thanks the EPSRC, for PhD studentships.De La Torre-Paredes, C.; Toscani, A.; Marín-Hernández, C.; Robson, JA.; Terencio, MC.; White, AJ.; Alcaraz, MJ.... (2017). Ex Vivo Tracking of Endogenous CO with a Ruthenium(II) Complex. Journal of the American Chemical Society. 139(51):18484-18487. https://doi.org/10.1021/jacs.7b11158S18484184871395

Designing basic income pilots for community development : What are the key community concerns? Evidence from citizen engagement in Northern England

olicymakers worldwide are realizing that traditional welfare systems need modernization. In the wake of the COVID-19 pandemic, and with economic, ecological, and social crises intensifying, these systems are being exposed as inefficient, ineffective, and unjust. Policymakers have therefore begun exploring Universal Basic Income (UBI) as a potential alternative. This is leading to rising interest in basic income trials, with pilots proposed or in the pipeline in many countries, including Scotland and Wales. However, pilots are often designed without meaningful community participation, which raises significant ethical and practical concerns. Through a series of qualitative workshops in Jarrow, one of the most deprived areas in the UK and an archetypal target for “Leveling Up” policy, we explored and categorized local concerns, hopes, and suggestions for piloting basic income in the area. This article presents those findings and thereby builds the knowledge base around community perspectives on local basic income pilots

Nonlinear modeling of venous leg ulcer healing rates

<p>Abstract</p> <p>Background</p> <p>The purpose of this manuscript was to determine whether the change in wound surface area over time could be described through nonlinear mathematics.</p> <p>Methods</p> <p>We studied 3,588 serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized trial of two topical wound treatments.</p> <p>Results</p> <p>A majority (72%) of VLUs exhibited surface area reduction via an exponential decay model, particularly during the early stages of healing. These results were consistent with the mechanics of wound contraction and epithelial cell proliferation, supported by the higher frequency at which exponential surface area reduction associated with full wound closure (35% of wounds that fit the exponential model healed vs. 21% of wounds that did not fit the exponential model completely healed during the study period, p = 0.018). Goodness-of-fit statistics suggested that much of the individual variation in healing could be described as nonlinear variation from the exponential model.</p> <p>Conclusion</p> <p>We believe that parameter estimates from a mathematical model may provide a more accurate quantification of wound healing rates, and that similar models may someday reach routine use in comparing the efficacy of various treatments in routine practice and in product registration trials.</p