Creating Interactive Three-Dimensional Applications to Visualise Novel Stent Grafts That Aid in the Treatment of Aortic Aneurysms.

Three-Dimensional (3D) medical animations incorporated into applications are highly beneficial for clinical outreach and medical communication purposes that work towards educating the clinician and patient. Aortic aneurysms are a clinically important area to communicate with multiple audiences about various treatment options; both abdominal and thoracic aortic aneurysms were selected to create 3D animations and applications to educate medical professionals and patients regarding treatment options. Fenestrated endovascular aortic repair (FEVAR) and thoracic endovascular aortic repair (TEVAR) are both tried and tested minimally invasive surgical methods for treating thoracic aortic aneurysms respectively. The Terumo Aortic Custom Relay Proximal Scalloped stent graft and Fenestrated Anaconda stent graft were both designed specifically for these procedures; however, it can be difficult to visually communicate to clinicians and patients in a straightforward way how these devices work. Therefore, we have developed two interactive applications that use 3D visualisation techniques to demonstrate how these aortic devices function and are implemented. The objective of these applications is to engage both clinicians and patients, therefore demonstrating that the addition of anatomically accurate 3D visualisations within an interactive interface would have a positive impact on public engagement while also ensuring that clinicians will have the best possible understanding of the potential uses of both devices, enabling them to exploit their key features to effectively broaden the treatable patient population.Detailed anatomical modelling and animation was used to generate realistic and accurate rendered videos showcasing both products. These videos were integrated into an interactive application within a modern, professional graphic interface that allowed the user to explore all aspects of the stent device. The resulting applications were broken down into three modules: deployment, clinical performance and features. Following application development, these applications were evaluated by professionals in the field. Overall, positive feedback was received regarding the user-friendly nature of the applications and highly effective animations to showcase the products. The clinical applications and feature modules were particularly successful, while the deployment modules had a neutral response. Biomedical applications such as these show great potential for communicating the key features of medical devices and promoting discussion between clinicians and patients; further testing would need to be conducted on a larger group of participants in order to validate the learning effectiveness of the applications.

Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial.

BACKGROUND: Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. METHODS: NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). FINDINGS: Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). INTERPRETATION: In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. FUNDING: EU Seventh Framework Programme for research, technological development and demonstration.

An optimised dosing regimen versus a standard dosing regimen of vancomycin for the treatment of late onset sepsis due to Gram-positive microorganisms in neonates and infants aged less than 90 days (NeoVanc): study protocol for a randomised controlled trial.

BACKGROUND: Vancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin's continued efficacy. METHODS: NeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excluding Staphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation. The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA. The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h. Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy. DISCUSSION: Based on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02790996. Registered on 7 April 2016. EudraCT, 2015-000203-89. Entered on 18 July 2016.

The £15 billion cost of ash dieback in Britain.

Invasive tree pests and diseases present some of the greatest global threats to forests, and the recent global acceleration in invasions has caused massive ecological damage [1,2]. Calls to improve biosecurity have, however, often lost out to economic arguments in favour of trade [3]. Human activities, such as trade, move organisms between continents, and interventions to reduce risk of introductions inevitably incur financial costs. No previous studies have attempted to estimate the full economic cost of a tree disease, and the economic imperative to improve biosecurity may have been underappreciated. We set out to estimate the cost of the dieback of ash, Fraxinus excelsior, caused by Hymenoscyphus fraxineus, in Great Britain, and investigate whether this may be the case [4].

Revising Pediatric Vancomycin Dosing Accounting for Nephrotoxicity in a Pharmacokinetic-Pharmacodynamic Model.

This study aimed to suggest an initial pediatric vancomycin dose regimen through population pharmacokinetic-pharmacodynamic modeling. A population pharmacokinetic approach was used to analyze vancomycin concentration-time data from a large pediatric cohort. Pharmacokinetic target attainment for patients with bloodstream isolates was compared with clinical outcome using logistic regression and classification and regression trees. Change in serum creatinine during treatment was used as an indicator of acute nephrotoxicity. Probability of acute kidney injury (50% increase from baseline) or kidney failure (75% increase from baseline) was evaluated using logistic regression. An initial dosing regimen was derived, personalized by age, weight, and serum creatinine, using stochastic simulations. Data from 785 hospitalized pediatric patients (1 day to 21 years of age) with suspected Gram-positive infections were collected. Estimated (relative standard error) typical clearance, volume of distribution 1, intercompartmental clearance, and volume of distribution 2 were (standardized to 70 kg) 4.84 (2.38) liters/h, 39.9 (8.15) liters, 3.85 (17.3) liters/h, and 37.8 (10.2) liters, respectively. While cumulative vancomycin exposure correlated positively with the development of nephrotoxicity (713 patients), no clear relationship between vancomycin area under the plasma concentration-time curve and efficacy was found (102 patients). Predicted probability of acute kidney injury and kidney failure with the optimized dosing regimen at day 5 was 10 to 15% and 5 to 10%, increasing by approximately 50% on day 7 and roughly 100% on day 10 across all age groups. This study presents the first data-driven pediatric dose selection to date accounting for nephrotoxicity, and it indicates that cumulative vancomycin exposure best describes risk of acute kidney injury and acute kidney failure.

Abundance distributions for tree species in Great Britain: A two-stage approach to modeling abundance using species distribution modeling and random forest.

High-quality abundance data are expensive and time-consuming to collect and often highly limited in availability. Nonetheless, accurate, high-resolution abundance distributions are essential for many ecological applications ranging from species conservation to epidemiology. Producing models that can predict abundance well, with good resolution over large areas, has therefore been an important aim in ecology, but poses considerable challenges. We present a two-stage approach to modeling abundance, combining two established techniques. First, we produce ensemble species distribution models (SDMs) of trees in Great Britain at a fine resolution, using much more common presence-absence data and key environmental variables. We then use random forest regression to predict abundance by linking the results of the SDMs to a much smaller amount of abundance data. We show that this method performs well in predicting the abundance of 20 of 25 tested British tree species, a group that is generally considered challenging for modeling distributions due to the strong influence of human activities. Maps of predicted tree abundance for the whole of Great Britain are provided at 1 km2 resolution. Abundance maps have a far wider variety of applications than presence-only maps, and these maps should allow improvements to aspects of woodland management and conservation including analysis of habitats and ecosystem functioning, epidemiology, and disease management, providing a useful contribution to the protection of British trees. We also provide complete R scripts to facilitate application of the approach to other scenarios.

Vancomycin toxicity in neonates: a review of the evidence.

PURPOSE OF REVIEW: Vancomycin is a first-line agent in the treatment of serious Gram-positive infections in the neonatal population. The published evidence on vancomycin toxicity in neonates is limited. This review summarizes preclinical studies and clinical trials describing vancomycin toxicity. We discuss proposed pathophysiology and summarize evidence supporting dose-response relationships, genetic and environmental determinants, and consider future research required to further define vancomycin toxicity. RECENT FINDINGS: Current dosing regimens for vancomycin result in subtherapeutic levels in a large proportion of patients. Higher daily doses have been proposed, which have led to concerns regarding increased toxicity. Nephrotoxicity occurs in 1-9% of neonates receiving currently recommended doses. The incidence is highest in those receiving concomitant nephrotoxic drugs. Vancomycin-associated ototoxicity is rare in patients of all ages. Exposure-toxicity relationships in relation to nephrotoxicity and ototoxicity have not been clearly defined in neonates receiving vancomycin. SUMMARY: Current evidence supports the favourable safety profile of vancomycin in neonates. Further studies that address safety concerns relating to high-dose intermittent dosing regimens are needed. Such studies must include robust and standardized definitions of renal and hearing impairment, and include follow-up of sufficient length to establish the long-term implications of experimental findings.

A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma.

Aberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor-suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to NRAS/BRAF activation, EMT-TF network undergoes a profound reorganization in favor of TWIST1 and ZEB1. This reversible switch cooperates with BRAF in promoting dedifferentiation and neoplastic transformation of melanocytes. We detected EMT-TF reprogramming in late-stage melanoma in association with enhanced phospho-ERK levels. This switch results in E-cadherin loss, enhanced invasion, and constitutes an independent factor of poor prognosis in melanoma patients.

ZEB/miR-200 feedback loop: at the crossroads of signal transduction in cancer.

Embryonic differentiation programs of epithelial-mesenchymal and mesenchymal-epithelial transition (EMT and MET) represent a mechanistic basis for epithelial cell plasticity implicated in cancer. Transcription factors of the ZEB protein family (ZEB1 and ZEB2) and several microRNA species (predominantly miR-200 family members) form a double negative feedback loop, which controls EMT and MET programs in both development and tumorigenesis. In this article, we review crosstalk between the ZEB/miR-200 axis and several signal transduction pathways activated at different stages of tumor development. The close association of ZEB proteins with these pathways is indirect evidence for the involvement of a ZEB/miR-200 loop in tumor initiation, progression and spread. Additionally, the configuration of signaling pathways involving ZEB/miR-200 loop suggests that ZEB1 and ZEB2 may have different, possibly even opposing, roles in some forms of human cancer.

Right ventricular dilation on CT pulmonary angiogram independently predicts mortality in pulmonary embolism.

BACKGROUND: The aim of this study was to determine the prognostic significance of right ventricular dilation on CT pulmonary angiogram in acute pulmonary embolism and to distinguish if this feature predicts mortality independently of the Pulmonary Embolism Severity Index, an established admission severity score. METHODS: A retrospective study of patients admitted with pulmonary embolism confirmed by CT pulmonary angiogram to three teaching hospitals in East Scotland between January 2005 and July 2007. Two radiologists judged presence of right ventricular dilation on CT pulmonary angiogram independently. The outcome of interest was 30 day mortality. Multivariable logistic regression was used to compare this outcome in patients with right ventricular dilation compared to those without right ventricular dilation, adjusting for Pulmonary Embolism Severity Index score. RESULTS: There were 585 patients included and 30.4% had right ventricular dilation on CT pulmonary angiogram. Patients with right ventricular dilation had increased 30 day mortality rates compared to patients without right ventricular dilation (12.4% vs. 5.4%; p=0.006). Survival analysis showed that a significantly greater proportion of deaths in the right ventricular dilation group occurred within the first 48h after admission compared to the group without right ventricular dilation (45.5% deaths vs. 9.1%; p=0.016). On multivariable analysis, adjusting for Pulmonary Embolism Severity Index score, right ventricular dilation was independently associated with increased 30 day mortality (OR 2.98; 95% CI 1.54-5.75; p=0.001). CONCLUSION: Right ventricular dilation on CT pulmonary angiogram is an independent predictor of 30 day mortality in acute pulmonary embolism.

Exercise improves cognitive responses to psychological stress through enhancement of epigenetic mechanisms and gene expression in the dentate gyrus.

BACKGROUND: We have shown previously that exercise benefits stress resistance and stress coping capabilities. Furthermore, we reported recently that epigenetic changes related to gene transcription are involved in memory formation of stressful events. In view of the enhanced coping capabilities in exercised subjects we investigated epigenetic, gene expression and behavioral changes in 4-weeks voluntarily exercised rats. METHODOLOGY/PRINCIPAL FINDINGS: Exercised and control rats coped differently when exposed to a novel environment. Whereas the control rats explored the new cage for the complete 30-min period, exercised animals only did so during the first 15 min after which they returned to sleeping or resting behavior. Both groups of animals showed similar behavioral responses in the initial forced swim session. When re-tested 24 h later however the exercised rats showed significantly more immobility behavior and less struggling and swimming. If rats were killed at 2 h after novelty or the initial swim test, i.e. at the peak of histone H3 phospho-acetylation and c-Fos induction, then the exercised rats showed a significantly higher number of dentate granule neurons expressing the histone modifications and immediate-early gene induction. CONCLUSIONS/SIGNIFICANCE: Thus, irrespective of the behavioral response in the novel cage or initial forced swim session, the impact of the event at the dentate gyrus level was greater in exercised rats than in control animals. Furthermore, in view of our concept that the neuronal response in the dentate gyrus after forced swimming is involved in memory formation of the stressful event, the observations in exercised rats of enhanced neuronal responses as well as higher immobility responses in the re-test are consistent with the reportedly improved cognitive performance in these animals. Thus, improved stress coping in exercised subjects seems to involve enhanced cognitive capabilities possibly resulting from distinct epigenetic mechanisms in dentate gyrus neurons.

Voluntary exercise impacts on the rat hypothalamic-pituitary-adrenocortical axis mainly at the adrenal level.

INTRODUCTION: Evidence is accumulating that the regular performance of exercise is beneficial for stress coping. However, the hypothalamic-pituitary-adrenocortical (HPA) axis of voluntarily exercising rats has never been comprehensively investigated. METHODS: Therefore, male Sprague-Dawley rats were given access to a running wheel in their home cage for 4 weeks in which they ran 4-7 km per night. RESULTS: After 4 weeks, the exercising animals showed significantly less body weight gain, less abdominal fat tissue, decreased thymus weight, and increased adrenal weight (relative to body weight). Furthermore, tyrosine hydroxylase (TH) mRNA levels were selectively increased in the right adrenal medulla indicating an increase in sympathoadrenomedullary capacity in exercising rats. No changes were observed in paraventricular corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and oxytocin mRNA levels. Mineralocorticoid receptor (MR) mRNA levels in hippocampus and glucocorticoid receptor (GR) mRNA levels in frontal cortex, parvocellular paraventricular nucleus and anterior pituitary were unchanged, whereas GR mRNA levels were increased in distinct hippocampal cell layers. Early morning baseline levels of plasma ACTH and corticosterone were similar in both groups. Interestingly, the response to different stressful stimuli (e.g. forced swimming, novelty) revealed that the exercising rats showed stressor-specific changes in HPA hormone responses. Forced swimming evoked a markedly enhanced response in corticosterone levels in the exercising rats. In contrast, if rats were exposed to a novel environment, exercising rats showed a much lower response in corticosterone than the control animals. However, the response in ACTH to either stressor was comparable between groups. Thus, in exercising rats physically demanding stressors evoke enhanced glucocorticoid responses whereas mild psychologically stressful stimuli such as novelty result in an attenuated glucocorticoid response. Interestingly, this attenuated hormone response corresponded with the observation that the exercising rats showed less anxious behaviour in the novelty situation. CONCLUSIONS: The differential responses in plasma corticosterone levels to different types of stress in the face of comparable responses in ACTH levels underscore the existence of critical regulatory control mechanisms at the level of the adrenal gland. We have hypothesized that changes in the sympathoadrenomedullary input may play an important role in these distinct glucocorticoid responses to stress. Our previous studies have shown similar changes in voluntarily exercising mice. Therefore, we conclude that the effects of exercise on the organism are not species-specific. Thus, our observations may have translational implications for the human situation.

Salmonella in foods: new enrichment procedure for TECRA Salmonella Visual Immunoassay using a single rv(R10) only, TT only, or dual rv(R10) and TT selective enrichment broths (AOAC official method 998.09): collaborative study.

A collaborative study was conducted to compare a new enrichment procedure for the TECRA Salmonella Visual Immunoassay (TSVIA) with the reference method given in the U.S. Food and Drug Administration's Bacteriological Analytical Manual (7th Ed.). Three food types (milk powder, pepper, and soy flour) were analyzed in Australia and 3 food types (milk chocolate, dried egg, and raw turkey) were analyzed in the United States. Thirty-eight collaborators participated in the study. The TECRA method was evaluated using both Rappaport-Vassiliadis R10 (RV(R10)) and tetrathionate (TT) broths for selective enrichment. M broth cultures arising from each of the 2 selective enrichment broths were tested in the TSVIA using 2 individual wells, one for each selective broth, and a single well to test the pooled selective enrichment broths. The results for the pooled enrichment broths were reported elsewhere. This study presents the results for the use of single enrichment broths, i.e., RV(R10) only or TT only, with the TSVIA. No significant differences (p > 0.05) were observed for the pairwise comparison of the proportion of positive samples for either RV(R10) or TT used as a single enrichment broth for the TSVIA with that for the reference method.