Global turbulence simulations of the tokamak edge region with GRILLIX

Turbulent dynamics in the scrape-off layer (SOL) of magnetic fusion devices is intermittent with large fluctuations in density and pressure. Therefore, a model is required that allows perturbations of similar or even larger magnitude to the time-averaged background value. The fluid-turbulence code GRILLIX is extended to such a global model, which consistently accounts for large variation in plasma parameters. Derived from the drift reduced Braginskii equations, the new GRILLIX model includes electromagnetic and electron-thermal dynamics, retains global parametric dependencies and the Boussinesq approximation is not applied. The penalisation technique is combined with the flux-coordinate independent (FCI) approach [F. Hariri and M. Ottaviani, Comput.Phys.Commun. 184:2419, (2013); A. Stegmeir et al., Comput.Phys.Commun. 198:139, (2016)], which allows to study realistic diverted geometries with X-point(s) and general boundary contours. We characterise results from turbulence simulations and investigate the effect of geometry by comparing simulations in circular geometry with toroidal limiter against realistic diverted geometry at otherwise comparable parameters. Turbulence is found to be intermittent with relative fluctuation levels of up to 40% showing that a global description is indeed important. At the same time via direct comparison, we find that the Boussinesq approximation has only a small quantitative impact in a turbulent environment. In comparison to circular geometry the fluctuations are reduced in diverted geometry, which is related to a different zonal flow structure. Moreover, the fluctuation level has a more complex spatial distribution in diverted geometry. Due to local magnetic shear, which differs fundamentally in circular and diverted geometry, turbulent structures become strongly distorted in the perpendicular direction and are eventually damped away towards the X-point

Enhanced triage for patients with suspected cardiac chest pain: the History and Electrocardiogram-only Manchester Acute Coronary Syndromes decision aid.

OBJECTIVES: Several decision aids can 'rule in' and 'rule out' acute coronary syndromes (ACS) in the Emergency Department (ED) but all require measurement of blood biomarkers. A decision aid that does not require biomarker measurement could enhance risk stratification at triage and could be used in the prehospital environment. We aimed to derive and validate the History and ECG-only Manchester ACS (HE-MACS) decision aid using only the history, physical examination and ECG. METHODS: We undertook secondary analyses in three prospective diagnostic accuracy studies that included patients presenting to the ED with suspected cardiac chest pain. Clinicians recorded clinical features at the time of arrival using a bespoke form. Patients underwent serial troponin sampling and 30-day follow-up for the primary outcome of ACS. The model was derived by logistic regression in one cohort and validated in two similar prospective studies. RESULTS: The HE-MACS model was derived in 796 patients and validated in cohorts of 474 and 659 patients. HE-MACS incorporated age, sex, systolic blood pressure plus five historical variables to stratify patients into four risk groups. On validation, 5.5 and 12.1% (pooled total 9.4%) patients were identified as 'very low risk' (potential immediate rule out) with a pooled sensitivity of 99.5% (95% confidence interval: 97.1-100.0%). CONCLUSION: Using only the patient's history and ECG, HE-MACS could 'rule out' ACS in 9.4% of patients while effectively risk stratifying remaining patients. This is a very promising tool for triage in both the prehospital environment and ED. Its impact should be prospectively evaluated in those settings

On order and disorder during the COVID-19 pandemic

Funding: Canadian Institute for Advanced Research.In this paper, we analyse the conditions under which the COVID‐19 pandemic will lead either to social order (adherence to measures put in place by authorities to control the pandemic) or to social disorder (resistance to such measures and the emergence of open conflict). Using examples from different countries (principally the United Kingdom, the United States, and France), we first isolate three factors which determine whether people accept or reject control measures. These are the historical context of state‐public relations, the nature of leadership during the pandemic and procedural justice in the development and operation of these measures. Second, we analyse the way the crisis is policed and how forms of policing determine whether dissent will escalate into open conflict. We conclude by considering the prospects for order/disorder as the pandemic unfolds.Publisher PDFPeer reviewe

Diagnostic accuracy of the T-MACS decision aid with a contemporary point-of-care troponin assay.

OBJECTIVES: The rapid turnaround time of point-of-care (POC) cardiac troponin (cTn) assays is highly attractive for crowded emergency departments (EDs). We evaluated the diagnostic accuracy of the Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid with a POC cTn assay. METHODS: In a prospective diagnostic accuracy study at eight EDs, we included patients with suspected acute coronary syndromes (ACS). Blood drawn on arrival and 3 hours later was analysed for POC cTnI (i-Stat, Abbott Point of Care). The primary outcome was a diagnosis of ACS, which included both an adjudicated diagnosis of acute myocardial infarction (AMI) based on serial laboratory cTn testing and major adverse cardiac events (death, AMI or coronary revascularisation) within 30 days. RESULTS: Of 716 patients included, 105 (14.7%) had ACS. Using serial POC cTnI concentrations over 3 hours could have 'ruled out' ACS in 198 (31.2%) patients with a sensitivity of 99.0% (95% CI 94.4% to 100.0%) and negative predictive value 99.5% (95% CI 96.5% to 99.9%). No AMIs were missed. T-MACS 'ruled in' ACS for 65 (10.4%) patients with a positive predictive value of 91.2% (95% CI 82.1% to 95.9%) and specificity 98.9% (97.6% to 99.6%). CONCLUSION: With a POC cTnI assay, T-MACS could 'rule out' ACS for approximately one-third of patients within 3 hours while 'ruling in' ACS for another 10%. The rapid turnaround time and portability of the POC assay make this an attractive pathway for use in crowded EDs or urgent care centres. Future work should also evaluate use in the prehospital environment

Advanced cardiovascular risk prediction in the emergency department: updating a clinical prediction model - a large database study protocol.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-10-01, epub 2021-10-07Publication status: PublishedFunder: Department of Health; Grant(s): NIHR300246Funder: national institute for health research; Grant(s): NIHR300246BackgroundPatients presenting with chest pain represent a large proportion of attendances to emergency departments. In these patients clinicians often consider the diagnosis of acute myocardial infarction (AMI), the timely recognition and treatment of which is clinically important. Clinical prediction models (CPMs) have been used to enhance early diagnosis of AMI. The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid is currently in clinical use across Greater Manchester. CPMs have been shown to deteriorate over time through calibration drift. We aim to assess potential calibration drift with T-MACS and compare methods for updating the model.MethodsWe will use routinely collected electronic data from patients who were treated using TMACS at two large NHS hospitals. This is estimated to include approximately 14,000 patient episodes spanning June 2016 to October 2020. The primary outcome of acute myocardial infarction will be sourced from NHS Digital's admitted patient care dataset. We will assess the calibration drift of the existing model and the benefit of updating the CPM by model recalibration, model extension and dynamic updating. These models will be validated by bootstrapping and one step ahead prequential testing. We will evaluate predictive performance using calibrations plots and c-statistics. We will also examine the reclassification of predicted probability with the updated TMACS model.DiscussionCPMs are widely used in modern medicine, but are vulnerable to deteriorating calibration over time. Ongoing refinement using routinely collected electronic data will inevitably be more efficient than deriving and validating new models. In this analysis we will seek to exemplify methods for updating CPMs to protect the initial investment of time and effort. If successful, the updating methods could be used to continually refine the algorithm used within TMACS, maintaining or even improving predictive performance over time.Trial registrationISRCTN number: ISRCTN41008456

Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines

INTRODUCTION: Bisphosphonates are inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can also directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-positive (ER+) breast cancer cells. METHODS: We examined the anti-proliferative properties of ibandronate on two ER+ breast cancer cell lines (MCF-7 and IBEP-2), and on one ER negative (ER-) cell line (MDA-MB-231). Experiments were performed in steroid-free medium to assess ER regulation and the effect of ibandronate in combination with estrogen or antiestrogens. RESULTS: Ibandronate inhibited cancer cell growth in a dose- and time-dependent manner (approximate IC(50): 10(-4 )M for MCF-7 and IBEP-2 cells; 3 × 10(-4 )M for MDA-MB-231 cells), partly through apoptosis induction. It completely abolished the mitogenic effect induced by 17β-estradiol in ER+ breast cancer cells, but affected neither ER regulation nor estrogen-induced progesterone receptor expression, as documented in MCF-7 cells. Moreover, ibandronate enhanced the growth inhibitory action of partial (4-hydroxytamoxifen) and pure (ICI 182,780, now called fluvestrant or Faslodex™) antiestrogens in estrogen-sensitive breast cancer cells. Combination analysis identified additive interactions between ibandronate and ER antagonists. CONCLUSION: These data constitute the first in vitro evidence for additive effects between ibandronate and antiestrogens, supporting their combined use for the treatment of bone metastases from breast cancer

Efficacy of teriparatide compared with risedronate on FRAX®-defined major osteoporotic fractures. results of the VERO clinical trial

Summary: FRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate. Introduction: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures. Methods: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 μg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval. Results: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23–0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. Conclusion: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. Clinical trial information: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41

Morpho-syntactic processing of Arabic plurals after aphasia: dissecting lexical meaning from morpho-syntax within word boundaries

Within the domain of inflectional morpho-syntax, differential processing of regular and irregular forms has been found in healthy speakers and in aphasia. One view assumes that irregular forms are retrieved as full entities, while regular forms are compiled on-line. An alternative view holds that a single mechanism oversees regular and irregular forms. Arabic offers an opportunity to study this phenomenon, as Arabic nouns contain a consonantal root, delivering lexical meaning, and a vocalic pattern, delivering syntactic information, such as gender and number. The aim of this study is to investigate morpho-syntactic processing of regular (sound) and irregular (broken) Arabic plurals in patients with morpho-syntactic impairment. Three participants with acquired agrammatic aphasia produced plural forms in a picture-naming task. We measured overall response accuracy, then analysed lexical errors and morpho-syntactic errors, separately. Error analysis revealed different patterns of morpho-syntactic errors depending on the type of pluralization (sound vs broken). Omissions formed the vast majority of errors in sound plurals, while substitution was the only error mechanism that occurred in broken plurals. The dissociation was statistically significant for retrieval of morpho-syntactic information (vocalic pattern) but not for lexical meaning (consonantal root), suggesting that the participants' selective impairment was an effect of the morpho-syntax of plurals. These results suggest that irregular plurals forms are stored, while regular forms are derived. The current findings support the findings from other languages and provide a new analysis technique for data from languages with non-concatenative morpho-syntax

The role of bisphosphonates in breast cancer: The present and future role of bisphosphonates in the management of patients with breast cancer

At least 25% of patients with breast cancer develop skeletal metastases, with bone the site of disease producing the greatest morbidity. It is apparent that the bisphosphonates present an important component of the treatment strategy. They are now the treatment of choice in tumour-induced hypercalcaemia, and they can reduce bone pain and skeletal complications such as pathological fractures. In addition, bisphosphonates are being increasingly evaluated in the prevention of bone metastases and to prevent and treat cancer therapy-induced osteoporosis. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate