Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid: single biomarker re-derivation and external validation in three cohorts.

BACKGROUND: The original Manchester Acute Coronary Syndromes model (MACS) 'rules in' and 'rules out' acute coronary syndromes (ACS) using high sensitivity cardiac troponin T (hs-cTnT) and heart-type fatty acid binding protein (H-FABP) measured at admission. The latter is not always available. We aimed to refine and validate MACS as Troponin-only Manchester Acute Coronary Syndromes (T-MACS), cutting down the biomarkers to just hs-cTnT. METHODS: We present secondary analyses from four prospective diagnostic cohort studies including patients presenting to the ED with suspected ACS. Data were collected and hs-cTnT measured on arrival. The primary outcome was ACS, defined as prevalent acute myocardial infarction (AMI) or incident death, AMI or coronary revascularisation within 30 days. T-MACS was built in one cohort (derivation set) and validated in three external cohorts (validation set). RESULTS: At the 'rule out' threshold, in the derivation set (n=703), T-MACS had 99.3% (95% CI 97.3% to 99.9%) negative predictive value (NPV) and 98.7% (95.3%-99.8%) sensitivity for ACS, 'ruling out' 37.7% patients (specificity 47.6%, positive predictive value (PPV) 34.0%). In the validation set (n=1459), T-MACS had 99.3% (98.3%-99.8%) NPV and 98.1% (95.2%-99.5%) sensitivity, 'ruling out' 40.4% (n=590) patients (specificity 47.0%, PPV 23.9%). T-MACS would 'rule in' 10.1% and 4.7% patients in the respective sets, of which 100.0% and 91.3% had ACS. C-statistics for the original and refined rules were similar (T-MACS 0.91 vs MACS 0.90 on validation). CONCLUSIONS: T-MACS could 'rule out' ACS in 40% of patients, while 'ruling in' 5% at highest risk using a single hs-cTnT measurement on arrival. As a clinical decision aid, T-MACS could therefore help to conserve healthcare resources

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

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

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

Extraskeletal benefits and risks of calcium, vitamin D and anti-osteoporosis medications

Drugs used for the prevention and the treatment of osteoporosis exert various favourable and unfavourable extra-skeletal effects whose importance is increasingly recognized notably for treatment selection. INTRODUCTION: The therapeutic armamentarium for the prevention and the treatment of osteoporosis is increasingly large, and possible extra-skeletal effects of available drugs could influence the choice of a particular compound. METHODS: The present document is the result of a national consensus, based on a systematic and critical review of the literature. RESULTS: Observational research has suggested an inverse relationship between calcium intake and cardiovascular diseases, notably through an effect on blood pressure, but recent data suggest a possible deleterious effect of calcium supplements on cardiovascular risk. Many diverse studies have implicated vitamin D in the pathogenesis of clinically important non-skeletal functions or diseases, especially muscle function, cardiovascular disease, autoimmune diseases and common cancers. The possible effects of oral or intravenous bisphosphonates are well-known. They have been associated with an increased risk of oesophageal cancer or atrial fibrillation, but large-scale studies have not found any association with bisphosphonate use. Selective oestrogen receptor modulators have demonstrated favourable or unfavourable extra-skeletal effects that vary between compounds. Strontium ranelate has a limited number of non-skeletal effects. A reported increase in the risk of venous thromboembolism is not found in observational studies, and very rare cases of cutaneous hypersensitivity reactions have been reported. Denosumab has been introduced recently, and its extra-skeletal effects still have to be assessed. CONCLUSION: Several non-skeletal effects of bone drugs are well demonstrated and influence treatment choices

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

Analytical considerations in deriving 99th percentile upper reference limits for high-sensitivity cardiac troponin assays: Educational recommendations from the IFCC committee on clinical application of cardiac bio-markers

The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers provides evidence-based educational documents to facilitate uniform interpretation and utilization of cardiac biomarkers in clinical laboratories and practice. The committee’s goals are to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay in clinical practice. Measurement of high-sensitivity cardiac troponin (hs-cTn) assays is a cornerstone in the clinical evaluation of patients with symptoms and/or signs of acute cardiac ischemia. To define myocardial infarction, the Universal Definition of Myocardial Infarction requires patients who manifest with features suggestive of acute myocardial ischemia to have at least one cTn concentration above the sex-specific 99th percentile upper reference limit (URL) for hs-cTn assays and a dynamic pattern of cTn concentrations to fulfill the diagnostic criteria for MI. This special report provides an overview of how hs-cTn 99th percentile URLs should be established, including recommendations about prescreening and the number of individuals required in the reference cohort, how statistical analysis should be conducted, optimal preanalytical and analytical protocols, and analytical/biological interferences or confounds that can affect accurate determination of the 99th percentile URLs. This document also provides guidance and solutions to many of the issues posed.publishedVersio

Validation of SOLPS-ITER Simulations against the TCV-X21 Reference Case

This paper presents a quantitative validation of SOLPS-ITER simulations against the TCV-X21 reference case and provides insights into the neutral dynamics and ionization source distribution in this scenario. TCV-X21 is a well-diagnosed diverted L-mode sheath-limited plasma scenario in both toroidal field directions, designed specifically for the validation of turbulence codes [D.S. Oliveira, T. Body, et al 2022 Nucl. Fusion 62 096001]. Despite the optimization to reduce the impact of the neutral dynamics, the absence of neutrals in previous turbulence simulations of TCV-X21 was identified as a possible explanation for the disagreements with the experimental data in the divertor region. This motivates the present study with SOLPS-ITER that includes kinetic neutral dynamics via EIRENE. Five new observables are added to the extensive, publicly available TCV-X21 dataset. These are three deuterium Balmer lines in the divertor and neutral pressure in the common and private flux regions. The quantitative agreement metric is combined with the conjugate gradient method to approach the SOLPS-ITER input parameters that return the best overall agreement with the experiment. A proof-of-principle of this method results in a modest improvement in the level-of-agreement; shortcomings of the method and how to improve it are discussed. Alternatively, a scan of the particle and heat diffusion coefficients shows an improvement of 10.4% beyond the agreement level achieved by the gradient method. The result is found for an increased transport coefficient compared to what is usually used for TCV L-mode plasmas, suggesting the need for accurate self-consistent turbulence models for predictive boundary simulations. The simulations indicate that ~65% of the total ionization occurs in the SOL, motivating the inclusion of neutrals in future turbulence simulations towards improved agreement with the experiment

DD-dimensions Dirac fermions BEC-BCS cross-over thermodynamics

An effective Proca Lagrangian action is used to address the vector condensation Lorentz violation effects on the equation of state of the strongly interacting fermions system. The interior quantum fluctuation effects are incorporated as an external field approximation indirectly through a fictive generalized Thomson Problem counterterm background. The general analytical formulas for the $d$-dimensions thermodynamics are given near the unitary limit region. In the non-relativistic limit for $d=3$, the universal dimensionless coefficient $\xi ={4}/{9}$ and energy gap $\Delta/\epsilon_f ={5}/{18}$ are reasonably consistent with the existed theoretical and experimental results. In the unitary limit for $d=2$ and T=0, the universal coefficient can even approach the extreme occasion $\xi=0$ corresponding to the infinite effective fermion mass $m^*=\infty$ which can be mapped to the strongly coupled two-dimensions electrons and is quite similar to the three-dimensions Bose-Einstein Condensation of ideal boson gas. Instead, for $d=1$, the universal coefficient $\xi$ is negative, implying the non-existence of phase transition from superfluidity to normal state. The solutions manifest the quantum Ising universal class characteristic of the strongly coupled unitary fermions gas.Comment: Improved versio