Towards validated multiscale simulations for fusion.

Harnessing energy produced by thermonuclear fusion reactions has the potential to provide a clean and inexpensive source of energy to Earth. However, throughout the past seven decades, physicists learned that creating our very own fusion energy source is very difficult to achieve. We constructed a component-based, multiscale fusion workflow to model fusion plasma inside the core of a tokamak device. To ensure the simulation results agree with experimental values, the model needs to undergo the process of verification, validation and uncertainty quantification (VVUQ). This paper will go over the VVUQ work carried out in the multiscale fusion workflow (MFW), with the help of the EasyVVUQ software library developed by the VECMA project. In particular, similarity of distributions from simulation and experiment is explored as a validation metric. Such initial validation measures provide insights into the accuracy of the simulation results. This article is part of the theme issue 'Reliability and reproducibility in computational science: implementing verification, validation and uncertainty quantification in silico'.

Application of the extreme scaling computing pattern on multiscale fusion plasma modelling.

The extreme scaling pattern of the ComPat project is applied to a multi-scale workflow relevant to the magnetically confined fusion problem. This workflow combines transport, turbulence and equilibrium codes (together with additional auxiliaries such as initial conditions and numerical module), which aims at calculating the behaviour of a fusion plasma on long (transport) time scales based on information from much faster (turbulence) time scales. Initial findings of profile measurements are reported in this paper and indicate that, depending on the chosen performance metric for defining 'cost', such as time to completion, efficiency and total energy consumption of the mutliscale workflow, different choices on the number of cores would be made when determining the optimal execution configuration. A variant of the workflow which increases the inherent parallelism is presented, and shown to produce equivalent results at (typically) lower cost compared with the original workflow. This article is part of the theme issue 'Multiscale modelling, simulation and computing: from the desktop to the exascale'.

Synthesis of enantiopure substituted piperidines via an aziridinium ring expansion.

Herein we report a novel methodology for the asymmetric synthesis of 3-substituted piperidines from readily available chiral building blocks. This method, which features a novel irreversible dihydropyrole-tetrahydropyridine ring expansion, allows the introduction of a large variety of substituents at the 3-position and permits substitution at the 2- and 6-position giving mono-, di-, or trisubstituted piperidines with high diastereocontrol.

Copper and zinc balance in exercising horses fed 2 forms of mineral supplements.

Studies comparing the absorption and retention of various forms of trace minerals in horses have yielded mixed results. The objective of this study was to compare Cu and Zn absorption and retention in exercising horses where the mineral was supplemented in the sulfate or organic chelate form. Nine mature horses were used in a modified switchback design experiment consisting of seven 28-d periods. Horses were fed a diet consisting of 50% concentrate and 50% hay that was balanced to meet the energy, protein, Ca, and P requirements for horses performing moderate-intensity exercise. Horses were subjected to a controlled mineral repletion-depletion diet sequence before feeding the experimental diet to standardize mineral status across horses. The experimental diet was designed to provide 90% of the 1989 NRC for Cu and Zn, with supplemental mineral provided in the inorganic sulfate form (CuSO(4) and ZnSO(4)) or the organic chelate form (Cu-Lys and Zn-Met). Feed, fecal, urine, and water samples collected during a total collection during the last 4 d of the experimental diet periods were analyzed to determine apparent absorption and retention of Cu and Zn from the 2 mineral forms. A formulation error caused horses receiving the organic chelate diet to consume about 3 times the amount of Cu and Zn compared with those fed the sulfate-supplemented diet. Copper and Zn intake and fecal excretion were greater (P < 0.05) for horses consuming the organic chelate-supplemented diet. Apparent absorption values for all horses were negative. Apparent Cu absorption and retention as a percentage of intake were greater for horses fed the organic chelate diet (P < 0.05). It is unknown why excretion of Cu and Zn by the horses during the total collection exceeded the mineral intake. Although Cu-Lys seemed to be better absorbed than CuSO(4) and absorption of Zn-Met and ZnSO(4) were not different, these results are tempered by the observation of abnormally high fecal and urinary excretion values for Cu and Zn in the present study.

Magnetic shear damping of dissipative drift wave turbulence.

The influence of local and global magnetic field line shear on structure formation and transport in dissipative drift-Alfvén turbulence is explored. It is found that the generation of zonal flow shear is connected to magnetic shear in ways not accounted previously. The concept of a locally sheared slab flux tube model (including toroidicity) is introduced in order to extend previous analyses to general local variations of magnetic field line shear. It is shown that local shear damping is efficient even when flux surface averaged shear is low.

Effects of beta-blockade on neurohumoral responses and neurochemical markers in pacing-induced heart failure.

We investigated neurohumoral profiles and transmitter and neuroenzyme markers of cardiac autonomic innervation in control (unpaced) dogs and three groups of dogs with pacing-induced heart failure (paced, paced + beta-adrenergic blockade, and paced + cardiac denervation). Left ventricular ejection fraction decreased significantly and to a comparable extent in all paced groups. Pacing increased plasma norepinephrine (NE); increases in NE were not attenuated but instead tended to be exaggerated by treatment with propranolol or cardiac denervation. Atrial hypertrophy occurred in all paced groups compared with the control group. However, atrial and right ventricular hypertrophy were not as pronounced in the paced plus cardiac denervation group as in the paced and paced plus propranolol groups. Pacing also depleted neuropeptide Y and NE from all heart chambers; propranolol treatment did not modify these local tissue changes. Pacing caused selective depletion of neuroenzymes predominantly in the left ventricle; again, propranolol did little to modify these changes. In this study of paced animals with experimentally maintained cardiac dysfunction, failure to modify noradrenergic responses with intrapericardial cardiac denervation suggests that noncardiac sources contribute predominantly to high plasma NE. Failure to modify neurohumoral, neuropeptide, and neuroenzyme responses with beta-antagonist suggests this treatment has little practical direct influence on sympathetic vasomotor activity or neuronal function in heart failure.

The effect of histamine and cyclic adenosine monophosphate on myosin light chain phosphorylation in human umbilical vein endothelial cells.

Histamine causes adjacent endothelial cells to retract from each another. We examined phosphorylation of the 20-kD myosin light chain (MLC20) in human umbilical vein endothelial cells (HUVECs) exposed to histamine to determine if we could find evidence to support the hypothesis that retraction of these cells in response to histamine represents an actomyosin-initiated contraction of the endothelial cytoskeleton. We found that MLC20 in HUVECs was constitutively phosphorylated with approximately 0.2 mol phosphate/mol MLC20. Histamine increased MLC20 phosphorylation by 0.18 +/- 0.05 mol phosphate/mol MLC20. This peak increase in phosphorylation occurred 30 s after initiating histamine exposure, persisted through 90s, and returned to control levels by 5 min. Agents that increase HUVEC cAMP prevent cell retraction in response to histamine. An increase in HUVEC cAMP decreased MLC20 phosphorylation by 0.18 +/- 0.02 mol phosphate/mol MLC20 and prevented the increase in MLC20 phosphorylation after exposure to histamine. Tryptic peptide maps of phosphorylated myosin light chain indicated that myosin light chain kinase phosphorylated MLC20 in HUVECs under basal, cAMP-, and histamine-stimulated conditions. Phosphoaminoacid analysis of the monophosphorylated peptide indicated that, in contrast to smooth muscle cells, ser19 and thr18 monophosphorylation occurs in HUVECs. On the basis of our results, modulation of myosin light chain kinase activity may be an important regulatory step in the control of endothelial barrier function.

Lidocaine and dextran sulfate inhibit leukocyte accumulation but not postischemic contractile dysfunction in a canine model.

Leukocytes have been implicated as a possible factor in the pathogenesis of postischemic contractile dysfunction, probably through the release of oxygen free radicals. Lidocaine and dextran sulfate are known to inhibit leukocyte adherence to endothelial cells in vitro and in vivo. In an acute open-chest canine model both agents were found to inhibit the augmented accumulation of indium-111-labeled leukocytes in briefly ischemic and subsequently reperfused myocardium. Pharmacologic inhibition of leukocyte accumulation by lidocaine and dextran sulfate, however, was not associated with improvement in postischemic contractile dysfunction.

Cardiac geometry and mass changes associated with pacing-induced cardiomyopathy in the dog.

We evaluated the effects of chronic rapid pacing (240 beats/min) on ventricular geometry and function and on cardiac mass in a canine model. Forty dogs were studied by two-dimensional echocardiography before and after 45 days of pacing. Compared with sham-operated control animals, the paced animals had significant increases in end-diastolic and end-systolic volume and a decrease in ejection fraction. The increase in ventricular volume was primarily the result of dilation of the short axis of the ventricular lumen, without significant changes in the long-axis dimension. Paced animals had biatrial hypertrophy but no change in ventricular or total cardiac mass.

Transthoracic defibrillation: effect of dual-pathway sequential pulse shocks and single-pathway biphasic pulse shocks in a canine model.

To determine whether dual-pathway sequential shocks and single-pathway biphasic shocks improved the efficacy of transthoracic defibrillation, we delivered single or sequential truncated waveform shocks of variable duration, voltage, and direction (polarity) to three groups of closed-chest dogs. Dual-pathway sequential shocks were assessed in group 1 (eight animals), biphasic shocks with a single pathway were compared in 11 dogs (group 2), and the effect of varying the duration of the biphasic shocks was assessed in group 3 (four animals). There was no improvement in success rates of the intervention shocks compared with a standard single "control" shock at any energy level. In this experimental model unidirectional or biphasic sequential shocks given over single or dual pathways were not superior to standard single-pulse transthoracic defibrillation.

Clinical and experimental aspects of myocardial stunning.

Although the mechanisms involved in stunning remain incompletely defined, it appears that intracellular calcium overload, sarcoplasmic reticulum dysfunction, and the generation of OFR are important components of post-ischemic myocyte dysfunction. It is likely that a variety of mechanisms, some possibly remaining to be elucidated, are operative in the pathogenesis of stunning, and that the contribution of a particular process may be influenced by the model and the method of inducing ischemia. Myocardial stunning has been shown to be prevalent in patients with diverse cardiac diseases. Small clinical trials have suggested that electrocardiography, echocardiography, and radionuclide imaging techniques may be useful in identifying patients with stunned myocardium. In patients with depressed cardiac performance due to stunning, therapy with inotropic agents may recruit the viable but injured myocardium to contract and improve cardiac output in the short term. An important issue that will be addressed over the next decade is whether aggressive therapy aimed at reducing myocardial stunning in stable patients should be attempted. Some authorities have suggested that stunning may represent an adaptive response to limit reperfusion injury, and that interfering with this response may not be beneficial in the long term. Further investigation into the cellular and molecular basis of ischemic injury should provide insight into these and other important aspects of myocardial stunning. Methods of attenuating postischemic ventricular dysfunction that appear convincing in the research laboratory may not translate to clinical benefit when applied to humans.

Cocaine-induced myocardial infarction in patients with normal coronary arteries.

OBJECTIVE: To review the reported cases of myocardial infarction temporally related to recreational and topical anesthetic use of cocaine, with special regard for underlying etiologic factors in patients subsequently found to have normal coronary arteries. DATA SOURCES: Personal records of three cases and a comprehensive literature review using MEDLINE and supplemented by Index Medicus and the bibliographies of case reports. DATA SYNTHESIS: A total of 114 cases of cocaine-induced myocardial infarction were identified. The coronary anatomy was defined by angiography or autopsy in 92 patients, 38% of whom had normal coronary arteries. In these 35 patients (average age, 32; range, 21 to 60 years), myocardial infarction typically involved the anterior left ventricular wall (77%). Moderate cigarette smoking with one or fewer associated coronary risk factors was prevalent (68%). Focal coronary vasospasm was shown convincingly in only two cases. Intracoronary thrombus was initially found on 9 of 11 angiograms (82%) done within 12 hours of the myocardial infarction. Experimental evidence suggests that cocaine has direct and indirect sympathomimetic effects on vascular smooth muscle, attenuates endothelium vasodilator capacity, exerts a potent depressant effect on cardiac myocytes, and promotes atherogenesis. CONCLUSIONS: Cocaine-induced myocardial infarction in patients with normal coronary arteries probably involves adrenergically mediated increases in myocardial oxygen consumption, vasoconstriction of large epicardial arteries or small coronary resistance vessels, and coronary thrombosis. Accelerated atherosclerosis and impairment of endothelium vasodilator function may occur after chronic cocaine use.

The natural anticoagulant protein S is decreased in male smokers.

Protein S is a natural anticoagulant plasma protein; familial deficiency is associated with thrombotic complications. Since smoking carries an increased risk of myocardial infarction and stroke, we investigated the protein S system of men who smoke. In plasma, free protein S is functionally active and protein S bound to C4b binding protein is inactive. Male smokers (n = 24) have lower total protein S than nonsmokers (n = 24) (16.8 +/- 4.3 micrograms/ml versus 19.8 +/- 5.1 micrograms/ml, p less than 0.02). C4b binding protein levels are higher (p less than 0.05) in smokers (212 +/- 47 micrograms/ml versus 186 +/- 52 micrograms/ml). Free protein S is significantly lower in smokers (6.9 +/- 2.3 micrograms/ml versus 8.0 +/- 1.9 micrograms/ml, p = 0.02). These alterations in protein S may contribute to the thrombotic complications associated with smoking.

Free radicals from plastic syringes.

We have found that disposable sterile plastic syringes can leach free radicals into the fluids they hold. The free radical we observe appears to be a nitroxide (aminoxyl radical) because in aqueous solution it produces a 1:1:1 three line spectrum with a hyperfine splitting constant of 16.9 G.

Pneumococcal meningitis due to psoas abscess.

We have described a patient who had meningitis from local extension of a primary pneumococcal abscess of the psoas muscle. With open surgical drainage and high-dose penicillin therapy, the patient did well and was discharged without neurologic sequelae.

Heparin-induced thrombocytopenia. A common but controllable condition.

Because of the widespread use of heparin in the management of hospitalized patients, heparin-induced thrombocytopenia is a common condition. Clinical diagnosis is based on exclusion. Serious bleeding is uncommon, but thrombosis is a rare complication that can be catastrophic. Prompt recognition of heparin-induced thrombocytopenia and rational use of other antithrombotic agents are essential for optimal patient management.

Unexplained thromboembolism. When to suspect antithrombin III, protein C, or protein S deficiency.

Patients with recurrent or unusual thromboembolic events may have abnormalities in regulation of hemostasis because of inherited or acquired deficiencies of antithrombin III, protein C, or protein S. A working knowledge of the clotting process and a high degree of suspicion are needed to guide the clinician in this difficult diagnosis. Prompt and appropriate anticoagulant therapy can be lifesaving in these patients.

Postgonococcal conjunctivitis due to Chlamydia trachomatis.

We describe a case in which Chlamydia trachomatis was the etiologic agent of postgonococcal conjunctivitis in an adolescent female. This case report demonstrates the need for considering C. trachomatis as the cause of persistent or recurrent conjunctivitis in a sexually active patient. Clinicians should be aware of the possibility of concurrent infections with Neisseria gonorrhoeae and C. trachomatis and should treat the patient accordingly.