Molecular Dynamics Simulations of Weak Detonations

Detonation of a three-dimensional reactive non-isotropic molecular crystal is modeled using molecular dynamics simulations. The detonation process is initiated by an impulse, followed by the creation of a stable fast reactive shock wave. The terminal shock velocity is independent of the initiation conditions. Further analysis shows supersonic propagation decoupled from the dynamics of the decomposed material left behind the shock front. The dependence of the shock velocity on crystal nonlinear compressibility resembles solitary behavior. These properties categorize the phenomena as a weak detonation. The dependence of the detonation wave on microscopic potential parameters was investigated. An increase in detonation velocity with the reaction exothermicity reaching a saturation value is observed. In all other respects the model crystal exhibits typical properties of a molecular crystal.Comment: 38 pages, 20 figures. Submitted to Physical Review

Utility of the ACC/AHA Lesion Classification to Predict Outcomes After Contemporary DES Treatment:Individual Patient Data Pooled Analysis From 7 Randomized Trials

BACKGROUND: Use of the modified American College of Cardiology (ACC)/American Heart Association (AHA) lesion classification as a prognostic tool to predict short‐ and long‐term clinical outcomes after percutaneous coronary intervention in the modern drug‐eluting stent era is uncertain. METHODS AND RESULTS: Patient‐level data from 7 prospective, randomized trials were pooled. Clinical outcomes of patients undergoing single lesion percutaneous coronary intervention with second‐generation drug‐eluting stent were analyzed according to modified ACC/AHA lesion class. The primary end point was target lesion failure (TLF: composite of cardiac death, target vessel myocardial infarction, or ischemia‐driven target lesion revascularization). Clinical outcomes to 5 years were compared between patients treated for noncomplex (class A/B1) versus complex (class B2/C) lesions. Eight thousand five hundred sixteen patients (age 63.1±10.8 years, 70.5% male) were analyzed. Lesions were classified as A, B1, B2, and C in 7.9%, 28.5%, 33.7%, and 30.0% of cases, respectively. Target lesion failure was higher in patients undergoing percutaneous coronary intervention of complex versus noncomplex lesions at 30 days (2.0% versus 1.1%, P=0.004), at 1 year (4.6% versus 3.0%, P=0.0005), and at 5 years (12.4% versus 9.2%, P=0.0001). By multivariable analysis, treatment of ACC/AHA class B2/C lesions was significantly associated with higher rate of 5‐year target lesion failure (adjusted hazard ratio, 1.39 [95% CI, 1.17–1.64], P=0.0001) driven by significantly higher rates of target vessel myocardial infarction and ischemia‐driven target lesion revascularization. CONCLUSIONS: In this pooled large‐scale analysis, treating complex compared with noncomplex lesions according to the modified ACC/AHA classification with second‐generation drug‐eluting stent was associated with worse 5‐year clinical outcomes. This historical classification system may be useful in the contemporary era for predicting early and late outcomes following percutaneous coronary intervention

Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week.

Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).Dr Farkouh has received research grants from Amgen, Novo Nordisk, and Novartis. Dr Stone has received speaker honoraria from Infraredx; has served as a consultant to Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Miracor, Neovasc, Abiomed, Ancora, Vectorious, Elucid Bio, Occlutech, CorFlow, Apollo Therapeutics, Impulse Dynamics, Cardiomech, Gore, and Amgen; and has equity/ options from Ancora, Cagent, Applied Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, Valfix, and Xenter. Dr Godoy is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.S

Titanium, Sinusitis, and the Yellow Nail Syndrome

Yellow nail syndrome is characterized by nail changes, respiratory disorders, and lymphedema. In a yellow nail patient with a skeletal titanium implant and with gold in her teeth, we found high levels of titanium in nail clippings. This study aims to examine the possible role of titanium in the genesis of the yellow nail syndrome. Nail clippings from patients with one or more features of the yellow nail syndrome were analyzed by energy dispersive X-ray fluorescence. Titanium was regularly found in finger nails in patients but not in control subjects. Visible nail changes were present in only half of the patients. Sinusitis with postnasal drip and cough was the most common complaint. The dominant source of titanium ions was titanium implants in the teeth or elsewhere. The titanium ions were released through the galvanic action of dental gold or amalgam or through the oxidative action of fluorides. In other patients the titanium was derived from titanium dioxide in drugs and confectionary. Stopping galvanic release of titanium ions or canceling exposure to titanium dioxide led to recovery. In one patient with a titanium implant, the symptoms recurred after renewed exposure to titanium. Yellow nail syndrome is caused by titaniu

Ultrasensitivity of the Bacillus subtilis sporulation decision

Starving Bacillus subtilis cells execute a gene expression program resulting in the formation of stress-resistant spores. Sporulation master regulator, Spo0A, is activated by a phosphorelay and controls the expression of a multitude of genes, including the forespore- specific sigma factor σF and the mother cell-specific sigma factor σE. Identification of the system-level mechanism of the sporulation decision is hindered by a lack of direct control over Spo0A activity. This limitation can be overcome by using a synthetic system in which Spo0A activation is controlled by inducing expression of phosphorelay kinase KinA. This induction results in a switch-like increase in the number of sporulating cells at a threshold of KinA. Using a combination of mathematical modeling and single-cell microscopy, we investigate the origin and physiological significance of this ultrasensitive threshold. The results indicate that the phosphorelay is unable to achieve a sufficiently fast and ultrasensitive response via its positive feedback architecture, suggesting that the sporulation decision is made downstream. In contrast, activation of σF in the forespore and of σE in the mother cell compartments occurs via a cascade of coherent feed-forward loops, and thereby can produce fast and ultrasensitive responses as a result of KinA induction. Unlike σF activation, σE activation in the mother cell compartment only occurs above the KinA threshold, resulting in completion of sporulation. Thus, ultrasensitive σE activation explains the KinA threshold for sporulation induction. We therefore infer that under uncertain conditions, cells initiate sporulation but postpone making the sporulation decision to average stochastic fluctuations and to achieve a robust population response

Outcome of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs

Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, P=0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (P=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, P<0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115)