Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Simulating biochemical networks at the particle level and in time and space: Green's function reaction dynamics

We present a technique, called Green's function reaction dynamics (GFRD), for particle-based simulations of reaction-diffusion systems. GFRD uses a maximum time step such that only single particles or pairs of particles have to be considered. For these particles, the Smoluchowski equations are solved analytically using Green's functions, which are used to set up an event-driven algorithm. We apply the technique to a model of gene expression. Under biologically relevant conditions, GFRD is up to 5 orders of magnitude faster than conventional particle-based schemes. © 2005 The American Physical Society

Green's-function reaction dynamics: A particle-based approach for simulating biochemical networks in time and space

We have developed a new numerical technique, called Green's-function reaction dynamics (GFRD), that makes it possible to simulate biochemical networks at the particle level and in both time and space. In this scheme, a maximum time step is chosen such that only single particles or pairs of particles have to be considered. For these particles, the Smoluchowski equation can be solved analytically using Green's functions. The main idea of GFRD is to exploit the exact solution of the Smoluchoswki equation to set up an event-driven algorithm, which combines in one step the propagation of the particles in space with the reactions between them. The event-driven nature allows GFRD to make large jumps in time and space when the particles are far apart from each other. Here, we apply the technique to a simple model of gene expression. The simulations reveal that spatial fluctuations can be a major source of noise in biochemical networks. The calculations also show that GFRD is highly efficient. Under biologically relevant conditions, GFRD is up to five orders of magnitude faster than conventional particle-based techniques for simulating biochemical networks in time and space. GFRD is not limited to biochemical networks. It can also be applied to a large number of other reaction-diffusion problems

Velocity distributions in dilute granular systems

We investigate the idea that velocity distributions in granular gases are determined mainly by η, the coefficient of restitution and q, which measures the relative importance of heating (or energy input) to collisions. To this end, we study by numerical simulation the properties of inelastic gases as functions of η, concentration I, and particle number N with various heating mechanisms. For a wide range of parameters, we find Gaussian velocity distributions for uniform heating and non-Gaussian velocity distributions for boundary heating. Comparison between these results and velocity distributions obtained by other heating mechanisms and for a simple model of a granular gas without spatial degrees of freedom, shows that uniform and boundary heating can be understood as different limits of q, with q1 and q1 respectively. We review the literature for evidence of the role of q in the recent experiments. © 2005 The American Physical Society

Relation between the insulin receptor number in cells, autophosphorylation and insulin-stimulated Ras.GTP formation

We showed previously that upon insulin stimulation of an insulin receptor overexpressing cell linme,o st of the p2lras warsa pidly converted into the GTP bound state (Burgering, B. M. T., Medema, R. H., Maassen, J. A., Van de Wetering, M. L., Van der Eb, A. J., McCormick, F., and Bos, J. L. (1991) EMBO J. 10, 1103-1109). To determine whether this process also occurs in cells expressing physiologically relevant numbers of insulin receptors, insulin stimulated Ras-GTP formation was quantitated in Chinese hamster ovary (CH0)-derivecde ll lines expressing varying numbers of insulin receptors. In the parental CH09 cells, expressing only 5.103 insulin receptors, insulin stimulation for 3 min increased Ras*GTP levels with 10%.U pon increasing the numbero f insulin receptors in these cells, Ras-GTP levels increased almost proportionally until a plateau value of 60% is reached at high receptor numbers. Thesed ata show that receptor overexpression is not a prerequisite for insulin-stimulated Ras-GTP formation. Thye ield of Ras-GTP generated is 0.2-1.0 mol/mol autophosphorylated insulin receptor in CH09- and NIH3T3-derived cell linesre, - spectively. These values argue against signal-amplifying processes between the insulin receptor and p2 lras. To determine whether receptor autophosphorylation is required for Rase GTP formation, NIH3cTe3ll s overexpressing insulin receptors were stimulated witah monoclonal antibody which activates the receptor and subsequent glucose transport without inducing detectable autophosphorylation. Also, CHO cells expressing the mutant Ser’200 receptor, which has markedly impaired tyrosyl autophosphorylation but is capable of mediating insulin-stimulated metabolic effects CinH O cells, were used. In both cases, no Ras. GTP formation was observed. Furthermore, Rat- 1-derived cell lines expressing mutant palras, which is permanently in the active GTP-bound form, still responded to insulin by increasing the glucose uptake. These results support our hypothesis that Ras-GTP formation is activated by the tyrosyl-phosphorylated insulin receptor and suggest that an active Ras. GTP complex does not mediate metabolic signaling

The Continuous π-Calculus: A Process Algebra for Biochemical Modelling

Abstract. We introduce the continuous π-calculus, a process algebra for modelling behaviour and variation in molecular systems. Key features of the language are: its expressive succinctness; support for diverse interaction between agents via a flexible network of molecular affinities; and operational semantics for a continuous space of processes. This compositional semantics also gives a modular way to generate conventional differential equations for system behaviour over time. We illustrate these features with a model of an existing biological system, a simple oscillatory pathway in cyanobacteria. We then discuss future research directions, in particular routes to applying the calculus in the study of evolutionary properties of biochemical pathways.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma

BACKGROUND Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5x10(9) TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P < 0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab