Applying System Engineering to Pharmaceutical Safety

While engineering techniques are used in the development of medical devices and have been applied to individual healthcare processes, such as the use of checklists in surgery and ICUs, the application of system engineering techniques to larger healthcare systems is less common. System safety is the part of system engineering that uses modeling and analysis to identify hazards and to design the system to eliminate or control them. In this paper, we demonstrate how to apply a new, safety engineering static and dynamic modeling and analysis approach to healthcare systems. Pharmaceutical safety is used as the example in the paper, but the same approach is potentially applicable to other complex healthcare systems. System engineering techniques can be used in re-engineering the system as a whole to achieve the system goals, including both enhancing the safety of current drugs while, at the same time, encouraging the development of new drugs

Control of neoclassical tearing modes by Sawtooth control

The onset of a neoclassical tearing mode (NTM) depends on the existence of a large enough seed island. It is shown in the Joint European Torus that NTMs can be readily destabilized by long-period sawteeth, such as obtained by sawtooth stabilization from ion-cyclotron heating or current drive. This has important implications for burning plasma scenarios, as alpha particles strongly stabilize the sawteeth. It is also shown that, by adding heating and current drive just outside the inversion radius, sawteeth are destabilized, resulting in shorter sawtooth periods and larger beta values being obtained without NTMs

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors

The JAK2 V617F mutation present in over 95% of Polycythemia Vera patients and in 50% of Essential Thrombocythemia and Primary Myelofibrosis patients renders the kinase constitutively active. In the absence of a three-dimensional structure for the full-length protein, the mechanism of activation of JAK2 V617F has remained elusive. In this study, we used functional mutagenesis to investigate the involvement of the JH2 αC helix in the constitutive activation of JAK2 V617F. We show that residue F595, located in the middle of the αC helix of JH2, is indispensable for the constitutive activity of JAK2 V617F. Mutation of F595 to Ala, Lys, Val or Ile significantly decreases the constitutive activity of JAK2 V617F, but F595W and F595Y are able to restore it, implying an aromaticity requirement at position 595. Substitution of F595 to Ala was also able to decrease the constitutive activity of two other JAK2 mutants, T875N and R683G, as well as JAK2 K539L, albeit to a lower extent. In contrast, the F595 mutants are activated by erythropoietin-bound EpoR. We also explored the relationship between the dimeric conformation of EpoR and several JAK2 mutants. Since residue F595 is crucial to the constitutive activation of JAK2 V617F but not to initiation of JAK2 activation by cytokines, we suggest that small molecules that target the region around this residue might specifically block oncogenic JAK2 and spare JAK2 wild-type

Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1

Myeloproliferative neoplasms (MPNs) originate from genetically transformed hematopoietic stem cells that retain the capacity for multilineage differentiation and effective myelopoiesis. Beginning in early 2005, a number of novel mutations involving Janus kinase 2 (JAK2), Myeloproliferative Leukemia Virus (MPL), TET oncogene family member 2 (TET2), Additional Sex Combs-Like 1 (ASXL1), Casitas B-lineage lymphoma proto-oncogene (CBL), Isocitrate dehydrogenase (IDH) and IKAROS family zinc finger 1 (IKZF1) have been described in BCR-ABL1-negative MPNs. However, none of these mutations were MPN specific, displayed mutual exclusivity or could be traced back to a common ancestral clone. JAK2 and MPL mutations appear to exert a phenotype-modifying effect and are distinctly associated with polycythemia vera, essential thrombocythemia and primary myelofibrosis; the corresponding mutational frequencies are ∼99, 55 and 65% for JAK2 and 0, 3 and 10% for MPL mutations. The incidence of TET2, ASXL1, CBL, IDH or IKZF1 mutations in these disorders ranges from 0 to 17% these latter mutations are more common in chronic (TET2, ASXL1, CBL) or juvenile (CBL) myelomonocytic leukemias, mastocytosis (TET2), myelodysplastic syndromes (TET2, ASXL1) and secondary acute myeloid leukemia, including blast-phase MPN (IDH, ASXL1, IKZF1). The functional consequences of MPN-associated mutations include unregulated JAK-STAT (Janus kinase/signal transducer and activator of transcription) signaling, epigenetic modulation of transcription and abnormal accumulation of oncoproteins. However, it is not clear as to whether and how these abnormalities contribute to disease initiation, clonal evolution or blastic transformation

The biorthogonal decomposition as a tool for investigating fluctuations in plasmas

International audienceThe investigation of fluctuation phenomena in plasmas often necessitates the analysis of spatiotemporal signals. It is shown how such signals can be analyzed using the biorthogonal decomposition, which splits them into orthogonal spatial and temporal modes. The method, also referred to as the singular value decomposition, allows complex spatiotemporal patterns to be decomposed into a few coherent modes that are often easier to interpret. This is illustrated with two applications to fluctuating soft x-ray and magnetic signals, as measured in a tokamak. Emphasis is given to the physical interpretation of the biorthogonal components and their link with known physical models is discussed. It is shown how new insight can be gained in the interpretation of spatiotemporal plasma dynamics

Density fluctuations associated with the sawtooth internal disruption

Fluctuations specially related to the sawtooth internal disruption has been observed on TFR tokamak plasmas by analyzing the fluctuations density with CO$_2$ laser light scattering. The time localization is clearly connected with the successive phases of the relaxation process. Some specific fluctuations appear in relation to the kink motion, but te main burst corresponds to the collapse phase. We concentrate our study on this strong burst and show first its frequency and wave number spectral properties and the corresponding pseudo dispersion relation. The fluctuations are spatially localized. They are within the interior of the $q = 1$ surface and extend approximately 120° azimuthally. Taking into account the twisting of the central plasma during the turbulent kink phase, this location agrees with the azimuthal position of the $\ll$ sooner and faster $\gg$ outgoing heat flux. The power level of these fluctuations is two orders of magnitude larger than the local quasi-stationary turbulence. These observations are in fair agreement with the predictions of the sawtooth disruption model previously proposed by Andreoletti. The observed specific fluctuations show several similarities with the so-called $\ll$ magnétodrift turbulence $\gg$ described in the model.
Des fluctuations, spécifiquement reliées à la relaxation interne en dent de scie, ont été observées sur le tokamak TFR en analysant la densité fluctuante par diffusion de la lumière émise par un laser CO$_2$. La localisation temporelle observée est clairement liée aux phases successives du processus de relaxation. Ces fluctuations sont observables pendant le mouvement hélicoïdal $\ll$ kink $\gg$, mais la bouffée principale correspond à la phase d'effondrement de la température. Notre étude concerne cette forte bouffée de densité fluctuante , nous montrons d'abord les propriétés spectrales en fréquence et en nombre d'onde et la pseudo-relation de dispersion correspondante. Les fluctuations sont localisées dans l'espace ; elles se situent à l'intérieur de la surface $q = 1$ et leur extension azimutale est d'environ 120°. Compte tenu du vrillage du plasma central durant la phase de mouvement $\ll$ kink $\gg$ turbulent, cette localisation correspond à la position azimutale où le flux de chaleur, sortant de la zone centrale du plasma, apparait le plus tôt et évolue le plus rapidement. Le niveau de puissance de ces fluctuations est deux ordres de grandeur plus élevé que celui de la turbulence quasi-stationnaire locale. Ces observations sont en bon accord avec les prédictions du modèle de disruption en dent de scie proposé par Andréoletti. Les fluctuations spécifiques observées présentent plusieurs similitudes avec la turbulence $\ll$ magnétodrift $\gg$ décrite dans ce modèle.