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1
Keldermann, R. H., M. P. Nash, H. Gelderblom, V. Y. Wang, and A. V. Panfilov. "Electromechanical wavebreak in a model of the human left ventricle." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 1 (2010): H134—H143. http://dx.doi.org/10.1152/ajpheart.00862.2009.
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In the present report, we introduce an integrative three-dimensional electromechanical model of the left ventricle of the human heart. Electrical activity is represented by the ionic TP06 model for human cardiac cells, and mechanical activity is represented by the Niederer-Hunter-Smith active contractile tension model and the exponential Guccione passive elasticity model. These models were embedded into an anatomic model of the left ventricle that contains a detailed description of cardiac geometry and the fiber orientation field. We demonstrated that fiber shortening and wall thickening during normal excitation were qualitatively similar to experimental recordings. We used this model to study the effect of mechanoelectrical feedback via stretch-activated channels on the stability of reentrant wave excitation. We found that mechanoelectrical feedback can induce the deterioration of an otherwise stable spiral wave into turbulent wave patterns similar to that of ventricular fibrillation. We identified the mechanisms of this transition and studied the three-dimensional organization of this mechanically induced ventricular fibrillation.
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Pravdin, Sergey, Pavel Konovalov, Hans Dierckx, Olga Solovyova, and Alexander V. Panfilov. "Drift of Scroll Waves in a Mathematical Model of a Heterogeneous Human Heart Left Ventricle." Mathematics 8, no. 5 (2020): 776. http://dx.doi.org/10.3390/math8050776.
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Rotating spiral waves of electrical excitation underlie many dangerous cardiac arrhythmias. The heterogeneity of myocardium is one of the factors that affects the dynamics of such waves. In this paper, we present results of our simulations for scroll wave dynamics in a heterogeneous model of the human left ventricle with analytical anatomically based representation of the geometry and anisotropy. We used a set of 18 coupled differential equations developed by ten Tusscher and Panfilov (TP06 model) which describes human ventricular cells based on their measured biophysical properties. We found that apicobasal heterogeneity dramatically changes the scroll wave dynamics. In the homogeneous model, the scroll wave annihilates at the base, but the moderate heterogeneity causes the wave to move to the apex and then continuously rotates around it. The rotation speed increased with the degree of the heterogeneity. However, for large heterogeneity, we observed formation of additional wavebreaks and the onset of complex spatio-temporal patterns. Transmural heterogeneity did not change the dynamics and decreased the lifetime of the scroll wave with an increase in heterogeneity. Results of our numerical experiments show that the apex may be a preferable location of the scroll wave, which may be important for development of clinical interventions.
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Satish, Helan, and M. Ramasubba Reddy. "Reentry in cardiac ventricular epicardial tissue due to SCN5A L812Q gene mutation: a computational study." Biomedical Physics & Engineering Express 8, no. 3 (2022): 035023. http://dx.doi.org/10.1088/2057-1976/ac605c.
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Abstract Cardiovascular diseases are the major cause of sudden death. Brugada syndrome is an inherited rare disease, that leads to death due to ventricular fibrillation (VF). Brugada Syndrome is related to mutations in the genes that encode SCN5A, a subunit of sodium ion channel (NaV). This computational study investigates the mechanism of loss of function gene mutation (SCN5A L812Q) in sodium ion channel that leads to spiral wave and further develops into VF in an epicardial tissue with homozygous condition. Study was made on wild type, L812Q heterozygous mutated and homozygous mutated ventricular tissues. Ten Tusscher human ventricular cell model (TP06) was used for the simulation study. VF is developed when a spiral wave that causes ventricular arrhythmia breaks. This leads to the formation of multiple spiral waves that are activated on different regions of the ventricles called wave break. This is observed in the epicardial tissue with homozygous condition as the effect of SCN5A L812Q gene mutation. This indicates that VF occurs in the SCN5A L812Q gene mutated homozygous ventricular epicardial tissue that may further lead to Brugada syndrome.
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Mangileva, Daria, Pavel Konovalov, Arsenii Dokuchaev, Olga Solovyova, and Alexander V. Panfilov. "Period of Arrhythmia Anchored around an Infarction Scar in an Anatomical Model of the Human Ventricles." Mathematics 9, no. 22 (2021): 2911. http://dx.doi.org/10.3390/math9222911.
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Rotating nonlinear waves of excitation in the heart cause dangerous cardiac arrhythmias. Frequently, ventricular arrhythmias occur as a result of myocardial infarction and are associated with rotation of the waves around a post-infarction scar. In this paper, we perform a detailed in silico analysis of scroll waves in an anatomical model of the human ventricles with a generic model of the infarction scar surrounded by the gray zone with modified properties of the myocardial tissue. Our model includes a realistic description of the heart shape, anisotropy of cardiac tissue and a detailed description of the electrical activity in human ventricular cells by a TP06 ionic model. We vary the size of the scar and gray zone and analyze the dependence of the rotation period on the injury dimensions. Two main regimes of wave scrolling are observed: the scar rotation, when the wave rotates around the scar, and the gray zone rotation, when the wave rotates around the boundary of the gray zone and normal tissue. The transition from the gray zone to the scar rotation occurs for the width of gray zone above 10–20 mm, depending on the perimeter of the scar. We compare our results with simulations in 2D and show that 3D anisotropy reduces the period of rotation. We finally use a model with a realistic shape of the scar and show that our approach predicts correctly the period of the arrhythmia.
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Konovalov, Pavel, Daria Mangileva, Arsenii Dokuchaev, Olga Solovyova, and Alexander V. Panfilov. "Rotational Activity around an Obstacle in 2D Cardiac Tissue in Presence of Cellular Heterogeneity." Mathematics 9, no. 23 (2021): 3090. http://dx.doi.org/10.3390/math9233090.
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Waves of electrical excitation rotating around an obstacle is one of the important mechanisms of dangerous cardiac arrhythmias occurring in the heart damaged by a post-infarction scar. Such a scar is also surrounded by the region of heterogeneity called a gray zone. In this paper, we perform the first comprehensive numerical study of various regimes of wave rotation around an obstacle surrounded by a gray zone. We use the TP06 cellular ionic model for human cardiomyocytes and study how the period and the pattern of wave rotation depend on the radius of a circular obstacle and the width of a circular gray zone. Our main conclusions are the following. The wave rotation regimes can be subdivided into three main classes: (1) functional rotation, (2) scar rotation and the newly found (3) gray zone rotation regimes. In the scar rotation regime, the wave rotates around the obstacle, while in the gray zone regime, the wave rotates around the gray zone. As a result, the period of rotation is determined by the perimeter of the scar, or gray zone perimeter correspondingly. The transition from the scar to the gray rotation regimes can be determined from the minimal period principle, formulated in this paper. We have also observed additional regimes associated with two types of dynamical instabilities which may affect or not affect the period of rotation. The results of this study can help to identify the factors determining the period of arrhythmias in post-infarction patients.
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Kümmel, Daniel, Jürgen J. Müller, Yvette Roske, Rolf Misselwitz, Konrad Büssow, and Udo Heinemann. "The structure of the TRAPP subunit TPC6 suggests a model for a TRAPP subcomplex." EMBO reports 6, no. 8 (2005): 787–93. http://dx.doi.org/10.1038/sj.embor.7400463.
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Park, Sung-Hoon, Jinyoung Hwang, Dong-Jin Yun, Sangeui Lee, Sang Hyun Lee, and InTaek Han. "Size Effect of Particulate Filler on Electrical Resistivity of Carbon Nanotube Polymer Composites: Transition of Excluded Volume Effects." International Symposium on Microelectronics 2014, no. 1 (2014): 000268–71. http://dx.doi.org/10.4071/isom-tp36.
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Hybrid Carbon nanotube (CNT) composites consisting more than two different kind fillers have received considerable attention which could improve electrical conductivity and mechanical properties. Incorporation of micro-scale second filler, excluded volume is created that effectively creates a segregated network of nanotube. Even if there were successful trials with theoretical model in second filler composite system, it was not fully understood how the electrical conductivity increase with respect to shape (or size) of second filler. Aim of the present research is an understanding of size effect of particulate filler on electrical resistivity of carbon nanotube polymer composites. Depending on size of particulate filler, conductivity of carbon nanotube polymer composites are changed (increase or decrease) indicating there is transition of excluded volume effects. For example, enhanced conductivity was observed in cooperation with micro-size second filler while decreased conductivity was observed for nano-size filler.
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Lederer, Martin, Javad Zarbakhsh, Rui Huang, Thomas Detzel, and Brigitte Weiss. "Thermomechanical Stresses in Copper Films at Elevated Temperature." Additional Conferences (Device Packaging, HiTEC, HiTEN, and CICMT) 2010, HITEC (2010): 000129–35. http://dx.doi.org/10.4071/hitec-jzarbakhsh-tp16.
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Thermomechanical stresses in metallic films are a root cause for material fatigue which limits the lifetime of electronic devices. Since the yield stress of metals is temperature dependent, plastic deformations during thermal cycling are increased at elevated temperature. This effect reduces the reliability of electronic parts. In order to investigate this problem, a 20μm thick copper film was deposited on a silicon wafer. After annealing at 400°C, the sample was exposed to thermal cycles in the temperature range between room temperature and 600°C. The different values for the CTE of copper and silicon lead to a curvature of the sample. The wafer curvature was measured by a multi-laser beam method. On the basis of the experimental results, a new theoretical model was developed, which describes the stress evolution in the film during thermal cycling. In this investigation, the relation between wafer curvature and film stress is calculated by analogy to a model by Freund [1] which is an improvement to the well known Stoney formula. In addition to the elastic response, the new model considers plasticity of the copper film as well as temperature dependence of creep. It is demonstrated that the model can well describe the experiment and thus thermomechanical stress in copper films.
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Hu, Yixin, Daihong Liu, Yongchun Deng, et al. "Changes in Degree Centrality and Functional Connectivity after the First Cycle of Neoadjuvant Chemotherapy in Newly Diagnosed Breast Cancer: A Longitudinal Study." Disease Markers 2022 (November 28, 2022): 1–11. http://dx.doi.org/10.1155/2022/8270100.
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Purpose. To evaluate the longitudinal changes of brain degree centrality (DC) and functional connectivity (FC) in breast cancer patients after the first cycle of neoadjuvant chemotherapy (NAC). Methods. Thirty-five breast cancer patients were included in the NAC group. Resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological test were performed at baseline before NAC (time point 0, TP0) and after the first cycle of NAC (time point 1, TP1). The healthy controls (HC) included 30 healthy subjects and received the same rs-fMRI scan and neuropsychological test as the above-mentioned NAC group at one time point. DC and FC analyses were conducted to assess brain connectivity of all participants. Receiver operating characteristic (ROC) curve was used to assess the ability of DC and FC in distinguishing patients before and after chemotherapy. Results. In the NAC group, the Self-Rating Anxiety Scale scores decreased significantly over time. At TP0 and TP1, the Digital Span Test forward score of the NAC group was significantly lower than that of the HC group. In the NAC group, DC in the right middle frontal gyrus and left precentral gyrus/middle frontal gyrus decreased significantly at TP1, and FC between the left precentral gyrus/middle frontal gyrus and bilateral precuneus was significantly reduced at TP1. Through ROC analysis, we found that the area under the curve (AUC) of DC, FC, and the combined model in distinguishing patients in TP0 or TP1 was 0.7886, 0.7665, and 0.8278, respectively. Conclusions. Brain connectivity, involving executive and motor function related brain areas, changes in the short term after NAC treatment in breast cancer patients.
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Bunel, Catherine, and Franck Murray. "Ultra thin, low ESL and high frequency performance of high density silicon capacitors." International Symposium on Microelectronics 2016, no. 1 (2016): 000060–63. http://dx.doi.org/10.4071/isom-2016-tp26.
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Abstract The very high capacitance platform (now up to 900 nF/mm2) of the 3D Silicon capacitor technology presents many advantages for signal integrity, performance improvement, and miniaturization. In this paper, we will illustrate these advantages for communication infrastructure and high speed processors. The intrinsic IPDiA Silicon capacitors construction and the simplified equivalent electrical models will be compared with the multilayer ceramic capacitor (MLCC) model. We will also demonstrate how the Silicon capacitors are better candidates for performance, miniaturization and integration thanks to their low profile. The thickness has been a limiting factor for ceramic capacitors and we believe that Silicon capacitors will help to address this profile challenge. On top of the competitive overview of performances specific to the Ultra Wide Broadband Capacitors - like signal integrity, frequency response, linearity, and dielectric absorption - the additional Silicon capacitor technology benefits will be detailed. Design recommendations will be given to those who want to optimize performance. Perspectives and roadmap for the future will be disclosed.
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Ibrahim, Akhmad Fadli, La Ode Ichlas Syahrullah Yunus, Yuvita Satriani Djuli, and Azhar Aras Mubarak. "Karakteristik Termal Kolektor Pelat Datar Model Serpentine Pada Pemanas Air Tenaga Surya." Jurnal Teknik Mesin Sinergi 20, no. 1 (2022): 89. http://dx.doi.org/10.31963/sinergi.v20i1.3466.
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Kolektor pelat datar model serpentine perlu diketahui karakteristik unjuk kerjanya sebagai pemanas air tenaga surya. Penelitian ini bertujuan untuk mengetahui distribusi temperatur pada pipa, pelat absorber dan efisiensi kolektor pelat datar model serpentine pada pemanas air tenaga surya. Penelitian eksperimental dilakukan dengan membuat kolektor pelat datar dan pipa saluran fluida model serpentine dengan jarak pipa 108 mm dan panjang 8479 mm. Selanjutnya kolektor model serpentine tersebut diaplikasikan pada alat uji pemanas air tenaga surya. Pengambilan data dilakukan setiap 5 menit mulai pukul 08.00 sampai 16.00 WITA dengan debit aliran 1 liter/menit. Hasil penelitian menunjukkan karakteristik kenaikan temperatur rata-rata pelat absorber pada titik bawah (Tp1), titik tengah (Tp3) dan titik atas (Tp5) adalah sebesar 4,1oC. Karakteristik temperatur rata-rata pipa saluran fluida model serpentine pada titik bawah (Tp2), titik tengah (Tp4) dan titik atas (Tp6) adalah sebesar 5,2oC. Efisiensi aktual rata-rata kolektor model serpentine 45,22% dan temperatur rata-rata air keluaran 40,3oC pada debit 1 liter/menit. Kolektor surya pelat datar model serpentine dapat diaplikasikan untuk penggunaan skala domestik untuk menghemat penggunaan energi listrik.
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SIMMONS, MICHAEL J., LISA M. RAGATZ, IAN R. SINCLAIR, MICHAEL W. THORP, JARED T. BUSCHETTE, and CRAIG D. GRIMES. "Maternal enhancement of cytotype regulation in Drosophila melanogaster by genetic interactions between telomeric P elements and non-telomeric transgenic P elements." Genetics Research 94, no. 6 (2012): 339–51. http://dx.doi.org/10.1017/s0016672312000523.
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SummaryThe X-linked telomeric P elements (TPs) TP5 and TP6 regulate the activity of the entire P element family because they are inserted in a major locus for the production of Piwi-interacting RNAs (piRNAs). The potential for this cytotype regulation is significantly strengthened when either TP5 or TP6 is combined with a non-telomeric X-linked or autosomal transgene that contains a P element. By themselves, none of the transgenic P elements have any regulatory ability. Synergism between the telomeric and transgenic P elements is much greater when the TP is derived from a female. Once an enhanced regulatory state is established in a female, it is transmitted to her offspring independently of either the telomeric or transgenic P elements – that is, it works through a strictly maternal effect. Synergistic regulation collapses when either the telomeric or the transgenic P element is removed from the maternal genotype, and it is significantly impaired when the TPs come from stocks heterozygous for mutations in the genes aubergine, piwi or Su(var)205. The synergism between telomeric and transgenic P elements is consistent with a model in which P piRNAs are amplified by alternating, or ping-pong, targeting of primary piRNAs to sense and antisense P transcripts, with the sense transcripts being derived from the transgenic P element and the antisense transcripts being derived from the TP.
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Chen, Ming Qiang, Shao Min Liu, Feng Li, Zhong Lian Yang, and Ye Zhang. "The Study on Curing Kinetics of Lignin Based Epoxy Resin System Using Non-Isothermal DSC Method." Advanced Materials Research 788 (September 2013): 223–27. http://dx.doi.org/10.4028/www.scientific.net/amr.788.223.
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The synthesis of Lignin Base Epoxy Resin was based on industrial alkali lignin, and lignin-based epoxy resin curing characteristics were analyzed using the thermal weight loss technology under the oxygen atmosphere conditions. In light of the infra-red analysis of raw materials, the curing reaction kinetic parameters of lignin-based epoxy resin system were calculated using the Kissinger-Crane and Flynn-Wall-Ozawa method, and the curing reaction kinetics model of lignin-based epoxy resin system was established. The results showed that the kinetic parameters obtained using two methods were approximate, which validated that the curing reaction was consistent with the principle of the first-order reaction model. Initial curing temperature Ti0=454.88 K, curing temperature Tp0=507.55 K, and terminal temperature Tf0=598.77 K of lignin-based epoxy resin system were obtained when the extrapolation method was applied.
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Yuan, Cadmus, René Kregting, Willem van Driel, Sander Gielen, An Xiao, and G. Q. (Kouchi) Zhang. "Overview on Thermal and Mechanical Challenges of High Power RF Electronic Packaging." International Symposium on Microelectronics 2011, no. 1 (2011): 000418–29. http://dx.doi.org/10.4071/isom-2011-tp6-paper4.
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High Power RF electronics is one of the essential parts for wireless communication, including the personal communication, broadcasting, microwave radar, etc. Moreover, high efficient high power electronics has entered the ISM market, such as the power generator of microwave oven. Power electronics requires a close co-development of digital-analog mixed circuit design, high power IC manufacturing technologies, and high power packaging design/process, in order to guarantee their performance and lifetime. In this paper, we overviewed our works on the packaging/assembly development of high power packages, including three parts: (1) Thermal simulation and die bond defect control (2) Mechanical integrity model for soft package heatsink implementation (3) Al wire multiphysics modeling and reliability of plastic power package.
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Humaish, Hussein, and . "The Effect of Magnitude and Direction of Heat Flow on the Thermal Conductivity for Insulation Materials (Glass Wool) by Using Probe Method." International Journal of Engineering & Technology 7, no. 4.20 (2018): 536. http://dx.doi.org/10.14419/ijet.v7i4.20.26414.
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The thermal energy of building is determined by the thermal properties of the materials and how to install these materials in the elements of buildings according to the direction of heat transfer. The effectiveness of thermal insulation (glass wool) is dependent on its thermal conductivity which is varies in different directions of fibers of glass wool. Glass wool is formed of fibers and binders tangled together during the industrial process to provide some elasticity. The experimental values of thermal conductivity of the insulation materials are changed according to magnitude of the heat power and direction of fiber arrangement. The thermal conductivity for insulation materials has been measured by using probe method, Huekseflux ® TP02 used to measure the thermal conductivity by emit the flow perpendicular and parallel to the fibers of glass wool. Two samples of yellow glass wool (density 68 kg/m3) with dimensions (10 ×10 ×30) cm have been used. Hot Disk bulk isotropic module has been used to evaluate thermal conductivity. TPS source (Hot Disk probe reference: 4922) characterized by a diameter of 14.61 mm has been selected. COMSOL® multiphysics axisymmetric 2D model has been used to follow the axial and the radial directions of the heat transfer.
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Schafet, Natalja, Bruno Schrempp, Manfred Spraul, Ulrich Becker, and Herbert Güttler. "Location of the Critical Solder Joint of a PBGA under Temperature Cycling Load for SAC and SnPb Solder. Results of Experiments vs. FE-Simulations on System and Board Level." International Symposium on Microelectronics 2011, no. 1 (2011): 000409–17. http://dx.doi.org/10.4071/isom-2011-tp6-paper3.
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PBGAs with SnPb and SnAgCu (SAC) solder joints were stressed with temperature cycles on board- and system-level. A significant influence of the different solder materials on the location of the most damaged PBGA solder balls was observed in the experiment. The reason for this experimental finding was investigated and explained by FE–simulation. The simulations of the PBGAs were done on package-, board- and system-level (PCB within a metal housing). For the system level simulation a 2-step sub-model technique described in [1] was used. Through such an approach the transient PCB deformation and the transient temperature field within the ECU-housing can be incorporated into a creep simulation of the PBGA solder joints. The creep results for both SnPb and SnAgCu solder joints from the board- and system-level simulation were compared. The calculated damage factor due to the ECU-housing influence is different for PBGA with SnPb and SAC solder joints. The simulation results were validated step by step with measurements and experiments: warpage of the non-soldered PBGA, mechanical strain and temperature on the mounted PCB, crack length evaluation of all PBGA solder joints.
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BELINCO, CARINA, STEPHANIE N. DIPRIMA, RYAN E. WOLFF, MICHAEL W. THORP, JARED T. BUSCHETTE, and MICHAEL J. SIMMONS. "Cytotype regulation in Drosophila melanogaster: synergism between telomeric and non-telomeric P elements." Genetics Research 91, no. 6 (2009): 383–94. http://dx.doi.org/10.1017/s0016672309990322.
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SummaryThe X-linked telomeric P elements TP5 and TP6 interact synergistically with non-telomeric P elements to repress hybrid dysgenesis. In this repression, the telomeric P elements exert maternal effects, which, however, are not sufficient to establish synergism with the non-telomeric P elements. Once synergism is established, the capacity to repress dysgenesis in the offspring of a cross persists for at least two generations after removing the telomeric P element from the genotype. At the molecular level, synergism between telomeric and non-telomeric P elements is correlated with effective elimination of P-element mRNA in the germ line. Maternally transmitted mutations in the genes aubergine, piwi and Suppressor of variegation 205 [Su(var)205] block the establishment of synergism between telomeric and non-telomeric P elements, and paternally transmitted mutations in piwi and Su(var)205 disrupt synergism that has already been established. These findings are discussed in terms of a model of cytotype regulation of P elements based on Piwi-interacting RNAs (piRNAs) that are amplified by cycling between sense and antisense species.
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Liao, Yanling, Robyn D. Moir, and Ian M. Willis. "Interactions of Brf1 Peptides with the Tetratricopeptide Repeat-Containing Subunit of TFIIIC Inhibit and Promote Preinitiation Complex Assembly." Molecular and Cellular Biology 26, no. 16 (2006): 5946–56. http://dx.doi.org/10.1128/mcb.00689-06.
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ABSTRACT The binding of Brf1 to the tetratricopeptide repeat (TPR)-containing transcription factor IIIC (TFIIIC) subunit (Tfc4) represents a rate-limiting step in the ordered assembly of the RNA polymerase III initiation factor TFIIIB. Tfc4 contains multiple binding sites for Brf1 within its amino terminus and adjacent TPR arrays, but the access of Brf1 to these sites is limited by autoinhibition. Moreover, the Brf1 binding sites in Tfc4 overlap with sites important for the subsequent recruitment of another TFIIIB subunit, Bdp1, implying that repositioning of Brf1 is required after its initial interaction with Tfc4. As a starting point for dissecting the steps in TFIIIC-directed assembly of TFIIIB, we conducted yeast two-hybrid screens of Brf1 peptide libraries against different TPR-containing Tfc4 fragments. Short, biochemically active peptides were identified in three distinct regions of Brf1. Two peptides defined conserved but distal regions of Brf1 that participate in stable binding of Brf1 to TFIIIC-DNA. Remarkably, a third peptide that binds specifically to TPR6-9 of Tfc4 was found to promote the formation of both TFIIIC-DNA and Brf1-TFIIIC-DNA complexes and to reduce the mobility of these complexes in native gels. The data are consistent with this peptide causing a conformational change in TFIIIC that overcomes Tfc4 autoinhibition of Brf1 binding and suggest a structural model for the Brf1-Tfc4 interaction.
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Tsaur, Grigory, Alexander Popov, Tatyana Riger, et al. "Concordance and Prognostic Significance of Minimal Residual Disease Detection in Peripheral Blood and Bone Marrow Samples of Infants with MLL-rearranged Acute Lymphoblastic Leukemia Treated By MLL-Baby Protocol." Blood 124, no. 21 (2014): 2404. http://dx.doi.org/10.1182/blood.v124.21.2404.2404.
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Abstract Background. Minimal residual disease (MRD) is powerful tool for prediction of treatment outcome in leukemia patients of various age groups, including infants with acute lymphoblastic leukemia (ALL). In the vast majority of cases only bone marrow (BM) samples are used for MRD detection. Objective. To estimate prognostic significance of MRD in peripheral blood (PB) and BM by qualitative detection of different MLL fusion gene transcripts in infant ALL enrolled into MLL-Baby protocol. Methods. Fifty three infants (20 boys and 33 girls) with median age of 5.3 months (range 0.03-11.80) and defined MLL rearrangements were included in the current study. Among them there were 25 patients (47.2%) carrying MLL-AFF1 fusion gene transcripts, 10 (18.9%) MLL-MLLT3-positive cases, 9 (17.0%) MLL-MLLT1-positive cases, 5 (9.4%) MLL-MLLT10-positive cases and 4 (7.5%) MLL-EPS15-positive ones. MRD evaluation was performed by detection of MLL fusion gene transcripts in BM and PB samples using real-time PCR and nested RT-PCR with sensitivity non-less than 1E-04. MRD-negativity was defined as absence of fusion gene transcripts in both assays. Median of follow-up period in the observed group was 5.2 years. Time points (TP) for MRD assessment were as follows: day 15 of remission induction (TP1), at the end of remission induction (TP2), after each course of ATRA administration (TP3-TP7). Informed consent was obtained in all cases. Results. We estimated 142 paired BM/PB samples. 77 samples were double positive, 43 were double negative Thus concordance between MRD results in BM and PB samples achieved 84.5%. Concordance varied between different TPs of MLL-Baby protocol from 79.0% to 100%. The highest concordance rate was at TP4 and TP7 (92.3% and 100%, respectively). Interestingly, all discrepant results (22 samples 15.5%) were BM-positive/PB-negative. Median level of ABL gene, used for normalization, was similar in BM and PB samples (4.85E+04 vs 4.95E+04, respectively, p=0.760). Evaluation of prognostic significance of MRD in BM in TP1-TP7 revealed that TP4 was the earliest TP when discriminative data between MRD-positive and MRD-negative patients were obtained. MRD-positivity at TP4 in BM led to unfavorable outcome. Event-free survival was significantly lower in MRD-positive group (n=22) in comparison to MRD-negative one (n=31) (0.06±0.06 vs 0.70±0.09 p=0.0001), while cumulative incidence of relapse in MRD-positive patients was remarkably higher (0.92±0.01 vs 0.29±0.08, p<0.0001). MRD-positivity at this TP in BM was the only significant factor in the diagnostic model where initial risk factors (age at diagnosis, initial WBC count, immunophenotype, CNS disease, presence of MLL-AF4) were combined to response criteria (number of blast cells at day 8 of dexamethasone prophase and MRD in BM at TP4) (Table). The only TP when MRD data obtained from PB samples had prognostic value was TP6. In this TP cumulative incidence of relapse in MRD-positive patients was significantly higher in comparison to MRD-negative ones (0.88±0.11 vs 0.25±0.13, respectively, p=0.003). However these data did not bring any extra advantages as compared to TP4 in BM. Conclusions. Despite high qualitative concordance rate between MRD detection in BM and PB samples we could not show prognostic value of MRD monitoring in PB by fusion gene transcripts. Univariate and multivariate analysis revealed that MRD-positivity at TP4 in BM was the only significant and independent prognostic factor of unfavorable outcome in the observed group of patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Pravdin, Sergei F., Timofei I. Epanchintsev, and Alexander V. Panfilov. "Overdrive pacing of spiral waves in a model of human ventricular tissue." Scientific Reports 10, no. 1 (2020). http://dx.doi.org/10.1038/s41598-020-77314-5.
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AbstractHigh-voltage electrical defibrillation remains the only reliable method of quickly controlling life-threatening cardiac arrhythmias. This paper is devoted to studying an alternative approach, low-voltage cardioversion (LVC), which is based on ideas from non-linear dynamics and aims to remove sources of cardiac arrhythmias by applying high-frequency stimulation to cardiac tissue. We perform a detailed in-silico study of the elimination of arrhythmias caused by rotating spiral waves in a TP06 model of human cardiac tissue. We consider three parameter sets with slopes of the APD restitution curve of 0.7, 1.1 and 1.4, and we study LVC at the baseline and under the blocking of INa and ICaL and under the application of the drugs verapamil and amiodarone. We show that pacing can remove spiral waves; however, its efficiency can be substantially reduced by dynamic instabilities. We classify these instabilities and show that the blocking of INa and the application of amiodarone increase the efficiency of the method, while the blocking of ICaL and the application of verapamil decrease the efficiency. We discuss the mechanisms and the possible clinical applications resulting from our study.
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Leenknegt, L., K. Zeppenfeld, A. Panfilov, and H. Dierckx. "Insights into the intracardiac electrogram from analytical and numerical modelling." EP Europace 24, Supplement_1 (2022). http://dx.doi.org/10.1093/europace/euac053.567.
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Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): FWO-Flanders, KU Leuven internal starting grant Introduction and Purpose Cardiac electrograms (EGMs) are one of the most important recordings obtained during electroanatomical voltage mapping and lie at the basis for planning most clinical electrophysiological interventions. Despite its widespread use, the relation of EGM shape and amplitude to the underlying excitation patterns and properties of cardiac tissue is not completely understood. Recent clinical studies [1] have provided important new guidelines on the relation between EGM amplitudes and the thickness of myocardial walls. The aim of this study is to quantify the effect of the wall thickness on EGM amplitudes and duration using analytical and in-silico approaches. Methods We study bipolar EGMs both in-silico and analytically in a homogeneous slab of cardiac tissue (70 x 70 x L mm), where L = 2, 5, or 10 mm, with parallel fiber direction. Simulations were performed using the cardiac electrophysiology simulator openCARP [2]. Cardiac cells were described by the ten Tusscher-Panfilov 2006 model (TP06) [4] with epicardial tissue parameters. A plane wave propagating along the fiber direction was initiated. The extracellular voltage at 147 points arranged in a hemisphere around a point was measured to study the effect of bipolar electrode orientation (see Fig. 1A [3]). In addition, we developed an analytical approach to obtain an EGM, using an equivalent dipole representation of the depolarization wavefront and analytical evaluation of the corresponding integrals. Results Fig. 1B and 1C show the dependency of the EGM properties on the electrode orientation, as represented by the angles α (incidence angle) and β (angle between electrode and propagation direction) [3]. Solid lines represent data from a state-of-the-art numerical methodology, the dashed lines show our analytical estimations. Both the peak-to-peak amplitude and EGM width are well approximated by our theory for all orientations of the electrodes. Fig. 2 shows how the EGM is influenced by the myocardial wall thickness L. Both the amplitude and the duration are in good agreement with our theory. We observe that the amplitude as well as the width increase with the slab thickness, confirming the result in [1] but also delivering an accurate analytical expression for this change. It may thus allow to discriminate effects of thickness and other factors affecting the EGMs, such as substrate abnormalities, for example. Conclusion We developed an analytical approach which can correctly describe the amplitude, duration, and shape of the depolarization part of the EGM. Our theory agrees with the previous in-silico and clinical studies on the influence of catheter orientation [3,5], and wall thickness [1,3]. Subsequent work in this direction is expected to provide better guidelines for clinical interpretation of EGMs, accounting for the effects of the thickness of myocardial wall in the characterization of the substrate of cardiac arrhythmias.
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Chiang, Terrance, Sean Harvey, Arjun V. Pendharkar, Michelle Y. Cheng, and Gary K. Steinberg. "Abstract TP106: Automated Assessment of Behavioral Function After Experimental Stroke." Stroke 51, Suppl_1 (2020). http://dx.doi.org/10.1161/str.51.suppl_1.tp106.
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Introduction: Manual scoring of behavior tests is commonly used for assessing motor deficits after stroke, however, it is labor intensive and subject to bias. These limitations lead to inconsistent assessment between research groups and non-reproducible data. In this study, we investigated the feasibility of an automated motor deficit assessment system, Erasmus ladder, in two ischemic stroke models. Methods: Distal middle cerebral artery occlusion (dMCAO n=10) or transient middle cerebral artery occlusion (tMCAO 30 minutes, n=15) were performed on male C57BL6J mice (11-13 weeks) to generate cortical ischemic stroke, with. Naïve mice (n=10) were used as controls. Immunohistochemistry was performed on brains collected at post-stroke day (PD) 30 to assess for infarct size (MAP2) and inflammation (CD68). Mice without infarct in both cortex and striatum were excluded from the study. Behavior was assessed using Erasmus ladder at pre-stroke baseline (4 unperturbed and 4 perturbed sessions) and on PD 7, 14, 21, and 28 (all perturbed sessions). Results: Erasmus ladder detected significant motor deficits in the tMCAO model, specifically in the pre- and post- perturbed times as well as several key step types (HH long). Analyses in the tMCAO model reveal changes in various step patterns and their capability to react to the perturbation (obstacle). These significant motor deficits after tMCAO were detectable until PD28. We also observed a sustained decline in the use of affected limb compared to unaffected limb until PD28. While this trend is also present in dMCAO model, motor deficits were detected in the dMCAO only at early timepoints (PD7) and the difference subsided by PD28. Conclusion: We have assessed the data collected by Erasmus ladder on mice that underwent two commonly used stroke models (tMCAO and dMCAO). Our data showed that Erasmus ladder can detect long term motor deficit including reduced use of affected limb, step pattern, and motor reaction to obstacle. This automated instrument is effective in detecting motor deficits in the tMCAO model and thus, can be used to evaluate treatments for enhancing recovery after stroke.
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Hosseini, Thomas K., Alexander B. Remsik, Veena A. Nair, Anthony H. Bui, and Vivek PRABHAKARAN. "Abstract TP60: Stroke Recovery Using Brain Computer Interface." Stroke 53, Suppl_1 (2022). http://dx.doi.org/10.1161/str.53.suppl_1.tp60.
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Introduction: Non-invasive electroencephalographic (EEG) based brain-computer interface (BCI) therapy has been shown to increase upper extremity mobility in stroke survivors with persistent upper extremity motor impairment. Previous studies have shown that in order to evoke movement from a particular motor system, sensory cues are combined in an essentially linear model. That is, the feedback from each sensory system is summed and torque is generated as a function of the summed signal. This subanalysis aims to evaluate the efficacy of EEG-based BCI-functional electrical stimulation (FES). The goal was to determine whether greater sensory feedback improves BCI task performance in stroke survivors with upper extremity motor impairment. Methods: Data were acquired from 31 ischemic stroke patients, with persistent upper extremity motor impairment (mean age = 66 years old, F = 14, M = 17, mean time since stroke onset = 100 months). Participants were kept in one group and all patients received two types of therapies: BCI-only therapy followed by BCI-FES therapy. Participants were instructed to move either their left or right hand to control a virtual cursor in a cursor and target task. A successful trial was recorded if the participant successfully moved the cursor into the target area. The task was first performed with only visual stimulation, then participants received cutaneous stimulation via the paired FES in addition to the visual display of the cursor and target. EEG data was acquired using BCI2000 software and a 16 channel EEG cap. Results: Although improvement was seen for participants when they received BCI therapy as well as when they received BCI-FES therapy, BCI performance scores over time were not significantly different from one another (p = 0.13). The BCI-only and BCI-FES pre-study averages were 5.58 (SD = 1.64) and 5.86 (SD = 1.66) respectively and the post-study averages were 5.99 (SD = 1.41) and 6.33 (SD = 1.75) respectively. Conclusions: For chronic stroke survivors, both BCI visual only and BCI-FES intervention may help promote restoration of upper extremity motor function at similar rates.
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Xie, Dong, Fangyi Xu, Wenchao Zhu, et al. "Delta radiomics model for the prediction of progression-free survival time in advanced non-small-cell lung cancer patients after immunotherapy." Frontiers in Oncology 12 (October 6, 2022). http://dx.doi.org/10.3389/fonc.2022.990608.
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ObjectiveTo assess the validity of pre- and posttreatment computed tomography (CT)-based radiomics signatures and delta radiomics signatures for predicting progression-free survival (PFS) in stage III-IV non-small-cell lung cancer (NSCLC) patients after immune checkpoint inhibitor (ICI) therapy.MethodsQuantitative image features of the largest primary lung tumours were extracted on CT-enhanced imaging at baseline (time point 0, TP0) and after the 2nd-3rd immunotherapy cycles (time point 1, TP1). The critical features were selected to construct TP0, TP1 and delta radiomics signatures for the risk stratification of patient survival after ICI treatment. In addition, a prediction model integrating the clinicopathologic risk characteristics and phenotypic signature was developed for the prediction of PFS.ResultsThe C-index of TP0, TP1 and delta radiomics models in the training and validation cohort were 0.64, 0.75, 0.80, and 0.61, 0.68, 0.78, respectively. The delta radiomics score exhibited good accuracy for distinguishing patients with slow and rapid progression to ICI treatment. The predictive accuracy of the combined prediction model was higher than that of the clinical prediction model in both training and validation sets (P&lt;0.05), with a C-index of 0.83 and 0.70, respectively. Additionally, the delta radiomics model (C-index of 0.86) had a higher predictive accuracy compared to PD-L1 expression (C-index of 0.50) (P&lt;0.0001).ConclusionsThe combined prediction model including clinicopathologic characteristics (tumour anatomical classification and brain metastasis) and the delta radiomics signature could achieve the individualized prediction of PFS in ICIs-treated NSCLC patients.
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Shin, Yerim, Jee Suk Chang, Yeseul Kim, et al. "Mathematical prediction with pretreatment growth rate of metastatic cancer on outcomes: implications for the characterization of oligometastatic disease." Frontiers in Oncology 13 (May 29, 2023). http://dx.doi.org/10.3389/fonc.2023.1061881.
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BackgroundOligometastatic disease (OMD) represents an indolent cancer status characterized by slow tumor growth and limited metastatic potential. The use of local therapy in the management of the condition continues to rise. This study aimed to investigate the advantage of pretreatment tumor growth rate in addition to baseline disease burden in characterizing OMDs, generally defined by the presence of ≤ 5 metastatic lesions.MethodsThe study included patients with metastatic melanoma treated with pembrolizumab. Gross tumor volume of all metastases was contoured on imaging before (TP-1) and at the initiation of pembrolizumab (TP0). Pretreatment tumor growth rate was calculated by an exponential ordinary differential equation model using the sum of tumor volumes at TP-1 and TP0 and the time interval between TP-1. and TP0. Patients were divided into interquartile groups based on pretreatment growth rate. Overall survival, progression-free survival, and subsequent progression-free survival were the study outcomes.ResultsAt baseline, median cumulative volume and number of metastases were 28.4 cc (range, 0.4-1194.8 cc) and 7 (range, 1-73), respectively. The median interval between TP-1 and TP0 was -90 days and pretreatment tumor growth rate (×10-2 days-1) was median 4.71 (range -0.62 to 44.1). The slow-paced group (pretreatment tumor growth rate ≤ 7.6 ×10-2 days-1, the upper quartile) had a significantly higher overall survival rate, progression-free survival, and subsequent progression-free survival compared to those of the fast-paced group (pretreatment tumor growth rate &gt; 7.6 ×10-2 days-1). Notably, these differences were prominent in the subgroup with &gt;5 metastases.ConclusionPretreatment tumor growth rate is a novel prognostic metric associated with overall survival, progression-free survival, and subsequent progression-free survival among metastatic melanoma patients, especially patients with &gt;5 metastases. Future prospective studies should validate the advantage of disease growth rate plus disease burden in better defining OMDs.
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Cohen, Audrey S., Jesse A. Potestas, Nidha Sha, et al. "Abstract TP206: Vascular Risk Factors And Stimulant Use Among Stroke Patients." Stroke 53, Suppl_1 (2022). http://dx.doi.org/10.1161/str.53.suppl_1.tp206.
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Background: In 2019, an estimated 7.3 US million adults had used stimulants in the past year. Stimulant use is associated with increased stroke risk, yet the prevalence of common stroke risk factors (RFs) in patients who use stimulants is not well described. We sought to examine the association between stimulant use and the presence of stroke risk factors (RFs) in stroke patients. Methods: We conducted an IRB approved retrospective review of ischemic and hemorrhagic stroke patients admitted 9/2019 through 9/2020. Inclusion criteria were age ≥18 and completion of a urine drug screen (UDS) on admission. Logistic regression was used to model the association of RFs (hypertension, type 2 diabetes (DMII), hyperlipidemia, atrial fibrillation, and coronary disease) to acute stimulant use, adjusting for socio-demographic characteristics. Results: Among 1878 patients screened, 814 (43.3%) had a UDS. UDS was more common in younger (median age 60 vs 67), male (60.4% vs 47.6%) and Black (35.6% vs 27.5%) and Hispanic (22.0% vs 21.6%) patients. Of those with UDS, 72(8.84%) had cocaine and/or amphetamine detected and 660 (81.08%) were UDS negative. After controlling for age, sex, race, and insurance status, hypertension (OR 2.28, 95%CI 1.17-4.41) was positively associated with stimulant use while DMII was negatively associated (OR 0.39, 95%CI 0.19-0.81). Other RFs were not associated with stimulant use. Conclusion: Despite being younger, stroke patients with stimulant-positive UDS had a higher prevalence of hypertension, a leading risk factor for recurrent stroke, than UDS-negative patients. This group may represent a high-risk population that may benefit from targeted interventions for secondary stroke prevention. Differences in screening by sex, race, and age may lead to missed opportunities for assessment of recurrent stroke risk. A standard approach to drug screening may eliminate these biases.
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Sakai, Yu, Quy Cao, Pouyan Pasyar, et al. "Abstract TP86: Systematic Review Of Aortic Atherosclerotic Plaque In Cryptogenic Stroke." Stroke 54, Suppl_1 (2023). http://dx.doi.org/10.1161/str.54.suppl_1.tp86.
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Introduction: In patients with cryptogenic stroke (CS), complex aortic plaque may be a potential underlying etiology. We performed a systematic review to determine the prevalence of complex aortic plaque in CS patients. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines (PROSPERO: CRD42022300865). PubMed and EMBASE databases were searched from Jan 1980 to Nov 2021 for studies assessing aortic (ascending, arch, descending) plaque by transesophageal echocardiogram (TEE), CT/CTA, or MRI in at least 10 CS patients. Prevalence rates were pooled using a random-effects model. I 2 statistics assessed heterogeneity. An Egger’s test assessed publication bias. Results: From 2712 articles, 31 met inclusion criteria. Ascending, arch, and descending aorta were assessed in 65%, 100%, 55% of studies, respectively. Studies investigated aortic plaque by TEE (84%), CT/CTA (19%) and MRI (16%). The prevalence of complex aortic plaque in 4666 CS patients was heterogeneous across studies and yielded a summary prevalence of 30% (95% CI 23-38%, I 2 = 96%; Figure 1) contrasting with 11% (95% CI 5-20%, I 2 =83%) in 677 patients without stroke. Prevalence rates in women and men were 26% (95% CI 14%-43%, I 2 = 94%) and 35% (95% CI 21-52%, I 2 = 97%), respectively. To investigate geographic differences, 14 studies from Europe were pooled (32%, 95% CI 23-43%, I 2 =93%), 3 from the Middle East (34%, 95% CI 11-67%, I 2 =94%) and 3 from the US (28%, 95% CI 13-51%, I 2 =90%). No publication bias was detected (p=0.66). Sources of heterogeneity included patient selection, imaging technology (e.g, transducer frequency) and plaque measurement criteria. Conclusions: Studies suggest a prevalence rate of complex aortic plaque in approximately 30% of CS patients. However, significant heterogeneity in the results indicate a need for less variability in CS patient selection and more reproducible imaging methods/criteria for detecting complex aortic plaque.
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Norris, David, and Drew G. Levy. "Abstract T P206: An Executable Graphical Model for In Silico Prototyping of Processes for Acute Stroke Care." Stroke 46, suppl_1 (2015). http://dx.doi.org/10.1161/str.46.suppl_1.tp206.
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Background: Strong evidence shows neurologic outcomes in acute ischemic stroke (AIS) worsen with delay from symptom onset to thrombolytic therapy. Yet this onset-to-treatment (OTT) time has not decreased in most systems of care over the past decade. Even the in-hospital, “door-to-needle” (DTN) component of this delay is unimproved, notwithstanding exceptions in institutions where innovative quality improvement efforts have borne fruit. Objective: Provide a basis for visualizing, communicating, and simulating stroke care system configuration and performance to facilitate the quality improvement efforts necessary for reducing DTN and OTT times in AIS. Methods: We developed an executable, graphical model of acute stroke care, employing the hierarchical colored Petri net (CPN) formalism. The top level of the hierarchy sets the epidemiologic context, including demographics and background processes like stroke prevention and onset. At deeper levels, we elaborate time-critical processes that contribute to OTT: stroke recognition, EMS activation and transport, and many emergency department (ED) processes. Key ED innovations described in the literature were modeled: EMS prenotification, a direct-to-imaging transport strategy, process parallelism, and telestroke capability. Results: Our CPN model has provided a platform for detailed, realistic prototyping and simulation of acute stroke care processes. The performance characteristics of process configurations with multiple, interacting innovations were evaluated and compared. Conclusions: In silico care process prototyping permits evaluation of proposed innovations in simulated settings. Using an intensively graphical simulation modeling methodology adds value by promoting “visual consensus” regarding care process structure and function, among stakeholders in a quality improvement initiative.
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Loveless, Mark O., Aaron Kamauu, and Andrew Wilson. "Abstract TP406: Mapping Stroke Team Network Structure and Function to Enhance Acute Stroke Care Quality Improvement Efforts." Stroke 47, suppl_1 (2016). http://dx.doi.org/10.1161/str.47.suppl_1.tp406.
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Background: Acute ischemic stroke (AIS) clinical outcomes are time-dependent and are influenced by the organization and capability of the care delivery system. The focus of stroke care quality improvement has emphasized process and procedure. Integrating a systematic assessment of the structure and inter-dependencies of the stroke care team members has the potential to enhance the understanding of the overall function of the team and strengthen existing quality improvement efforts. Objective: Describe a multi-modal quality improvement approach consisting of process/clinical outcome measures, workflow analysis and personnel structure mapping of acute stroke care teams. Method: Key site-specific hospital characteristics, including the variability of stroke treatment processes of individual teams, were identified. A critical path analysis was created based on a standard acute stroke care process model. Stroke care team structures and inter-dependencies were mapped based on the responses to a short survey and the responses were analyzed using open source network analytic software (Gephi). Analysis results were interpreted in context of the characteristics of the hospital units. Results: The care team personnel structures were overlayed on the stroke care process pathways to create a final synthesis of the process and team structure ( (Example in figure below). Critical path analyses combined with previously unidentified opportunities to strengthen the individual team member interactions were linked to process/clinical outcomes. Opportunities for site-specific improvement in both process and personnel organization and communication were identified. Case studies will be presented. Conclusion: A clinical microsystems analytic approach that includes formal site-specific representations of the care team structure is feasible and provides a valuable addition to process analysis for quality improvement programs.
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Kidwell, Chelsea S., Reza Jahan, Jeffrey Gornbein, et al. "Abstract T P26: Combining Clinical and Imaging Data to Develop a Highly Predictive Model of Outcomes in the MR RESCUE Trial." Stroke 46, suppl_1 (2015). http://dx.doi.org/10.1161/str.46.suppl_1.tp26.
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Background: Identifying patient characteristics that predict outcomes in acute ischemic stroke may assist in triaging those who are candidates for endovascular therapies. We sought to identify predictors of outcome in the overall Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) cohort and compare results to the previously validated Totaled Health Risks in Vascular Events (THRIVE) score. Methods: MR RESCUE randomized 118 acute ischemic stroke patients with multimodal imaging to embolectomy or standard care within 8 hours of onset. For this analysis, we investigated 17 baseline variables (e.g. age, predicted core volume, time to enrollment) and 8 intermediate variables (e.g. hemorrhagic transformation, day 7 recanalization, final infarct volume) with the potential to impact outcomes (day 90 mRS). The baseline variables were analyzed employing bivariate and multivariate methods (random forest and logistic regression). Two models were developed, one including only significant baseline variables, and the second also incorporating significant intermediate variables. Results: A multivariate model (Table) employing only baseline covariates achieved an overall accuracy (C statistic) of 85% in predicting poor outcome (day 90 mRS 3-6) compared to 80.5% for the THRIVE score. A second model (Table) adding significant intermediate variables achieved 89% accuracy in predicting day 90 mRS. Conclusions: In the MR RESCUE trial, advanced imaging variables, including predicted core volume and site of vessel occlusion, contributed to a highly accurate multivariable model of outcome. In the development phase, this model achieved higher accuracy than the THRIVE score. Future studies are needed to validate this model in an independent cohort.
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Otero Ortega, Laura, María Gutiérrez Fernández, Berta Rodríguez Frutos, et al. "Abstract TP96: Functional Recovery and White Matter Repair After Exosomes Administration in Different Experimental Animal Models of Stroke." Stroke 47, suppl_1 (2016). http://dx.doi.org/10.1161/str.47.suppl_1.tp96.
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Introduction: Extracellular vesicles such as exosomes has opened a new field of research. Exosomes are able to transfer DNAs, mRNAs, microRNAs, non-coding RNAs, proteins, trophic factors and lipids associated with brain plasticity enhancement after stroke. Aim: To investigate white matter repair after exosomes administration in two experimental models of subcortical stroke: ischemic and hemorrhage. Material/Methods: Subcortical ischemic stroke was induced by Endothelin-1 and Collagenase IV was used to induce subcortical hemorrhagic stroke into striatum. Intravenous exosomes or saline only were administrated at 24h after cerebral infarct as treatment. Exosomes were isolated from culture of adipose mesenchymal stem cell and they were characterized by Nanoshight, Electronic microscope, Western blot and Immunofluorescence. Proteins contained into exosomes were analyzed by Orbitrab. We analyzed functional recovery by Rotarod, beam walking and Rogers tests. Lesion volume and tract connectivity were studied by magnetic resonance image. Anterograde and retrograde tracers were used to analyze axonal sprouting. Myelin formation was analyzed by cryomielin. Results: Proteomics analysis of exosomes identified more than 1400 proteins, many of them involved in intercellular communication. DiI labeled-Exosomes were detected in brain and peripheral organs (liver, lung and spleen). After 28 days, treated groups showed smaller functional deficit compared to control groups in both hemorrhagic and ischemic models. Moreover, treated group showed an increase in tract connectivity at 7 and 28 days compared to control groups. Also, animals which received exosomes showed an increase axonal sprouting and myelin formation at 28 days after stroke in both hemorrhagic and ischemic stroke. The treated groups also showed higher levels of white matter-associated markers in the injured area than the control groups. Conclusion: White matter integrity in different subcortical strokes is in part restored by exosomes treatment, probably mediated by repair molecular factors implicated in axonal sprouting, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery in both kinds of strokes.
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Page, Shyanne, Ronak Patel, and Abraham Alahmad. "Abstract TP86: The Ischemic Blood-brain Barrier In A Dish: Use Of Patient-derived Stem Cells To Model The Response Of The Neurovascular Unit To Oxygen-glucose Deprivation Stress." Stroke 48, suppl_1 (2017). http://dx.doi.org/10.1161/str.48.suppl_1.tp86.
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The blood-brain barrier (BBB) constitutes a component of the neurovascular unit formed by specialized brain microvascular endothelial cells (BMECs) surrounded by astrocytes, pericytes and neurons. During ischemic stroke injury, the BBB constitutes the first responding element resulting in the opening of the BBB and eventually neural cell death by excitotoxicity. A better understanding of the cellular mechanisms underlying the opening of the BBB during ischemic stroke is essential to identify targets to restore such barrier function after injury. Current in vitro models of the human BBB, based on primary or immortalized BMECs monocultures, display poor barrier properties but also lack one or two cellular components of the neurovascular unit.In this study, we designed an integrative in vitro model of the BBB by generating BMECs, astrocytes and neurons using patient-derived BMECs from two iPSC lines (IMR90-c4 and CTR66M). We were able to obtain all three cell types from these two cell lines. iPSC-derived BMECs showed barrier properties similar or better barrier function than hCMEC/D3 monolayer (an immortalized adult somatic BMEC). Furthermore, iPSC—derived astrocytes were capable to induce barrier properties in BMECs upon co-cultures. whereas iPSC-derived neurons were capable to form extensive and branched neurites. Upon OGD stress, iPSC-derived BMECs showed a disruption of their barrier function as early as 6 hours of OGD stress and showed a complete disruption by 24 hours. Such disruption was reversed by reoxygenation. Interestingly such barrier disruption occurs through a VEGF-independent mechanism. In the other hand, iPSC-derived neurons showed a significant decrease in cell metabolic activity preceding neurites pruning. Finally, astrocytes showed the most robust phenotype, as we noted no cell death by 24 hours OGD.In this study, we demonstrated the ability to differentiate three cell types from the same patient in two iPSC lines. We also demonstrated the ability of these cells to respond to OGD/reoxygenation stress in agreement with the current literature. We are currently investigating the molecular mechanisms by which OGD/reoxygenation drive the cellular response in these cell types.
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Young, Brittany A., Fawad Yousuf, Sadia Waheed, and Jessica Lee. "Abstract TP306: The Problem With Transitions: An Evaluation of Appointment Compliance in the Transition of Care Clinic." Stroke 51, Suppl_1 (2020). http://dx.doi.org/10.1161/str.51.suppl_1.tp306.
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Background: Stroke is the fifth leading cause of death in the US and a leading cost of disability. The National Transitions of Care (TOC) Coalition has developed a conceptual model of transitional care that defines TOC as an efficient transfer, verification, and clarification of information between communicating providers. The TOC model assumes that, not only are providers accountable in communicating and receiving pertinent information, but most important, that patients and families are engaged throughout the process. Post-stroke treatment non-adherence may impact morbidity and mortality, hospital readmission rates, recurrent stroke risk, and may lead to decreased quality of life. To improve post-acute stroke care, we developed an Advance Practice Provider (APP) driven Stroke TOC Clinic at our institution. We sought to compare rates of appointment adherence in this clinic with that of previously routine 90 day follow up, hypothesizing that a sooner appointment would be associated with greater appointment adherence, given the acuity of the diagnosis of stroke. Methods: A single center retrospective chart review was conducted for all stroke patients who were discharged home and scheduled for an appointment in the TOC Clinic between June 1, 2018 to August 31, 2018. TOC appointments were scheduled within 3-14 days. Adherence rates were compared to routine 90-day follow-up visits between March 1, 2014 to June 30, 2014. Results: During the study period, 143 patients were offered a TOC follow-up appointment. Each patient was contacted, via phone, within 48 hours of hospital discharge by an APP. 58% of patients (n=83) completed appointments; whereas, 24.5% (n=35) no-showed, and 17.5% (n=25) declined/cancelled the appointment. Compared to the 2014 routine stroke follow-up patients, 58% (n=204) completed appointments; whereas, 32% (n=113) no-showed, and 10% (n=36) declined/cancelled the appointment. Conclusions: The results were contrary to the hypothesis. No show rates were not different between the 2018 TOC follow-up group as compared to the 2014 routine follow-up group. The study is ongoing by evaluating other factors that may affect show rates (ie patient gender, geographic location, and insurance status) and how this affects post-acute stroke care.
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Vigilante, Nicholas, Karan Patel, Solomon Oak, Miriam Butler, Jesse M. Thon, and James E. Siegler. "Abstract TP106: Outcomes Following Off-label Glyburide In Large Hemispheric Infarction: A Single-center Experience." Stroke 54, Suppl_1 (2023). http://dx.doi.org/10.1161/str.54.suppl_1.tp106.
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Background: One in 10 ischemic strokes are large hemispheric infarctions (LHI), half of which cause cerebral edema that can lead to significant mortality. Our center implemented a protocol using acute glyburide in patients with LHI to determine its safety and efficacy in reducing formation of cerebral edema. Methods: Consecutive adult patients at our center (10/2019-08/2021) with LHI who met criteria for the CHARM trial were treated with glyburide per an institutional protocol (2.5mg per nasogastric tube twice daily for 3 days) with multi-disciplinary oversight. Unadjusted logistic regression was used to estimate odds of a favorable shift in 90-day modified Rankin Scale (mRS), with adjustment for age, pre-stroke mRS, National Institutes of Health Stroke Scale (NIHSS) and large vessel occlusion (LVO). Propensity-score matching was used to model shift in 90-day mRS. Safety events were also assessed. Results: Of 1684 stroke patients treated at our center, 95 met criteria for CHARM and were included, among whom 21 completed the glyburide protocol (28 attempted) and 67 received standard-of-care (SOC); 34 patients were propensity-matched (nglyburide=17). Compared to SOC (n=67), patients treated with glyburide (n=21) had similar pre-stroke mRS, NIHSS, and LVOs, but were younger (median 61y vs. 67y, p<0.01). Glyburide was not associated with a favorable shift in 90-day mRS in unadjusted (OR 1.40, 95%CI 0.51-3.88) or adjusted regression (OR 0.71, 95%CI 0.17-2.94), or following propensity score matching (OR 1.39, 95%CI 0.32-6.07). There was no significant reduction in midline shift in unadjusted, adjusted, or propensity score-matched models (p>0.05). Two patients required D50 rescue, and 1 did not complete the protocol due to recurrent hypoglycemia. Conclusions: In this single center analysis, glyburide was found to have a low risk of hypoglycemic events. Despite the small sample size, there was no signal of better clinical or imaging outcomes in treated patients.
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Loe, Adrian Kwan Ho, Roshane Francis, Jieun Seo, et al. "Uncovering the dosage-dependent roles of Arid1a in gastric tumorigenesis for combinatorial drug therapy." Journal of Experimental Medicine 218, no. 6 (2021). http://dx.doi.org/10.1084/jem.20200219.
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Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.
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Huang, Lei, Evan Snyder, and Jean-Pyo Lee. "Abstract T P76: Human Neural Stem Cells Rapidly Ameliorate Symptomatic Inflammation In Ischemic-Reperfusion Cerebral Injury." Stroke 45, suppl_1 (2014). http://dx.doi.org/10.1161/str.45.suppl_1.tp76.
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Ischemic stroke injury results not only from ischemia but also from reperfusion. Stroke causes a loss of cerebral parenchyma and its associated cells, disruption of neuronal connections, compromise of the blood-brain barrier, and inflammation. We tested whether exogenously engrafted human neural stem cells (hNSCs) could migrate rapidly and extensively to damaged regions following intracranial transplantation and counteract a number of these pathological processes. We used a stroke mouse model with middle cerebral artery occlusion (MCAO) to induce focal ischemia followed by reperfusion. We transplanted hNSCs 24 hours after MCAO to correspond to the upregulation of endogenous proinflammatory cytokines, which can act as stem cell-recruiting factors. We found that 24 hrs post-transplantation, engrafted hNSCs had migrated extensively to the lesion, brain infarct volume was reduced, and behavioral function was significantly improved compared to MCAO controls. Because the time course of this repair was too short for cell replacement, we hypothesized that the mechanisms of therapeutic action are anti-inflammatory. Microglial activation and proinflammatory gene expression (TNF-α, IL-6, and IL-1β) were reduced, and blood-brain barrier damage was ameliorated in hNSC-transplanted mice. Our findings demonstrate clear benefits of transplanting hNSCs during the early stages of ischemic stroke.
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Zeiler, Steven R., Robert B. Hubbard, Ellen M. Gibson, et al. "Abstract T P86: Paradoxical Motor Recovery From a First Stroke By Re-opening a Sensitive Period With a Second Stroke." Stroke 46, suppl_1 (2015). http://dx.doi.org/10.1161/str.46.suppl_1.tp86.
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Background and Purpose: After stroke, there is a time-limited period of increased responsiveness to training due to heightened plasticity, which is thought to be induced by ischemia itself. Using a mouse model we have previously shown that most training-associated recovery after a caudal forelimb area (CFA - rodent primary motor cortex) stroke occurs in the first week and is attributable to reorganization in the medial premotor area (also called agranular medial cortex - AGm). The idea of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and lead to paradoxically enhanced recovery from the first stroke. To test this prediction, we induced a second focal stroke in the medial premotor area of mice with incomplete recovery after a first focal stroke in CFA. Methods: C57Bl/6 mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance after which they underwent photocoagulation-induced stroke in CFA. After a 7 day post-stroke delay, the mice were then retrained for 21 days. A second photocoagulation-induced stroke was then induced in the medial premotor area and the mice were re-trained for 8 days after only a one-day delay. Results: Focal CFA stroke led to a decrement in skilled prehension. Training-associated recovery of prehension begun 7 days after stroke induction was incomplete even with 21 days of training. At post-stroke day 21, a second focal stroke in the medial premotor area was induced, which now led to a dramatic response to training with recovery to normal performance after 8 days of training. Conclusions: Together, these data indicate that new ischemia can re-open a sensitive period and mediate full recovery from a previous stroke. Future work will need to characterize what the critical molecular pathways are that ischemia triggers.
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Ali, Syed F., Gregg Fonarow, Eric Smith, et al. "Abstract TP306: Characteristics and Outcomes Among Patients Transferred to Regional Stroke Centers Across the United States for Specialized Stroke Care." Stroke 47, suppl_1 (2016). http://dx.doi.org/10.1161/str.47.suppl_1.tp306.
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Intro: Many patients are transferred to stroke centers for advanced stroke care, especially after IV tPA. We sought to determine differences in the baseline characteristics and outcomes between AIS cases presenting directly to stroke centers’ front doors vs. transfers-in from another regional acute care hospital. Methods: Using data from the national GWTG-Stroke registry, we analyzed 970,390 AIS cases (01/2010 - 03/14). Patients at hospitals with high transfer-in rates (>15%) were selected (284 hospitals, 303,739 patients). Due to large sample size, instead of p-values, standardized differences were reported. Multivariable model (MV) examined the association of transfer-in vs. front door with the primary and secondary outcomes, adjusting for patient and hospital characteristics including NIHSS. Results: High volume transfer-in hospitals admitted 31% of their patients via transfer. Transfer-in patients were younger, more often white and non-Hispanic. They had similar stroke risk factors except for hypertension and previous stroke/TIA which were less common. Transfer-in had worse initial NIHSS, more often had altered consciousness and language disturbance. Transfer-in patients had longer length of hospital stay, higher mRS at discharge, and were less often discharged home. In-hospital mortality was ∼ 3% higher in transfer-in as compared with front-door. Among tPA treated patients, sICH < 36hr was more common in transfer-in patients. On MV, transfer-in patients had overall worse outcomes as shown by the higher odds of in-hospital mortality, longer length of stay, and not able to ambulate independently at discharge (Table). Conclusion: Many hospitals receive high volumes of stroke patients via transfer. Because transfer-in patients have worse outcomes, these patients have the potential to negatively influence institutional outcomes rates. Transfer-in patients should be carefully accounted for in risk adjusted models of hospital outcomes.
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Rosenman, Marc, Elissa Oh, Christopher T. Richards, et al. "Abstract TP306: Risk of Stroke After ED Visits at Which No Diagnosis of TIA or Stroke was Recorded." Stroke 48, suppl_1 (2017). http://dx.doi.org/10.1161/str.48.suppl_1.tp306.
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Introduction: Unrecognized, high-risk conditions like transient ischemic attack (TIA) are missed opportunities to initiate timely preventive treatment to reduce the risk of subsequent stroke, disability, and death. Up to 50% of patients with a TIA may have a subsequent disabling stroke, many within 30 days. Hypothesis: Among patients with an Emergency Department (ED) visit at which no diagnosis of TIA or stroke was recorded, analysis of electronic health record (EHR) data can help predict risk of subsequent stroke. Methods: We performed a retrospective cohort study of EHR data (2011-2015) from a high-volume comprehensive stroke center with an annual ED volume of >85,000. Patients age 60-89 years who were discharged to home from the ED in <24 hours without ICD-9 diagnosis of TIA or stroke were included for analysis. If patients had >1 qualifying index visit during the study period, we used the first. For each patient we determined presence or absence during the ED visit of a head CT and/or any of these strings in the ED chief complaint (“Symptoms”): slur, speech, aphasia, confuse, word, difficult, comprehen, weak, clumsy, clumsiness, droop, paralysis, move, moving, face, or facial (but not “facial injury”). In four mutually-exclusive categories, CT (Yes/No) by Symptoms (Yes/No), we calculated rate of stroke in the 30, 90, and 365-day periods after discharge from the ED. Ischemic stroke ascertainment was based on diagnostic codes at subsequent ED or hospital visits. Results: Among 40,450 patients, mean age was 69 years, and 59% were women. Race was 57% white, 15% African-American, 23% other, and 4% unknown. Numbers of patients and rates of stroke by category are shown in the table. Conclusion: This simple approach established a clinically meaningful risk gradient across four groups. Present and future work to refine this model may contribute to comparative effectiveness research that evaluates management and triage strategies for patients across the stroke risk spectrum.
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Ortega-Gutierrez, Santiago, Darko Quispe-Orozco, Sebastian Schafer, et al. "Abstract TP76: Quantitative Comparison of Multidetector CT and Cone-Beam CT Perfusion Maps in Large Vessel Occlusion Stroke Patients Undergoing Mechanical Thrombectomy." Stroke 51, Suppl_1 (2020). http://dx.doi.org/10.1161/str.51.suppl_1.tp76.
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Cerebral perfusion evaluation using CT or MR perfusion is the gold standard modality to select large vessel occlusion (LVO) stroke patients presenting >6 hours from symptom onset. The availability of cone beam C-arm CT perfusion (CBCTP) in angiography suites could reduce time to endovascular revascularization. We aimed to evaluate the reliability of using CBCTP when compared to multidetector CT perfusion (MDCTP). In this prospective, single-arm, interventional study, 14 LVO anterior circulation thrombectomy patients underwent both a 128 slice MDCTP in the ED and a CBCTP <30 minutes apart prior to groin puncture. CBCTP was acquired using a prototype acquisition mode enabling 10 consecutive C-Arm rotations with nearly continuous data acquisition. A total of 60 cc of contrast layered with 60 cc of saline were injected covering arterial inflow, parenchymal phase and venous outflow. Image data was reconstructed into CBF, CBV, MTT and TTP maps. Three types of measurements were used to compare modalities. In measurement 1, 6 circular regions of interest (ROI) (400mm 2 ) were placed in the anterior arterial territory. In measurement 2, circular ROIs were placed in the ASPECTS regions (cortical 300mm 2 , subcortical 200mm 2 ). In measurement 3, a ROI was drawn around the entire affected area. All ROIs were placed in the basal ganglia and supraganglionic level of both brain sides. Rates (unaffected/affected area) between MDCTP and CBCTP were compared for all sequences. The intraclass correlation coefficient (ICC) was calculated using a single rater, consistency, two-way random-effects model. Measurement 1 found a moderate degree of agreement between MDCTP and CBCTP in CBF, CBV, MTT and TTP rates with ICCs of 0.58 (CI 0.42 - 0.69), 0.65 (CI 0.53 - 0.74), 0.77 (CI 0.68 - 0.83) and 0.52 (CI 0.35 - 0.65). In measurement 2, moderate agreement was found in CBF, CBV and MTT rates; with ICCs of 0.51 (CI 0.32 - 0.65), 0.57 (CI 0.4 - 0.69) and 0.62 (CI 0.47 - 0.73). The results of measurement 3 found an excellent (ICC=0.95, CI 0.88 - 0.98), good (ICC=0.83, CI 0.62 - 0.9) and moderate (ICC=0.7, CI 0.34 - 0.87), degree of agreement in the CBV, MTT and CBF rates, respectively. These results demonstrate promising accuracy of CBCTP in the evaluating ischemic tissue in patient presenting with LVO acute stroke.
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Vagal, Achala, Heidi Sucharew, Shyam Prabhakaran, et al. "Abstract T P46: Final Infarct Volume Discriminates Outcome In Mild Strokes." Stroke 46, suppl_1 (2015). http://dx.doi.org/10.1161/str.46.suppl_1.tp46.
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Introduction: Final infarct volume (FIV) is a well-established predictor of outcomes in moderate and severe stroke. However, our knowledge of how FIV predicts disability in the mild stroke population is very limited. Our objective was to determine if FIV could differentiate good versus poor outcome after mild stroke. We hypothesized that smaller FIV will be associated with favorable clinical outcome. Methods: We used a retrospective, multicenter registry for consecutive patients who presented with mild stroke (NIHSS ≤ 5) within 24 hours of stroke onset. The imaging data included baseline head CT, noninvasive vascular imaging and follow up imaging (24-72 hour MR/3-5 day CT). Baseline ASPECTS, proximal arterial occlusion (PAO), collateral scores and FIV (using MIPAV) were assessed by core lab. Clinical data included age, sex, baseline NIHSS and 90 day modified Rankin Scale (mRS). Logistic regression was used to evaluate associations between favorable outcome (mRS 0-1) and imaging and clinical data, and to determine a data-driven cut-point for FIV based on the maximal sensitivity and specificity of the receiver operating characteristic curve. Results: Among 90 patients with mild stroke, 3 who received intravenous thrombolysis and 22 who did not have follow-up imaging were excluded, leaving 65 patients (mean age 86 years, 38% female, median NIHSS score 4) in whom FIV calculations were performed. An optimal FIV cut-point at 20 cc was identified, for differentiating between favorable and poor outcomes (area under curve 0.73, 95% CI: 0.58-0.88). Of the 45 patients with FIV <20 cc, 37 (82%) had a favorable outcome compared to 5 out of 14 (36%) with FIV ≥ 20 cc (P<.01). In the multivariable model, FIV ≥ 20cc remained strongly associated with poor outcome (adjusted OR, 0.11; 95% CI, 0.02- 0.50, P<.01), irrespective of age, gender, stroke severity, ASPECTS and PAO. A higher collateral score was also found to be associated with favorable outcome (adjusted OR, 2.43; 95% CI, 1.12- 5.27, P=0.02). Conclusions: A final infarct volume cut point of 20 cc was found to best differentiate between the likelihood of good versus poor outcome in patients with mild stroke. Further validation of FIV as a surrogate marker is essential to improve risk prediction in mild stroke patients.
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Harmon, Elisabeth, Andrea Doan, Jesus Bautista-Garrido, Joo Eun Jung, Sean P. Marrelli, and Gab Seok Kim. "Abstract TP206: Scrnaseq Revealed Increased Microglial Expression Of Interferon-induced Transmembrane 3 (ifitm3) In Stroke And Other Inflammatory Conditions In The Brain." Stroke 54, Suppl_1 (2023). http://dx.doi.org/10.1161/str.54.suppl_1.tp206.
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Microglia (MG) play critical roles in modulating inflammation and interferon signaling is a driver of neuroinflammation in various neurodegenerative diseases. Recently, Ifitm3 (a member of the “interferon-inducible transmembrane” family) has been revealed as a molecular mediator between neuroinflammation and neurodegeneration. However, expression of Ifitm3 in MG under inflammatory conditions, is not well described. Methods: To define the expression of Ifitm3 following stroke, permanent distal middle cerebral artery occlusion was performed with aged mice (18-22 mos). Brains were isolated at post-stroke day (PSD) 14 for single-cell RNAseq (scRNAseq), and at PSD 3, 7, and 14 for immunostaining and qRT-PCR. Primary microglial culture was established to evaluate mRNA levels of Ifitm3 and other pro-inflammatory genes to cytokine treatment. Results: Our scRNAseq revealed that Ifitm3 is among the top 10 genes upregulated in MG following stroke in aged brains. To validate these findings, we utilized a stroke model in aged mice and primary cell culture. We found that ischemic injury causes an induction of Ifitm3 in the striatum and peri-infarcted area following stroke, with peak induction PSD 7 (n=3-5, p<0.01). We also examined the induction of other Ifitm gene mRNA in brains following stroke. Interestingly, among Ifitm family members, only Ifitm3 was markedly induced in the damaged cortex of PSD 3 brains (n=4-6). We found that Ifitm3 expression is induced in primary MG following treatment with proinflammatory mediators (TNFα/IFNγ) for 6 hours (n=5-6, p<0.05) or for 24 hours (n=7-8, p<0.01). TNFα/IFNγ treatment also induced increased expression of inflammasome component gene, Il1b and Casp1 . There was a close correlation between Ifitm3 and Casp1 expression, suggesting a potential of Ifitm3 in inflammasome activation. Conclusions: We demonstrated the profound induction of Ifitm3 in activated MG within the stroke brain in aged mice and in response to inflammatory factors in primary microglia culture. These studies identify Ifitm3 as a novel player involved in microglial modulation in response to a variety of inflammatory conditions. Future studies are warranted to determine if Ifitm3 deletion or inhibition can reduce neuroinflammation in the stroke brain.
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Carmona-Mora, Paulina, Glen C. Jickling, Xinhua Zhan, et al. "Abstract P744: Gene Transcript Clusters Distinguish Time-Dependent Expression Patterns in Monocytes, Neutrophils and Whole Blood After Ischemic Stroke Injury." Stroke 52, Suppl_1 (2021). http://dx.doi.org/10.1161/str.52.suppl_1.p744.
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Introduction: After ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. We previously showed that peripheral blood cells display different gene expression profiles after IS and these transcriptional programs reflect the changes in immune processes in response to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of the changes of molecular and cellular pathways involved in acute brain injury. Methods: We analyzed the transcriptomic profiles of 33 IS patients in isolated monocytes, neutrophils and whole blood. RNA-sequencing was performed on all the stroke samples as well as 12 controls with vascular risk factors (diabetes and/or hypertension and/or hypercholesterolemia). To identify differentially expressed genes, subjects were split into time points (TPs) from stroke onset (TP1= 0-24 h; TP2= 24-48 h; and TP3= > 48 h), and controls were assigned TP0. A linear regression model including time and the interaction of diagnosis x TP with cutoff of p<0.02 and fold-change>|1.2| was used. Time dependent changes were analyzed using artificial neural networks to identify clusters of genes that behave in a similar way across TPs. Results: Unique patterns of temporal expression were distinguished for the three sample types. These include genes not expressed in TP0 that peak only within the first 24 h, others that peak or decrease in TP2 and TP3, and more complex patterns. Genes that peak at TP1 in monocytes and neutrophils are related to cell adhesion and leukocyte differentiation/migration, respectively. Early peaks in whole blood occur in genes related to transcriptional regulation. In monocytes, interleukin pathways are enriched across all TPs, whereas there is a trend of suppression after 24 h in neutrophils. The inflammasome pathway is enriched in the earlier TPs in neutrophils, while not enriched in monocytes until over 48 hours. Conclusion: Our analyses on gene expression dynamics and cluster patterns allow identification of key genes and pathways at different time points following ischemic injury that are valuable as IS biomarkers and may be possible treatment targets.
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Fourteau, Kévin, Pascal Hagenmuller, Jacques Roulle, and Florent Domine. "On the use of heated needle probes for measuring snow thermal conductivity." Journal of Glaciology, January 12, 2022, 1–15. http://dx.doi.org/10.1017/jog.2021.127.
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Abstract Heated needle probes provide the most convenient method to measure snow thermal conductivity. Recent studies have suggested that this method underestimates snow thermal conductivity; however the reasons for this discrepancy have not been elucidated. We show that it originates from the fact that, while the theory behind the method assumes that the measurements reach a logarithmic regime, this regime is not reached within the standard measurement procedure. Using the needle probe without this logarithmic regime leads to thermal conductivity underestimations of tens of percents. Moreover, we show that the poor thermal contact between the probe and the snow due to insertion damages results in a further underestimation. Thus, we encourage the use of fixed needle probes, set up before the snow season and buried under snowfalls, rather than hand-inserted probes. Finally, we propose a method to correct the measurements performed with such fixed needle probes buried in snow. This correction is based on a lookup table, derived specifically for the Hukseflux TP02 needle probe model, frequently used in snow studies. Comparison between corrected measurements and independent estimations of snow thermal conductivity obtained with numerical simulations shows an overall improvement of the needle probe values after application of the correction.
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Tita, Anne C., Mouhammad A. Jumaa, Kavit B. Shah, and Syed F. Zaidi. "Abstract T P6: Is HbA1c a Predictor of Outcome in Ischemic Stroke Patients Who Undergo Intra-Arterial Treatment?" Stroke 45, suppl_1 (2014). http://dx.doi.org/10.1161/str.45.suppl_1.tp6.
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Objective: Elevated blood glucose levels adversely affect the outcome of patients with acute ischemic stroke (AIS). We sought to study the predictive value of admission hemoglobin A1c (HbA1c) in AIS patients’ outcomes following intra-arterial stroke treatment (IAT). METHODS: We reviewed records of AIS patients who underwent IAT at our center from July 2012 - July 2013. The following data were collected and analyzed: patients’ demographics, baseline characteristics, treatment times and methods, rate of symptomatic and asymptomatic intracerebral hemorrhage, and favorable clinical outcome defined as modified Rankin score (mRS) ≤ 2 at 90 days or at last observation for patients treated within the last 90 days. HbA1c level was checked as part of routine stroke admission orders on all patients. RESULTS: Seventy consecutive patients who underwent IAT were identified. There were 42 (60%) females with mean cohort age of 64.4. The median ASPECT score was 9 (IQR 8-9) and baseline median National Institute of Health Stroke Scale Score was 18 (IQR 14-21). Overall 33 (47.1%) patients had favorable outcome. There were 15/70 (21.4%) asymptomatic and 2/70 (2.8%) symptomatic hemorrhages following IAT. Patients who developed hemorrhagic complications (17/70, 24%) following IAT had higher mean HbA1c levels (6.5 vs 5.9), however this finding was not statistically significant (ttest, p=0.09). Patients with favorable outcomes had lower mean admission HbA1c 5.9 (95% CI 5.6-6.2) versus 6.4 (95% CI 5.9-6.8). This finding was statistically significant (t-test, p 0.04). Multivariate logistic regression model identified low age (OR 0.93, 95%CI 0.88-0.99, p=0.03) as the only predictor of favorable outcome. CONCLUSION: Our study results indicate that admission HbA1c is a predictor of outcome in patients undergoing IAT for AIS. The value of this finding should be explored in a larger cohort.
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Burgermeister, Simon, Hubert S. Gabryś, Lucas Basler, et al. "Improved Survival Prediction by Combining Radiological Imaging and S-100B Levels Into a Multivariate Model in Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibition." Frontiers in Oncology 12 (April 14, 2022). http://dx.doi.org/10.3389/fonc.2022.830627.
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PurposeWe explored imaging and blood bio-markers for survival prediction in a cohort of patients with metastatic melanoma treated with immune checkpoint inhibition.Materials and Methods94 consecutive metastatic melanoma patients treated with immune checkpoint inhibition were included into this study. PET/CT imaging was available at baseline (Tp0), 3 months (Tp1) and 6 months (Tp2) after start of immunotherapy. Radiological response at Tp2 was evaluated using iRECIST. Total tumor burden (TB) at each time-point was measured and relative change of TB compared to baseline was calculated. LDH, CRP and S-100B were also analyzed. Cox proportional hazards model and logistic regression were used for survival analysis.ResultsiRECIST at Tp2 was significantly associated with overall survival (OS) with C-index=0.68. TB at baseline was not associated with OS, whereas TB at Tp1 and Tp2 provided similar predictive power with C-index of 0.67 and 0.71, respectively. Appearance of new metastatic lesions during follow-up was an independent prognostic factor (C-index=0.73). Elevated LDH and S-100B ratios at Tp2 were significantly associated with worse OS: C-index=0.73 for LDH and 0.73 for S-100B. Correlation of LDH with TB was weak (r=0.34). A multivariate model including TB change, S-100B, and appearance of new lesions showed the best predictive performance with C-index=0.83.ConclusionOur analysis shows only a weak correlation between LDH and TB. Additionally, baseline TB was not a prognostic factor in our cohort. A multivariate model combining early blood and imaging biomarkers achieved the best predictive power with regard to survival, outperforming iRECIST.
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Romero-Márquez, Constantino, Gustavo Pérez-Anzúrez, Maximino Huerta-Bravo, Rufino López-Ordaz, and Agustín Ruíz-Flores. "Fertilidad en yeguas y caracterización de la dinámica ovárica." Nova Scientia 14, no. 28 (2022). http://dx.doi.org/10.21640/ns.v14i28.2786.
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La baja fertilidad es una de las mayores dificultades que enfrenta la reproducción equina. El diámetro folicular preovulatorio puede utilizarse como predictor del celo. Métodos: Se estudió la evolución del diámetro folicular (DF) durante un ciclo estral en 43 yeguas, con 550 ± 34 kg PV, edad 6.00 ± 2.30 años y 4.42 ± 0.39 de condición corporal (CC), sin problemas reproductivos o sanitarios. Los celos se detectaron y los DF se midieron diariamente; las yeguas con DF > 38 mm se inseminaron, y la preñez se diagnosticó 16 d post inseminación. Las variables evaluadas fueron: duración del celo (Dcelo) y del ciclo estral (Dciclo); DF al día 21 (DF21), al inicio del celo (Dfcelo) y a la inseminación artificial (DFIA); diámetro del cuerpo lúteo (DCL), y tasa de preñez (TP16). Los efectos fijos incluidos en el modelo fueron: edad de la yegua, CC, Dcelo, Dciclo, número de folículos, tiempo que tardó en presentarse el celo después del día 21 (Celoh), Dfcelo, y DF21. Los análisis estadísticos se realizaron con los procedimientos MIXED y GLIMMIX de SAS. Resultados: La edad (p £ 0.0221) y el Dcelo (p £ 0.036) fueron significativas para la mayoría de las variables de respuesta analizadas. Las yeguas de 9-11 años tuvieron los mayores Dciclo, DCL y DF. La covariable Dfcelo fue significativa (p £ 0.0056) para DCL y DF21; mientras que DF21 lo fue (p £ 0.0001) para Celoh, Dfcelo y DFIA. El crecimiento folicular mostró una tendencia cúbica, con una reducción en la tasa de crecimiento días previos a la ovulación. Conclusión: La edad de la yegua, DF21 y Dfcelo, ayudan a predecir la presentación del celo. El conocimiento de la dinámica ovárica ayuda al apareamiento al tiempo correcto en yeguas.
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Wiatrak, Benita, Edward Krzyżak, Berenika Szczęśniak-Sięga, Marta Szandruk-Bender, Adam Szeląg, and Beata Nowak. "Effect of tricyclic 1,2-thiazine derivatives in neuroinflammation induced by preincubation with lipopolysaccharide or coculturing with microglia-like cells." Pharmacological Reports, September 21, 2022. http://dx.doi.org/10.1007/s43440-022-00414-8.
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Abstract Background Alzheimer’s disease (AD) is considered the most common cause of dementia among the elderly. One of the modifiable causes of AD is neuroinflammation. The current study aimed to investigate the influence of new tricyclic 1,2-thiazine derivatives on in vitro model of neuroinflammation and their ability to cross the blood–brain barrier (BBB). Methods The potential anti-inflammatory effect of new tricyclic 1,2-thiazine derivatives (TP1, TP4, TP5, TP6, TP7, TP8, TP9, TP10) was assessed in SH-SY5Y cells differentiated to the neuron-like phenotype incubated with bacterial lipopolysaccharide (5 or 50 μg/ml) or THP-1 microglial cell culture supernatant using MTT, DCF-DA, Griess, and fast halo (FHA) assays. Additionally, for cultures preincubated with 50 µg/ml lipopolysaccharide (LPS), a cyclooxygenase (COX) activity assay was performed. Finally, the potential ability of tested compounds to cross the BBB was evaluated by computational studies. Molecular docking was performed with the TLR4/MD-2 complex to assess the possibility of binding the tested compounds in the LPS binding pocket. Prediction of ADMET parameters (absorption, distribution, metabolism, excretion and toxicity) was also conducted. Results The unfavorable effect of LPS and co-culture with THP-1 cells on neuronal cell viability was counteracted with TP1 and TP4 in all tested concentrations. Tested compounds reduced the oxidative and nitrosative stress induced by both LPS and microglia activation and also reduced DNA damage. Furthermore, new derivatives inhibited total COX activity. Additionally, new compounds would cross the BBB with high probability and reach concentrations in the brain not lower than in the serum. The binding affinity at the TLR4/MD-2 complex binding site of TP4 and TP8 compounds is similar to that of the drug donepezil used in Alzheimer's disease. The ADMET analysis showed that the tested compounds should not be toxic and should show high intestinal absorption. Conclusions New tricyclic 1,2-thiazine derivatives exert a neuroregenerative effect in the neuroinflammation model, presumably via their inhibitory influence on COX activity and reduction of oxidative and nitrosative stress.