ALBERT

Description: 〈span〉〈div〉Abstract〈/div〉We study anthropogenic noise sources seen on seismic recordings along the central section of the San Jacinto fault near Anza, southern California. The strongest signals are caused by freight trains passing through the Coachella Valley north of Anza. Train‐induced transients are observed at distances of up to 50 km from the railway, with durations of up to 20 min, and spectra that are peaked between 3 and 5 Hz. Additionally, truck traffic through the Coachella Valley generates a sustained hum with a similar spectral signature as the train transients but with lower amplitude. We also find that wind turbine activity in northern Baja California introduces a seasonal modulation of 1– to 5‐Hz energy across the Anza network. We show that the observed train‐generated transients can be used to constrain shallow attenuation structure at Anza. Using the results from this study as well as available borehole data, we further evaluate the performance of approaches that have been used to detect nonvolcanic tremor at Anza. We conclude that signals previously identified as spontaneous tremor (〈a href="https://pubs.geoscienceworld.org/bssa#rf21"〉Hutchison and Ghosh, 2017〈/a〉) were probably generated by other nontectonic sources such as trains.〈/span〉

Description: 〈span〉〈div〉ABSTRACT〈/div〉This article gives an overview of machine learning (ML) applications in MyShake—a crowdsourcing global smartphone seismic network. Algorithms from classification, regression, and clustering are used in the MyShake system to address various problems, such as artificial neural network (ANN) and convolutional neural network (CNN) to distinguish earthquake motions, spatial–temporal clustering using density‐based spatial clustering of applications with noise (DBSCAN) to detect earthquakes from phone aggregated information, and random forest regression to learn from existing physics‐based relationships. Beyond existing efforts, this article also presents a vision of the role of ML in some new directions and challenges. Using MyShake as an example, this article demonstrates the promising combination of ML and seismology.〈/span〉

Description: 〈span〉〈div〉ABSTRACT〈/div〉MyShake is a growing smartphone‐based network for seismological research applications. We study how dense array analysis of the seismic wavefield recorded by smartphones may enhance microearthquake monitoring in urban environments. In such areas, the microearthquake signal‐to‐noise ratio on smartphones is not well constrained. We address this issue by compiling a seismic noise model for the Los Angeles (LA) metropolitan area using over 500,000 seismograms recorded by stationary phones running MyShake. We confirm that smartphone noise level is reduced during nighttime, and identify strong noise sources such as major traffic highways, the LA airport, and the Long Beach seaport. The noise analysis shows that stationary smartphones are sensitive to human‐induced ground motions, and therefore smartphone‐derived seismograms may be used to infer the elastic properties of the shallow subsurface. We employ array backprojection analysis on synthetic data to estimate what fraction of LA’s smartphone user population is required to install MyShake to enable the location of events whose induced ground motions are below the smartphone noise level. We find that having 0.5% of LA’s population download the MyShake app would be sufficient to accurately locate M〉1 events recorded during nighttime by stationary phones located at epicentral distances 〈5  km. Currently, the MyShake user coverage in LA is approaching a value that will allow us to locate events whose magnitude is near the regional catalog’s magnitude of completeness.〈/span〉

Description: 〈span〉〈div〉ABSTRACT〈/div〉This article gives an overview of machine learning (ML) applications in MyShake—a crowdsourcing global smartphone seismic network. Algorithms from classification, regression, and clustering are used in the MyShake system to address various problems, such as artificial neural network (ANN) and convolutional neural network (CNN) to distinguish earthquake motions, spatial–temporal clustering using density‐based spatial clustering of applications with noise (DBSCAN) to detect earthquakes from phone aggregated information, and random forest regression to learn from existing physics‐based relationships. Beyond existing efforts, this article also presents a vision of the role of ML in some new directions and challenges. Using MyShake as an example, this article demonstrates the promising combination of ML and seismology.〈/span〉

Description: 〈span〉〈div〉ABSTRACT〈/div〉MyShake is a growing smartphone‐based network for seismological research applications. We study how dense array analysis of the seismic wavefield recorded by smartphones may enhance microearthquake monitoring in urban environments. In such areas, the microearthquake signal‐to‐noise ratio on smartphones is not well constrained. We address this issue by compiling a seismic noise model for the Los Angeles (LA) metropolitan area using over 500,000 seismograms recorded by stationary phones running MyShake. We confirm that smartphone noise level is reduced during nighttime, and identify strong noise sources such as major traffic highways, the LA airport, and the Long Beach seaport. The noise analysis shows that stationary smartphones are sensitive to human‐induced ground motions, and therefore smartphone‐derived seismograms may be used to infer the elastic properties of the shallow subsurface. We employ array backprojection analysis on synthetic data to estimate what fraction of LA’s smartphone user population is required to install MyShake to enable the location of events whose induced ground motions are below the smartphone noise level. We find that having 0.5% of LA’s population download the MyShake app would be sufficient to accurately locate M〉1 events recorded during nighttime by stationary phones located at epicentral distances 〈5  km. Currently, the MyShake user coverage in LA is approaching a value that will allow us to locate events whose magnitude is near the regional catalog’s magnitude of completeness.〈/span〉

Description: 〈span〉〈div〉Abstract〈/div〉We study anthropogenic noise sources seen on seismic recordings along the central section of the San Jacinto fault near Anza, southern California. The strongest signals are caused by freight trains passing through the Coachella Valley north of Anza. Train‐induced transients are observed at distances of up to 50 km from the railway, with durations of up to 20 min, and spectra that are peaked between 3 and 5 Hz. Additionally, truck traffic through the Coachella Valley generates a sustained hum with a similar spectral signature as the train transients but with lower amplitude. We also find that wind turbine activity in northern Baja California introduces a seasonal modulation of 1– to 5‐Hz energy across the Anza network. We show that the observed train‐generated transients can be used to constrain shallow attenuation structure at Anza. Using the results from this study as well as available borehole data, we further evaluate the performance of approaches that have been used to detect nonvolcanic tremor at Anza. We conclude that signals previously identified as spontaneous tremor (〈a href="https://pubs.geoscienceworld.org/bssa#rf21"〉Hutchison and Ghosh, 2017〈/a〉) were probably generated by other nontectonic sources such as trains.〈/span〉

Description: 〈span〉〈div〉Abstract〈/div〉MyShake harnesses private and personal smartphones to build a global seismic network. It uses the accelerometers embedded in all smartphones to record ground motions induced by earthquakes, returning recorded waveforms to a central repository for analysis and research. A demonstration of the power of citizen science, MyShake expanded to six continents within days of being launched and has recorded 757 earthquakes in the first 2 yr of operation. The data recorded by MyShake phones have the potential to be used in scientific applications, thereby complementing current seismic networks. In this article, we (1) report the capabilities of smartphone sensors to detect earthquakes by analyzing the earthquake waveforms collected by MyShake; (2) determine the maximum epicentral distance at which MyShake phones can detect earthquakes as a function of magnitude; and (3) then determine the capabilities of the MyShake network to estimate the location, origin time, depth, and magnitude of earthquakes. In the case of earthquakes for which MyShake has provided four or more phases (〈span〉P〈/span〉‐ or 〈span〉S〈/span〉‐wave signals) and an azimuthal gap 〈180° (21 events), the median (± standard deviations) of the location, origin time, and depth errors are 2.7 (±2.8) km, 0.2 (±1.2) s, and 0.1 (±4.9) km, respectively, relative to the U.S. Geological Survey global catalog locations. Magnitudes are also estimated and have a mean error of 0.0 and standard deviation of 0.2. These preliminary results suggest that MyShake could provide basic earthquake catalog information in regions that currently have no traditional networks. With an expanding MyShake network, we expect the event detection capabilities to improve and provide useful data on seismicity and hazards.〈/span〉

Description: 〈span〉〈div〉Abstract〈/div〉MyShake harnesses private and personal smartphones to build a global seismic network. It uses the accelerometers embedded in all smartphones to record ground motions induced by earthquakes, returning recorded waveforms to a central repository for analysis and research. A demonstration of the power of citizen science, MyShake expanded to six continents within days of being launched and has recorded 757 earthquakes in the first 2 yr of operation. The data recorded by MyShake phones have the potential to be used in scientific applications, thereby complementing current seismic networks. In this article, we (1) report the capabilities of smartphone sensors to detect earthquakes by analyzing the earthquake waveforms collected by MyShake; (2) determine the maximum epicentral distance at which MyShake phones can detect earthquakes as a function of magnitude; and (3) then determine the capabilities of the MyShake network to estimate the location, origin time, depth, and magnitude of earthquakes. In the case of earthquakes for which MyShake has provided four or more phases (〈span〉P〈/span〉‐ or 〈span〉S〈/span〉‐wave signals) and an azimuthal gap 〈180° (21 events), the median (± standard deviations) of the location, origin time, and depth errors are 2.7 (±2.8) km, 0.2 (±1.2) s, and 0.1 (±4.9) km, respectively, relative to the U.S. Geological Survey global catalog locations. Magnitudes are also estimated and have a mean error of 0.0 and standard deviation of 0.2. These preliminary results suggest that MyShake could provide basic earthquake catalog information in regions that currently have no traditional networks. With an expanding MyShake network, we expect the event detection capabilities to improve and provide useful data on seismicity and hazards.〈/span〉

Description: Juvenile and chronic myelomonocytic leukemias (JMML and CMML) are aggressive myeloid malignancies categorized as myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). Chemotherapy has little benefit for MDS/MPN patients, and new therapies are needed. We have used mouse models investigate the potential of signal transduction inhibitors in MDS/MPN, as JMML and CMML are associated with mutations in NRAS, KRAS, PTPN11, CBL, or NF1 that activate Ras signaling. Conditional Mx1-Cre, KrasLSL-D12 (designated KrasD12) mice develop an aggressive and fully penetrant MDS/MPN characterized by leukocytosis, splenomegaly, anemia, and death by 10-16 weeks of age. Mx1-Cre, Nf1flox/- mice (hereafter Nf1Δ/-) undergo conditional loss of Nf1. These mice also develop MDS/MPN, but the disease is more indolent. We and others have investigated inhibition of effector networks downstream of Ras, such as the Raf/MEK/ERK (MAPK) and phosphotidylinositol-3 kinase (PI3K)/Akt pathways. We previously showed that the MEK inhibitor PD0325901 induced sustained hematologic improvement in both KrasD12 and Nf1Δ/- mice. We also have reported that the class I PI3K inhibitor GDC-0941 improves hematologic function and prolongs survival in KrasD12 mice. However, GDC-0941 and other PI3K inhibitors attenuate both PI3K/Akt and Raf/MEK/ERK pathways due to effects of PI3K upstream of Ras. Therefore, the benefit from GDC-0941 could have been due to its modulation of Raf/MEK/ERK signaling. Here, we specifically test the importance of Akt signaling in MDS/MPN in KrasD12 and Nf1 mouse models using the allosteric inhibitor MK-2206. This compound binds to the interface of the PH and kinase domains of Akt1, Akt2, and Akt3, and does not inhibit any of 250 other kinases at 1 µM. MK-2206 induced substantial improvement in both KrasD12 and Nf1Δ/- mice. Mice treated with MK-2206 had pronounced reduction in leukocytosis, reticulocytosis and splenomegaly, increased hemoglobin concentration, and prolonged survival. MK-2206 had no hematologic effects in control WT mice, indicating some selectivity against aberrant hematopoiesis. Importantly, MK-2206 inhibited Akt but not Raf/MEK/ERK or Jak/STAT signaling. This demonstrates that canonical PI3K/Akt signaling plays an important role in Ras-driven MDS/MPN. Furthermore, combined inhibition of MEK and Akt with PD0325901+MK-2206 yielded a greater improvement in splenomegaly than either agent alone in both KrasD12 and Nf1Δ/- models. Akt has multiple effectors relevant to hematopoiesis and leukemia. Of these, mTOR is of particular interest for targeted cancer therapy. Therefore, we tested the response of KrasD12 mice to rapamycin, a partial inhibitor of mTOR with preferential activity against the mTORC1 complex. KrasD12 mice demonstrated variable responses to rapamycin, with approximately half undergoing a complete and durable hematologic response and the remainder having no response. Together, these studies further implicate PI3K/Akt signaling as a pathogenic effector downstream of Ras in MDS/MPN and support the idea that inhibitors targeting this pathway may have a role in treatment of JMML or CMML. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Recombinant FXIII (rFXIII) represents a new treatment opportunity for patients with congenital FXIII A-subunit deficiency. Monthly prophylaxis with 35 IU/kg rFXIII was shown to effectively control bleeding with an annualized bleeding rate (ABR) of 0.138 bleeds requiring treatment per patient per year and an excellent safety profile (Inbal A, et al. Blood 2012;119:5111-7). PK analysis revealed first-order elimination of rFXIII with a geometric mean half-life of 13.6 days. All patients had a mean FXIII trough activity level of 〉0.1 IU/mL (Kerlin B, et al.JTH 2013;11:235). The PK profile was independent of age, supporting that monthly dosing with a fixed 35 IU/Kg rFXIII regimen for all patients with FXIII A-subunit deficiency (regardless of age) was adequate for prophylaxis (Brand-Staufer B, et al. Blood 2013;122:3613. Williams M, et al. Haemophilia 2014;20:99–105). Due to the novel nature of this recombinant molecule, a phase 3b safety extension program was offered to bridge to product availability, the extensive interim results of which are analyzed here. Methods The mentorTM2 trial is an ongoing safety extension trial to the pivotal mentorTM1 trial (Figure). All patients were dosed with 35 IU/kg rFXIII every 4th week. Figure. The Novo Nordisk clinical trial program for recombinant Factor 13 Figure. The Novo Nordisk clinical trial program for recombinant Factor 13 A planned interim analysis for mentorTM2 trial was performed (data cut-off: 31-DEC-2013). The Berichrom® FXIII activity assay was used for measurement of FXIII activity. Results Sixty patients have been enrolled into mentorTM2; baseline patient demographics are presented in the Table. Of these 60, 34 patients were enrolled from the mentorTM1 trial, and 26 new patients were enrolled. Table. Age, median (range) 26 (7-77) Age, mean (range) 31 (7-77) Male sex, n (%) 38 (63) Race, n (%) Black or African American American Indian or Alaska Native White Asian* Other Unknown** 6 (10)1 (2)34 (57)9 (15)6 (10)4 (7) Body Mass Index, median (range) 23.7 (12.8-36.9) Height in cm, median (range) 167.0 (131.0-187.5) Weight in kg, median (range) 67.5 (22.0-119.4) * Including 5 Japanese ** French patients are marked as unknown as per the French authorities guideline In mentorTM2, 60 patients had 2,157 exposures (monthly dosing), corresponding to a total of 168 patient years. The ABR was 0.042 bleeds/patient/year overall, 0.012 bleeds/patient/year for spontaneous bleeds, and 0.030 bleeds/patient/year for traumatic bleeds. In total 6 patients experienced 7 bleeds requiring FXIII treatment (5 trauma-induced and 2 spontaneous). Of these 7 bleeds, 1 trauma-induced muscular bleed was treated with rFXIII with excellent hemostatic response. No intracranial, internal organ or severe gastrointestinal bleeds occurred during the trial period. Mean FXIII trough levels were greater than 0.10 IU/mL in all patients. No thromboembolic events, fatal adverse events or adverse events leading to withdrawal were reported. Serious adverse events were few (16 events in 10 patients) and were evaluated by the investigators as unlikely related to trial drug. No anti-rFXIII antibodies were detected. Discussion Prophylaxis of bleeding of patients with congenital FXIII A-subunit deficiency with rFXIII in the mentor™ trials program has demonstrated very effective bleed control, with an excellent safety profile. The ABR in the ongoing mentorTM2 safety extension trial was 0.042, which is lower than the rate of 0.138 seen in the mentor™1 pivotal study. A bleeding rate of 0.042 corresponds to an average patient having 1 bleed approximately every 24 years. One patient who had a traumatic breakthrough bleed was treated with rFXIII with excellent outcome. These efficacy data, combined with comprehensive PK- and safety data, represent the largest data collection in congenital FXIII A-subunit deficiency in the world, and provide extensive evidence for the safety and efficacy of monthly prophylaxis with 35 IU/kg rFXIII. Disclosures Fukutake: Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen Idec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kaketsuken: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SRL, Inc: Consultancy; LSI Medience Corporation: Consultancy, Honoraria, Speakers Bureau; Chugai Pharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; TORII PHARMACEUTICAL CO., LTD.: Honoraria; Sekisui Medical CO., LTD: Honoraria, Research Funding, Speakers Bureau. Carcao:Baxter, Bayer, Biogen, Novo Nordisk, Pfizer, CSL Behring, Octapaharma : Honoraria, Research Funding, Speakers Bureau. Kerlin:Bayer HealthCare US: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oldenburg:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rosholm:Novo Nordisk: Employment, Equity Ownership. Garly:Novo Nordisk: Employment, Equity Ownership. Nugent:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding.