bluuebunny/crossref_metadata_2025 huggingface dataset:
ASSOCIATION OF MULTIMORBIDITY WITH INCIDENT SHINGLES AMONG OLDER AMERICANS
Authors: Kang Hyewon , Crimmins Eileen , Ailshire Jennifer A
Published: November 2019

Older adults with multimorbidity are susceptible to shingles due to deterioration of immune function related to coexisting chronic disorders and immunological change. Although the association between individual chronic diseases and incident shingles has been documented, little is known about the effect of having multiple conditions on the risk for developing a new case of the disease. Multimorbidity is a normal condition with advanced aging. This paper examines risk of shingles onset associated with multimorbidity defined as having one or more chronic diseases including hypertension, diabetes, cancer, heart disease, lung disease, arthritis, and stroke) among older American. Data for this study come from the 1992 -2016 Health and Retirement Study. The study finds that risk for onset of shingles linearly increases with number of chronic disorders when age, gender, and race/ethnicity were adjusted (adjusted OR: 1.58, 95% CI; 1.37, 1.80 for those with 1 chronic condition vs adjusted OR: 3.43, 95% CI: 2.21, 5.53 for those with 6 conditions). The risks for multimorbidity were little changed after additional adjustments for socioeconomic status and health behaviors. The effect of multimorbidity on developing shingles is greater among young-old adults in their 50s than among the older-old adults aged 80 and higher. Our finding challenges the single-disease framework that is often used in previous studies examining risk factors for shingles. Our finding highlights the need for primary prevention and treatment of multimorbidity for reduction of shingles cases among older adults, especially young old adults in 50s.
LANGUAGE USE, LITERACY SKILLS, AND ONLINE HEALTH INFORMATION-SEEKING IN LATER LIFE AMONG HISPANICS IN THE U.S.
Authors: Millar Roberto J , Sahoo Shalini , Yamashita Takashi , Cummins Phyllis
Published: November 2019

Online platforms, which are often in English, have become a common source of health information. Accordingly, language skills have been shown to be important for health information-seeking. In the United States, the use of online health information is generally low among Hispanics, particularly those with limited English proficiency. What is less clear, however, is how different measures of English proficiency may be linked to online health information seeking in later life. This study examines the associations between language spoken at home, literacy skills, and online health information seeking among middle age and older Hispanics in the U.S. Data of Hispanic adults aged 40 years and older (n = 315) come from the 2012/2014 Program for International Assessment of Adult Competencies (PIAAC). We used binary logistic regression models with complex sampling weights to examine online health information seeking as a function of primary language use at home (Spanish vs. English) and literacy skill assessment scores (low – high: 0 – 500 points). Results indicated that speaking Spanish at home (OR = 0.317, p < 0.05) is a negative predictor, and greater literacy skills (OR = 1.011, p < 0.05) is a positive predictor of online health information seeking. Findings from this study clarify possible health information disadvantages by limited English proficiency and lower literacy skills. We discuss how the impact of primary language use and literacy skills should be incorporated into future health communication and policy initiatives to address the barriers to health information among middle-aged and older Hispanic adults.
ANTIDEPRESSANT USE AND MORTALITY RISK IN OLDER ADULTS WITH HISTORY OF STROKE
Authors: Lenox Madison B , Tran Victor , Tworek Grace , Solow Andrew , Hincapie Diana
Published: November 2019

The American Stroke Association reports stroke as the fourth leading cause of death in the United States, with 66% of hospitalized cases being older adults. Recovery from stroke is a public health issue, as post-stroke depression (PSD) is a significant concern. Approximately 20-23% of stroke survivors identified co-occurring diagnoses, which are associated with physical, functional, and cognitive limitations and increased mortality risk. Antidepressant use has exhibited its efficacy in treating PSD. This study explores the association between antidepressant use and mortality risk in older adults with history of stroke. Older adults aged 65 and older (N=3631, 55.4% female, 72.6% Caucasian, Mage=79.64 years, SDage=7.29 years, MEd=14.55 years, SDEd=8.269 years) with history of stroke were selected from the National Alzheimer’s Coordinating Center database to explore the association between antidepressant use and mortality. A chi-squared test of independence was calculated comparing antidepressant use and mortality rates. A significant association was found (χ2 (1) = 15.933, p < .001) between current antidepressant use and mortality. Findings suggest antidepressant use is associated with lower mortality rates in subjects with a history of stroke. Implications include highlighting the role psychologists play in the early identification of PSD and early antidepressant intervention post-stroke to increase life longevity. Although findings only infer association, they demonstrate evidence for the link between PSD, antidepressant use, and lower mortality rates. Future directions include exploring other forms of depression treatment and mechanisms of antidepressant use. Limitations include examining potential moderators (e.g., gender, SES, type of stroke), and substance use within this population.
Sharpness of the 410-km discontinuity from the P410s and P2p410s seismic phases
Authors: Vinnik Lev , Deng Yangfan , Kosarev Grigoriy , Oreshin Sergey , Zhang Zhou , Makeyeva Larissa
Published: November 2019

Sharpness of the 410-km boundary is of interest because it is sensitive to water content in the transition zone. We evaluate the width of the 410-km discontinuity with a new seismic method. Our estimates are inferred from the amplitude ratio of the P2p410s and P410s seismic phases that are detected in P-wave receiver functions. We applied this method to seismic recordings from arrays of broad-band stations deployed in central Fennoscandia, southern Africa and southern China. The obtained estimates of width of the 410-km discontinuity range from 10 to 22 km and always exceed the width of 7 km which is expected for anhydrous conditions. The enlarged width may be interpreted in terms of hydrous conditions, but we have found only one region (the eastern Yangtze Craton in China) where the broad 410-km discontinuity, as expected, is accompanied by a broad transition zone. Water in the transition zone may be a kind of a global phenomenon, but evidence of the enlarged width of the transition zone may be missing in most of our data because the reference seismic model is affected by water, as well.
Time-lapse velocity imaging via deep learning
Authors: Yuan Congcong , Zhang Xiong , Jia Xiaofeng , Zhang Jie
Published: November 2019

It is of great significance and a great challenge to quickly and effectively monitor subsurface time-lapse velocities in the earth. Over the past few decades, regularized iterative methods, such as traveltime and waveform inversions, have been presented to monitor velocity changes. Due to high processing cost, these iterative methods have been hardly employed in practice to investigate the subsurface velocity changes in real time. In this study, we propose a new time-lapse imaging technique that effectively eliminates these limitations and directly produces accurate velocity changes from the time-lapse data. The approach uses a fully convolutional neural network (FCN) to perform the inverse problem. The network architecture consists of a contracting path to quickly extract the features of waveform data and a symmetric expanding path to yield an accurate velocity model. With the known baseline velocity and data, we cast a mapping between time-lapse data and target velocity changes via the proposed FCN algorithm. Along with the observed time-lapse data, this mapping will generate a predictive estimation of the target velocity changes. We demonstrate the efficiency and accuracy of our approach in three 2D synthetic tests. The proposed technique is able to invert the velocity changes successfully with much higher efficiency than the regular double-difference full waveform inversion.
Modulation of hepatocyte sialylation drives spontaneous fatty liver disease and inflammation
Authors: Oswald Douglas M , Jones Mark B , Cobb Brian A
Published: November 2019

Circulatory protein glycosylation is a biomarker of multiple disease and inflammatory states and has been applied in the clinic for liver dysfunction, heart disease and diabetes. With the notable exception of antibodies, the liver produces most of the circulatory glycoproteins, including the acute phase proteins released as a function of the inflammatory response. Among these proteins is β-galactoside α2,6-sialyltransferase (ST6Gal1), an enzyme required for α2,6-linked sialylation of glycoproteins. Here, we describe a hepatocyte-specific conditional knockout of ST6Gal1 (H-cKO) using albumin promoter-driven Cre-lox recombination. We confirm the loss of circulatory glycoprotein α2,6 sialylation and note no obvious dysfunction or pathology in young H-cKO mice, yet these mice show robust changes in plasma glycoprotein fucosylation, branching and the abundance of bisecting GlcNAc and marked changes in a number of metabolic pathways. As H-cKO mice aged, they spontaneously developed fatty liver disease characterized by the buildup of fat droplets in the liver, inflammatory cytokine production and a shift in liver leukocyte phenotype away from anti-inflammatory Kupffer cells and towards proinflammatory M1 macrophages. These findings connect hepatocyte and circulatory glycoprotein sialylation to the regulation of metabolism and inflammation, potentially identifying the glycome as a new target for liver-driven disease.
Left atrial appendage aneurysm
Authors: Jiang Bo , Wang Xi , Liu Feng , Song Long
Published: November 2019

Left atrial appendage aneurysm is an infrequent abnormality presenting as atrial tachyarrhythmias, progressive dyspnoea, atypical chest pain and systemic thromboembolism. Surgical excision is considered to prevent fatal complications, even in asymptomatic cases. We describe the case of a 44-year-old woman with a history of acute cerebral infarction caused by emboli from a giant left atrial appendage aneurysm, which is the largest one reported to date. Histopathology and Masson staining confirmed the final diagnosis.
Social Media and Beliefs about Climate Change: A Cross-National Analysis of News Use, Political Ideology, and Trust in Science
Authors: Diehl Trevor , Huber Brigitte , Gil de Zúñiga Homero , Liu James
Published: November 2019

This study explores the individual- and country-level factors that influence how getting news from social media relates to people’s beliefs about anthropogenic climate change. Concepts of psychological distance and motivated reasoning are tested using multilevel analysis with survey data in 20 countries (N = 18,785). Results suggest that using social media for news is associated with a decrease in climate skepticism across the sample. However, social context at the individual-level (conservative political ideology and low trust in science) and at the macro-level (high gross domestic product and individualism) moderate the effect, and therefore reduce social media’s potential to inform the public about climate change. This study contributes to conversations about the ability of emerging media to address science issues, particularly in developing countries.
Engaging Ethicists in Animal Research Policymaking
Authors: Hvitved Angela N
Published: November 2019

The significance of ethical considerations for animal research policy has long been acknowledged, but the role of philosophical ethics in the policymaking process has been less clear. By comparing the ethical framework of animal research policy with that for human subjects research, this article considers how the legacies of these two policy areas influence current policy and suggests that ethicists and ethical scholarship have been underutilized in developing animal research policy. An important aspect of policymaking is gathering and responding to input provided by various stakeholders. Given their expertise in a highly relevant area, ethicists should be considered key stakeholders in animal research policy deliberations. This article explores the role of ethicists and ethical scholarship in influencing animal research policy and suggests that a more robust engagement with the professional ethics community throughout the deliberative process is vital for policymakers to adequately account for ethical considerations.
Circulating Extracellular Vesicle Tissue Factor Activity During Orthohantavirus Infection Is Associated With Intravascular Coagulation
Authors: Schmedes Clare M , Grover Steven P , Hisada Yohei M , Goeijenbier Marco , Hultdin Johan , Nilsson Sofie , Thunberg Therese , Ahlm Clas , Mackman Nigel , Fors Connolly Anne-Marie
Published: November 2019

Background

Puumala orthohantavirus (PUUV) causes hemorrhagic fever with renal syndrome (HFRS). Patients with HFRS have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine whether circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients.

Methods

Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n = 27) and those who did not (n = 61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and platelets.

Results

Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity were significantly associated with plasma tPA and PAI-1, suggesting that endothelial cells could be a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared with those who did not, even after adjustment for sex and age. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with area under the curve = 0.63 (95% confidence interval, 0.51–0.76) and P = .046.

Conclusions

Plasma EVTF activity during HFRS is associated with intravascular coagulation.
Deep Instability in the Phylogenetic Backbone of Heteroptera is Only Partly Overcome by Transcriptome-Based Phylogenomics
Authors: de Moya Robert S , Weirauch Christiane , Sweet Andrew D , Skinner Rachel K , Walden Kimberly K O , Swanson Daniel R , Dietrich Christopher H , Johnson Kevin P
Published: November 2019

Heteroptera is a diverse suborder of insects that includes many plant pests, human disease vectors, and nuisance pests, but also beneficial insects. Previous analyses have supported recognition of seven monophyletic infraorders. A clade comprising Leptopodomorpha, Pentatomomorpha, and Cimicomorpha is also well-accepted, but relationships among the early-diverging lineages, including the aquatic infraorders (Nepomorpha and Gerromorpha), have remained poorly resolved and controversial. Phylogenomic analyses of 2,159 gene alignments derived from Illumina sequencing of transcriptomes were employed to explore the stability of relationships among major heteropteran lineages. These analyses included maximum likelihood analyses of amino acid and nucleotide sequences, as well as multi-species coalescent analysis and quartet sampling. All analyses favored a sister position of the Nepomorpha to the remaining Heteroptera. The placement of the Nepomorpha and other ambiguously supported nodes, including some within the Pentatomomorpha were explored with quartet sampling. Results of quartet sampling revealed only a slight majority of quartets supported the placement of the Nepomorpha, and some varying alternate topologies were supported within the Pentatomomorpha. These results highlight the instability of deep nodes that divide aquatic and other early-diverging lineages within the Heteroptera, suggesting that some relationships remain difficult to resolve even with large amounts of data. In addition, despite the large amount of transcriptome data analyzed, quartet sampling revealed considerable underlying conflict for some nodes, even where bootstrap support is high, emphasizing the importance of considering multiple clade support values when analyzing phylogenomic datasets.
Distinguishing between Contact and Administration of Heroin from a Single Fingerprint using High Resolution Mass Spectrometry
Authors: Costa Catia , Ismail Mahado , Stevenson Derek , Gibson Brian , Webb Roger , Bailey Melanie
Published: November 2019

Fingerprints have been proposed as a promising new matrix for drug testing. In previous work it has been shown that a fingerprint can be used to distinguish between drug users and nonusers. Herein, we look at the possibility of using a fingerprint to distinguish between dermal contact and administration of heroin. Fingerprint samples were collected from (i) 10 patients attending a drug rehabilitation clinic, (ii) 50 nondrug users and (iii) participants who touched 2 mg street heroin, before and after various hand cleaning procedures. Oral fluid was also taken from the patients. All samples were analyzed using a liquid chromatography—high resolution mass spectrometry method validated in previous work for heroin and 6-AM. The HRMS data were analyzed retrospectively for morphine, codeine, 6-acetylcodeine and noscapine. Heroin and 6-AM were detected in all fingerprint samples produced from contact with heroin, even after hand washing. In contrast, morphine, acetylcodeine and noscapine were successfully removed after hand washing. In patient samples, the detection of morphine, noscapine and acetylcodeine (alongside heroin and 6-AM) gave a closer agreement to patient testimony on whether they had recently used heroin than the detection of heroin and 6-AM alone. This research highlights the importance of washing hands prior to donating a fingerprint sample to distinguish recent contact with heroin from heroin use.
International migration, cross-cultural interaction, and the development of personal wisdom
Authors: Kutor Senanu K. , Raileanu Alexandru , Simandan Dragos
Published: November 2019

Drawing on semi-structured in-depth interviews with Romanian immigrants in Ontario, Canada, conducted between 2014 and 2018, this article explores how the experiences acquired by the Romanian immigrants through migration and multicultural intercourse facilitate the development of personal wisdom. We show how our research participants perceived these geographical processes of migration and place-based multiethnic cohabitation to account for their growing wiser than their earlier selves. Specifically, we organize the description of these perceptions into three interrelated themes: (1) changes in perspective, (2) the learning of new things, and (3) the role of place in fostering wisdom. Against this background, the article also highlights the boundary conditions within which these processes may or may not foster the development of wisdom, acknowledging that not all migratory and multicultural experiences lead to prosocial and adaptive outcomes. Our discussion of these boundary conditions with the research participants coalesced into five recurrent themes: (1) adaptation to the new environment and social system, (2) the role of the host environment as a boundary condition, (3) the problem of unmet expectations, (4) the magnitude of the cultural shocks, and (5) the language barrier. Bearing the complex politics of these boundary conditions in mind, we argue that the experience of international migration and subsequent cross-cultural interaction can be usefully understood as a ‘fertile ground’ for the flourishing of personal wisdom, which itself can act as an individual and collective resource for cohabitation in multicultural settings.
The GALAH survey: temporal chemical enrichment of the galactic disc
Authors: Lin Jane , Asplund Martin , Ting Yuan-Sen , Casagrande Luca , Buder Sven , Bland-Hawthorn Joss , Casey Andrew R , De Silva Gayandhi M , D’Orazi Valentina , Freeman Ken C , Kos Janez , Lind K , Martell Sarah L , Sharma Sanjib , Simpson Jeffrey D , Zwitter Tomaž , Zucker Daniel B , Minchev Ivan , Čotar Klemen , Hayden Michael , Horner Jonti , Lewis Geraint F , Nordlander Thomas , Wyse Rosemary F G , Žerjal Maruša
Published: November 2019

We present isochrone ages and initial bulk metallicities ($\rm [Fe/H]_{bulk}$, by accounting for diffusion) of 163 722 stars from the GALAH Data Release 2, mainly composed of main-sequence turn-off stars and subgiants ($7000\, \mathrm{ K}> T_{\mathrm{ eff}}> 4000\, \mathrm{ K}$ and $\log g>3$ dex). The local age–metallicity relationship (AMR) is nearly flat but with significant scatter at all ages; the scatter is even higher when considering the observed surface abundances. After correcting for selection effects, the AMR appears to have intrinsic structures indicative of two star formation events, which we speculate are connected to the thin and thick discs in the solar neighbourhood. We also present abundance ratio trends for 16 elements as a function of age, across different $\rm [Fe/H]_{bulk}$ bins. In general, we find the trends in terms of [X/Fe] versus age from our far larger sample to be compatible with studies based on small (∼100 stars) samples of solar twins, but we now extend them to both sub- and supersolar metallicities. The α-elements show differing behaviour: the hydrostatic α-elements O and Mg show a steady decline with time for all metallicities, while the explosive α-elements Si, Ca, and Ti are nearly constant during the thin-disc epoch (ages $\lesssim \! 12$ Gyr). The s-process elements Y and Ba show increasing [X/Fe] with time while the r-process element Eu has the opposite trend, thus favouring a primary production from sources with a short time delay such as core-collapse supernovae over long-delay events such as neutron star mergers.
Radiative stellar feedback in galaxy formation: Methods and physics
Authors: Hopkins Philip F , Grudić Michael Y , Wetzel Andrew , Kereš Dušan , Faucher-Giguère Claude-André , Ma Xiangcheng , Murray Norman , Butcher Nathan
Published: November 2019

Radiative feedback (RFB) from stars plays a key role in galaxies, but remains poorly understood. We explore this using high-resolution, multifrequency radiation-hydrodynamics (RHD) simulations from the Feedback In Realistic Environments (FIRE) project. We study ultrafaint dwarf through Milky Way mass scales, including H+He photoionization; photoelectric, Lyman Werner, Compton, and dust heating; and single+multiple scattering radiation pressure (RP). We compare distinct numerical algorithms: ray-based LEBRON (exact when optically thin) and moments-based M1 (exact when optically thick). The most important RFB channels on galaxy scales are photoionization heating and single-scattering RP: in all galaxies, most ionizing/far-UV luminosity (∼1/2 of lifetime-integrated bolometric) is absorbed. In dwarfs, the most important effect is photoionization heating from the UV background suppressing accretion. In MW-mass galaxies, metagalactic backgrounds have negligible effects; but local photoionization and single-scattering RP contribute to regulating the galactic star formation efficiency and lowering central densities. Without some RFB (or other ‘rapid’ FB), resolved GMCs convert too-efficiently into stars, making galaxies dominated by hyperdense, bound star clusters. This makes star formation more violent and ‘bursty’ when SNe explode in these hyperclustered objects: thus, including RFB ‘smoothes’ SFHs. These conclusions are robust to RHD methods, but M1 produces somewhat stronger effects. Like in previous FIRE simulations, IR multiple-scattering is rare (negligible in dwarfs, $\sim 10{{\ \rm per\ cent}}$ of RP in massive galaxies): absorption occurs primarily in ‘normal’ GMCs with AV ∼ 1.
Pulsation and rotation in NGC 6811: the Kepler short-cadence stars
Authors: Rodríguez E , Balona L A , López-González M J , Ocando S , Martín-Ruiz S , Rodríguez-López C
Published: November 2019

We have analysed a selected sample of 36 Kepler short-cadence stars in the field of NGC 6811. The results reveal that all the targets are variable: two red giant stars with solar-like oscillations, 21 main-sequence pulsators (16 δ Scuti and five γ Doradus stars), and 13 rotating variables. Three new γ Doradus (γ Dor) variables (one is a hot γ Dor star) are detected in this work together with five new rotating variables. An in-depth frequency analysis of the δ Scuti (δ Sct) and γ Dor stars in the sample shows that the frequency spectra are very rich, in particular for the δ Sct-type variables. They present very dense frequency distributions and wide diversity in frequency patterns, even for stars being members of the cluster and with very similar location in the Hertzsprung–Russell (H–R) diagram. Rotational modulation is found for a high percentage of these main-sequence pulsating stars, which is an indication of stellar activity being common on the surfaces of these hot stars. In some cases, activity dominates the luminosity variations. Significant amplitude variability is also detected in at least some of the pulsation modes of highest amplitude in almost all the δ Sct stars. One of the δ Sct pulsators is a member of a binary system with the pulsating component tidally distorted. This system also shows strong stellar activity, including several flares that probably originate in the δ Sct component.
The perturbed FLRW metric on all scales: Newtonian limit and top-hat collapse
Authors: Finke Andreas
Published: November 2019

The applicability of a linearized perturbed FLRW metric to the late, lumpy universe has been subject to debate. We consider in an elementary way the Newtonian limit of the Einstein equations with this ansatz for the case of structure formation in late-time cosmology, on small and on large scales, and argue that linearizing the Einstein tensor produces only a small error down to arbitrarily small, decoupled scales (e.g. solar system scales). On subhorizon patches, the metric scale factor becomes a coordinate choice equivalent to choosing the spatial curvature, and not a sign that the FLRW metric cannot perturbatively accommodate very different local physical expansion rates of matter; we distinguish these concepts, and show that they merge on large scales for the Newtonian limit to be globally valid. Furthermore, on subhorizon scales, a perturbed FLRW metric ansatz does not already imply assumptions on isotropy, and effects beyond a FLRW background, including those potentially caused by nonlinearities of GR, may be encoded into nontrivial boundary conditions. The corresponding cosmologies have already been developed in a Newtonian setting by Heckmann and Schücking and none of these boundary conditions can explain the accelerated expansion of the universe. Our analysis of the field equations is confirmed on the level of solutions by an example of pedagogical value, comparing a collapsing top-hat overdensity (embedded into a cosmological background) treated in such perturbative manner to the corresponding exact solution of GR, where we find good agreement even in the regimes of strong density contrast
Hyperbolic Orbits in the Solar System: Interstellar Origin or Perturbed Oort Cloud Comets?
Authors: Higuchi Arika , Kokubo Eiichiro
Published: November 2019

We study the dynamical properties of objects in hyperbolic orbits passing through the inner Solar system in the context of two different potential sources: interstellar space and the Oort cloud. We analytically derive the probability distributions of eccentricity, e, and perihelion distance, q, for each source and estimate the numbers of objects produced per unit of time as a function of these quantities. By comparing the numbers from the two sources, we assess which origin is more likely for a hyperbolic object having a given eccentricity and perihelion distance. We find that the likelihood that a given hyperbolic object is of interstellar origin increases with decreasing eccentricity and perihelion. Conversely, the likelihood that a hyperbolic object has been scattered from the Oort cloud by a passing star increases with decreasing eccentricity and increasing perihelion. By carefully considering their orbital elements, we conclude that both 1I/2017 U1 ’Oumuamua (e ≃ 1.2 and q ≃ 0.26 au) and 2I/2019 Q4 Borisov (e ≃ 3.3 and q ≃ 2 au) are most likely of interstellar origin, not scattered from the Oort cloud. However, we also find that Oort cloud objects can be scattered into hyperbolic orbits like those of the two known examples, by sub-stellar and even sub-Jovian mass perturbers. This highlights the need for better characterization of the low mass end of the free-floating brown dwarf and planet population.
corrfunc – a suite of blazing fast correlation functions on the CPU
Authors: Sinha Manodeep , Garrison Lehman H
Published: November 2019

The two-point correlation function (2PCF) is the most widely used tool for quantifying the spatial distribution of galaxies. Since the distribution of galaxies is determined by galaxy formation physics as well as the underlying cosmology, fitting an observed correlation function yields valuable insights into both. The calculation for a 2PCF involves computing pair-wise separations and consequently, the computing time-scales quadratically with the number of galaxies. The next-generation galaxy surveys are slated to observe many millions of galaxies, and computing the 2PCF for such surveys would be prohibitively time-consuming. Additionally, modern modelling techniques require the 2PCF to be calculated thousands of times on simulated galaxy catalogues of at least equal size to the data and would be completely unfeasible for the next-generation surveys. Thus, calculating the 2PCF forms a substantial bottleneck in improving our understanding of the fundamental physics of the Universe, and we need high-performance software to compute the correlation function. In this paper, we present corrfunc – a suite of highly optimized, openmp parallel clustering codes. The improved performance of corrfunc arises from both efficient algorithms as well as software design that suits the underlying hardware of modern CPUs. corrfunc can compute a wide range of 2D and 3D correlation functions in either simulation (Cartesian) space or on-sky coordinates. corrfunc runs efficiently in both single- and multithreaded modes and can compute a typical two-point projected correlation function [wp(rp)] for ∼1 million galaxies within a few seconds on a single thread. corrfunc is designed to be both user-friendly and fast and is publicly available at https://github.com/manodeep/Corrfunc.
ATIM-03. ANTI-TGFß2 RNA THERAPEUTIC OT-101 INDUCES DURABLE OBJECTIVE RESPONSES IN PATIENTS WITH RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA MULTIFORME (GBM, WHO GRADE 4) OR ANAPLASTIC ASTROCYTOMA (AA, WHO GRADE 3)
Authors: Uckun Fatih , Qazi Sanjive , Hwang Larn , Nam David , Trieu Vuong
Published: November 2019

BACKGROUND

High-grade gliomas (HGG) are characterized by a T-cell exhaustion signature and pronounced T-cell hyporesponsiveness of their tumor microenvironment (TME). Transforming growth factor beta 2 (TGF-ß2) has been implicated as a key contributor to the immunosuppressive landscape of the TME in HGG. OT-101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive actions of TGF-ß2. Here we report the single-agent activity of OT-101 in adult patients with R/R HGG.

METHODS

In this phase 2 clinical trial (NCT00431561), OT-101 was administered with an intratumoral catheter using a convection enhanced delivery (CED) system. 77 patients received 4–11 cycles of OT-101 via continuous infusion over 7d. Response determinations were based on central review of MRI scans by an independent review committee according to standard and modified McDonald criteria. Standard statistical methods were applied for the analysis of data.

RESULTS

The median progression-free survival (PFS) and overall survival (OS) were 86d and 432d, respectively. 26 patients (33.8%) had marked reductions of their tumor volume after receiving OT-101: 19 achieved durable objective responses (CR: 3, PR: 16). The median time for 90% reduction of the baseline tumor volume was 11.7 months (Range: 4.9–57.7 months). The mean log reduction of the tumor volume was 2.2 ± 0.4 (Median = 1.4: Range: 0.4–4.5) logs. 7 had stable disease (SD) lasting > 6 months. The median PFS (1109d [95% CI: 992 - > 1423] vs. 37d [95% CI: 35 – 59] (Log-rank Chi Square = 69.9, P-value < 0.0001) and OS (1280d [95% CI: 1116- > 1743] vs. 240d [95% CI: 169 – 361] (Log-rank Chi Square = 47.0, P-value < 0.0001) of these 26 patients was significantly better than the PFS or OS of the remaining 51 patients.

CONCLUSION

Anti-TGFß2 RNA therapeutic OT-101 exhibits clinically meaningful single-agent activity and induces durable CR/PR/SD in R/R HGG patients.
ATIM-40. CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS PREDICT FAVORABLE RESPONSE TO IMMUNE CHECKPOINT THERAPY IN A RANDOMIZED TRIAL OF NIVOLUMAB AND BEVACIZUMAB IN RECURRENT GBM
Authors: Ahluwalia Manmeet , Grabowski Matthew , Alban Tyler , Otvos Balint , Bayik Defne , Saeed Bamashmos Anas , Rayman Patricia , Diaz-Montero Marcela , Reardon David , Wen Patrick , Peereboom David , Lathia Justin
Published: November 2019

Glioblastoma (GBM) creates an immunosuppressive environment that presents a challenge to efficacy of immunotherapeutic approaches. Results from the CheckMate-143 trial demonstrated responses in 8% of patients with nivolumab, underscoring the need for further insight into the mechanisms and markers of immune suppression and response. Given a limited set of biomarkers predictive of immunotherapy response in GBM, we explored the changes in immune cell populations in nivolumab and bevacizumab-treated GBM patients pre and post-treatment in order to help predict response. In these studies, we utilized traditional and newly developed approaches, including mass cytometry time-of-flight (CyTOF), single-cell RNA sequencing, and 10X Genomics simultaneous cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). We analyzed patients’ samples in a randomized, phase 2 study of nivolumab and bevacizumab at GBM first recurrence (NCT03452579). Nine patients were identified as responders or non-responders at 8 weeks after therapy initiation. Utilizing peripheral blood samples, we observed a 6.4-fold decrease in immunosuppressive myeloid-derived suppressor cells (MDSCs) between baseline and first imaging follow-up in responders compared to non-responders, with a 4.9-fold decrease in the granulocytic MDSC (G-MDSC) subtype in responders over non-responders. While no significant changes in overall T-cell numbers were noted, expression of PD-1 on CD4+ T cells was significantly elevated at baseline and follow-up in responders as compared to non-responders – signatures which were confirmed by CyTOF. Given these immunophenotypic changes, preliminary results of a detailed investigation of this cohort by CITE-seq indicate that responders had increased IL7R-positive T cells post-treatment, which was not observed in non-responders. These results are currently being validated in an additional 40 patients that have been enrolled. Altogether, differences in immunophenotypes that were specific to responders and non-responders were observed, and characterization of these immune populations may be helpful in identifying GBM patients likely to benefit from immunotherapy.
ACTR-05. PROCARBAZINE AND CCNU CHEMOTHERAPY FOR RECURRENT GLIOBLASTOMA WITH MGMT PROMOTER METHYLATION
Authors: Kil Hong Yong , Ho Yang Seung
Published: November 2019

BACKGROUND

While procarbazine, CCNU (lomustine), and vincristine (PCV) has been an alternative chemotherapy option for malignant gliomas, it is worth investigating whether the combination of only procarbazine and CCNU is comparable because vincristine adds toxicity with uncertain benefit. The purpose of this study was to evaluate the feasibility of procarbazine and CCNU chemotherapy for recurrent glioblastoma multiforme (GBM) with O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation.

METHODS

Eight patients with recurrent GBM following concurrent chemoradiotherapy and temozolomide (TMZ) adjuvant therapy were enrolled in this trial; they received no other chemotherapeutic agents or target therapy. They received CCNU (75 mg/m2) on day 1 and procarbazine (60 mg/m2) through days 11 and 24 every 4 weeks. The median cycle of CCNU and procarbazine was 3.5 (range: 2–6).

RESULTS

One patient achieved stable disease. The median progression-free survival (PFS) with procarbazine and CCNU chemotherapy was eight weeks (range: 5–73), and the PFS rates were 25% and 12.5% at 16 and 30 weeks, respectively. The median overall survival (OS) from the initial diagnosis to death was 40 months, and the median OS from the administration of procarbazine and CCNU chemotherapy to death was 9.7 months (95% confidence interval: 6.7–12.7). Serious adverse events were found at six visits, and two cases were considered to be grade 3 toxicities.

CONCLUSION

The efficacy of procarbazine and CCNU chemotherapy is not satisfactory. This study suggests the need to develop other treatment strategies for recurrent and TMZ-refractory GBM
ACTR-10. PHASE 0 TRIAL OF CERITINIB IN BRAIN METASTASES AND RECURRENT GLIOBLASTOMA
Authors: Fiorelli Roberto , Li Jing , Bao Xun , DeRogatis Alanna , Pennington-Krygier Chelsea , Kim Seongho , Mehta Shwetal , Sanai Nader
Published: November 2019

BACKGROUND

Ceritinib is an orally bioavailable, small molecule inhibitor for ALK/IGFR1/FAK, which are highly expressed in glioblastoma and brain metastases. Preclinical and clinical reports suggest ceritinib activity in central nervous system (CNS) malignancies, yet there is no direct evidence in patients. This study assessed the pharmacokinetics (PK) and pharmacodynamics (PD) of ceritinib in brain metastases and recurrent glioblastoma patients.

METHODS

Ten patients with brain metastases (n=3) or glioblastoma (n=7) exhibiting high expression of pSTAT5b/pFAK/pIGFR1 were treated with 10 days of oral ceritinib (750 mg daily) prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at ~ 4 and 24 h following the last dose. Total and unbound drug concentrations were determined using LC-MS/MS. PD response was assessed by immunohistochemical analysis of pALK, pFAK, pIGFR1, and pIRS1 staining in treated tumor and matched archival tissues.

RESULTS

Ceritinib was highly bound to human plasma protein (median fraction unbound (Fu), 1.4%) and to brain tumor tissue (median Fu, 0.073% and 0.14% in enhancing and non-enhancing regions respectively). There was a large interindividual variability in drug CNS penetration, with the median unbound concentrations in enhancing, non-enhancing, and CSF of 0.040, 0.006, and 0.012 µM, respectively. The median unbound tumor-to-plasma ratio was 2.44 and 0.33 in enhancing and non-enhancing areas, respectively. In one brain metastasis patient, drug binding to enhancing tumor was significantly lower (Fu, 1.62%), resulting in a higher unbound drug tumor and CSF concentration as compared to all other patients. In all patients, no pharmacodynamic response was detected in sampled tumor tissue.

CONCLUSION

Ceritinib is highly bound to plasma proteins and tumor tissues. Unbound drug concentrations in brain metastasis and glioblastoma appear insufficient for target modulation. Despite recent reports of clinical response, our findings suggest no role for ceritinib in treating glioblastoma and an unfavorable profile for brain metastases.
ACTR-12. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING
Authors: O’Brien Barbara , Penas-Prado Marta , Kamiya Carolos , Pei Weathers Shiao- , Yung Alfred , Loghin Monica , Harrison Rebecca , Bacha Jeffrey , Brown Dennis , Johnson Gregory , Langlands John , Schwartz Richard , Kanekal Sarath , Lopez Lorena , deGroot John
Published: November 2019

Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1–5 every 28 days. Almost all GBM patients experience recurrent/progressive disease, with a median survival after recurrence of 3–9 months. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine, induces double-strand breaks and acts independent of MGMT DNA repair. The current ongoing trial is a biomarker-driven Phase 2 study in MGMT-unmethylated BEV-naïve adult GBM. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) for MGMT-unmethylated GBM patients compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life. Thirty-five (35) subjects with recurrent GBM have received 40 mg/m2/day VAL-083 on days 1, 2, 3 of a 21-day cycle as the starting dose. Myelosuppression is the most common adverse event and a higher potential for this toxicity correlated with those patients who received a higher number of cycles of prior TMZ maintenance therapy, (>5 cycles vs. ≤5 cycles, p< 0.05). To minimize the potential for hematological toxicity in rGBM, subsequent subjects initiated treatment at 30 mg/m2/d VAL-083 x 3 consecutive days every 21 days. In addition, since TMZ is of limited value in the MGMT-unmethylated setting, a second arm in newly diagnosed GBM has been included to explore whether substituting TMZ with VAL-083 offers clinical benefit and extends the time to recurrence. Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.
ACTR-24. A RANDOMIZED PHASE II TRIAL OF VELIPARIB (V), RADIOTHERAPY (RT) AND TEMOZOLOMIDE (TMZ) IN PATIENTS (PTS) WITH UNMETHYLATED MGMT (uMGMT) GLIOBLASTOMA (GBM): THE VERTU STUDY
Authors: Khasraw Mustafa , Leanne McDonald Kerrie , Rosenthal Mark , Lwin Zarnie , Ashley David , Wheeler Helen , Barnes Elizabeth , Foote Matthew , Koh Eng-Siew , Sulman Erik , Back Michael , Buckland Michael , Sim Hao-Wen , Fisher Lauren , Leonard Robyn , Hall Merryn , Yip Sonia , Simes John
Published: November 2019

BACKGROUND

TMZ offers minimal benefit in pts with de novo uMGMT GBM. V is synergistic with RT and TMZ in uMGMT preclinical GBM models, safe when combined with either RT or TMZ clinically, but the triplet (V+RT+TMZ) is poorly tolerated. VERTU tested V in pts with uMGMT GBM.

METHODS

VERTU is a randomized Phase 2 trial comparing Standard Arm (Arm A), RT (60Gy/30 fractions) + TMZ (75mg/m2 daily) followed by TMZ (150–200mg/m2D 1–5) every 28 days for 6 cycles vs Experimental Arm (Arm B), RT (60Gy/30 fractions) + V (200mg PO BID) followed by TMZ (150–200mg/m2D 1–5) + V (40mg bid, D 1–7) every 28 days for 6 cycles in pts with de novo uMGMT GBM according to centralised testing.

RESULTS

125 pts were randomized 1:2 (41:84). The 2 groups were matched for age, sex, performance status and extent of resection. Median follow-up was 25.8 months and 91 pts had died. The 6-month Progression-Free Survival (6mPFS) for Arms A and B were 34% (95% CI 20–48) and 46% (95% CI 36–57) respectively. The median PFS for Arms A and B were 4.2m (95% CI 2.5–6.0) and 5.7m (95% CI 4.1–6.6) respectively (HR = 0.80, 95%CI 0.55–1.18). 55% of pts in both arms experienced Grade 3/4 adverse events (AEs) with no significant differences in frequency or severity between the arms. Most common Grade 3/4 AEs were thrombocytopenia, seizures, hyperglycaemia and diarrhoea.

CONCLUSION

VERTU demonstrated that a novel treatment strategy for patients with de novo uMGMT GBM was feasible and tolerable. The observed 6mPFS and PFS were similar in both arms. Overall survival and other endpoints will be presented. Central MRI review, biomarker analyses, including DNA repair and methylation signature analyses are ongoing.

(ANZCTR#ACTRN12615000407594).
ACTR-28. A CALL FOR INCREASED ROLE OF NEUROSURGEONS IN SURGICAL TRIALS FOR NON-GLIOMATOUS PRIMARY CNS TUMORS: A SYSTEMATIC REVIEW OF THE CLINICALTRIALS.GOV DATABASE
Authors: Mansouri Alireza , Beyn Michelle , Chow Clement , Pancholi Aditya , Boutet Alexandre , Elias Gavin , Germann Jurgen , Zadeh Gelareh
Published: November 2019

BACKGROUND

Surgery continues to be part of the mainstay of therapy for most primary CNS tumors. However, neurosurgical innovations advancing treatment options have stagnated. An understanding of past and current investigational trends is necessary to catalyze innovation in surgical trials.

OBJECTIVE

To evaluate the landscape of surgical clinical trials for non-diffusely infiltrating primary CNS tumors.

METHODS

ClinicalTrials.gov was searched on May 14th, 2019 for surgical/procedural trials based on non-diffusely infiltrating primary CNS tumors, with a focus on meningiomas, ependymomas, medulloblastomas, pituitary adenomas, vestibular scwhannomas, and chordomas. Key trial design parameters were extracted. Purely surgical interventions were classified as “technical” while fluorescence-guided and other intraoperative imaging modalities were classified as image-guided surgery. Any invasive mode of drug delivery (e.g. intra-arterial or intra-ventricular, local chemotherapy wafers, and oncolytic virus injection) was considered.

RESULTS

Among 944 total trial records (257 medulloblastomas, 254 ependymomas, 179 meningiomas, 156 pituitary adenomas, 56 vestibular schwannomas, and 48 chordomas) only 54 (5.7%) were procedural in nature. Ependymomas had the highest absolute number (18/254, 7%) while vestibular schwannomas had the highest percentage (6/56, 10.7%) of surgical trials. The majority of records were not randomized (41/54, 75.9%), not industry-funded (45/54, 83.3%), and were early Phase (30/54, 55.6%); there were only three Phase III trials. The relative number of new surgical trial registrations has not changed significantly over time (1990s: 5, 2000s: 19, and 2010s: 30). Approaches integrated with other disciplines, such as image-guided surgery (16/54, 29.6%) and local drug delivery (16/24, 29.6%), were among the leading categories of trials.

CONCLUSIONS

Despite the clinical role of surgery in management of non-diffusely infiltrating primary CNS tumors, a paucity of innovative surgical trials has been put forth. Multi-disciplinary approaches appear to be necessary for pushing the therapeutic envelope for individuals affected by these tumors, with imaging and drug development at the forefront.