bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors
Authors: Fan Bin , Mellinghoff Ingo K. , Wen Patrick Y. , Lowery Maeve A. , Goyal Lipika , Tap William D. , Pandya Shuchi S. , Manyak Erika , Jiang Liewen , Liu Guowen , Nimkar Tara , Gliser Camelia , Prahl Judge Molly , Agresta Sam , Yang Hua , Dai David 
Published: April 2019

Summary
Background Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD. PK and PD were assessed using validated liquid chromatography-tandem mass spectrometry assays. Results Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40–102 h after single dose). Exposure increased less than dose proportionally. Steady state was reached by day 15, with moderate accumulation across all tumors (1.5- to 1.7-fold for area-under-the-curve at 500 mg QD). None of the intrinsic and extrinsic factors assessed affected ivosidenib exposure, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. After multiple doses in patients with cholangiocarcinoma or chondrosarcoma, plasma 2-HG was reduced by up to 98%, to levels seen in healthy subjects. Exposure-response relationships for safety and efficacy outcomes were flat across the doses tested. Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500 mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors. Trial RegistrationClinicalTrials.gov (NCT02073994).
Comparing Incidence of Thrombosis in PICC and Midlines and Evaluating the Role of Anticoagulation, Site of Insertion, and Risk Factors
Authors: Zohourian Hajir , Schaubschlager Taylor , Phan Lee , Polsinelli Elizabeth , Hunter Kaydian , Timis Alexandra , Sanchez Darlene , Maini Archana , Hardigan Patrick , Carreon Arisha , Jani Vishal 
Published: April 2019

HighlightsNew practice models are in demand for prevention and reduction in rates of catheter thrombosis that can be devastating to the health care system and patients Risk factors for catheter thrombosis were analyzed retrospectively for their impact Site of insertion and overall use of anticoagulation at the time of catheter placement did not show any significant impact on incidence of thrombosis Several variables (i.e., triple lumen, critically ill) were used to create a clinical prediction score model
Retrogressive failure of a static granular layer on an inclined plane
Authors: Russell A. S. , Johnson C. G. , Edwards A. N. , Viroulet S. , Rocha F. M. , Gray J. M. N. T. 
Published: April 2019

When a layer of static grains on a sufficiently steep slope is disturbed, an upslope-propagating erosion wave, or retrogressive failure, may form that separates the initially static material from a downslope region of flowing grains. This paper shows that a relatively simple depth-averaged avalanche model with frictional hysteresis is sufficient to capture a planar retrogressive failure that is independent of the cross-slope coordinate. The hysteresis is modelled with a non-monotonic effective basal friction law that has static, intermediate (velocity decreasing) and dynamic (velocity increasing) regimes. Both experiments and time-dependent numerical simulations show that steadily travelling retrogressive waves rapidly form in this system and a travelling wave ansatz is therefore used to derive a one-dimensional depth-averaged exact solution. The speed of the wave is determined by a critical point in the ordinary differential equation for the thickness. The critical point lies in the intermediate frictional regime, at the point where the friction exactly balances the downslope component of gravity. The retrogressive wave is therefore a sensitive test of the functional form of the friction law in this regime, where steady uniform flows are unstable and so cannot be used to determine the friction law directly. Upper and lower bounds for the existence of retrogressive waves in terms of the initial layer depth and the slope inclination are found and shown to be in good agreement with the experimentally determined phase diagram. For the friction law proposed by Edwardset al.(J. Fluid. Mech., vol. 823, 2017, pp. 278–315,J. Fluid. Mech., 2019, (submitted)) the magnitude of the wave speed is slightly under-predicted, but, for a given initial layer thickness, the exact solution accurately predicts an increase in the wave speed with higher inclinations. The model also captures the finite wave speed at the onset of retrogressive failure observed in experiments.
Further additions to the genusMenegazziaA. Massal. (Parmeliaceae) in Australia, with a revised regional key
Authors: KANTVILAS Gintaras 
Published: April 2019

AbstractAn identification key to the 39 species ofMenegazziarecorded for Australia and its offshore islands (including Tasmania) is presented. Distribution patterns are discussed and summarized. Mainland Australia supports 19 species, with seven endemics, and shares 12 species with Tasmania, six with New Zealand and one with South America. The new species,Menegazzia williamsiiKantvilas from New South Wales, is described and is characterized by an inflated, fragile, esorediate thallus containing stictic acid but lacking isopigmentosin, 2-spored asci and an inspersed epihymenium. In addition,M. hypernotaBjerke, formerly known only from New Zealand, is recorded from Tasmania for the first time.
Integrative taxonomy: ghosts of past, present and future
Authors: Gómez Daglio Liza , Dawson Michael N 
Published: April 2019

AbstractDescribing species has been a formal, intellectually rich and influential applied and basic area of study for many of the past 260 years. While formally described eukaryotic diversity still falls short of estimated eukaryotic species diversity by many hundreds of thousands of species, some recent accounts have suggested a growing number of taxonomists are within reach of describing all extant species. We present a case study that illustrates, to the contrary, a recent ‘taxonomic impediment’ in part attributable to derogation of taxonomy as a scientific discipline: contemporary practice has re-interpreted taxonomy largely as an endeavour in enumerating species. We argue that challenges lie in (1) a poor understanding of taxonomy's epistemology; (2) excessive displacement of interest toward ecological or molecular studies; (3) over-interpretation of the contributions of multiple authors describing a species; and (4) perspectives that are strongly influenced by well-known taxa. The historical and recent literature on scyphozoans reveal ghosts of taxonomy's past that persist in the present, but suggest also that a renaissance enabled by integrative taxonomy is possible in the (near) future.
Dimensions of anxiety in Major depressive disorder and their use in predicting antidepressant treatment outcome: an iSPOT-D report
Authors: Braund Taylor A. , Palmer Donna M. , Williams Leanne M. , Harris Anthony W. F. 
Published: April 2019

AbstractBackgroundMajor depressive disorder (MDD) commonly co-occurs with clinically significant levels of anxiety. However, anxiety symptoms are varied and have been inconsistently associated with clinical, functional, and antidepressant treatment outcomes. We aimed to identify and characterise dimensions of anxiety in people with MDD and their use in predicting antidepressant treatment outcome.Method1008 adults with a current diagnosis of single-episode or recurrent, nonpsychotic, MDD were assessed at baseline on clinical features and cognitive/physiological functioning. Participants were then randomised to one of three commonly prescribed antidepressants and reassessed at 8 weeks regarding symptom change, as well as remission and response, on the 17-item Hamilton Rating Scale Depression (HRSD17) and the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16). Exploratory factor analysis was used on items from scales assessing anxiety symptoms, and resulting factors were assessed against clinical features and cognitive/physiological functioning. Factors were also assessed on their ability to predict treatment outcome.ResultsThree factors emerged relating to stress, cognitive anxiety, and somatic anxiety. All factors showed high internal consistency, minimal cross-loadings, and unique clinical and functional profiles. Furthermore, only higher somatic anxiety was associated with poorer QIDS-SR16remission, even after adjusting for covariates and multiple comparisons.ConclusionsAnxiety symptoms in people with MDD can be separated onto distinct factors that differentially respond to treatment outcome. Furthermore, these factors do not align with subscales of established measures of anxiety. Future research should consider cognitive and somatic symptoms of anxiety separately when assessing anxiety in MDD and their use in predicting treatment outcome.
Tempering the cosmic scope problem in Christian soteriology: hylemorphic animalism and Gregory of Nazianzus
Authors: RUTLEDGE JONATHAN CURTIS 
Published: April 2019

AbstractChristian scripture provides good reason to think that Christ's redemptive work has cosmic scope (cf. Colossians 1:19–20). Explanations of how Christ's work might extend to all creation (including any sufficiently human-like extraterrestrials) have not, however, received significant sustained attention in theology. In this article, I consider two attempts to explain the cosmic scope of redemption, and after identifying shortcomings with each explanation, I offer a philosophical anthropology (hylemorphic animalism), which when combined with a principle of soteriology due to Gregory of Nazianzus provides a full explanation for how Christ's redemptive work might extend to all creation.
The making of the Second English Coronation Ordo
Authors: Pratt David 
Published: April 2019

AbstractThis article reassesses the Second English Coronation Ordo in the light of its relationship to Carolingian sources. The dependence of the Ordo on a distinctive West Frankish source, here termed the Leiden Ordo, has many implications, since the Leiden Ordo seems likely to have been composed for the anointing of Charles the Straightforward by Fulk of Rheims in January 893. This finding provides a probable context for the importing of West Frankish ordines in King Alfred's dealings with Rheims. It also strengthens the case for placing the Second Ordo in the mid- or late 890s, rather than early in Athelstan's reign. Anointing practices were directly implicated in the ‘crisis of authority’ affecting the Carolingian world in the late ninth century. The new understanding of the Second Ordo adds a further dimension to King Alfred's efforts to promote the ‘kingdom of the Anglo-Saxons’, and has wider implications for the development of royal ordines in western Europe.
Latin, Old English and documentary practice at Worcester from Wærferth to Oswald
Authors: Gallagher Robert , Tinti Francesca 
Published: April 2019

AbstractThis article analyses the uses of Latin and Old English in the charters of Worcester cathedral, which represents one of the largest and most linguistically interesting of the surviving Anglo-Saxon archives. Specifically focused on the period encompassing the episcopates of Wærferth and Oswald (c. 870 to 992), this survey examines a time of intense administrative activity at Worcester, contemporaneous with significant transformations in the political and cultural life of Anglo-Saxon England more generally. In doing so, this article argues that when writing in either Latin or the vernacular, charter draftsmen responded to a number of variables; language choice did not simply reflect varying levels of literacy. Furthermore, the frequent cases of code-switching found in tenth-century Worcester documents mark this community out as exceptional, suggesting that attitudes towards the interaction between the two languages could vary considerably between institutions.
Wulfstan's noble pagans
Authors: Reinhard Ben 
Published: April 2019

AbstractGiven his frequently expressed hostility to pagans, Wulfstan's apparent commendation of their devotion at the beginning of the Sermo Lupi has long been a source of scholarly frustration. While the passage is without parallel in Wulfstan's Old English writings, it is mirrored closely by several other texts in Wulfstanian manuscripts, including a previously unedited tract titled De ueneratione sacerdotum. These tracts provide the best analogues for the passage in the Sermo Lupi, explaining how it came to be written and giving a glimpse into how Wulfstan composed the sermon.
Exploring the association of infant receptive language and pitch variability in fathers’ infant-directed speech
Authors: QUIGLEY Jean , NIXON Elizabeth , LAWSON Sarah 
Published: April 2019

AbstractThe objective of this study was to examine the links between prosodic features of paternal Infant-Directed Speech (IDS) and child characteristics. Pitch variability measures were extracted from the speech samples of 50 fathers during unstructured play with their two-year-old children. Evidence for a link between child receptive language ability (measured by the Bayley Scales of Infant Development III) and fathers’ pitch variability was obtained from Multiple Hierarchical Regression. Findings support the hypothesis that fathers tailor their speech to their children. This is one of the few studies to examine the relationship between fathers’ IDS and child language ability.
Medial Temporal Lobe Atrophy is Related to Learning Strategy Changes in Amnestic Mild Cognitive Impairment
Authors: Zhang Liling , Sun Wen-hao , Xing Mengya , Wang Yue , Zhang Yuanyuan , Sun Qingna , Cheng Yan , Shi Chuan , Zhang Nan 
Published: April 2019

AbstractObjective: Deficits in the semantic learning strategy were observed in subjects with amnestic mild cognitive impairment (aMCI) in our previous study. In the present study, we explored the contributions of executive function and brain structure changes to the decline in the semantic learning strategy in aMCI. Methods: A neuropsychological battery was used to test memory and executive function in 96 aMCI subjects and 90 age- and gender-matched healthy controls (HCs). The semantic clustering ratio on the verbal learning test was calculated to evaluate learning strategy. Medial temporal lobe atrophy (MTA) and white matter hyperintensities (WMH) were measured on MRI with the MTA and Fazekas visual rating scales, respectively. Results: Compared to HCs, aMCI subjects had poorer performance in terms of memory, executive function, and the semantic clustering ratio (P < .001). In aMCI subjects, no significant correlation between learning strategy and executive function was observed. aMCI subjects with obvious MTA demonstrated a lower semantic clustering ratio than those without MTA (P < .001). There was no significant difference in the learning strategies between subjects with high-grade WMH and subjects with low-grade WMH. Conclusion: aMCI subjects showed obvious impairment in the semantic learning strategy, which was attributable to MTA but independent of executive dysfunction and subcortical WMH. These findings need to be further validated in large cohorts with biomarkers identified using volumetric brain measurements. (JINS, 2019, 25, 706–717)
Reconciling the Long‐Term Relationship Between Reservoir Pore Pressure Depletion and Compaction in the Groningen Region
Authors: Smith Jonathan D. , Avouac Jean‐Philippe , White Robert S. , Copley Alex , Gualandi Adriano , Bourne Stephen 
Published: April 2019

AbstractThe Groningen gas reservoir, situated in the northeast of the Netherlands is western Europe's largest gas reservoir. Due to gas production measurable subsidence and seismicity has been detected across this region, attributed to the deformations induced by reservoir pore pressure depletion. We investigate the surface displacement history using a principal component analysis‐based inversion method to combine a diverse set of optical leveling, interferometric synthetic aperture radar, and Global Positioning System data to better constrain reservoir compaction and subsidence history. The generated compaction model is then used in combination with prior pressure depletion models to determine a reservoir uniaxial compressibility. The best fitting model of uniaxial compressibility is time independent but spatially variable. The absence of evidence for any significant time delay between changes in depletion and compaction rates supports an instantaneous poroelastic reservoir response. The absence of nonlinear yielding at the largest compaction strains suggests that anelastic deformations are a minor part of reservoir compaction.
Role of Greenland Freshwater Anomaly in the Recent Freshening of the Subpolar North Atlantic
Authors: Dukhovskoy D. S. , Yashayaev I. , Proshutinsky A. , Bamber J. L. , Bashmachnikov I. L. , Chassignet E. P. , Lee C. M. , Tedstone A. J. 
Published: April 2019

AbstractThe cumulative Greenland freshwater flux anomaly has exceeded 5,000 km3 since the 1990s. The volume of this surplus freshwater is expected to cause substantial freshening in the North Atlantic. Analysis of hydrographic observations in the subpolar seas reveals freshening signals in the 2010s. The sources of this freshening are yet to be determined. In this study, the relationship between the surplus Greenland freshwater flux and this freshening is tested by analyzing the propagation of the Greenland freshwater anomaly and its impact on salinity in the subpolar North Atlantic based on observational data and numerical experiments with and without the Greenland runoff. A passive tracer is continuously released during the simulations at freshwater sources along the coast of Greenland to track the Greenland freshwater anomaly. Tracer budget analysis shows that 44% of the volume of the Greenland freshwater anomaly is retained in the subpolar North Atlantic by the end of the simulation. This volume is sufficient to cause strong freshening in the subpolar seas if it stays in the upper 50–100 m. However, in the model the anomaly is mixed down to several hundred meters of the water column resulting in smaller magnitudes of freshening compared to the observations. Therefore, the simulations suggest that the accelerated Greenland melting would not be sufficient to cause the observed freshening in the subpolar seas and other sources of freshwater have contributed to the freshening. Impacts on salinity in the subpolar seas of the freshwater transport through Fram Strait and precipitation are discussed.
Applying Machine Learning to Improve Simulations of a Chaotic Dynamical System Using Empirical Error Correction
Authors: Watson Peter A. G. 
Published: April 2019

AbstractDynamical weather and climate prediction models underpin many studies of the Earth system and hold the promise of being able to make robust projections of future climate change based on physical laws. However, simulations from these models still show many differences compared with observations. Machine learning has been applied to solve certain prediction problems with great success, and recently, it has been proposed that this could replace the role of physically‐derived dynamical weather and climate models to give better quality simulations. Here, instead, a framework using machine learning together with physically‐derived models is tested, in which it is learnt how to correct the errors of the latter from time step to time step. This maintains the physical understanding built into the models, while allowing performance improvements, and also requires much simpler algorithms and less training data. This is tested in the context of simulating the chaotic Lorenz '96 system, and it is shown that the approach yields models that are stable and that give both improved skill in initialized predictions and better long‐term climate statistics. Improvements in long‐term statistics are smaller than for single time step tendencies, however, indicating that it would be valuable to develop methods that target improvements on longer time scales. Future strategies for the development of this approach and possible applications to making progress on important scientific problems are discussed.
Anthropogenic Aerosols, Greenhouse Gases, and the Uptake, Transport, and Storage of Excess Heat in the Climate System
Authors: Irving D. B. , Wijffels S. , Church J. A. 
Published: April 2019

AbstractThe largest contributor to the planetary energy imbalance is well‐mixed greenhouse gases (GHGs), which are partially offset by poorly mixed (and thus northern midlatitude dominated) anthropogenic aerosols (AAs). To isolate the effects of GHGs and AAs, we analyze data from the CMIP5 historical (i.e., all natural and anthropogenic forcing) and single forcing (GHG‐only and AA‐only) experiments. Over the duration of the historical experiment (1861–2005) excess heat uptake at the top of the atmosphere and ocean surface occurs almost exclusively in the Southern Hemisphere, with AAs canceling the influence of GHGs in the Northern Hemisphere. This interhemispheric asymmetry in surface heat uptake is eliminated by a northward oceanic transport of excess heat, as there is little hemispheric difference in historical ocean heat storage after accounting for ocean volume. Data from the 1pctCO2 and RCP 8.5 experiments suggests that the future storage of excess heat will be skewed toward the Northern Hemisphere oceans.
Shelf‐Basin Interactions and Water Mass Residence Times in the Western Arctic Ocean: Insights Provided by Radium Isotopes
Authors: Kipp Lauren E. , Kadko David C. , Pickart Robert S. , Henderson Paul B. , Moore Willard S. , Charette Matthew A. 
Published: April 2019

AbstractRadium isotopes are produced through the decay of thorium in sediments and are soluble in seawater; thus, they are useful for tracing ocean boundary‐derived inputs to the ocean. Here we apply radium isotopes to study continental inputs and water residence times in the Arctic Ocean, where land‐ocean interactions are currently changing in response to rising air and sea temperatures. We present the distributions of radium isotopes measured on the 2015 U.S. GEOTRACES transect in the Western Arctic Ocean and combine this data set with historical radium observations in the Chukchi Sea and Canada Basin. The highest activities of radium‐228 were observed in the Transpolar Drift and the Chukchi shelfbreak jet, signaling that these currents are heavily influenced by interactions with shelf sediments. The ventilation of the halocline with respect to inputs from the Chukchi shelf occurs on time scales of ≤19–23 years. Intermediate water ventilation time scales for the Makarov and Canada Basins were determined to be ~20 and >30 years, respectively, while deep water residence times in these basins were on the order of centuries. The radium distributions and residence times described in this study serve as a baseline for future studies investigating the impacts of climate change on the Arctic Ocean.