Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

Gadfly petrels Pterodroma spp. are among the most threatened bird taxa. Conservation interventions have been successfully developed and applied for some gadfly petrel species, but a substantial gap remains in conservation science for this group in the tropical Pacific Ocean. The Vanuatu Petrel Pterodroma [cervicalis] occulta is an ideal exemplar to develop a pipeline for conservation science in tropical Pacific gadfly petrels as it is subject to many of the challenges facing other gadfly petrel taxa in the region. We review over 40 pelagic Vanuatu Petrel records and five research expeditions to the only known colony on the island of Vanua Lava, Vanuatu. These records provide a baseline from which to recommend conservation research actions for the taxon. The population status, taxonomy, distribution, and threat profile of the taxon are all poorly known, and these areas are high priorities for future research.

ABSTRACT IMPACT: The pathophysiologic features of a metabolomic endotype that predicts patient outcomes due to sepsis have the potential to direct new therapies that target immune dysregulation and bioenergetic insufficiency. OBJECTIVES/GOALS: Acute respiratory failure (ARF) requiring mechanical ventilation is a frequent complication of sepsis and other disorders. It is associated with high morbidity and mortality. Despite its severity and prevalence, little is known about metabolic and bioenergetic changes that accompanying ARF. METHODS/STUDY POPULATION: In this study, semiquantitative and quantitative ultrahigh performance liquid chromatography mass spectrometry (UHPLC MS) analysis was performed on patient serum collected from the Trial with Acute Respiratory failure patients: evaluation of Global Exercise Therapies (TARGET). Serum from survivors (n=15) and nonsurvivors (n=15) was collected at day 1 and day 3 after admission to the medical intensive care unit as well as at discharge in survivors. Pathway analysis of the biochemical changes was performed to determine whether the disruption in specific metabolic pathways can identify the bioenergetic and metabolomic profile of these patients. RESULTS/ANTICIPATED RESULTS: Significant metabolomic differences were related to biosynthetic intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, and decreased acyl-glycerophosphocholines in nonsurvivors compared to survivors. The metabolites associated with poor outcomes are substrates of enzymatic processes dependent on NAD(P), while the abundance of NAD cofactors rely on the bioavailability of dietary vitamins B1, B2 and B6. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with an alteration of the glutathione-dependent drug metabolism as characterized by the substantial differences observed in the acetaminophen metabolome. DISCUSSION/SIGNIFICANCE OF FINDINGS: This metabolomic endotype represents a previously unappreciated association between severity of outcomes and micronutrient deficiency, thus pointing to new pharmacologic targets and highlighting the need for nutritional remediation upon hospitalization to improve patient outcomes due to ARF.

Microvascular health is a main determinant of coronary blood flow reserve and myocardial vascular resistance. Extracardiac capillary abnormality has been reported in subjects at increased coronary heart disease risk, such as prehypertension, hypertension, diabetes, hyperlipidemia, and atherosclerosis. We have reported cardiovascular dysfunction in a cohort of maternal nutrient reduction (MNR)-induced intrauterine growth restriction (IUGR) baboon offspring. Here we test the hypothesis that there is oral capillary rarefaction associated with MNR-induced IUGR. Capillary density was quantified using in vivo high-power capillaroscopy on seven middle-aged (~10.7 yr; human equivalent ~40 yr) male IUGR baboons and seven male age-matched controls in the lateral buccal and inferior labial mucosa. While no difference was found between groups in either area by fraction area or optical density for these vascular beds derived from fetal preductal vessels, further studies are needed on post-ductal vascular beds, retina, and function.

Objectives: This study examined the effects of anodal transcranial direct current stimulation (a-tDCS) on sentence and word comprehension in healthy adults. Methods: Healthy adult participants, aged between 19 and 30 years, received either a-tDCS over the left inferior frontal gyrus (n=18) or sham stimulation (n=18). Participants completed sentence comprehension and word comprehension tasks before and during stimulation. Accuracy and reaction times (RTs) were recorded as participants completed both tasks. Results: a-tDCS was found to significantly decrease RT on the sentence comprehension task compared to baseline. There was no change in RT following sham stimulation. a-tDCS was not found to have a significant effect on accuracy. Also, a-tDCS did not affect accuracy or RTs on the word comprehension task. Conclusions: The study provides evidence that non-invasive anodal electrical stimulation can modulate sentence comprehension in healthy adults, at least compared to their baseline performance. (JINS, 2019, 25, 331–335)

A 141m ice core was recovered from Combatant Col (51.385° N, 125.258° W; 3000ma.s.l.), Mount Waddington, Coast Mountains, British Columbia, Canada. Records of black carbon, dust, lead and water stable isotopes demonstrate that unambiguous seasonality is preserved throughout the core, despite summer surface snowmelt and temperate ice. High accumulation rates at the site (>4 m ice eq. a-1) limit modification of annual stratigraphy by percolation of surface meltwater. The ice-core record spans the period 1973–2010. An annually averaged time series of lead concentrations from the core correlates well with historical records of lead emission from North America, and with ice-core records of lead from the Greenland ice sheet. The depth-age scale for the ice core provides sufficient constraint on the vertical strain to allow estimation of the age of the ice at bedrock. Total ice thickness at Combatant Col is ~250 m; an ice core to bedrock would likely contain ice in excess of 200 years in age. Accumulation at Combatant Col is significantly correlated with both regional precipitation and large-scale geopotential height anomalies.

We show that geophysical methods offer an effective means of quantifying snow thickness and density. Opportunistic (efficient but non-optimized) seismic refraction and ground-penetrating radar (GPR) surveys were performed on Storglaciären, Sweden, co-located with a snow pit that shows the snowpack to be 1.73 m thick, with density increasing from ∼120 to ∼500 kg m–3 (with a +50 kg m–3 anomaly between 0.73 and 0.83 m depth). Depths estimated for two detectable GPR reflectors, 0.76 ±0.02 and 1.71 ± 0.03 m, correlate extremely well with ground-truth observations. Refraction seismic predicts an interface at 1.90 ± 0.31 m depth, with a refraction velocity (3730 ± 190 ms–1) indicative of underlying glacier ice. For density estimates, several standard velocity-density relationships are trialled. In the best case, GPR delivers an excellent density estimate for the upper snow layer (observed = 321 ± 74 kg m–3, estimated = 319 ± 10 kgm–3) but overestimates the density of the lower layer by 20%. Refraction seismic delivers a bulk density of 404 ±22 kgm–3 compared with a ground-truth average of 356 ± 22 kg m–3. We suggest that geophysical surveys are an effective complement to mass-balance measurements (particularly for controlling estimates of snow thickness between pits) but should always be validated against ground-truth observations.

A sediment succession from Højby Sø, a lake in eastern Denmark, covering the time period 9400-7400 cal yr BP was studied using high-resolution geochemistry, magnetic susceptibility, pollen, macrofossil, diatom, and algal pigment analysis to investigate responses of the terrestrial and aquatic ecosystems to the 8.2 ka cold event. A reduced pollen production by thermophilous deciduous tree taxa in the period c. 8250–8000 cal yr BP reveal that the forest ecosystem was affected by low temperatures during the summer and winter/early-spring seasons. This finding is consistent with the timing of the 8.2 ka cold event as registered in the Greenland ice cores. At Højby Sø, the climate anomaly appears to have started 200–250 yr earlier than the 8.2 ka cold event as the lake proxy data provide strong evidence for a precipitation-induced distinct increase in catchment soil erosion beginning around 8500 cal yr BP. Alteration of the terrestrial environment then resulted in a major aquatic ecosystem change with nutrient enrichment of the lake and enhanced productivity, which lasted until c. 7900 cal yr BP.

Proglacial lakes, formed during retreat of the Laurentide ice sheet, evolved quickly as outlets became ice-free and the earth deformed through glacial isostatic adjustment. With high-resolution digital elevation models (DEMs) and GIS methods, it is possible to reconstruct the evolution of surface hydrology. When a DEM deforms through time as predicted by our model of viscoelastic earth relaxation, the entire surface hydrologic system with its lakes, outlets, shorelines and rivers also evolves without requiring assumptions of outlet position. The method is applied to proglacial Lake Oshkosh in Wisconsin (13,600 to 12,900 cal yr BP). Comparison of predicted to observed shoreline tilt indicates the ice sheet was about 400 m thick over the Great Lakes region. During ice sheet recession, each of the five outlets are predicted to uplift more than 100 m and then subside approximately 30 m. At its maximum extent, Lake Oshkosh covered 6600 km2 with a volume of 111 km3. Using the Hydrologic Engineering Center-River Analysis System model, flow velocities during glacial outburst floods up to 9 m/s and peak discharge of 140,000 m3/s are predicted, which could drain 33.5 km3 of lake water in 10 days and transport boulders up to 3 m in diameter.

The Protoplanetary Discussions conference—held in Edinburgh, UK, from 2016 March 7th–11th—included several open sessions led by participants. This paper reports on the discussions collectively concerned with the multi-physics modelling of protoplanetary discs, including the self-consistent calculation of gas and dust dynamics, radiative transfer, and chemistry. After a short introduction to each of these disciplines in isolation, we identify a series of burning questions and grand challenges associated with their continuing development and integration. We then discuss potential pathways towards solving these challenges, grouped by strategical, technical, and collaborative developments. This paper is not intended to be a review, but rather to motivate and direct future research and collaboration across typically distinct fields based on community-driven input, to encourage further progress in our understanding of circumstellar and protoplanetary discs.

The current volume brings together contributions from two separate editors. The first is a collection of texts edited by Peter Clarke that evidence Cardinal Thomas Wolsey's legatine powers to grant dispensations and other papal graces and his exercise of these powers during the 1520s in Henry VIII's realm. The second is a text edited by Michael Questier. It takes the form of glosses on and suggested readings of the Elizabethan statute law which imposed treason penalties on Catholic clergy who exercised their office in reconciling to Rome (i.e. absolving from schism and heresy) and on those who availed themselves of this sacramental power. The rationale for linking these contributions in a single volume is threefold. First, both generally concern Catholicism in Tudor England, especially the authority of Catholic clergy there both before and after the break with Rome. Secondly and more specifically, they regard the role of these clergy as agents of papal authority in Tudor England. Wolsey was appointed as a papal legate in 1518 and obtained legatine powers from successive popes on a scale unparalleled in pre-Reformation England, notably to grant dispensations, and he exercised these dispensing powers there extensively; he was thus the papal agent par excellence in Tudor England on the eve of the Reformation. The Elizabethan ‘tolerationist’ text, by contrast, seeks to deny that Catholic clergy necessarily functioned as agents of papal authority. They were not, therefore, all without exception traitors to the queen, even though one literal reading of the statute book might give the impression that this was what the State had meant. Instead, so this manuscript claimed, the statutes themselves could be read in such a way as to imply that the legislators themselves accepted that the Catholic clergy's priestly functions did not depend exclusively on papal supremacy (unlike Wolsey's legatine status) or even a malign anti-popish understanding of the papacy as a legal and ecclesiastical entity. Therefore the exercise of their faculties could not automatically be interpreted as treasonable. Coincidentally Wolsey's activity as a papal agent led to him being attainted him with treason, and although the charge did not relate to his dispensing powers, four years after Wolsey's fall Henry VIII forbade his subjects to petition Rome or its agents for the kinds of graces Wolsey had issued. He established the Faculty Office to issue such graces instead, and its authority depended on royal, not papal, supremacy. Both contributions, therefore, concern the relationship between Catholic clergy and supreme authority in the English Church, wherever this was deemed to lie. Thirdly, both contributions illuminate the limits of the law and flexibility in interpreting and applying it. Wolsey's graces in effect limited the operation of canon law: his dispensations suspended it in specific instances, notably regarding marriage and ordination; and he also granted licences permitting activity that it normally forbade, such as clergy not residing in their benefices. The ‘tolerationist’ text implies, although with arguments which at times seem rather specious, that the Elizabethan State was, even in its more draconian utterances, to some extent drawing in its horns. Both contributions, therefore, concern apparently binding law which might be relaxed in Tudor England with regard to Catholic clergy (as well as laity in the case of Wolsey's papal graces).