Objectives/Goals: People with insulin-treated diabetes face hypoglycemia risk due to imperfect insulin replacement and impaired counterregulation. We identified the dopamine antagonist, metoclopramide, as a potential treatment. Hypothesis: Treatment with metoclopramide will prevent the development of impaired counterregulatory response to hypoglycemia. Methods/Study Population: In a pre-clinical model, diabetes was induced in 10-week-old Sprague-Dawley rats with streptozotocin (STZ, 65 mg/kg IP). Rats were divided into three groups: 1) diabetic controls (STZ+RS, n = 6), 2) recurrent hypoglycemia (STZ+RH, n = 7), and 3) recurrent hypoglycemia + metoclopramide (STZ+RH+MET, 3 mg/kg IP, n = 7). After 3 days, all rats underwent a hyperinsulinemic (50 mU/kg/min) and hypoglycemic (~45 mg/dl) clamp. In the clinical trial, adults with Type 1 diabetes (age 20–60, ≥5 years duration) were enrolled in a phase II, double-blinded, placebo-controlled trial. Awareness status was assessed via Gold score, and subjects maintained drug regimens and underwent two hyperinsulinemic-hypoglycemic clamps (where blood glucose was lowered to 100, 65, 55, and 45 mg/dl) to assess counterregulation. Results/Anticipated Results: In the pre-clinical model, glucose infusion rates (GIR) to maintain hypoglycemia were higher in STZ+RH (27±0.9 mg/kg/min) than STZ+RS (19±0.8 mg/kg/min, p Discussion/Significance of Impact: Metoclopramide improves glucoregulatory, sympathoadrenal, and counterregulatory responses to hypoglycemia in pre-clinical models, suggesting dopaminergic regulation. While clinical data are still blinded, increased epinephrine and growth hormone responses suggest treatment may preserve or restore counterregulation.

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.

The behavioural reactions and blood Cortisol levels of cattle stunned using a penetrating captive-bolt pistol whilst standing free in a stunning box were compared with those obtained from cattle similarly stunned but with their heads held in a hydraulically operated chin-lift type of head restrainer. Few (8 out of 55) animals voluntarily put their heads into the restrainer, most had to be ‘persuaded’ to use the head-restrainer; some (5 out of 24) could not be. The mean time between entry into the stunning pen and the stun for 23 free standing animals was 5.6s and for 19 animals which could be persuaded to use the head restrainer was 34.2s. The Cortisol levels in the blood taken at the stick, from 30 animals stunned while standing free was 67.6 nmoVlitre while that from 30 stunned while head-restrained was 143.1 nmolHitre. The behaviour and Cortisol results suggest that enforced usage of this type of head restrainer could be a cause of distress to the cattle involved.

The updated vancomycin guideline for treatment of serious methicillin-resistant Staphylococcus aureus infections prompted institutions to convert from trough to area-under-the-curve monitoring. The physician perception of the transition, coupled with that of pharmacists, was measured by pre- and postimplementation surveys. Both groups believed safety would be increased without efficacy changes.

A zirconolite glass-ceramic material is a candidate wasteform for immobilisation of chlorine contaminated plutonium residues, in which plutonium and chlorine are partitioned to the zirconolite and aluminosilicate glass phase, respectively. A preliminary investigation of chlorine speciation was undertaken by analysis of Cl K-edge X-ray Absorption Near Edge Spectroscopy (XANES), to understand the incorporation mechanism. Cl was found to be speciated as the Cl- anion within the glass phase, according to the characteristic chemical shift of the X-ray absorption edge. By comparison with Cl K-edge XANES data acquired from reference compounds, the local environment of the Cl- anion is most closely approximated by the mineral marialite, in which Cl is co-ordinate to 4 x Na and/or Ca atoms.

Solar coronal dimmings have been observed extensively in the past two decades and are believed to have close association with coronal mass ejections (CMEs). Recent study found that coronal dimming is the only signature that could differentiate powerful flares that have CMEs from those that do not. Therefore, dimming might be one of the best candidates to observe the stellar CMEs on distant Sun-like stars. In this study, we investigate the possibility of using coronal dimming as a proxy to diagnose stellar CMEs. By simulating a realistic solar CME event and corresponding coronal dimming using a global magnetohydrodynamics model (AWSoM: Alfvén-wave Solar Model), we first demonstrate the capability of the model to reproduce solar observations. We then extend the model for simulating stellar CMEs by modifying the input magnetic flux density as well as the initial magnetic energy of the CME flux rope. Our result suggests that with improved instrument sensitivity, it is possible to detect the coronal dimming signals induced by the stellar CMEs.

In support of the disposal system safety case for a geological disposal facility (GDF) there is a requirement to consider 'what-if' hypothetical scenarios for post-closure nuclear criticality. Although all such scenarios are considered very unlikely, one 'what-if' scenario is the mobilization of fissile material from a number of waste packages and its slow accumulation within the GDF or the immediate surroundings. Should sufficient fissile material accumulate a quasi-steady-state (QSS) transient criticality event could result. A computer model has been developed to understand the evolution and consequences of such an event.

Since a postulated QSS criticality could persist for many millennia, building confidence in the modelling approach is difficult. However, the Oklo natural reactors in Africa operated for similar durations around two billion years ago, providing a natural analogue for comparison. This paper describes the modelling approach, its application to hypothetical criticality events for a GDF, and how the model can be compared to Oklo. The model results are found to be in agreement with the observational evidence from Oklo, building confidence in the use of the QSS model to simulate postulated post-closure criticality events in GDFs.

In support of the Radioactive Waste Management (RWM) safety case for a geological disposal facility (GDF) in the UK, there is a regulatory requirement to consider the likelihood and consequences of nuclear criticality. Waste packages are designed to ensure that criticality is not possibleduring the transport and operational phases of a GDF and for a significant period post-closure. However, over longer post-closure timescales, conditions in the GDF will evolve.

For waste packages containing spent fuel, it can be shown that, under certain conditions, package flooding couldresult in a type of criticality event referred to as 'quasi-steady-state' (QSS). Although unlikely, this defines a 'what-if' scenario for understanding the potential consequences of post-closure criticality. This paper provides an overview of a methodology to understand QSS criticality andits application to a spent fuel waste package.

The power of such a hypothetical criticality event is typically estimated to be a few kilowatts: comparable with international studies of similar systems and the decay heat for which waste packages are designed. This work has built confidencein the methodology and supports RWM's demonstration that post-closure criticality is not a significant concern.

A geological disposal facility (GDF) will include fissile materials that could, under certain conditions, lead to criticality. Demonstration of criticality safety therefore forms an important part of a GDF's safety case.

Containment provided by the waste package will contributeto criticality safety during package transport and the GDF operational phase. The GDF multiple-barrier system will ensure that criticality is prevented for some time after facility closure. However, on longer post-closure timescales, conditions in the GDF will evolve and it is necessary todemonstrate: an understanding of the conditions under which criticality could occur; the likelihood of such conditions occurring; and the consequences of criticality should it occur.

Work has addressed disposal of all of the UK's higher-activity wastes in three illustrative geologies.This paper, however, focuses on presenting results to support safe disposal of spent fuel, plutonium and highlyenriched uranium in higher-strength rock.

The results support a safety case assertion that post-closure criticality is of low likelihood and, if it was to occur, the consequenceswould be tolerable.

This paper reexamines the stratigraphy, sources, and paleoclimatic significance of Holocene Bignell Loess in the central Great Plains. A broadly similar sequence of loess depositional units and paleosols was observed in thick Bignell Loess sections up to 300 km apart, suggesting that these sections record major regional changes in the balance between dust deposition and pedogenesis. New optical ages, together with previously reported radiocarbon ages, indicate Bignell Loess deposition began 9000–11,000 yr ago and continued into the late Holocene; some Bignell Loess is <1000 yr old. There is little evidence that Holocene Loess was derived from flood plain sources, as previously proposed. Instead, thick Bignell Loess occurs mainly near the downwind margins of inactive dune fields, particularly atop escarpments facing the dunes. Thus, the immediate loess source was dust produced when the dunes were active. Previous work indicates that widespread episodes of dune activity are likely to have resulted from drier-than-present climatic conditions. The regionally coherent stratigraphy of Bignell Loess can be interpreted as a near-continuous record of climatically driven variation in dune field activity throughout the Holocene.

Field collections of over-wintering and summer adults and nymphs of Lygus lineolaris (Palisot de Beauvois) (Hemiptera: Miridae), Lygus borealis (Kelton), and Lygus elisus Van Duzee were made weekly in five fields in Saskatchewan in 1998 and 1999. The crops sampled were alfalfa, Medicago sativa L. (Leguminosae), canola, Brassica napus L. (Cruciferae), and mustard, Sinapis alba L. (Cruciferae), at Vonda, and alfalfa and canola at Saskatoon. In alfalfa, the most abundant Lygus spp. found in May and June were over-wintering adult L. lineolaris and (or) L. borealis; the predominant species in mid-June to early July was L. borealis; and the population from mid-July to late August was dominated by L. lineolaris. In canola, adult populations of Lygus spp. were not found until mid-June. The predominant species, L. lineolaris, probably over-wintering adults, was first detected in canola at the early bud stage in late June to early July; high numbers of L. lineolaris adults occurred in canola in mid-August. Populations of Lygus spp. in organic mustard were negligible. Dissections of field-collected Lygus spp. nymphs revealed parasitism in up to 70% of the midsummer population in alfalfa. In contrast, less than 1% of the late-season Lygus spp. population, primarily L. lineolaris in canola and L. lineolaris and L. borealis in alfalfa, was parasitized.

Plant bugs in the genus Lygus (Hahn) (Hemiptera: Miridae) are sporadic pests of canola, Brassica napus L. (Brassicaceae) and Brassica rapa L., in western Canada and infestations appear to have become increasingly common and severe in recent years. Surveys conducted from 1998 to 2000 identified a "northern" assemblage in the boreal ecoregion that was dominated by Lygus lineolaris (Palisot de Beauvois), with minor representation of Lygus borealis (Kelton), Lygus elisus (Van Duzee), and Lygus keltoni (Schwartz). A "southern" assemblage in the grassland ecoregions was dominated by L. keltoni, with a substantial abundance of L. elisus and L. borealis and with few L. lineolaris in the driest areas. The assemblage from the parkland ecoregion was variable but with few L. elisus. The boreal plains and parkland ecoregions of Alberta had the most serious and persistent infestations of Lygus spp. Relative species composition of the Lygus assemblage at the bolting stage was not related to the overall abundance of these bugs at the early pod stage. Lygus species assemblages were similar in terms of composition and relative abundance at the bolting and early pod stages of canola. A shift in species proportions in favour of L. lineolaris in the north and L. keltoni in the south and a decrease of L. elisus has taken place relative to studies conducted in the 1980's.

We investigated an international outbreak of Salmonella Agona with a distinct PFGE pattern associated with an Irish Food company (company X) producing pre-cooked meat products sold in various food outlet chains in Europe. The outbreak was first detected in Ireland. We undertook national and international case-finding, food traceback and microbiological investigation of human, food and environmental samples. We undertook a matched case-control study on Irish cases. In total, 163 cases in seven European countries were laboratory-confirmed. Consumption of food from food outlet chains supplied by company X was significantly associated with being a confirmed case (mOR 18·3, 95% CI 2·2–149·2) in the case-control study. The outbreak strain was isolated from the company's pre-cooked meat products and production premises. Sufficient evidence was gathered to infer the vehicles of infection and sources of the outbreak and to justify the control measures taken, which were plant closure and food recall.