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.

The maintenance of cross-cultural variation and arbitrary traditions in human populations is a key question in cultural evolution. Conformist transmission, the tendency to follow the majority, was previously considered central to this phenomenon. However, recent theory indicates that cognitive biases can greatly reduce its ability to maintain traditions. Therefore, we expanded prior models to investigate two other ways that cultural variation can be sustained: payoff-biased transmission and norm reinforcement. Our findings predict that both payoff-biased transmission and reinforcement can enhance conformist transmission's ability to maintain traditions. However, payoff-biased transmission can only sustain cultural variation if it is functionally related to environmental factors. In contrast, norm reinforcement readily generates and maintains arbitrary cultural variation. Furthermore, reinforcement results in path-dependent cultural dynamics, meaning that historical traditions influence current practices, even though group behaviours have changed. We conclude that environmental variation probably plays a role in functional cultural traditions, but arbitrary cultural variation is more plausibly due to the reinforcement of norm compliance.

Understanding the generation of large-scale magnetic fields and flows in magnetohydro-dynamical (MHD) turbulence remains one of the most challenging problems in astrophysical fluid dynamics. Although much work has been done on the kinematic generation of large-scale magnetic fields by turbulence, relatively little attention has been paid to the much more difficult problem in which fields and flows interact on an equal footing. The aim is to find conditions for long-wavelength instabilities of stationary MHD states. Here, we first revisit the formal exposition of the long-wavelength linear instability theory, showing how long-wavelength perturbations are governed by four mean field tensors; we then show how these tensors may be calculated explicitly under the ‘short-sudden’ approximation for the turbulence. For MHD states with relatively little disorder, the linear theory works well: average quantities can be readily calculated, and stability to long-wavelength perturbations determined. However, for disordered basic states, linear perturbations can grow without bound and the purely linear theory, as formulated, cannot be applied. We then address the question of whether there is a linear response for sufficiently weak mean fields and flows in a dynamical (nonlinear) evolution, where perturbations are guaranteed to be bounded. As a preliminary study, we first address the nature of the response in a series of one-dimensional maps. For the full MHD problem, we show that in certain circumstances, there is a clear linear response; however, in others, mean quantities – and hence the nature of the response – can be difficult to calculate.

Children’s externalizing behaviors are associated with impairments across the lifespan. Developmental psychopathology theories propose transactional (bidirectional) associations between child externalizing behaviors and parenting during childhood and adolescence. Yet, these foundational relations in early childhood are not well-studied. Utilizing a large, mixed-sex sample, we examined the reciprocal nature of parenting and child externalizing behaviors across early childhood using robust repeated-measures models. Repeated measures data were drawn from a socioeconomically diverse, longitudinal pregnancy cohort of 1287 (64% Black, 31% White) mother-child dyads at four time points (ages one to six). Three variables were included in cross-lagged panel models: observed parenting quality, child externalizing symptoms, and a maternal risk composite. In covariate-adjusted models, higher parenting quality at Wave 1 predicted lower child externalizing symptoms at Wave 2. Higher externalizing symptoms at Wave 1 and Wave 2 predicted lower parenting quality at Wave 2 and Wave 3, respectively. Maternal risk and parenting quality were not significantly associated. Findings showed both parent-driven and child-driven effects across early childhood that did not vary by child sex. The transactional nature of the parent-child relationship begins in infancy, underscoring the importance of early screening and provision of supports for families to minimize and prevent the development of serious psychopathology.

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.

Background: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations. Delandistrogene moxeparvovec is an investigational gene transfer therapy, developed to address the underlying cause of DMD. We report findings from Part 1 (52 weeks) of the two-part EMBARK trial (NCT05096221). Methods: Key inclusion criteria: Ambulatory patients aged ≥4-<8 years with a confirmed DMD mutation within exons 18–79 (inclusive); North Star Ambulatory Assessment (NSAA) score >16 and <29 at screening. Eligible patients were randomized 1:1 to intravenous delandistrogene moxeparvovec (1.33×1014 vg/kg) or placebo. The primary endpoint was change from baseline in NSAA total score to Week 52. Results: At Week 52 (n=125), the primary endpoint did not reach statistical significance, although there was a nominal difference in change from baseline in NSAA total score in the delandistrogene moxeparvovec (2.6, n=63) versus placebo groups (1.9, n=61). Key secondary endpoints (time to rise, micro-dystrophin expression, 10-meter walk/run) demonstrated treatment benefit in both age groups (4-5 and 6-7 years; p<0.05).There were no new safety signals, reinforcing the favorable and manageable safety profile observed to date. Conclusions: Based on the totality of functional assessments including the timed function tests, treatment with delandistrogene moxeparvovec indicates beneficial modification of disease trajectory.

With many non-human primates (NHPs) showing continued population decline, there is an ongoing need to better understand their ecology and conservation threats. One such threat is the risk of disease, with various bacterial, viral and parasitic infections previously reported to have damaging consequences for NHP hosts. Strongylid nematodes are one of the most commonly reported parasitic infections in NHPs. Current knowledge of NHP strongylid infections is restricted by their typical occurrence as mixed infections of multiple genera, which are indistinguishable through traditional microscopic approaches. Here, modern metagenomics approaches were applied for insight into the genetic diversity of strongylid infections in South-East and East Asian NHPs. We hypothesized that strongylid nematodes occur in mixed communities of multiple taxa, dominated by Oesophagostomum, matching previous findings using single-specimen genetics. Utilizing the Illumina MiSeq platform, ITS-2 strongylid metabarcoding was applied to 90 samples from various wild NHPs occurring in Malaysian Borneo and Japan. A clear dominance of Oesophagostomum aculeatum was found, with almost all sequences assigned to this species. This study suggests that strongylid communities of Asian NHPs may be less species-rich than those in African NHPs, where multi-genera communities are reported. Such knowledge contributes baseline data, assisting with ongoing monitoring of health threats to NHPs.

Folate and choline are methyl donor nutrients that may play a role in fetal brain development. Animal studies have reported that prenatal folate and choline supplementation are associated with better cognitive outcomes in offspring and that these nutrients may interact and affect brain development. Human studies that have investigated associations between maternal prenatal folate or choline levels and neurodevelopmental outcomes have reported contradictory findings and no human studies have examined the potential interactive effect of folate and choline on children’s neurodevelopment. During the second trimester of pregnancy, maternal red blood cell folate was measured from blood samples and choline intake was estimated using a 24-h dietary recall in 309 women in the APrON cohort. At 3–5 years of age, their children’s neurodevelopment was assessed using the Wechsler Preschool and Primary Scales of Intelligence – Fourth EditionCND, NEPSY-II language and memory subtests, four behavioral executive function tasks, and the Movement Assessment Battery for Children – Second Edition. Adjusted regressions revealed no associations between maternal folate and choline levels during pregnancy and most of the child outcomes. On the Dimensional Change Card Sort, an executive function task, there was an interaction effect; at high levels of choline intake (i.e., 1 SD above the mean; 223.03 mg/day), higher maternal folate status was associated with decreased odds of receiving a passing score (β = −0.44; 95%CI −0.81, −0.06). In conclusion, maternal folate status and choline intake during the second trimester of pregnancy were not associated with children’s intelligence, language, memory, or motor outcomes at 3–4 years of age; however, their interaction may have an influence children’s executive functions.

In 1952 Sinclair Hood found a large deposit of pottery in front of the Great Poros Wall at Mycenae and published a brief account of its discovery the following year. In 1966 Elizabeth French published a paper discussing the pottery, assigning it an early Late Helladic IIIB1 date. From these accounts, we know that the deposit appeared in four trenches: Prehistoric Cemetery Central (PCC) III, where it sat on a surface of hard tramped earth; PCC IV, where it lay on bedrock; and PCC III Extension East and Area VII, where it rested on white clay plaster floors. But otherwise we learn little about the stratigraphy of these four trenches. Using Hood's unpublished excavation notebook, this paper examines the stratigraphy of the trenches associated with the deposit and uncovers the archaeological history of the area. In doing so, it reveals several omissions in the published accounts, most notably that there was another surface immediately below the white clay plaster floor in PCC III Extension East and a deposit of pottery associated with it. The pottery from this layer, designated Level 3, was mistakenly included by French in her paper. Fifty-four decorated sherds from Level 3 were kept, seven of which were illustrated by French. Most of the sherds come from small stirrup jars; kylikes, including the Zygouries type; Group A deep bowls; and stemmed bowls. The five most popular motifs on the sherds are the flower, whorl-shell, wavy line, parallel chevrons and panelled patterns. The shapes and motifs reflect those in the main pottery deposit and indicate a date of early Late Helladic IIIB1 for the group. The conclusion emphasises the importance of using excavation notebooks in research.

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.

Previous studies have shown that male mink (Mustela vison) removed from their mothers at seven weeks of age develop more tail-biting than males left with their mothers until six months. Mink in the wild do not damage their own pelts in this way, and such behaviour may well be an indication of chronic stress.

The aim of this experiment was to investigate further the causes of tail-biting by considering female young as well as male, and by lowering the age at which the late-weaned ‘ mink were separated from their mother to 11 weeks, by which age their period of socialization should be complete. This was to generate results of more practical use to farmers, who cannot leave all young with their mothers until six months of age for reasons of space. Mink removed from their mothers at seven or eleven weeks of age did indeed differ in the incidence of tail-biting. Early-weaned ‘females were more likely than late-weaned females to have bitten their tails at six months of age. A similar result was evident as a trend for both sexes at ten months. Furthermore, at this age, some animals ‘ tail tips were completely bald and such animals were all early-weaned.

Where provided with plastic drinker dishes, early-weaned animals were also more likely to chew these. Thus weaning age had long-lasting effects on a number of oral behaviour patterns. These results suggest that young animals predisposed to tail-bite might be diverted by the provision of other objects to chew, and that if problems of over-crowding are avoided, leaving mink kits with their mothers until 11 weeks might improve their welfare.

Although cats’ popularity as pets rivals that of dogs, cats are little studied, and people's abilities to read this apparently ‘inscrutable’ species have attracted negligible research. To determine whether people can identify feline emotions from cats’ faces, participants (n = 6,329) each viewed 20 video clips of cats in carefully operationalised positively (n =10) or negatively valenced states (n = 10) (cross-factored with low and high activity levels). Obvious cues (eg open mouths or fully retracted ears) were eliminated. Participants’ average scores were low (11.85/20 correct), but overall above chance; furthermore, 13% of participants were individually significantly successful at identifying the valence of cats’ states (scoring ≥ 15/20 correct). Women were more successful at this task than men, and younger participants more successful than older, as were participants with professional feline (eg veterinary) experience. In contrast, personal contact with cats (eg pet-owning) had little effect. Cats in positive states were most likely to be correctly identified, particularly if active rather than inactive. People can thus infer cats’ affective states from subtle aspects of their facial expressions (although most find this challenging); and some individuals are very good at doing so. Understanding where such abilities come from, and precisely how cats’ expressions change with affective state, could potentially help pet owners, animal care staff and veterinarians optimise feline care and welfare.

Stress cues can affect the welfare of animals in close proximity and are possibly useful non-invasive indicators of the emitters’ welfare. To facilitate their study in murids, we tested whether rats’ stress odours could be collected and stored using an enfleurage-type technique. ‘Donor’ rats were individually exposed to a compound stressor (carried circa 75 m inside a novel container, then euthanised with rising carbon dioxide) while on blotting paper dotted with melted vegetable lard. These sheets were sealed, left at room temperature for 2-5 h, and then ‘bioassayed’ by a blind observer for their effects on conspecifics. Compared with control sheets (exposed to unstressed rats, to CO2 alone, or untreated), stress-exposed sheets significantly affected the unconditioned behaviour of 16 pairs of detector rats trained to enter an arena from their home cage to obtain sucrose. When used to line this arena, the stress-exposed sheets significantly increased: i) rats’ latencies to eat, to place front feet into, and to completely step into the arena and ii) shuttling movements between arena and home cage. These pilot data thus suggest that odours produced by stressed rats can be simply and successfully collected and stored for several hours, though certain potential confounds (eg urine volume) may conceivably be alternative explanations for the observed effects. Future work should control for urine volume, and assess whether fat is needed for optimal odour absorption by paper and for how long sheets can be stored at various temperatures. Much fundamental work is also still needed on the nature, functions, and sources of stress odours.

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.