The deleterious effects of adversity are likely intergenerational, such that one generation’s adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children’s behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.

OBJECTIVES/GOALS: Our overall objective is to investigate the relationship between radiologic features of meningioma with recently identified histopathological and molecular biomarkers, and to apply a machine learning (ML) approach to further demonstrate their utility in predicting clinical outcomes. METHODS/STUDY POPULATION: We have enrolled a cohort of 84 patients with meningioma diagnosed on the basis of conventional gadolinium-enhanced MRI imaging features since September 2019. Each patient has demographic and clinical data, Ga-68-DOTATATE MRI/PET SUV and dynamic metrics, DCE-MRI perfusion parameters, and histopathologic data. Various tumor subregions will be segmented semi-automatically and later confirmed by experienced neuroradiologist. Histopathologic data will include histologic grade, mitotic rate, Ki67 proliferative index, and presence of WHO established atypical histologic features, immunohistochemical parameters, and established high-grade molecular features. We will use supervised learning techniques to develop algorithms for predicting molecular features from imaging phenotypes. RESULTS/ANTICIPATED RESULTS: Anticipated results - advancements in understanding the molecular biomarkers of meningiomas has uncovered genetic alterations and epigenetic changes that more accurately determine tumor behavior. Currently, the imaging correlates of these molecular biomarkers are unknown, and utilizing radiographic data to predict prognosis and imaging-based classifications of meningiomas have not yet been investigated. Validated imaging correlates of molecular biomarkers not only provide an in-vivo assessment of tumor biology, but can also be integrated with histopathologic features ( radiopathomics models’) for more accurate disease prognostication. We anticipate that our results will identify surrogate imaging features for some of the recently emerged molecular biomarkers of meningioma. DISCUSSION/SIGNIFICANCE: There is a paucity of data on the importance of imaging phenotypes in determining tumor biology. This work has the potential of significant clinical impact by enabling a priori molecular characterization of meningiomas at the time of new diagnosis or recurrence, thereby allowing a personalized medicine approach to treatment planning.

OBJECTIVES/GOALS: We aimed to determine if GLP-1 receptor agonists exert beneficial effects on surrogate measures of cardiovascular function independently of weight loss. Our objective was to compare the outcomes between GLP-1 receptor agonist treatment versus a similar drug without cardiovascular benefit versus weight loss through diet alone. METHODS/STUDY POPULATION: We enrolled 88 individuals with obesity (BMI ≥ 30kg/m2) and pre-diabetes and randomized them in a 2:1:1 ratio to 14 weeks of the GLP-1 receptor agonist liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or hypocaloric diet. Sitagliptin blocks degradation of endogenous GLP-1 but does not cause weight loss or lower adverse cardiovascular outcomes. Treatment was double-blinded and placebo-controlled for drug, and unblinded for diet. Primary endpoints were flow-mediated dilation (FMD) to assess endothelial vasodilatory function, and plasminogen activator inhibitor-1 (PAI-1) to assess endothelial fibrinolytic function. We used a general linear model for each outcome and included gender as a covariate for FMD. Baseline characteristics were similar. Mean age was 50, with 32% men and 13% black. RESULTS/ANTICIPATED RESULTS: At 14 weeks, diet and liraglutide caused weight loss (diet -4.3 ± 3.2 kg, P<0.01; liraglutide -2.7 ± 3.2, P<0.01), while sitagliptin did not (-0.7 ± 2.0, P=0.17). Diet did not improve FMD at 14 weeks compared to baseline (+0.9%, 95% CI [-1.5, 3.3], P=0.46). FMD tended to increase after liraglutide and sitagliptin but was not significant (liraglutide +1.2 [-0.3, 2.8], P=0.12; sitagliptin +1.6 [-0.6, 3.8], P=0.15). Given that liraglutide and sitagliptin work through the same GLP-1 pathway, we combined the liraglutide and sitagliptin groups for overall effect on FMD, which was significantly improved from baseline (+1.4 [0.1, 2.8], P=0.04). Diet and liraglutide improved PAI-1 at 14 weeks (diet -4.4U/mL, [-8.5, -0.2], P=0.04; liraglutide -3.4 [-6.0, -0.7], P=0.01), while sitagliptin did not (-1.4 [-5.1, 2.3], P=0.46). DISCUSSION/SIGNIFICANCE: Activation of the GLP-1 pathway by liraglutide or sitagliptin improves FMD independent of weight loss, while PAI-1 improvement is weight-loss dependent and is only seen after liraglutide or diet. Our study suggests the cardiovascular benefit of liraglutide may be due to combined improvements in endothelial vasodilatory and fibrinolytic function.

Consumption of sugar-sweetened beverages (SSB) by infants and young children are less explored in Asian populations. The Growing Up in Singapore Towards healthy Outcomes cohort study examined associations between SSB intake at 18 months and 5 years of age, with adiposity measures at 6 years of age. We studied Singaporean infants/children with SSB intake assessed by FFQ at 18 months of age (n 555) and 5 years of age (n 767). The median for SSB intakes is 28 (interquartile range 5·5–98) ml at 18 months of age and 111 (interquartile range 57–198) ml at 5 years of age. Association between SSB intake (100 ml/d increments and tertile categories) and adiposity measures (BMI standard deviation scores (sd units), sum of skinfolds (SSF)) and overweight/obesity status were examined using multivariable linear and Poisson regression models, respectively. After adjusting for confounders and additionally for energy intake, SSB intake at age 18 months were not significantly associated with later adiposity measures and overweight/obesity outcomes. In contrast, at age 5 years, SSB intake when modelled as 100 ml/d increments were associated with higher BMI by 0·09 (95 % CI 0·02, 0·16) sd units, higher SSF thickness by 0·68 (95 % CI 0·06, 1·44) mm and increased risk of overweight/obesity by 1·2 (95 % CI 1·07, 1·23) times at age 6 years. Trends were consistent with SSB intake modelled as categorical tertiles. In summary, SSB intake in young childhood is associated with higher risks of adiposity and overweight/obesity. Public health policies working to reduce SSB consumption need to focus on prevention programmes targeted at young children.

In the 2015 review paper ‘Petawatt Class Lasers Worldwide’ a comprehensive overview of the current status of high-power facilities of ${>}200~\text{TW}$ was presented. This was largely based on facility specifications, with some description of their uses, for instance in fundamental ultra-high-intensity interactions, secondary source generation, and inertial confinement fusion (ICF). With the 2018 Nobel Prize in Physics being awarded to Professors Donna Strickland and Gerard Mourou for the development of the technique of chirped pulse amplification (CPA), which made these lasers possible, we celebrate by providing a comprehensive update of the current status of ultra-high-power lasers and demonstrate how the technology has developed. We are now in the era of multi-petawatt facilities coming online, with 100 PW lasers being proposed and even under construction. In addition to this there is a pull towards development of industrial and multi-disciplinary applications, which demands much higher repetition rates, delivering high-average powers with higher efficiencies and the use of alternative wavelengths: mid-IR facilities. So apart from a comprehensive update of the current global status, we want to look at what technologies are to be deployed to get to these new regimes, and some of the critical issues facing their development.

Ecological theory predicts an inverse association between population size and extinction risk, but most previous paleontological studies have failed to confirm this relationship. The reasons for this discrepancy between theory and observation remain poorly understood. In this study, we compiled a global database of gastropod occurrences and collection-level abundances spanning the Early Permian through Early Jurassic (Pliensbachian). Globally, the database contains 5469 occurrences of 496 genera and 2156 species from 839 localities. Within the database, 30 collections distributed across seven stages contain at least 75 specimens and ten genera—our minimum criteria for within-collection analysis of extinction selectivity. We use logistic regression analysis, based on global and local measures of population size and stage-level extinction patterns in Early Permian through Early Jurassic marine gastropods, to assess the relationship between abundance and extinction risk. We find that global genus occurrence frequency is inversely associated with extinction risk (i.e., positively associated with survival) in 15 of 16 stages examined, statistically significantly so in five stages. Although correlation between geographic range and occurrence frequency may account for some of this association, results from multivariable regression analysis suggest that the association between occurrence frequency and extinction risk is largely independent of geographic range. Within local assemblages, abundance (number of individuals) is also inversely associated with extinction risk. The strength of association is consistent across time and modes of fossil preservation. Effect strength is poorly constrained, particularly in analyses of local collections. In addition to limited power due to small sample size, this poor constraint may result from confounding by ecological variables not controlled for in the analyses, by taphonomic or collection biases, or from non-monotonic relationships between abundance and extinction risk. Two factors are likely to account for the difference between our results and those of most previous studies. First, many previous studies focused on the end-Cretaceous mass extinction event; the extent to which these results can be generalized to other intervals remains unclear. Second, previous findings of nonselective extinction could result from insufficient statistical power rather than the absence of an underlying effect, because nonselective extinction is generally used as the null hypothesis for statistical convenience. Survivorship patterns in late Paleozoic and early Mesozoic gastropods suggest that abundance has been a more important influence on extinction risk through the Phanerozoic than previously appreciated.

Recent cladistic analyses have all suggested a diapsid origin of ichthyosaurs. However, an intermediate evolutionary stage of the lower temporal region of ichthyosaurian skull between basal diapsids and derived ichthyosaurs has been absent from the fossil record. Here we describe the cranial skeleton of a new mixosaurid ichthyosaur specimen with a well-preserved lower temporal region from the Anisian Guanling Formation of eastern Yunnan. It is characterized by the most primitive lower temporal region within known ichthyosaurs. The primitive characters of the lower temporal region include both external and internal separation between the jugal and the quadratojugal, an anterior process of the quadratojugal, an apparent posteroventral process of the jugal, and a large lower temporal opening surrounded by the jugal, the postorbital, the squamosal, and the quadratojugal. The lower temporal region of this specimen provides the most direct evidence to the diapsid origin of ichthyosaurs. It also suggests that the disappearance of the lower temporal fenestra is caused initially by the reduction of the lower temporal arcade rather than the enlargement of the surrounding bones.