Background: Chordomas are rare malignant skull-base/spine cancers with devastating neurological morbidities and mortality. Unfortunately, no reliable prognostic factors exist to guide treatment decisions. This work identifies DNA methylation-based prognostic chordoma subtypes that are detectable non-invasively in plasma. Methods: Sixty-eight tissue samples underwent DNA methylation profiling and plasma methylomes were obtained for available paired samples. Immunohistochemical staining and publicly available methylation and gene expression data were utilized for validation. Results: Unsupervised clustering identified two prognostic tissue clusters (log-rank p=0.0062) predicting disease-specific survival independent of clinical factors (Multivariable Cox: HR=16.5, 95%CI: 2.8-96, p=0.0018). The poorer-performing cluster showed immune-related pathway promoter hypermethylation and higher immune cell abundance within tumours, which was validated with external RNA-seq data and immunohistochemical staining. The better-performing cluster showed higher tumour cellularity. Similar clusters were seen in external DNA methylation data. Plasma methylome-based models distinguished chordomas from differential diagnoses in independent testing sets (AUROC=0.84, 95%CI: 0.52-1.00). Plasma methylomes were highly correlated with tissue-based signals for both clusters (r=0.69 & 0.67) and leave-one-out models identified the correct cluster in all plasma cases. Conclusions: Prognostic molecular chordoma subgroups are for the first time identified, characterized, and validated. Plasma methylomes can detect and subtype chordomas which may transform chordoma treatment with personalized approaches tailored to prognosis.

Anti-corruption efforts are inherently political. Corruption charges can be levied against political opponents as an instrument of repression; they can also be used against troublesome allies in the same party coalition to further consolidate power. In this paper, we focus on Indonesia and ask: Do major corruption charges follow a presidential electoral cycle—and if so, how? We contend charges against prominent members of the government coalition are more likely to happen before an election, allowing the government to replace intra-party rivals with loyal allies. Conversely, charges against prominent opposition members are more likely to happen after an election when fears of retaliation are low, opportunities for credit-claiming are high, and there is an incentive to remove veto players who may inhibit implementing the government's agenda. To test this argument, we use an original, newly assembled dataset of all major corruption charges—i.e., those involving high-profile politicians and garnering international attention—in Indonesia from 1998–2015 as reported in the Associated Press. We find a significant and robust relationship between the electoral calendar and major corruption charges. This relationship is robust across presidential administrations. These results yield insights into how anti-corruption efforts can become a political tool and counsel caution about the effectiveness of “good governance,” especially in new democracies. Finally, we discuss how contextual political factors external to Indonesia's anti-corruption commission, reinforce this empirical pattern.

OBJECTIVES/GOALS: Exposure to arsenic, cadmium, manganese, and lead have been linked to adverse neurocognitive outcomes in adults/children, but effects in adolescents are not fully characterized. This study aims to examine the association between exposure to a mixture of metals (As, Cd, Mn, Pb, Se) and cognitive function in adolescents. METHODS/STUDY POPULATION: The Metals, Arsenic, & Nutrition in Adolescents Study (MANAS) is a cross-sectional study of 572 Bangladeshi adolescents. Blood levels of As, Cd, Mn, Pb, and Se were measured via ICP-MS. An abbreviated Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered, with subtests assessing cognitive function and executive function tasks. Linear regression and Bayesian kernel machine regression (BKMR) were used to examine associations between individual metals, the overall mixture of metals, and cognitive function as measured by the CANTAB. RESULTS/ANTICIPATED RESULTS: Linear regression showed that As (B=−2.40) and Mn (B=−5.31) were negatively associated with Spatial Working Memory (p<0.05). Negative associations were also observed between Cd and Spatial Recognition Memory (SRM) (B=−2.77, p<0.05), and between Pb and Delayed Match to Sample (DMS), a measure of visual recognition and memory (B=−3.67, p<0.05). Se and Spatial Span Length (B=0.92, p<0.05) were seen to be positively associated. BKMR showed no overall effect of the mixture but indicated that Pb was negatively associated with DMS, and that Cd was negatively associated with SRM. Se was positively associated with Planning, Reaction Time, and Spatial Span. Posterior inclusion probability consistently rated Se as the most influential mixture component. DISCUSSION/SIGNIFICANCE: Se was positively associated with cognition, while Mn and As were linked to poorer working memory, and Cd and Pb were associated with poorer visual recognition and memory. We saw agreement between linear regression and BKMR in analyzing metal mixture exposures. Findings suggest interventions aimed at adolescents might influence lifelong cognition.

Large-eddy simulations of turbulent flow in partially filled pipes are conducted to investigate the effect of secondary currents on the friction factor, first- and second-order statistics and large-scale turbulent motion. The method is validated first and simulated profiles of the mean streamwise velocity, normal stresses and turbulent kinetic energy (TKE) are shown to be in good agreement with experimental data. The secondary flow is stronger in half- and three-quarters full pipes compared with quarter full or fully filled pipe flows, respectively. The origin of the secondary flow is examined by both the TKE budget and the steamwise vorticity equation, providing evidence that secondary currents originate from the corner between the free surface and the pipe walls, which is where turbulence production is larger than the sum of the remaining terms of the TKE budget. An extra source of streamwise vorticity production is found at the free surface near the centreline bisector, due to the two-component asymmetric turbulence there. The occurrence of dispersive stresses (due to secondary currents) reduces the contribution of the turbulent shear stress to the friction factor, which results in a reduction of the total friction factor of flows in half and three-quarters full pipes in comparison to a fully filled pipe flow. Furthermore, the presence of significant secondary currents inhibits very-large-scale motion (VLSM), which in turn reduces the strength and scales of near-wall streaks. Subsequently, near-wall coherent structures generated by streak instability and transient growth are significantly suppressed. The absence of VLSM and less coherent near-wall turbulence structures is supposedly responsible for the drag reduction in partially filled pipe flows relative to a fully filled pipe flow at an equivalent Reynolds number.

Experiments are conducted in a wave tank to investigate wave scattering by a three-dimensional submerged horizontal rectangular plate in a channel. The free-surface elevation around the plate is presented for various water depths and depths of submergence of the plate. The wave forces and moments are obtained using an underwater load measuring system. The numerical simulations are performed with a parallelized three-dimensional boundary element method. The numerical set-up follows closely the set-up of the laboratory experiments. The numerical results are compared with the experimental results for non-breaking waves. In most cases a good agreement is found for the free-surface elevation, the vertical force and the moment. A physical interpretation of the flow around the plate is provided. The pressure distribution on the lower surface of the plate differs from the linear distribution from the leading edge to the trailing edge that is obtained in the equivalent two-dimensional problem. The reflection by the lateral walls is investigated.

We surveyed healthcare professionals at a cancer center regarding their knowledge and perceptions of antibiotic use. Most knew the term “antimicrobial stewardship.” Nurses and other staff were less likely than pharmacists or providers to answer knowledge-based questions correctly. Opportunities exist to improve antibiotic knowledge among cancer center staff.

Prior to the COVID-19 pandemic, adolescents (N = 1,330; Mages = 15 and 16; 50% female), mothers, and fathers from nine countries (China, Colombia, Italy, Jordan, Kenya, Philippines, Sweden, Thailand, United States) reported on adolescents’ internalizing and externalizing problems, adolescents completed a lab-based task to assess tendency for risk-taking, and adolescents reported on their well-being. During the pandemic, participants (Mage = 20) reported on changes in their internalizing, externalizing, and substance use compared to before the pandemic. Across countries, adolescents’ internalizing problems pre-pandemic predicted increased internalizing during the pandemic, and poorer well-being pre-pandemic predicted increased externalizing and substance use during the pandemic. Other relations varied across countries, and some were moderated by confidence in the government’s handling of the pandemic, gender, and parents’ education.

Background: We describe an infant with a diagnosis of GM3 synthase deficiency, presenting with severe neuroirritability from birth. He required multiple admissions due to extreme agitation and caregiver burnout. Multiple pharmacological agents were tried, and the effect of each medication was modest and short-lasting at best. The literature on the management of neuroirritability in children with progressive genetic and metabolic conditions is sparse, and a neuroirritability management protocol has yet to be developed at our institution. Methods: We searched for relevant primary research and articles on PubMed. We reviewed the evidence of each pharmacological agent and added non-pharmacological strategies. We developed management guidelines for neuroirritability at our hospital. This protocol was reviewed by several pediatric neurologists and pediatric palliative care specialists at the Stollery and SickKids Hospitals. Results: We present the Pediatric Neuroirritability Management Protocol for the Stollery Children’s Hospital. Conclusions: Further study is required to assess whether this protocol can be adapted to treat irritability in the context of other neurological conditions such as hypoxic-ischemic encephalopathy and non-accidental injury. In addition, we will expand our guidelines to include other symptoms such as spasticity, dystonia, and autonomic dysfunction.

This study investigates water waves generated by a bottom obstacle translating at a subcritical speed in constant water depth, using a combination of analytical and numerical approaches. The newly derived analytical solutions reveal two types of waves – the transient free waves that propagate radially outwards, and the trapped wave that stays on top of the translating bottom obstacle. Closed-form asymptotic solutions for both the free surface and the flow velocities are derived in the far field, and near the leading wave or in the shallow water limit. The far-field leading waves are mathematically shown to be insensitive to the exact shape of the obstacle. Numerical long-wave models are employed to examine effects unaccountable by the linear analytical solutions. Nonlinear effects are found to cause only small deviations from the linear solutions. The effects of the obstacle's acceleration and deceleration are also examined numerically. Overall, the idealised linear analytical solutions predict well the characteristics of water waves generated by a bottom obstacle, and therefore can serve as the cornerstone of a theory-based model for quickly predicting the tsunamis generated by a submarine landslide.

How can the growing personalization of power be identified and measured ex ante? Extant measures in the authoritarian literature have traditionally focused on institutional constraints and more recently on individual behaviour – such as purging opposition members from (and packing allies into) government bodies. This article offers a different strategy that examines leaders’ individual rhetoric. It focuses on patterns of pronoun usage for the first person. The author argues that as leaders personalize power, they are less likely to use ‘I’ (a pronoun linked to credit claiming and blame minimizing) and more likely to use ‘we’ (the leader speaks for – or with – the populace). To test this argument, the study focuses on all major, scheduled speeches by all chief executives in the entire Chinese-speaking world – that is, China, Singapore and Taiwan – since independence. It finds a robust pattern between first-person pronouns and political constraints. To ensure the results are not driven by the Chinese sample, the rhetoric of four other political leaders is considered: Albania's Hoxha, North Korea's Kim Il Sung, Hungary's Orbán and Ecuador's Correa. The implications of this project suggest that how leaders talk can provide insights into how they perceive their rule.