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Triple Negative Breast Cancer (TNBC) is a heterogeneous disease lacking known molecular drivers and effective targeted therapies. Cytotoxic chemotherapy remains the mainstay of treatment for TNBCs, which have significantly poorer survival rates compared to other breast cancer subtypes. In addition to changes within the coding genome, aberrant enhancer activity is a well-established contributor to tumorigenesis. Here we use H3K27Ac chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map the active cis-regulatory landscape in TNBC. We identify distinct disease subtypes associated with specific enhancer activity, and over 2,500 unique superenhancers acquired by tumor cells but absent from normal breast tissue. To identify potential actionable disease drivers, we probed the dependency on genes that associate with tumor-specific enhancers by CRISPR screening. In this way we identify a number of tumor-specific dependencies, including a previously uncharacterized dependency on the TGFβ pseudo-receptor BAMBI.

Empirical audit and review is an approach to assessing the evidentiary value of a research area. It involves identifying a topic and selecting a cross-section of studies for replication. We apply the method to research on the psychological consequences of scarcity. Starting with the papers citing a seminal publication in the field, we conducted replications of 20 studies that evaluate the role of scarcity priming in pain sensitivity, resource allocation, materialism, and many other domains. There was considerable variability in the replicability, with some strong successes and other undeniable failures. Empirical audit and review does not attempt to assign an overall replication rate for a heterogeneous field, but rather facilitates researchers seeking to incorporate strength of evidence as they refine theories and plan new investigations in the research area. This method allows for an integration of qualitative and quantitative approaches to review and enables the growth of a cumulative science.

Background Seizures, strokes, and intracranial hemorrhage are common and feared complications in children receiving extracorporeal membrane oxygenation (ECMO) support. Researchers and clinicians have proposed and deployed methods for monitoring and detecting neurologic injury, but best practices are unknown. We sought to characterize clinicians’ approach to electroencephalography (EEG) and brain imaging modalities in children supported by ECMO. Methods We performed a retrospective observational cohort study among US Children’s Hospitals participating in the Pediatric Health Information System (PHIS) from 2016 to 2021. We identified hospitalizations containing ECMO support. We stratified these admissions by pediatric, neonatal, cardiac surgery, and non-cardiac surgery. We characterized the frequency of EEG, cranial ultrasound, brain computed tomography (CT), magnetic resonance imaging (MRI), and transcranial Doppler during ECMO hospitalizations. We reported key diagnoses (stroke and seizures) and the prescription of antiseizure medication. To assess hospital variation, we created multilevel logistic regression models. Results We identified 8746 ECMO hospitalizations. Nearly all children under 1 year of age (5389/5582) received a cranial ultrasound. Sixty-two percent of the cohort received an EEG, and use increased from 2016 to 2021 (52–72% of hospitalizations). There was marked variation between hospitals in rates of EEG use. Rates of antiseizure medication use (37% of hospitalizations) and seizure diagnoses (20% of hospitalizations) were similar across hospitals, including high and low EEG utilization hospitals. Overall, 37% of the cohort received a CT and 36% received an MRI (46% of neonatal patients). Stroke diagnoses (16% of hospitalizations) were similar between high- and low-MRI utilization hospitals (15% vs 17%, respectively). Transcranial Doppler (TCD) was performed in just 8% of hospitalizations, and 77% of the patients who received a TCD were cared for at one of five centers. Conclusions In this cohort of children at high risk of neurologic injury, there was significant variation in the approach to EEG and neuroimaging in children on ECMO. Despite the variation in monitoring and imaging, diagnoses of seizures and strokes were similar across hospitals. Future work needs to identify a management strategy that appropriately screens and monitors this high-risk population without overuse of resource-intensive modalities.

Stellar occultations, when a distant object passes in front of a star and casts a shadow on Earth, are a powerful tool to probe the physical properties of solar system bodies. They enable precise size and shape measurements and can reveal rings, satellites, atmospheres, or surface features. Here we present results from two stellar occultations by Hi'iaka, dwarf planet Haumea's largest satellite, observed in April 2021. The second event yielded the first documented multi-chord occultation involving a trans-Neptunian satellite other than Charon. Combining these data with photometric observations, we find that Hi'iaka is a triaxial ellipsoid with a volume-equivalent diameter of 370 ± 20 km and a density of 640 ± 80 kg/m³, indicating a porous interior. The visible geometric albedo is , (∼ higher than Haumea's). The combination of low density and rapid rotation (9.68 ± 0.02 hours), under the assumption of a homogeneous body, indicates that Hi'iaka deviates from hydrostatic equilibrium.

Plastic pollution is distributed patchily around the world’s oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and nonbreeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species

Background: The approval of the first SARS-COV-2 vaccines for COVID-19 were accompanied by unprecedented efforts to provide vaccination to healthcare workers and first responders. More information about vaccine uptake in this group is needed to better refine and target educational messaging. Methods: HCA Healthcare used federal guidance and internal experience to create a systemwide mass vaccination strategy. A closed point-of-dispensing (POD) model was developed and implemented. The previously developed enterprise-wide emergency operations strategy was adapted and implemented, which allowed for rapid development of communications and operational processes. A tiering strategy based on recommendations from the National Academies was used in conjunction with human resources data to determine vaccine eligibility for the first phase of vaccination. A comprehensive data and reporting strategy was built to connect human resources and vaccine consent data for tracking vaccination rates across the system. Results: Vaccination of employed and affiliated colleagues began December 15, 2020, and was made available based on state-level release of tiers. Within the first 6 weeks, in total, 203,544 individuals were eligible for vaccine based on these criteria. Of these, 181,282 (89.1%) consented to and received vaccine, 19,788 (9.7%) declined, and 2,474 (1.2%) indicated that they had already been vaccinated. Of those eligible, the highest acceptance of vaccine was among the job codes of specialists and professionals (n = 7,914 total, 100% consent), providers (n = 23,335, 99.6%,), and physicians (n = 3,218, 98.4%). Vaccine was most likely to be declined among job codes of clerical and other administrative (n = 12,889 total, 80.1% consent), clinical specialists and professionals (n = 22,853, 81.0%,) and aides, orderlies and technicians (n = 17,803, 82.6%,). Registered nurses made up the largest eligible population (n = 56,793), and 89.5% of those eligible consented to receive vaccination. Average age among those who consented was slightly older (48.3 years) than those that declined (44.7 years), as was length of employment tenure (6.9 vs 5.0 years). Conclusion: A large-scale, closed POD, mass vaccination program was able to vaccinate nearly 200,000 healthcare workers for SARS-CoV-2 in 6 weeks. This program was implemented in acute-care sites across 20 different US states, and it was able to meet the various state-level requirements for management of processes, product, and required reporting. The development of a standardized strategy and custom, centralized monitoring and reporting facilitated insight into the characteristics of early vaccine adopters versus those who decline vaccination. These data can aid in the refining and targeting of educational materials and messaging about the SARS-CoV-2 vaccine. Funding: No Disclosures: None

The brain is a disproportionately large consumer of fuel, estimated to expend ~20% of the whole-body energy budget, and therefore it is critical to adequately control brain fuel expenditures while satisfying its on-demand needs for continued function. The brain is also metabolically vulnerable as the inability to adequately fuel cellular processes that support information transfer between cells leads to rapid neurological impairment. We show here that a genetic driver of early onset epileptic encephalopathy (EOEE), SLC13A5, a Na /citrate cotransporter (NaCT), is critical for gating the activation of local presynaptic glycolysis. We show that SLC13A5 is in part localized to a presynaptic pool of membrane-bound organelles and acts to transiently clear axonal citrate during electrical activity, in turn activating phosphofructokinase 1. We show that loss of SLC13A5 or mistargeting to the plasma membrane results in suppressed glycolytic gating, activity dependent presynaptic bioenergetic deficits and synapse dysfunction.

We study the phase diagram of a one-dimensional balls-in-boxes (BIB) model that has been proposed as an effective model for the spatial-volume dynamics of (2+1)-dimensional causal dynamical triangulations (CDT). The latter is a statistical model of random geometries and a candidate for a nonperturbative formulation of quantum gravity, and it is known to have an interesting phase diagram, in particular including a phase of extended geometry with classical properties. Our results corroborate a previous analysis suggesting that a particular type of potential is needed in the BIB model in order to reproduce the droplet condensation typical of the extended phase of CDT. Since such a potential can be obtained by a minisuperspace reduction of a (2+1)-dimensional gravity theory of the Hořava-Lifshitz type, our result strengthens the link between CDT and Hořava-Lifshitz gravity.