While clozapine has risks, relative risk of fatality is overestimated. The UK pharmacovigilance programme is efficient, but comparisons with other drugs can mislead because of reporting variations. Clozapine actually lowers mortality, partly by reducing schizophrenia-related suicides, but preventable deaths still occur. Clozapine should be used earlier and more widely, but there should be better monitoring and better management of toxicity.

Seismic imaging in 3-D holds great potential for improving our understanding of ice sheet structure and dynamics. Conducting 3-D imaging in remote areas is simplified by using lightweight and logistically straightforward sources. We report results from controlled seismic source tests carried out near the West Antarctic Ice Sheet Divide investigating the characteristics of two types of surface seismic sources, Poulter shots and detonating cord, for use in both 2-D and 3-D seismic surveys on glaciers. Both source types produced strong basal P-wave and S-wave reflections and multiples recorded in three components. The Poulter shots had a higher amplitude for low frequencies (<10 Hz) and comparable amplitude at high frequencies (>50 Hz) relative to the detonating cord. Amplitudes, frequencies, speed of source set-up, and cost all suggested Poulter shots to be the preferred surface source compared to detonating cord for future 2-D and 3-D seismic surveys on glaciers.

In 2022, highly pathogenic avian influenza (HPAI) A(H5N1) virus clade 2.3.4.4b became enzootic and caused mass mortality in Sandwich Tern Thalasseus sandvicensis and other seabird species across north-western Europe. We present data on the characteristics of the spread of the virus between and within breeding colonies and the number of dead adult Sandwich Terns recorded at breeding sites throughout north-western Europe. Within two months of the first reported mortalities, 20,531 adult Sandwich Terns were found dead, which is >17% of the total north-western European breeding population. This is probably an under-representation of total mortality, as many carcasses are likely to have gone unnoticed and unreported. Within affected colonies, almost all chicks died. After the peak of the outbreak, in a colony established by late breeders, 25.7% of tested adults showed immunity to HPAI subtype H5. Removal of carcasses was associated with lower levels of mortality at affected colonies. More research on the sources and modes of transmission, incubation times, effective containment, and immunity is urgently needed to combat this major threat for colonial seabirds.

Knowledge graphs have become a common approach for knowledge representation. Yet, the application of graph methodology is elusive due to the sheer number and complexity of knowledge sources. In addition, semantic incompatibilities hinder efforts to harmonize and integrate across these diverse sources. As part of The Biomedical Translator Consortium, we have developed a knowledge graph–based question-answering system designed to augment human reasoning and accelerate translational scientific discovery: the Translator system. We have applied the Translator system to answer biomedical questions in the context of a broad array of diseases and syndromes, including Fanconi anemia, primary ciliary dyskinesia, multiple sclerosis, and others. A variety of collaborative approaches have been used to research and develop the Translator system. One recent approach involved the establishment of a monthly “Question-of-the-Month (QotM) Challenge” series. Herein, we describe the structure of the QotM Challenge; the six challenges that have been conducted to date on drug-induced liver injury, cannabidiol toxicity, coronavirus infection, diabetes, psoriatic arthritis, and ATP1A3-related phenotypes; the scientific insights that have been gleaned during the challenges; and the technical issues that were identified over the course of the challenges and that can now be addressed to foster further development of the prototype Translator system. We close with a discussion on Large Language Models such as ChatGPT and highlight differences between those models and the Translator system.

We argue that Madole & Harden's distinction between shallow versus deep genetic causes can bring some clarity to causal claims arising from genome-wide association studies (GWASs). However, the authors argue that GWAS only finds shallow genetic causes, making GWAS commensurate with the environmental studies they hope to supplant. We also assess whether their distinction applies best to explanations or causes.

The U.S. Department of Agriculture–Agricultural Research Service (USDA-ARS) has been a leader in weed science research covering topics ranging from the development and use of integrated weed management (IWM) tactics to basic mechanistic studies, including biotic resistance of desirable plant communities and herbicide resistance. ARS weed scientists have worked in agricultural and natural ecosystems, including agronomic and horticultural crops, pastures, forests, wild lands, aquatic habitats, wetlands, and riparian areas. Through strong partnerships with academia, state agencies, private industry, and numerous federal programs, ARS weed scientists have made contributions to discoveries in the newest fields of robotics and genetics, as well as the traditional and fundamental subjects of weed–crop competition and physiology and integration of weed control tactics and practices. Weed science at ARS is often overshadowed by other research topics; thus, few are aware of the long history of ARS weed science and its important contributions. This review is the result of a symposium held at the Weed Science Society of America’s 62nd Annual Meeting in 2022 that included 10 separate presentations in a virtual Weed Science Webinar Series. The overarching themes of management tactics (IWM, biological control, and automation), basic mechanisms (competition, invasive plant genetics, and herbicide resistance), and ecosystem impacts (invasive plant spread, climate change, conservation, and restoration) represent core ARS weed science research that is dynamic and efficacious and has been a significant component of the agency’s national and international efforts. This review highlights current studies and future directions that exemplify the science and collaborative relationships both within and outside ARS. Given the constraints of weeds and invasive plants on all aspects of food, feed, and fiber systems, there is an acknowledged need to face new challenges, including agriculture and natural resources sustainability, economic resilience and reliability, and societal health and well-being.

OBJECTIVES/GOALS: This report evaluates participants’experiences from three universities who assembled a complex grant proposal related to research on post-acute sequala of COVID-19 (PASC), also called long COVID. Activities reviewed ranged from the assembly of the team to responses to reviews by the National Center for Advancing Translational Sciences (NCATS). METHODS/STUDY POPULATION: Data were collected by means of semi-structured interviews, conducted and recorded on Zoom, with a sample of 15 scientists and staff both during proposal assembly and following proposal review. The sample comprised 40% of the total team equally selected from the 3 universities, The interview protocol was reviewed by the IRB at UTMB and the interviews were recorded on Zoom, and analyzed by means of the constant comparative strategy in the grounded theory method of qualitative research. Given the relatively small number of interviews in this project, we paid special attention to preserving the confidentiality of respondents. Only the verbal tracks of the interviews were professionally transcribed. Respondents were asked to suggest changes for future inter-organizational proposals. RESULTS/ANTICIPATED RESULTS: FIRST INTERVIEWS *LEADERSHIP: The scope of leadership opportunities was expanded as sub-teams in specific areas such as community engagement were formed. *TEAM: Each university’s community engagement team specializes in a different ethnic clientele, precluding a singular statement for the proposal. SECOND INTERVIEWS *LEADERSHIP: Staff members noted that the team concept too easily evolved into a bureaucratic format, resulting in less negotiation and more direction. *ASSEMBLY TASKS: The Writing Team turned out to be one of the most critical staff teams. *COMMUNICATION: The behavioral scientists in community engagement do not necessarily share paradigms (e.g., public health, psychology, and social work). They had difficulty generating productive communication and a unified statement for the proposal. DISCUSSION/SIGNIFICANCE: The scientists, as a group, suggested that future proposals should focus on one general topic, such as the microbiome, as opposed to attempting to integrate widely divergent interests. The scientists as a group should decide a priori whether to treat innovative ideas such as machine learning science as a science or a service.

OBJECTIVES/GOALS: Recent NCATS funding announcements emphasize pursuing domain-agnostic translational science projects that seek to transform the system of science. We aimed to articulate the social responsibility of translational science, defined as prioritizing improved health outcomes and decreased disparities. METHODS/STUDY POPULATION: We focused on the framing of social responsibilities of translational science and distinctions between (a) domain-agnostic translational science that aims to transform the system of science and (b) translational research that takes place within a specific therapeutic area. We reviewed CTSA funding calls, translational research ethics papers, and statements by leaders in the field of translational science. We integrated the social responsibilities of improving health outcomes and decreasing disparities with the values of translational science, which prioritize the relevance, usability, and sustainability of translational interventions. RESULTS/ANTICIPATED RESULTS: We drew on our review of the literature and case studies to offer guidance aimed at helping to ensure that differently positioned actors and entities within the translational ecology can advance the values of translational science while also fulfilling the social responsibilities of translational science. We specify how (a) Funders and policymaking institutions, (b) Organizations such as research universities and CTSA institutes, (c) Translational health science teams working on innovative translational science projects, and (d) Individual translational scientists can all contribute to ensuring that translational science fulfills its ethical obligations and social responsibilities. DISCUSSION/SIGNIFICANCE: The social responsibility of translational science can be fulfilled by centering its efforts to develop useful, sustainable, and relevant innovations. These criteria clarify how social responsibilities manifest in practice and can help funders shape and guide the next era of translational discovery.

Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2; Gen2) at 18 years; HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP; quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant’s fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.