Current evidence underscores a need to transform how we do clinical research, shifting from academic-driven priorities to co-led community partnership focused programs, accessible and relevant career pathway programs that expand opportunities for career development, and design of trainings and practices to develop cultural competence among research teams. Failures of equitable research translation contribute to health disparities. Drivers of this failed translation include lack of diversity in both researchers and participants, lack of alignment between research institutions and the communities they serve, and lack of attention to structural sources of inequity and drivers of mistrust for science and research. The Duke University Research Equity and Diversity Initiative (READI) is a program designed to better align clinical research programs with community health priorities through community engagement. Organized around three specific aims, READI-supported programs targeting increased workforce diversity, workforce training in community engagement and cultural competence, inclusive research engagement principles, and development of trustworthy partnerships.

Almost 12 % of the human population have insufficient access to food and hence are at risk from nutrient deficiencies and related conditions, such as anaemia and stunting. Ruminant meat and milk are rich in protein and micronutrients, making them a highly nutritious food source for human consumption. Conversely, ruminant production contributes to methane (CH4) emissions, a greenhouse gas (GHG) with a global warming potential (GWP) 27–30 times greater than that of carbon dioxide (CO2). Nonetheless, ruminant production plays a crucial role in the circular bioeconomy in terms of upcycling agricultural products that cannot be consumed by humans, into valuable and nutritional food, whilst delivering important ecosystem services. Taking on board the complexities of ruminant production and the need to improve both human and planetary health, there is increasing emphasis on developing innovative solutions to achieve sustainable ruminant production within the ‘One Health’ framework. Specifically, research and innovation will undoubtedly continue to focus on (1) Genetics and Breeding; (2) Animal nutrition and (3) Animal Health, to achieve food security and human health, whilst limiting environmental impact. Implementation of resultant innovations within the agri-food sector will require several enablers, including large-scale investment, multi-actor partnerships, scaling, regulatory approval and importantly social acceptability. This review outlines the grand challenges of achieving sustainable ruminant production and likely research and innovation landscape over the next 15 years and beyond, specifically outlining the pathways and enablers required to achieve sustainable ruminant production within the One Health framework.

Female genital schistosomiasis (FGS) is a chronic disease manifestation of the waterborne parasitic infection Schistosoma haematobium that affects up to 56 million women and girls, predominantly in sub-Saharan Africa. Starting from early childhood, this stigmatizing gynaecological condition is caused by the presence of Schistosoma eggs and associated toxins within the genital tract. Schistosoma haematobium typically causes debilitating urogenital symptoms, mostly as a consequence of inflammation, which includes bleeding, discharge and lower abdominal pelvic pain. Chronic complications of FGS include adverse sexual and reproductive health and rights outcomes such as infertility, ectopic pregnancy and miscarriage. FGS is associated with prevalent human immunodeficiency virus and may increase the susceptibility of women to high-risk human papillomavirus infection. Across SSA, and even in clinics outside endemic areas, the lack of awareness and available resources among both healthcare professionals and the public means FGS is underreported, misdiagnosed and inadequately treated. Several studies have highlighted research needs and priorities in FGS, including better training, accessible and accurate diagnostic tools, and treatment guidelines. On 6 September, 2024, LifeArc, the Global Schistosomiasis Alliance and partners from the BILGENSA Research Network (Genital Bilharzia in Southern Africa) convened a consultative, collaborative and translational workshop: ‘Female Genital Schistosomiasis: Translational Challenges and Opportunities’. Its ambition was to identify practical solutions that could address these research needs and drive appropriate actions towards progress in tackling FGS. Here, we present the outcomes of that workshop – a series of discrete translational actions to better galvanize the community and research funders.

Objectives/Goals: Monensin is FDA approved for use in veterinary medicine. Recent studies pointed to its potent anticancer activity. Since de novo drug discovery process typically takes 10 to 15 years and requires an investment of approximately $1.3 to $3 billion, drug repositioning can bypass several steps in this process and increase the potential for success. Methods/Study Population: Cell viability assays were conducted on human MDA-MB-231, MDA-MB-468, and MCF10A breast cancer cell lines and mouse EO771 and 4T1 breast cancer cell lines. MDA-MB-231 cell line was used in all the studies unless specified otherwise. Time course levels of Bcl-2, Bak, p62, and LC3II were assessed via Western blotting with GAPDH as a loading control. Proteomics analysis was conducted by the IDEA National Resource for Quantitative Proteomics. Time course levels of major histocompatibility complex (MHC) I and II and calreticulin were evaluated using flow cytometry. At least three biological replicates have been conducted for each experiment. Results/Anticipated Results: Monensin and several of its novel analogs were potent toward human and mouse breast cancer cell lines. Furthermore, they induced apoptotic cell death as evidenced by Annexin V/PI assay, downregulation of Bcl-2, and upregulation of Bak in MDA-MB-231 cells. Proteomics analysis revealed that several molecular pathways related to MHC class I and II antigen presentation were significantly altered following treatment with these compounds. Additionally, monensin and its analogs significantly increased the expression of MHC class I and II. Our studies also showed that monensin and its analogs increase the surface calreticulin levels. Treatment of MDA-MB-231 cells with these compounds also resulted in an increase in p62 and LC3II expression, suggesting a disruption of the autophagic process. Discussion/Significance of Impact: These results suggest that monensin and its analogs not only exhibit anti-breast cancer cell activity but also modulate immune-related pathways. By disrupting autophagy and enhancing calreticulin levels, these compounds may potentiate antitumor immune responses, providing a promising avenue for drug repositioning in cancer therapy.

Objectives/Goals: Manual skin assessment in chronic graft-versus-host disease (cGVHD) can be time consuming and inconsistent (>20% affected area) even for experts. Building on previous work we explore methods to use unmarked photos to train artificial intelligence (AI) models, aiming to improve performance by expanding and diversifying the training data without additional burden on experts. Methods/Study Population: Common to many medical imaging projects, we have a small number of expert-marked patient photos (N = 36, n = 360), and many unmarked photos (N = 337, n = 25,842). Dark skin (Fitzpatrick type 4+) is underrepresented in both sets; 11% of patients in the marked set and 9% in the unmarked set. In addition, a set of 20 expert-marked photos from 20 patients were withheld from training to assess model performance, with 20% dark skin type. Our gold standard markings were manual contours around affected skin by a trained expert. Three AI training methods were tested. Our established baseline uses only the small number of marked photos (supervised method). The semi-supervised method uses a mix of marked and unmarked photos with human feedback. The self-supervised method uses only unmarked photos without any human feedback. Results/Anticipated Results: We evaluated performance by comparing predicted skin areas with expert markings. The error was given by the absolute difference between the percentage areas marked by the AI model and expert, where lower is better. Across all test patients, the median error was 19% (interquartile range 6 – 34) for the supervised method and 10% (5 – 23) for the semi-supervised method, which incorporated unmarked photos from 83 patients. On dark skin types, the median error was 36% (18 – 62) for supervised and 28% (14 – 52) for semi-supervised, compared to a median error on light skin of 18% (5 – 26) for supervised and 7% (4 – 17) for semi-supervised. Self-supervised, using all 337 unmarked patients, is expected to further improve performance and consistency due to increased data diversity. Full results will be presented at the meeting. Discussion/Significance of Impact: By automating skin assessment for cGVHD, AI could improve accuracy and consistency compared to manual methods. If translated to clinical use, this would ease clinical burden and scale to large patient cohorts. Future work will focus on ensuring equitable performance across all skin types, providing fair and accurate assessments for every patient.

Objectives/Goals: Osteoarthritis (OA) is a multifactorial disease where sustained gut inflammation is a continued source of inflammatory mediators driving degenerative processes in joints. The goal was to use spontaneous equine model to compare fecal and leukocyte microbiome and correlation to transcriptome in OA. Methods/Study Population: Seventy-six horses (31 OA, 45 controls) were enrolled by population-based sampling. Feces and peripheral blood mononuclear cells (PBMC) were collected. Horses were determined to have OA by clinical and radiographic evidence. Horses were excluded if they received medications or joint injections within two months. Fecal and circulating leukocyte bacterial microbial 16s-seq was performed. Bulk RNAseq of PBMC was performed by the Illumina platform. Gene expression data were mapped to the equine genome, and differential expression analysis was performed with DESeq2. Qiime2 was used for microbial analysis. Enrichment analysis was performed with a cluster profiler. Correlation analyses were performed between the datasets. Results/Anticipated Results: Beta and alpha microbial diversity differed in feces and PBMC of OA vs. healthy horses. Horses with OA had an increased Firmicutes to Bacteroidetes ratio compared with controls. The fecal microbiome of OA horses had significantly higher amounts of Firmicutes Oribacterium (q Discussion/Significance of Impact: These data suggest that altered microbiome and PBMC gene expression are associated with naturally occurring OA in the translational equine model. While Oribacterium has been detected in humans with rheumatoid arthritis, its role in OA warrants further proteomic and metabolomic profiling.

Objectives/Goals: Lung transplant is a life-saving surgery for patients with advanced lung diseases yet long-term survival remains poor. The clinical features and lung injury patterns of lung transplant recipients who die early versus those who survive longer term remain undefined. Here, we use cell-free DNA and rejection parameters to help elucidate this further. Methods/Study Population: Lung transplant candidacy prioritizes patients who have a high mortality risk within 2 years and will likely survive beyond 5 years. We stratified patients who died within 2 years of transplant as early death (n = 50) and those who survived past 5 years as long-term survivors (n = 53). Lung transplant recipients had serial blood collected as part of two prospective cohort studies. Cell-free DNA (cfDNA) was quantified using relative (% donor-derived cfDNA {%ddcfDNA}) and absolute (nuclear-derived {n-cfDNA}, mitochondrial-derived {mt-cfDNA}) measurements. As part of routine posttransplant clinical care, all patients underwent pulmonary function testing (PFT), surveillance bronchoscopy with bronchoalveolar lavage (BAL), transbronchial biopsy (TBBx), and donor-specific antibody testing (DSA). Results/Anticipated Results: Over the first 2 years after transplant, the number of episodes of antibody-mediated rejection (p) Discussion/Significance of Impact: Clinically, early-death patients perform worse on routine surveillance PFTs and experience a worse degree of CLAD. These patients also have higher levels of cfDNA as quantified by n-cfDNA and mt-cfDNA. These results provide preliminary evidence that early-death patients have worse allograft rejection, dysfunction, and molecular injury.

Since the 1950s, the United Nations (UN) has designated days (e.g., World Wetland Day), years (e.g., Year of the Gorilla) and decades (e.g., Decade on Biodiversity) with a commonly stated goal to raise awareness and funding for conservation-oriented initiatives, and these Days, Years and Decades of ‘…’ (hereafter ‘DYDOs’) continue. However, the effectiveness of these initiatives to achieve their stated objectives and to contribute to positive conservation outcomes is unclear. Here we used a binary analysis change model to evaluate the effectiveness of UN conservation-oriented DYDOs observed between 1974 and 2020. We also examined four case studies to understand the different strategies employed to meet specified conservation goals. We found that DYDOs apparently contributed to positive conservation outcomes when they were tied to social media campaigns and/or when they were strategically situated in current events or global discourse. Although the outcomes of DYDOs were varied, those with longer timescales and those that engaged local communities were more likely to be successful. We suggest that DYDO organizers should identify all possible paths of action through the lens of the change model outlined in this paper to strengthen the value and effectiveness of these initiatives in the future. Using this approach could help ensure that resources are used efficiently and effectively, and that initiatives yield positive conservation outcomes that benefit people and nature.

Maladaptive daydreaming is a distinct syndrome in which the main symptom is excessive vivid fantasising that causes clinically significant distress and functional impairment in academic, vocational and social domains. Unlike normal daydreaming, maladaptive daydreaming is persistent, compulsive and detrimental to one’s life. It involves detachment from reality in favour of intense emotional engagement with alternative realities and often includes specific features such as psychomotor stereotypies (e.g. pacing in circles, jumping or shaking one’s hands), mouthing dialogues, facial gestures or enacting fantasy events. Comorbidity is common, but existing disorders do not account for the phenomenology of the symptoms. Whereas non-specific therapy is ineffective, targeted treatment seems promising. Thus, we propose that maladaptive daydreaming be considered a formal syndrome in psychiatric taxonomies, positioned within the dissociative disorders category. Maladaptive daydreaming satisfactorily meets criteria for conceptualisation as a psychiatric syndrome, including reliable discrimination from other disorders and solid interrater agreement. It involves significant dissociative aspects, such as disconnection from perception, behaviour and sense of self, and has some commonalities with but is not subsumed under existing dissociative disorders. Formal recognition of maladaptive daydreaming as a dissociative disorder will encourage awareness of a growing problem and spur theoretical, research and clinical developments.

Beliefs about other players’ strategies are crucial in determining outcomes for coordination games. If players are to coordinate on an efficient equilibrium, they must believe that others will coordinate with them. In many settings there is uncertainty about beliefs as well as strategies. Do people consider these “higher-order” beliefs (beliefs about beliefs) when making coordination decisions? I design a modified stag hunt experiment that allows me to identify how these higher-order beliefs and uncertainty about higher-order beliefs matter for coordination. Players prefer to invest especially when they believe that others are “optimistic” that they will invest; but knowledge that others think them unlikely to invest does not cause players to behave differently than when they do not know what their partners think about them. Thus resolving uncertainty about beliefs can result in marked efficiency gains.

We replicate an influential study of monetary incentive effects by Jamal and Sunder (1991) to illustrate the difficulties of drawing causal inferences from a treatment manipulation when other features of the experimental design vary simultaneously. We first show that the Jamal and Sunder (1991) conclusions hinge on one of their laboratory market sessions, conducted only within their fixed-pay condition, that is characterized by a thin market and asymmetric supply and demand curves. When we replicate this structure multiple times under both fixed pay and pay tied to performance, our findings do not support Jamal and Sunder's (1991) conclusion about the incremental effects of performance-based compensation, suggesting that other features varied in that study likely account for their observed difference. Our ceteris paribus replication leaves us unable to offer any generalized conclusions about the effects of monetary incentives in other market structures, but the broader point is to illustrate that experimental designs that attempt to generalize effects by varying multiple features simultaneously can jeopardize the ability to draw causal inferences about the primary treatment manipulation.