Objectives/Goals: To investigate interventional clinical trial participation overall and by race, gender, and age. Methods/Study Population: We used Epic Cosmos, an aggregated, de-identified EHR platform including over 270 million patients, to examine overall clinical trial participation and the race, gender, and age composition of participants versus non-participants. Patients ≥5 years old with known race and gender and at least one healthcare encounter between 2021 and 2024 were included. Interventional trial enrollment was identified by a “research flag” indicating current or past participation in an interventional study within an Epic system contributing data to Cosmos. Race was categorized as American Indian, Asian, Black, Native Hawaiian, or White. Age-adjusted relative representation (RR) ratios were used to compare participation, with RR >1 indicating over-representation and RR Results/Anticipated Results: Of 130,455,189 patients meeting eligibility criteria, 0.52% (673,425) of patients were active or inactive in an interventional clinical trial. Results are shown in the figure below. The poorest representation was from Asian and NH/PI persons. Representation was most similar to the patient population for whites and AI/AN persons. Black males participated less and women, more than predicted by patient composition. Older patients participated more frequently than younger (age, mean (SD), y, 53 (22) vs. 46 (23); p Discussion/Significance of Impact: This is the first study we know of describing interventional trial participation in the USA across millions and millions of patients. Further research is needed to clarify whether these differences are due to the nature of the studies themselves (e.g., OB/GYN trials including only women, etc.) versus disparities in recruitment or otherwise.

Objectives/Goals: Large-scale tumor sequencing efforts have led to annotations of novel cancer hotspot mutations that may underlie driver or cooperative function. We have sought to define the molecular consequences of such hotspots associated with pediatric DICER1 syndrome cancers, with the ultimate goal of revealing novel targets that may inform new standards of care. Methods/Study Population: We have performed genomic analysis to identify tumor types (in TCGA and MSK-IMPACT patient data) for which mutations in the Dicer1 gene (encoding Dicer protein) emerge as the dominant signature of driver function. As Dicer is a critical RNA processing factor responsible for the generation of microRNAs, which are posttranscriptional gene regulatory molecules, we have modeled these mutations in human embryonic stem cells in order to study the direct effects on miRNAs and their target genes in an isogenic background. In addition to providing the required setting for unambiguous attribution of function to specific mutations, clonal human ES cells offer an opportunity for modeling of both developmental and cancer requirements associated with altered Dicer function. Results/Anticipated Results: Through generation of genomics and functional datasets from matched genotypes in Dicer mutated human ES cells, we have identified specific alterations in miRNAs and their effects on target genes. Unexpectedly, we found direct evidence for both loss of function and gain of function attributable to Dicer mutations. In addition, through integrated analysis of genomic data from tumor sequencing datasets and our human ES cell models, we have identified potential miRNA and target gene alterations that underlie tumorigenic potential, nominating gene candidates for targeted therapy in DICER1 syndrome. Direct mouse modeling of such candidate gene targets has revealed evidence for driver function of identified miRNA and their targets. Discussion/Significance of Impact: DICER1 syndrome cancers comprise a wide variety of rare pediatric tumor types. Presently, we still lack an effective standard of care. Furthermore, the previous lack of molecular profiling precluded targeted therapy opportunities. Our precise knock-in modeling of Dicer hotspots and deep profiling of relevant tumors now provide candidate targets.

Objectives/Goals: Opioid use disorder (OUD) at delivery increased between 1999 and 2014. Clinical guidelines include medication for OUD (MOUD) for pregnant women with OUD and is associated with better fetal outcomes. Few large studies have compared prenatal MOUD outcomes to no MOUD. We evaluated the association of documented MOUD prescription during pregnancy with maternal outcomes. Methods/Study Population: We utilized aggregated electronic health records using the TriNetX platform to conduct a retrospective cohort study of females, aged 1249 years with a childbirth CPT code and documented opioid use via ICD-10 codes in the nine months before delivery between 2014 and 2020, comparing patients with MOUD prescription of buprenorphine or methadone during the nine months before delivery to demographically matched patients without any documented MOUD, using hazard ratios and 95% CIs for outcomes occurring one week to one or three years after childbirth. Results/Anticipated Results: MOUD cohort (n = 6,945, 85.33% White; 82.77% Non-Hispanic or Latino) was associated with significantly higher subsequent documented MOUD prescription (HR, 9.26 [95% CI, 7.98–10.76]; 6.21 [95% CI, 5.60–6.88]) and new remission codes (HR, 2.79 [95% CI, 2.15–3.62]; 2.85 [95% CI, 2.38–3.40]) at one and three years, lower ED visits at one year (HR, 0.88 [95% CI, 0.81–0.96]), no significant association of ED visits at three years (0.95 [95% CI, 0.89–1.02]), higher outpatient visits (HR, 1.26 [95% CI, 1.20–1.32]; HR, 1.27 [95% CI, 1.21–1.33], and no significant association of inpatient visits at one and three years (HR, 0.93 [95% CI, 0.813–1.06]; 1.06 [95% CI, 0.96–1.18]) than the never-MOUD cohort (n = 4,708, 76.11% White; 75.68% non-Hispanic or Latino). Discussion/Significance of Impact: A documented prescription for MOUD during pregnancy is associated with newly documented remission of OUD, increased outpatient visits, decreased ED visits, and additional documented MOUD prescriptions suggestive of increased access to continuity care. Efforts to increase MOUD use in pregnancy may improve maternal outcomes.

Objectives/Goals: The never in mitosis kinase (NEK) family regulates vital processes, namely cell cycle progression, but their potential as therapeutic targets in TNBC has not been fully explored. Our studies aim to develop a toolkit to investigate the functional roles of NEKs in pathologies including carcinogenesis. Methods/Study Population: To assess differential NEK expression in normal and tumor tissues and correlation of gene expression with patient survival, we used Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier Plotter (KMPlot) pan-cancer analysis, respectively. Basal NEK protein levels were determined by immunoblot across a panel of cell lines, including breast cancer, osteosarcoma, hepatocellular carcinoma, and non-cancerous cells, to identify appropriate systems for evaluation of NEK function. Doxycycline-inducible cell lines were generated by transduction with lentiviral stocks of NEK shRNA and overexpression constructs and antibiotic selection. Expression was analyzed by qPCR and immunoblot. Results/Anticipated Results: Expression of NEK2, 4, 5, 6, 8, and 11 was higher in breast tumors compared to normal tissue by GEPIA analysis. Further examination using KMPlot showed a correlation between elevated NEK6 expression and decreased overall survival in patients with aggressive cancers. As an initial proof-of-concept study, we analyzed NEK6 protein expression in breast cancer cells. Levels of NEK6 were elevated in TNBC cells (MDA-MB-231) compared to hormone receptor positive (HR+) breast cancer cells (MCF7). Using complementary approaches to investigate the functional role of NEK6 in breast cancer, we depleted NEK6 expression using shRNAs in TNBC cells and expressed NEK6 in HR+ cells Discussion/Significance of Impact: Because kinase dysregulation promotes oncogenesis and metastasis, targeting kinases is a key strategy in therapeutic development. A NEK-specific molecular toolkit allows researchers to elucidate NEK functions and contributions to carcinogenesis, promoting advancement of novel therapies.

Objectives/Goals: The timing of neurosurgery is highly variable for post-hemorrhagic hydrocephalus (PHH) of prematurity. We sought to utilize microvascular imaging (MVI) in ultrasound (US) to identify biomarkers to discern the opportune time for intervention and to analyze the cerebrospinal fluid (CSF) characteristics as they pertain to neurosurgical outcome. Methods/Study Population: The inclusion criteria for the study are admission to the neonatal intensive care unit (NICU) with a diagnosis of Papile grade III or IV. Exclusion criteria are congenital hydrocephalus and hydrocephalus secondary to myelomeningocele/brain tumor/vascular malformation. We are a level IV tertiary referral center. Our current clinical care pathway utilizes brain US at admission and at weekly intervals. Patients who meet certain clinical and radiographic parameters undergo temporary or permanent CSF diversion. Results/Anticipated Results: NEL was implemented at our institution for PHH of prematurity in fall 2022. To date, we have had 20 patients who were diagnosed with grade III or IV IVH, of which 12 qualified for NEL. Our preliminary safety and feasibility results as well as the innovative bedside technique pioneered at our institution are currently in revision stages for publication. Preliminary results of the MVI data have yielded that hyperemia may confer venous congestion in the germinal matrix, which should then alert the neurosurgeon to delay any intervention to avoid progression of intraventricular blood. With regard to CSF characteristics, we anticipate that protein, cell count, hemoglobin, iron, and ferritin will decrease with NEL. Discussion/Significance of Impact: The timing of PHH of prematurity is highly variable. We expect that MVI will offer radiographic biomarkers to guide optimal timing of neurosurgical intervention. A better understanding of CSF characteristics could potentially educate the neurosurgeon with regard to optimal timing of permanent CSF diversion based on specific CSF parameters.

Data-based methods have gained increasing importance in engineering. Success stories are prevalent in areas such as data-driven modeling, control, and automation, as well as surrogate modeling for accelerated simulation. Beyond engineering, generative and large-language models are increasingly helping with tasks that, previously, were solely associated with creative human processes. Thus, it seems timely to seek artificial-intelligence-support for engineering design tasks to automate, help with, or accelerate purpose-built designs of engineering systems for instance in mechanics and dynamics, where design so far requires a lot of specialized knowledge. Compared with established, predominantly first-principles-based methods, the datasets used for training, validation, and test become an almost inherent part of the overall methodology. Thus, data publishing becomes just as important in (data-driven) engineering science as appropriate descriptions of conventional methodology in publications in the past. However, in mechanics and dynamics, quite widely, still traditional publishing practices are prevalent that largely do not yet take into account the rising role of data as much as that may already be the case in pure data-scientific research. This article analyzes the value and challenges of data publishing in mechanics and dynamics, in particular regarding engineering design tasks, showing that the latter raise also challenges and considerations not typical in fields where data-driven methods have been booming originally. Researchers currently find barely any guidance to overcome these challenges. Thus, ways to deal with these challenges are discussed and a set of examples from across different design problems shows how data publishing can be put into practice.

Eucalyptus cladocalyx, known for its drought tolerance, has complex wood anatomy influenced by environmental conditions. This study investigated the xylem response of E. cladocalyx seedlings to cyclic drought stress compared to continuous irrigation. Seedlings were subjected to alternating drought and watering cycles, and their growth, xylem traits and cambial activity were monitored. Continuously irrigated seedlings exhibited greater height and stem diameter growth than periodically irrigated ones. Xylem response between the periodic and continuous irrigations showed no significant differences. Vessel and fibre features showed significant temporal variation, with substantial interaction between treatment and time for vessel area, fibre area and fibre thickness and not for vessel frequency. The cambium remained active under drought conditions, indicating resilience. Overall, anatomical properties varied complexly and inconsistently across drought cycles, likely due to differences in drought intensity, strategies and genetic factors.