OBJECTIVES/GOALS: The objective of this study was to use NIH RePORTER (Research Portfolio Online Reporting Tools) to analyze K99 funding trends and determine if R00 to R01 or R21 achievement time correlates with the future success of an early-stage NIH-funded investigator. METHODS/STUDY POPULATION: All award data were collected from NIH RePORTER. All K99 awards and funding data in this study were limited to All Clinical Departments (ACD). All researchers (n = 1,148) and awards (n = 2,022) were identified through a K99 search from FY 2007 to FY 2022 across ACD. Historic trends in K99 awards and funding from NIH Fiscal Year (FY) 2007 to FY 2022 were investigated. An R00 dataset was generated from NIH RePORTER. The K99 to R00 achievement statistics from FY 2007 to FY 2022 was investigated. NIH annual datafiles for FY 2007 to FY 2021 were aggregated to generate a master datafile of all R01 (n = 395,505) and R21 awards (n = 61,766). R01 and R21 award data were linked to the researcher previously identified through the K99 search. The connection between K99/R00 awardees and subsequent R01 or R21 awards was focused on. RESULTS/ANTICIPATED RESULTS: From FY 2008 to FY 2022, the number of K99 awards per year increased 123.4%, from 94 to 210. Over the same period, after correcting for inflation, the NIH K99 budget increased 127.0% while the NIH program level budget increased 17.3%. For researchers who achieved their first R01 or R21 0–3 years versus 3–6 years after the start of their R00, their average funding per year since the start of the R00 phase was $467,425 versus $290,604, respectively (p < 0.001). In summary, NIH investment in the K99 award pathway has substantially outpaced the NIH program level budget increase, and there is a strong relationship between average funding per year since the start of the R00 phase and time from R00 to R01 or R21. DISCUSSION/SIGNIFICANCE: Our study offers additional evidence of the Matthew effect in science, where previous success generates future success. This analysis may be useful to clinical departments as they evaluate selecting new and retaining current biomedical scientists for independent research positions.

OBJECTIVES/GOALS: The goal of this study was to develop a clinically applicable technique to increase the precision of in vivo dose monitoring during radiation therapy by mapping the dose deposition and resolving the temporal dose accumulation while the treatment is being delivered in real time. METHODS/STUDY POPULATION: Ironizing radiation acoustic imaging (iRAI) is a novel imaging concept with the potential to map the delivered radiation dose on anatomic structure in real time during external beam radiation therapy without interrupting the clinical workflow. The iRAI system consisted of a custom-designed two-dimensional (2D) matrix transducer array with integrated preamplifier array, driven by a clinic-ready ultrasound imaging platform. The feasibility of iRAI volumetric imaging in mapping dose delivery and real-time monitoring of temporal dose accumulation in a clinical treatment plan were investigated with a phantom, a rabbit model, and a cancer patient. RESULTS/ANTICIPATED RESULTS: The total dose deposition and temporal dose accumulation in 3D space of a clinical C-shape treatment plan in a targeted region were first imaged and optimized in a phantom. Then, semi-quantitative iRAI measurements were achieved in an in vivo rabbit model. Finally, for the first time, real-time visualization of radiation dose delivered deep in a patient with liver metastases was performed with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the radiation dose deposition during treatment. DISCUSSION/SIGNIFICANCE: Described here is the pioneering role of an iRAI system in mapping the 3D radiation dose deposition of a complex clinical radiotherapy treatment plan. iRAI offers a cost-effective and practical solution for real-time visualization of 3D radiation dose delivery, potentially leading to personalized radiotherapy with optimal efficacy and safety.

Field studies were conducted to assess the efficacy of physical weed management of Palmer amaranth management in cucumber, peanut, and sweetpotato. Treatments were arranged in a 3 × 4 factorial in which the first factor included a treatment method of electrical, mechanical, or hand-roguing Palmer amaranth control and the second factor consisted of treatments applied when Palmer amaranth was approximately 0.3, 0.6, 0.9, or 1.2 m above the crop canopy. Four wk after treatment (WAT), the electrical applications controlled Palmer amaranth at least 27 percentage points more than the mechanical applications when applied at the 0.3- and 0.6-m timings. At the 0.9- and 1.2-m application timings 4 WAT, electrical and mechanical applications controlled Palmer amaranth by at most 87%. Though hand removal generally resulted in the greatest peanut pod count and total sweetpotato yield, mechanical and electrical control resulted in similar yield to the hand-rogued plots, depending on the treatment timing. With additional research to provide insight into the optimal applications, there is potential for electrical control and mechanical control to be used as alternatives to hand removal. Additional studies were conducted to determine the effects of electrical treatments on Palmer amaranth seed production and viability. Treatments consisted of electricity applied to Palmer amaranth at first visible inflorescence, 2 wk after first visible inflorescence (WAI) or 4 WAI. Treatments at varying reproductive maturities did not reduce the seed production immediately after treatment. However, after treatment, plants primarily died and ceased maturation, reducing seed production assessed at 4 WAI by 93% and 70% when treated at 0 and 2 WAI, respectively. Treatments did not have a negative effect on germination or seedling length.

The objective of this paper is to present the movement mechanisms of transport aircraft response to severe clear-air turbulence to obtain the loss of control prevention for pilot training in IATA – Loss of Control In-flight (LOC-I) program. The transport aircraft in transonic flight is subjected to severe clear-air turbulence, resulting in a sudden plunging motion with the abrupt change in flight attitude and gravitational acceleration. The comparative analyses of the flight environment and aircraft response to severe clear-air turbulence for two four-jet aircraft are studied. The one with a larger dropped-off altitude during the plunging motion will be chosen to construct the movement mechanism. The nonlinear unsteady aerodynamic model of the chosen transport is established through flight data mining and the fuzzy-logic modeling of artificial intelligence technique based on post-flight data. The crosswind before the turbulence encounter will easily induce a rolling motion and then the sudden plunging motion during the turbulence encounter. The influences of the varying vertical wind and crosswind on loss of control are presented. To formulate preventive actions, the situation awareness of varying crosswind encountering for the operational pilot will be studied further in the future. The present study is initiated to examine the possible mitigation concepts of accident prevention for the pilot training course of IATA – Loss of Control In-flight (LOC-I) program.

Empathy is argued to be a key factor for a successful design discussion. However, such causality cannot be empirically proven based on how empathy is currently defined in design community. Empathy is used as an umbrella construct, broad and encompassing of diverse phenomena, making it difficult to quantify. We suggest improving such a situation by introducing a definition of empathy based on psychology literature, which provides structure and guidance for studying the role of empathy in design. We first break empathy to components. Then, we review empathy as used in design. Finally, we synthetize the reviewed material. From this synthesis, we conclude that empathy in design shares several key components of empathy in psychology; particularly with state influences, top-down control process and emotional stimuli. These are present in design methods although they have not been studied using such terms. Incorporating psychological components of empathy into design can help conceptualising empathy from a different angle, thus opening interesting new avenues for future research. We hope that our treatment provides present and future designers with some useful guidance.

Background: The frontal eye fields (FEFs) are linked to oculomotor control and hypothesized to reside in the prefrontal cortex, where electrical stimulation reportedly evokes contraversive eye movements. The exact location and function of the FEFs in humans is controversial. Stereo-electroencephalography (SEEG) is a minimally invasive technique used to guide epilepsy surgery. It provides a unique opportunity to collect human neurophysiological data outside of the operating room and has been used by other groups to advance our understanding of specific brain functions. Methods: Two pediatric subjects undergoing non-lesional epilepsy workup were enrolled into this prospective, IRB-approved study, and received brain MRI prior to SEEG implantation. SEEG recordings were collected with video of the subjects’ eyes while performing gaze-related tasks. Results: Stimulation testing elicited contraversive head turning with or without eye deviation, and hemifacial spasm, depending on the site of stimulation. Low-threshold sites eliciting these stereotyped movements were located just deep to the inferior precentral gyrus. Stimulation of sites in the posterior middle frontal gyrus did not elicit eye movements. Conclusions: Our findings suggest that the FEFs are located more posteriorly than widely held, involving the motor cortex. Further testing in pediatric and adult subjects is warranted to confirm this hypothesis.

All disasters are local but implementing a hyperlocal response in the midst of a public health emergency is challenging. The availability of neighborhood-level qualitative data that are both timely and relevant to evolving objectives and operations is a limiting factor. In 2020, the New York City Department of Health and Mental Hygiene (NYC DOHMH) responded to the COVID-19 emergency using a novel, hyperlocal approach. Key to the implementation of this approach was the creation of the Community Assessment to Inform Rapid Response (CAIRR), a process for rapid collection and analysis of neighborhood-specific, objective-focused, qualitative data to inform tailored response operations. This paper describes the process of developing the CAIRR and its contribution to the NYC DOHMH’s hyperlocal response in order to guide other jurisdictions seeking to employ a hyperlocal approach in future disaster responses.

Antimicrobial stewardship programs (ASPs) can be expanded to the outpatient setting to serve as a first line of defense against coronavirus disease 19 (COVID-19) hospitalizations and to reduce the burden on emergency departments and acute-care hospitals. Given the numerous emergency use authorizations of monoclonal antibodies and oral antivirals, ASPs possess the expertise and leadership to direct ambulatory COVID-19 initiatives and transform it into a predominantly outpatient illness. In this review, we summarize the critical role and benefits of an ASP-championed ambulatory COVID-19 therapeutics program.

OBJECTIVES/GOALS: Nearly half of mothers who report electronic (e)-cigarette use during pregnancy believe e-cigarettes are less harmful than traditional cigarettes. We aim to determine the association of quitting e-cigarette use in pregnancy with the risk of preterm birth and low birth weight. METHODS/STUDY POPULATION: We conducted a cross-sectional study of women participating in the Pregnancy Risk Assessment Monitoring System and with live singleton birth during 2016-2019. Women were classified based on their e-cigarette use: before pregnancy only (quitters), last three months of pregnancy only (initiators), at both times (sustained users), and neither time (non-users). We used a modified Poisson regression to determine the association between quitting e-cigarette use and preterm birth (<37 weeks) and low birth weight (<2,500 grams) adjusting for demographic, social-economic, and behavior-related risk factors. Analyses were weighted to account for the survey design and non-response. RESULTS/ANTICIPATED RESULTS: Based on 150,950 women who responded to the survey, there were estimated 2.9% quitters, 0.2% initiators, 1.0% sustained users, and 95.9% non-users in the U.S. Compared to sustained e-cigarette users, quitters had a similar risk in preterm birth (adjusted risk ratio [ARR]: 0.84, 95% confidence interval [CI]: 0.65, 1.08) and a significantly reduced risk in low birth weight (ARR: 0.77, 95%CI: 0.61, 0.97) adjusting for traditional cigarette use, age, race/ethnicity, education, marital status, family income, prior preterm birth, prior live births, BMI prior to pregnancy, pregnancy weight gain, kotelchuck index, multivitamin use, drinking prior to pregnancy, year of birth, and residential state. DISCUSSION/SIGNIFICANCE: As FDA authorizes the sales of certain e-cigarettes, women smokers may switch to e-cigarettes, believing they are reducing harm. Our study shows that quitting e-cigarette use is associated with a reduction of low birth weight. Clear messaging is needed to help women cease e-cigarette use in pregnancy.

OBJECTIVES/GOALS: Using the covariate-rich Veteran Health Administration data, estimate the association between Proton Pump Inhibitor (PPI) use and severe COVID-19, rigorously adjusting for confounding using propensity score (PS)-weighting. METHODS/STUDY POPULATION: We assembled a national retrospective cohort of United States veterans who tested positive for SARS-CoV-2, with information on 33 covariates including comorbidity diagnoses, lab values, and medications. Current outpatient PPI use was compared to non-use (two or more fills and pills on hand at admission vs no PPI prescription fill in prior year). The primary composite outcome was mechanical ventilation use or death within 60 days; the secondary composite outcome included ICU admission. PS-weighting mimicked a 1:1 matching cohort, allowing inclusion of all patients while achieving good covariate balance. The weighted cohort was analyzed using logistic regression. RESULTS/ANTICIPATED RESULTS: Our analytic cohort included 97,674 veterans with SARS-CoV-2 testing, of whom 14,958 (15.3%) tested positive (6,262 [41.9%] current PPI-users, 8,696 [58.1%] non-users). After weighting, all covariates were well-balanced with standardized mean differences less than a threshold of 0.1. Prior to PS-weighting (no covariate adjustment), we observed higher odds of the primary (9.3% vs 7.5%; OR 1.27, 95% CI 1.13-1.43) and secondary (25.8% vs 21.4%; OR 1.27, 95% CI 1.18-1.37) outcomes among PPI users vs non-users. After PS-weighting, PPI use vs non-use was not associated with the primary (8.2% vs 8.0%; OR 1.03, 95% CI 0.91-1.16) or secondary (23.4% vs 22.9%;OR 1.03, 95% CI 0.95-1.12) outcomes. DISCUSSION/SIGNIFICANCE: The associations between PPI use and severe COVID-19 outcomes that have been previously reported may be due to limitations in the covariates available for adjustment. With respect to COVID-19, our robust PS-weighted analysis provides patients and providers with further evidence for PPI safety.

OBJECTIVES/GOALS: We aimed to determine if GLP-1 receptor agonists exert beneficial effects on surrogate measures of cardiovascular function independently of weight loss. Our objective was to compare the outcomes between GLP-1 receptor agonist treatment versus a similar drug without cardiovascular benefit versus weight loss through diet alone. METHODS/STUDY POPULATION: We enrolled 88 individuals with obesity (BMI ≥ 30kg/m2) and pre-diabetes and randomized them in a 2:1:1 ratio to 14 weeks of the GLP-1 receptor agonist liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or hypocaloric diet. Sitagliptin blocks degradation of endogenous GLP-1 but does not cause weight loss or lower adverse cardiovascular outcomes. Treatment was double-blinded and placebo-controlled for drug, and unblinded for diet. Primary endpoints were flow-mediated dilation (FMD) to assess endothelial vasodilatory function, and plasminogen activator inhibitor-1 (PAI-1) to assess endothelial fibrinolytic function. We used a general linear model for each outcome and included gender as a covariate for FMD. Baseline characteristics were similar. Mean age was 50, with 32% men and 13% black. RESULTS/ANTICIPATED RESULTS: At 14 weeks, diet and liraglutide caused weight loss (diet -4.3 ± 3.2 kg, P<0.01; liraglutide -2.7 ± 3.2, P<0.01), while sitagliptin did not (-0.7 ± 2.0, P=0.17). Diet did not improve FMD at 14 weeks compared to baseline (+0.9%, 95% CI [-1.5, 3.3], P=0.46). FMD tended to increase after liraglutide and sitagliptin but was not significant (liraglutide +1.2 [-0.3, 2.8], P=0.12; sitagliptin +1.6 [-0.6, 3.8], P=0.15). Given that liraglutide and sitagliptin work through the same GLP-1 pathway, we combined the liraglutide and sitagliptin groups for overall effect on FMD, which was significantly improved from baseline (+1.4 [0.1, 2.8], P=0.04). Diet and liraglutide improved PAI-1 at 14 weeks (diet -4.4U/mL, [-8.5, -0.2], P=0.04; liraglutide -3.4 [-6.0, -0.7], P=0.01), while sitagliptin did not (-1.4 [-5.1, 2.3], P=0.46). DISCUSSION/SIGNIFICANCE: Activation of the GLP-1 pathway by liraglutide or sitagliptin improves FMD independent of weight loss, while PAI-1 improvement is weight-loss dependent and is only seen after liraglutide or diet. Our study suggests the cardiovascular benefit of liraglutide may be due to combined improvements in endothelial vasodilatory and fibrinolytic function.

OBJECTIVES/GOALS: #NAME? METHODS/STUDY POPULATION: Cell culture & protein identification: human T cells were purified from healthy blood, then activated & cultured for 5d. CAR-T cells were collected from infusion bags of cancer patients undergoing CAR-T. Silver staining of naive & activated healthy T-cell lysates was compared; B-II spectrin was upregulated and confirmed by Western blot. Migration assays: naive & activated T-cells were imaged during migration on ICAM-1 and ICAM-1 + CXCL12 coated plates. T-cells were transfected with BII-spectrin cDNA & the chemokine dependence of migration was compared with controls. In-vivo studies: in a melanoma mouse model, BII-spectrin transfected or control T-cells were injected; tumors were followed with serial imaging. Human patient records were examined to correlate endogenous BII-spectrin levels and CAR-T response. RESULTS/ANTICIPATED RESULTS: Activated T-cells downregulate the cytoskeletal protein B-II spectrin compared to naive cells, leading to chemokine-independent migration in in vitro assays and off-target trafficking when CAR-T cells are given in vivo. Restoration of B-II spectrin levels via transfection restores chemokine-dependence of activated T-cells. In a mouse melanoma model, control mice injected with standard activated T-cells showed fewer cells in the tumor site and more cells in the off-target organs (spleen, lungs) when compared to mice injected with B-II spectrin transfected cells. Furthermore, among 3 human patients undergoing CAR-T therapy, those with higher endogenous B-II spectrin levels experienced fewer side-effects, measured by the neurotoxicity and cytokine release syndrome grades. DISCUSSION/SIGNIFICANCE: A major hurdle to widespread CAR-T therapy for cancer is significant, often fatal side-effects. Our work shows that the protein B-II spectrin is downregulated during CAR-T production, and that restoring B-II spectrin levels decreases side-effects while increasing tumor clearance--hopefully translating to better CAR-T regimens for the future.

Experimental studies of the influence of fluid–structure interaction on cloud cavitation about a stiff stainless steel (SS) and a flexible composite (CF) hydrofoil have been presented in Parts I (Smith et al., J. Fluid Mech., vol. 896, 2020a, p. A1) and II (Smith et al., J. Fluid Mech., vol. 897, 2020b, p. A28). This work further analyses the data and complements the measurements with reduced-order model predictions to explain the complex response. A two degrees-of-freedom steady-state model is used to explain why the tip bending and twisting deformations are much higher for the CF hydrofoil, while the hydrodynamic load coefficients are very similar. A one degree-of-freedom dynamic model, which considers the spanwise bending deflection only, is used to capture the dynamic response of both hydrofoils. Peaks in the frequency response spectrum are observed at the re-entrant jet-driven and shock-wave-driven cavity shedding frequencies, system bending frequency and heterodyne frequencies caused by the mixing of the two cavity shedding frequencies. The predictions capture the increase of the mean system bending frequency and wider bandwidth of frequency modulation with decreasing cavitation number. The results show that, in general, the amplitude of the deformation fluctuation is higher, but the amplitude of the load fluctuation is lower for the CF hydrofoil compared with the SS hydrofoil. Significant dynamic load amplification is observed at subharmonic lock-in when the shock-wave-driven cavity shedding frequency matches with the nearest subharmonic of the system bending frequency of the CF hydrofoil. Both measurements and predictions show an absence of dynamic load amplification at primary lock-in because of the low intensity of cavity load fluctuations with high cavitation number.