Grant R01 Research Articles

The ideal observer: The forgotten second half of signal detection theory

In his seminal text “Signal Detection Theory and Psychophysics” (1966), coauthored with John Swets, Dave Green identifies two parts to the theory. The first entails the psychophysical methodology and procedures required to separate sensory and decision processes in detection, the second compares human performance to that of a theoretical ideal observer that optimizes decisions based on the statistical properties of signals and the demands of the detection task. The first part has received far wider application in psychophysics, but there are demonstrable advantages to applying both. In this talk I will give examples from work in our lab where the analysis of ideal observers framed in the methodology has been used to (1) give mathematical meaning to the constructs of stimulus uncertainty and similarity in informational masking; (2) determine sensory constraints on the use of invariant acoustic cues in sound source identification; and (3) isolate a fixed effect of listeners in multi-talker speech segregation across experiments involving vastly different stimuli and psychophysical tasks. [Work supported by NIDCD grant R01 DC001262.]

Abstract OT2-07-01: Feasibility study to evaluate performance of the LUM Imaging System for intraoperative detection of residual tumor in breast cancer patients receiving and not receiving neoadjuvant therapy

Abstract Background: Microscopically tumor-free lumpectomy margins are critical for safe breast conserving surgery. With current tools, 15%-25% of lumpectomies have positive margins that require second surgical procedures and increase cost and patient discomfort. Additionally, current lumpectomy margin assessment techniques show poor performance in predicting residual disease at re-excision, with a PPV of 35%. Better detection tools are needed to identify residual cancer during the initial lumpectomy and reduce second operations. LUM015 is a protease-activated fluorescent imaging agent that accumulates in tumor cells and tumor associated macrophages after preoperative intravenous injection. The LUM Imaging System visualizes activated LUM015 in the lumpectomy cavity via a hand-held wide field detector and proprietary tumor detection software. This system has been tested in multiple single-site studies and two prospective multi-site studies enrolling >600 patients, and demonstrated successful detection of residual lumpectomy cavity tumor. Initial studies excluded the approximately 20% of patients receiving neoadjuvant therapy. Patchy tumor cell death with preoperative therapy can leave small, multifocal deposits of tumor invisible on pre-operative imaging and not palpable or visible during surgery. We now evaluate the LUM Imaging System in patients with and without neoadjuvant therapy. Trial Design and Specific Aims: This prospective, multi-center study at 6 US sites tests the LUM Imaging System in lumpectomy surgery after neoadjuvant therapy to evaluate potential impact of treatment-related tissue changes and tumor cell death on tumor detection algorithms. An initial cohort of 10 patients address the objective of algorithm development. A second cohort of 104 patients will further evaluate the feasibility of the LUM Imaging System after neoadjuvant therapy. A third cohort will enroll 208 patients who have not received neoadjuvant therapy. All cohorts are evaluated for safety and for reduction in residual tumor after LUM Imaging System guidance compared to standard of care lumpectomy. After excision of the main lumpectomy specimen, patients are randomized 3:1 to device or control arms. In the device arm, the cavity is imaged and margins with LUM015 signal are excised. Final comprehensive shaved margins are removed in both arms to evaluate extent of residual disease after the use of the LUM Imaging System or after standard lumpectomy. No LUM Imaging is performed in the control arm, however, all patients are injected with LUM015 to evaluate drug safety. Patient reported outcomes assessing re-excision concerns, breast appearance and preferences for treatment type are collected. Eligibility Criteria: This study seeks to enroll women 18 and older with histologically confirmed primary invasive breast cancer (IBC), ductal carcinoma in situ (DCIS) or a combination of IBC/DCIS undergoing a lumpectomy for their breast malignancy who have received any form of neoadjuvant treatment prior to surgery (cohorts 1 and 2) or who have not received any therapy prior to lumpectomy (cohort 3). Patients allergic to polyethylene glycol or intravenous contrast agents are excluded. Use of blue node mapping dyes before imaging with the LUM015 is not allowed per study protocol. Accrual and Study Progress: Cohort 1 has completed enrollment and interim analysis. No new risks specific to the neoadjuvant population were identified. LUM015 fluorescent signals measured in neoadjuvant patients were within the expected range, and no changes to the tumor detection algorithm were required. Cohorts 2 and 3 have enrolled a total of 38 patients. This trial is registered as NCT04440982. The NIH funds this study through a R01 grant issued to Massachusetts General Hospital. Citation Format: Irene L. Wapnir, Kelly K. Hunt, E Shelley Hwang, Kate Smith, Peter Blumencranz, David Carr, Jorge Ferrer, Heidi Santa Cruz, Alexandra Webster, Julia Shanno, Alexander Pogrebinsky, Manna Chang, Barbara L. Smith. Feasibility study to evaluate performance of the LUM Imaging System for intraoperative detection of residual tumor in breast cancer patients receiving and not receiving neoadjuvant therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-07-01.

Masking effects of amplitude modulation on frequency-modulated tones

Human sensitivity to frequency modulation (FM) is best for low carrier frequencies (<∼4–5 kHz) and slow modulation rates (<5–10 Hz). This high sensitivity is thought to be afforded by neural phase locking to temporal fine structure (TFS). At faster rates and higher carriers, TFS cues may no longer be available, with sensitivity to FM relying instead on conversion to amplitude modulation (AM) via cochlear filtering. One way to test this hypothesis is to measure the masking produced by additional AM, with the prediction that AM masking will be more pronounced when FM is encoded via AM than via TFS cues. This study tested AM masking of FM and of “simulated FM,” which involves out-of-phase AM dyads. FM detection was measured for carrier frequencies of 1 and 6 kHz and modulation rates of 2 and 20 Hz with and without AM masking. Preliminary results suggest that FM and simulated FM sensitivity is more affected by AM at fast than slow rates at both low and high carrier frequencies. Overall, the results do not provide support for the idea that AM interference can be used to distinguish between TFS- and envelope-based codes for FM. [Work supported by NIH grant R21 DC019409.]

Editorial Comment.

No AccessJournal of UrologyTranslational Research Article23 Feb 2023Editorial CommentThis article comments on the following:Detection of Bacteria in Bladder Mucosa of Adult Females Indira U. Mysorekar Indira U. MysorekarIndira U. Mysorekar Department of Medicine, Section of Infectious Diseases and Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003189.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, Publish Ahead of Print, pp. – REFERENCES 1. Detection of bacteria in bladder mucosa of adult females. J Urol.2023; 209(5):000-000. Google Scholar 2. . Effects of aging on urinary tract epithelial homeostasis and immunity. Dev Biol.2023; 493:29-39. Crossref, Medline, Google Scholar 3. Direct detection of tissue-resident bacteria and chronic inflammation in the bladder wall of postmenopausal women with recurrent urinary tract infection. J Mol Biol.2019; 431(21):4368-4379. Crossref, Medline, Google Scholar 4. . Bladder mucosal Cystitis cystica lesions are tertiary lymphoid tissues that correlate with recurrent UTI frequency in postmenopausal women. J Urol.2023. Link, Google Scholar Submitted August 11, 2022; accepted January 10, 2023; published 000. Support: This work was supported by NIH grants R01 AG052494, P20 DK119840, and R56 AG064634 to IUM. Conflict of Interest: IUM: Scientific advisory board: Luca Biologics. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology19 Jan 2023Detection of Bacteria in Bladder Mucosa of Adult Females Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Indira U. Mysorekar Department of Medicine, Section of Infectious Diseases and Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas More articles by this author Expand All Submitted August 11, 2022; accepted January 10, 2023; published 000. Support: This work was supported by NIH grants R01 AG052494, P20 DK119840, and R56 AG064634 to IUM. Conflict of Interest: IUM: Scientific advisory board: Luca Biologics. Advertisement PDF downloadLoading ...

Gender disparities in the National Institutes of Health funding for genitourinary oncology.

264 Background: Traditionally, women are under-represented in academic fields and thus less likely to receive grants and funds. Here we assessed the National Institutes of Health (NIH) funding trend in allocation of R401 grants in Genito-urinary oncology (GU) stratified by gender. Methods: The data were retrieved from the NIH RePORTER (Research Portfolio Online Reporting Tools Expenditure) using GU-related search terms from 2018-2021. The gender was categorized using Genderize. The number of citations, publications, H-index, and seniority were obtained from Scopus and Web of Science in September 2022. Consumer Price Index was used to adjust funding amount to 2021 equivalent U.S. dollars. Linear regression was used for analysis. Results: A total of 873 NIH-funded R01 grants amounting to $388.5 million were awarded for GU research. Women (n= 206; 23.6% [95% CI: 20.8%-26.4%]) received fewer grants than men (n= 667; 76.4% [95% CI: 73.6%-79.2%]). Trending from 2018 to 2021, there was no significant difference in the number of grants awarded among both men (173 to 181, p=0.78) and women (50 to 53, p=0.92) within their groups. Similarly, there was no significant change in the grant amount (in millions) awarded among men (74.2 to 78.7, p=0.47) and women (23.6 to 22.4, p=0.30). Prostate cancer accounted for the greatest proportion of grants (n=689; 78.9% [95% CI: 76.2%-81.6%]), amounting to 304.4 million in 4 years. Of the 269 co-Principal Investigator (PIs), 240 (89.2% [95% CI: 85.5%-92.9%]) were men and 29 (10.8% [95% CI: 7.1%-14.5%]) were women. Male PIs compared to female PIs had a higher no. of publications (135 vs 106, p<0.01). Funding amount was significantly associated with the number of publications (β=0.05; p<0.01), seniority (β=0.10; p=0.015), institution (p<0.01) and degrees (p=0.03). However, there was no significant association with gender (β=0.05; p=0.17). Conclusions: Our analysis shows continued gender disparity in R01 awards as only 1 in 5 grants were awarded to women during the fiscal years of 2018-2021. Thus, concerted efforts are required to bridge this gap and promote gender equity. [Table: see text]

The concentration threshold for condensation of multivalent molecules is set by by the maximum solubility product.

Clustering of weakly interacting multivalent biomolecules underlies the formation of membrane-less compartments known as condensates. As opposed to single component (homotypic) systems, the concentration dependence of multi-component (heterotypic) condensate formation is not well understood. We previously proposed the solubility product (SP), the product of monomer concentrations in the dilute phase, as a tool for understanding the concentration dependence of multi-component systems. In the current study, we further explore the limits of the SP concept using spatial Langevin dynamics and rule-based stochastic simulations. We show, for a variety of idealized molecular structures, how the maximum SP coincides with the onset of the phase transition, i.e., the formation of large clusters. We reveal the importance of intra-cluster binding in steering the free and cluster phase molecular distributions. We also show how structural features of biomolecules shape the solubility product profiles. The interplay of flexibility, length and steric hindrance of linker regions controls the phase transition threshold. Remarkably, when solubility products are normalized to non-dimensional variables and plotted against the concentration scaled to the threshold for phase transition, the curves all coincide independent of the structural features of the binding partners. Similar coincidence is observed for the normalized clustering vs. concentration plots. Overall, the principles derived from these systematic models will help guide and interpret in vitro and in vivo experiments on the biophysics of biomolecular condensates. (Supported by NIGMS grants R24 GM137787 and R01 GM132859.)

Monkeying around with monkeyflowers: Modeling pigmentation patterning mechanisms in Mimulus.

Mimulus (Monkeyflowers) is a diverse genus of angiosperms that produce many beautiful and unique pigmentation patterns. The basic mechanisms of pattern production have been tentatively described in certain species of Mimulus, and it is based on the reaction-diffusion system of a slow activator NEGAN (called a pre-pattern) and a fast inhibitor RTO. Such activator-inhibitor pair forms a Turing pattern, and we have shown that it generates various patterns in Monkeyflower petals. Using the modeling and simulation software VCell, the reaction-diffusion system can be spatially simulated with a series of differential equations. By changing the parameters of the math model or the shape of the pre-pattern, many different patterns emerge, corresponding to phenotypes observed in species of Mimulus. We aim to classify flower patterns, so they can be easily distinguished, and to identify key parameters and parameter regions that correspond to changes in patterns related to a mix of mutants in a plant, and trajectories in parameter space describing the lineage of patterns. (Supported by NIGMS grant R01 GM140092.)

There Must Be a Better Way.

The National Institutes of Health (NIH) R01 grant represents the gold standard for research independence across the United States. The barrier to entry for this grant mechanism is extremely high, with <10% of grants being funded. Interestingly, after this tremendously high barrier, there is very little accountability for the grantee to accomplish the aims that were originally proposed. While there is certainly value to requiring investigators to provide a logical and compelling research plan, excessive grant writing creates a large inefficiency. Thus, a "fail quickly" model, which is not without cost, should be considered. Such a model involves a much lower barrier to entry and much higher short-term accountability so that more aims can be tested in less time at lower cost.

Fewer Than One in 20 Current Academic Orthopaedic Surgeons Have Obtained National Institutes of Health Funding.

National Institutes of Health (NIH) funding is a key driver of orthopaedic research, but it has become increasingly difficult to obtain in recent years. An understanding of the types of grants that are commonly funded, how productive they are, and the factors associated with obtaining funding may help orthopaedic surgeons better understand how to earn grants. In this study, we sought to determine (1) the proportion of current academic orthopaedic surgeons who have obtained NIH grant funding, (2) the productivity of these grants by calculating grant productivity metrics, and (3) the factors (such as gender, subspecialty, and additional degrees) that are associated with obtaining grant funding. Current academic orthopaedic surgeons at the top 140 NIH-funded institutions were identified via faculty webpages; 3829 surgeons were identified. Demographic information including gender (men constituted 88% of the group [3364 of 3829]), academic rank (full professors constituted 22% [856 of 3829]), additional degrees (those with MD-PhD degrees constituted 3% [121 of 3829]), leadership positions, and orthopaedic subspecialty was collected. Funding histories from 1985 through 2021 were collected using the NIH Research Portfolio Online Reporting Tools Expenditures and Results. Grant type, funding, publications, and citations of each article were collected. A previously used grant impact metric (total citations per USD 0.1 million) was calculated to assess grant productivity. Multivariable binomial logistic regression was used to evaluate factors associated with obtaining funding. Four percent (150 of 3829) of academic orthopaedic surgeons obtained USD 338.3 million in funding across 301 grants, resulting in 2887 publications over the entire study period. The R01 was the most commonly awarded grant in terms of the total number awarded, at 36% (108 of 301), as well as by funding, publications, and citations, although other grant types including T32, F32, R03, R13, and R21 had higher mean grant impact metrics. There was no difference between men and women in the by-gender percentage of academic orthopaedic surgeons who obtained funding (4% [135 of 3229] versus 3% [15 of 450]; odds ratio 0.9 [95% confidence interval 0.5 to 1.7]; p = 0.80). A department having a single funded PhD researcher may be associated with surgeon-scientists obtaining grant funding, but with the numbers available, we could not demonstrate this was the case (OR 1.4 [95% CI 0.9 to 2.2]; p = 0.12). Fewer than one in 20 academic orthopaedic surgeons have received NIH funding. R01s are the most commonly awarded grant, although others demonstrate increased productivity metrics. Future studies should investigate the role of co-principal investigators on productivity and the role of different funding sources. Individuals should pursue both R01 and non-R01 grants, and departments should consider cultivating relationships with funded PhDs. The specific research infrastructure and departmental policies of the most productive institutions and grants should be surveyed and emulated.

Improving Self-management of Type 2 Diabetes in Latinx Patients: Protocol for a Sequential Multiple Assignment Randomized Trial Involving Community Health Workers, Registered Nurses, and Family Members

The rate of Type 2 diabetes mellitus (T2DM) among Mexican American individuals is 16.3%, about twice that of non-Hispanic White individuals. While a number of education approaches have been developed and shown to improve diabetes self-management behaviors and glycemic control for Spanish-speaking Latinx patients with T2DM, there is little research to guide health practitioners regarding which interventions to apply and when so that resources are used efficiently, and treatment outcomes are maximized. This study aimed to describe an adaptive intervention that integrates community mental health workers, diabetes nurse educators, family members, and patients as partners in care while promoting diabetes self-management for Mexican American individuals with T2DM. The project incorporates four evidence-based, culturally tailored treatments to determine what sequence of intervention strategies work most efficiently and for whom. Given the increasing prevalence of T2DM, achieving better control of diabetes and lowering the associated medical complications experienced disproportionally by Mexican American individuals is a public health priority. Funded by the National Institute of Nursing Research (National Institutes of Health grant R01 NR015809), this project used a sequential multiple assignment randomized trial and included 330 Spanish-speaking Latinx patients with T2DM. In the first phase of the study, subjects were randomly assigned to an evidence-based diabetes self-management educational program called Tomando Control delivered in a group format for 6, biweekly 1.5-hour sessions, led either by a community health worker or a diabetes nurse educator. In the second phase of the study, those subjects who did not improve their diabetes self-management behaviors were rerandomized to receive either an augmented version of Tomando Control or a multifamily group treatment focused on problem-solving. The primary outcome measure was the "Summary of Diabetes Self-Care Activities." Evaluations were made at baseline and at 3, 6, and 12 months. This study was funded in June 2016 for a period of 5 years. Institutional review board approval was obtained in November 2016. Between March 2017 and September 2020, a total of 330 patients were recruited from the outpatient primary care clinics of Olive View-UCLA Medical Center, with a brief hiatus between May 2020 and July 2020 due to COVID-19 restrictions. The study interventions were completed in December 2020. Data collection began in March 2017 and was completed in December 2021. Data analysis is expected to be completed in Spring 2023, and results will be published in Fall 2023. The results of this trial should help practitioners in selecting the optimal approach for improving diabetes self-management in Spanish-speaking, Latinx patients with T2DM. ClinicalTrials.gov NCT03092063; https://clinicaltrials.gov/ct2/show/NCT03092063. DERR1-10.2196/44793.

Oral booster vaccine antigen-Expression of full-length native SARS-CoV-2 spike protein in lettuce chloroplasts.

Oral booster vaccine antigen-Expression of full-length native SARS-CoV-2 spike protein in lettuce chloroplasts.

Comparison of academic productivity and funding support between United States and international medical graduate vascular surgeons

ObjectiveThe demand for vascular surgeons in the United States stands to far exceed the current supply. International medical graduates (IMGs) are not only vital to meeting the country’s growing health care needs, but also help to advance clinical research and medical education in the field of vascular surgery. Nearly 17% of practicing vascular surgeons in the United States are IMGs, yet little is known about their relative contributions to academic vascular surgery. Our study aims to compare the academic profiles and funding support for IMG vascular surgeons to that of their US medical graduate (USMG) counterparts. MethodsA cross-sectional study was performed on all IMG and USMG academic vascular surgeons practicing in US-based hospitals with vascular surgery residency and/or fellowship programs. In addition to the baseline surgeon characteristics, academic profiles and research output were also collected. Furthermore, the National Institutes of Health (NIH) research reporting tool and open payments database were queried for any funding/payments to surgeons in both groups. Matching for year of vascular surgery training program graduation was performed where appropriate. ResultsA total of 908 academic vascular surgeons were included; 759 (83.6%) were USMGs and 149 (16.4%) were IMGs. The median year of graduation was comparable between the two groups, but USMGs had a significantly higher proportion of female surgeons (23.6% vs 10.7%; P = .0003). There were no significant differences in the academic profiles and leadership positions between the two groups. Although research productivity is similar between the two groups, IMG surgeons were more likely to have first or senior-authorship papers (47.1% vs 37.5%; P < .001). Additionally, faculty departments chaired/cheifed by a USMG were less likely to be staffed with IMG vascular surgeons (1.6 surgeons vs 3.1 surgeons; P < .0001). Following grant analysis, USMG surgeons received more NIH R01 grants (5.7% vs 1.3%; P = .026). R01-funded surgeons had significantly greater research output by number of publications (121.0 vs 47.5), citations (3872 vs 938), H-index (32.0 vs 17.5), and average journal impact factor (>10: 86.7% vs 33.3%) (all P < .001). ConclusionsThe efforts to further diversify vascular surgery are vital to better serving an increasingly diverse US population, amid growing disparities in health care. Although IMGs account for a minority of academic vascular surgeons, and contribute significantly to their published research, they had less NIH R01 funding, warranting further investigation.

Protocol for a study on Sitting with Interruption and Whole-Body Cardiovascular Health (SWITCH) in middle-aged adults

BackgroundSedentary behavior (SB) is a biologically distinct yet understudied cardiovascular disease risk (CVD) factor. However, specific public health policy regarding the optimal strategy for SB interruption is unavailable. This paper outlines the protocol for part I of the Sitting with Interruption and Whole-Body Cardiovascular Health (SWITCH) study, including the rationale, objectives, methodology, and next steps. We additionally detail practical considerations that went into the development of the NIH R01 grant supporting this research. MethodsHealthy men and women (n = 56, aged 36–55) who are inactive (<90 min/wk. of moderate-to-vigorous intensity physical activities for past 3 months) and sedentary (sitting for >8 h/day), will be recruited for this randomized crossover trial. Specifically, participants will complete the following 4-h conditions: (i) SB with once/h 5 min walk break; (ii) SB with once/h 15 min stand break; (iii) SB with twice/h breaks (alternating 5 min walk and 15 min stand); and (iv) SB with no breaks (i.e., control). Focus group discussions will refine our socioecological SB reduction model. ResultsThe primary outcome will be change in aortic arterial stiffness (i.e., pulse wave velocity; PWV, m/s) for each substitution strategy relative to the control (SB with no breaks) condition. ConclusionsThe outcomes from this study will facilitate the design of a subsequent randomized controlled trial to test a mechanism-informed, feasible SB-reduction intervention and support the development of SB policy.

Urine-derived exosomes from individuals with IPF carry pro-fibrotic cargo.

MicroRNAs (miRNA) and other components contained in extracellular vesicles may reflect the presence of a disease. Lung tissue, sputum, and sera of individuals with idiopathic pulmonary fibrosis (IPF) show alterations in miRNA expression. We designed this study to test whether urine and/or tissue derived exosomal miRNAs from individuals with IPF carry cargo that can promote fibrosis. Exosomes were isolated from urine (U-IPFexo), lung tissue myofibroblasts (MF-IPFexo), serum from individuals with IPF (n=16) and age/sex-matched controls without lung disease (n=10). We analyzed microRNA expression of isolated exosomes and their in vivo bio-distribution. We investigated the effect on ex vivo skin wound healing and in in vivo mouse lung models. U-IPFexo or MF-IPFexo expressed miR-let-7d, miR-29a-5p, miR-181b-3p and miR-199a-3p consistent with previous reports of miRNA expression obtained from lung tissue/sera from patients with IPF. In vivo bio-distribution experiments detected bioluminescent exosomes in the lung of normal C57Bl6 mice within 5 min after intravenous infusion, followed by distribution to other organs irrespective of exosome source. Exosomes labeled with gold nanoparticles and imaged by transmission electron microscopy were visualized in alveolar epithelial type I and type II cells. Treatment of human and mouse lung punches obtained from control, non-fibrotic lungs with either U-IPFexo or MF-IPFexo produced a fibrotic phenotype. A fibrotic phenotype was also induced in a human ex vivo skin model and in in vivo lung models. Our results provide evidence of a systemic feature of IPF whereby exosomes contain pro-fibrotic miRNAs when obtained from a fibrotic source and interfere with response to tissue injury as measured in skin and lung models. This work was supported in part by Lester and Sue Smith Foundation and The Samrick Family Foundation and NIH grants R21 AG060338 (SE and MKG), U01 DK119085 (IP, RS, MTC).

How Well Are Pharmacists Represented in National Institutes of Health R01 Funding to United States Schools of Pharmacy?

Pharmacists are essential healthcare providers but historically are not well represented as principal investigators (PIs) of R01 grants by the United States (US) National Institutes of Health (NIH). Pharmacy organizations have taken steps to provide pharmacists with research training to improve their chances of achieving PI status. We conducted a retrospective cohort study using data from the NIH RePORTER website about R01 grants awarded to PIs affiliated with US Schools of Pharmacy (SOPs) for the fiscal years 2005-2019. Information regarding professional degrees was supplemented using data from the PIs' institutional website profiles and other internet-based sources. Only doctorate degrees obtained within the US were included for clinically related degrees. Data regarding more than one year of funding for the same project, equipment supplements, and diversity supplements were excluded to focus on unique projects in year one of funding. PhDs were the primary unique PIs of R01 grants at US SOPs (&gt;90%). Pharmacist representation as unique PIs increased over the 15 years but was still only 10.1% for the years 2015-2019. There was a higher percentage of female pharmacists as unique PIs than female non-pharmacists. Pharmacists are currently underrepresented as unique PIs for NIH R01 grants. This conclusion is limited by not knowing how many pharmacist R01 applications were submitted.

Health disparities in regional anesthesia and analgesia for the management of acute pain in trauma patients.

Health disparities in regional anesthesia and analgesia for the management of acute pain in trauma patients.

Theme and Variation: Structuring Thrombus Formation from Jugular/Arterial Puncture Wounds to Occlusive Clots in a Mouse Model

Hemostasis in veins and arteries has been assumed to be different processes, e.g., white vs. red clots. We took the unbiased experimental approaches of 3D EM across full clot volumes and high-resolution heat mapping of platelet activation state to probe for commonalities and variations using controlled mouse models. Remarkably, the thrombi formed, 5 min post-puncture, in the jugular vein and femoral artery showed considerable consistency in organization. There were vaulted cavities within the puncture wound and apparent extravascular capping of the puncture hole to produce bleeding cessation. Notable differences in the venous thrombi were a greater activation of platelets lining the surfaces of the vaulted columns, an outcome that we attribute to lowr flow rates resulting in the longer retention of activating signals, and in the "hanging drop” nature of the arterial thrombi anchored to the extrema with an outward, extravascular bulge of the thrombus. We attribute these variations to arterial vessel wall properties and higher flow rates. At 20 min post-puncture, the intravascular crown of the venous wound thrombi was enriched in loosely adherent platelets in a low activation state. Similarly, the outer portion of the intravascular arterial thrombus was rich in low activation platelets including obviously discoid platelets. Strikingly, the arterial thrombus was subject to rebleeding and ate 20 min displayed fractured extravascular features indicative of an unstable clot. The puncture wound thrombi form in the relatively small volume of the immediate wound site. In contrast, occlusive clots fill the cylindrical volume of the vessel. To us, the overall structure of the wound thrombi suggested a predictive hypothesis for induced occlusive clotting. We propose that 1) the exposed intima lining the arterial vessel wall provides a cylindrical substratum for the generation of a tightly adherent platelet layer anchoring the forming clot and 2) the central volume of the clot resembles the intravascular crown of the puncture wound thrombus. Hence, the prediction of a central volume of the occlusive clot consisting of loosely adherent to discoid shaped platelets. That was result found for FeCl3 induced femoral clots by wide area-TEM (WA-TEM) i.e., a central volume rich in discoid shaped platelet and few red blood cells were trapped in the tightly adherent rim of the clot.. Using sequential block face SEM, we have begun to image and volume render carotid clots by sequential block face SEM. Analysis of 5,000 sequential images from the downstream half of the carotid clot, showed that the structure gradually tapered in a conical manner and contains few red blood cells. We propose that there are indeed organizational themes shared by the puncture wound thrombus in venous or arterial settings and the occlusive clot in which vascular damage is restricted to the endothelial cell layer. Work was supported by NIH grants (BS) R01 HL155519 and P20 HL146373 (Joel Bennett, principal investigator), R35 HL150118 (SWW) and by intramural NIBIB research program (RDL). An occlusive FeCl3 clot in the carotid artery of a C57BL/6 mouse imaged by sequential block face SEM over a length of 1.2 millimeters.A. cross section of the clot 200 microns in from the mid-occlusion starting point for sectioning. B. Zoom of A) to illustrate the low level of trapped red blood cells within the clot. C. cross section of the clot 900 microns in from the starting point showing how the clot has now tapered down and fills a minor portion of the artery. D. Rendering of 1.2 millimeters of the clot (blue), vessel wall (green) and in gray a single plane image. Flow was from left to right. Note that the clot progressively tapers to a point in the downstream direction.Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

National Institutes of Health Diversity Supplement Awards by Medical School.

Increasing medical school faculty diversity is an urgent priority. National Institutes of Health (NIH) diversity supplements, which provide funding and career development opportunities to individuals underrepresented in research, are an important mechanism to increase faculty diversity. Analyze diversity supplement utilization by medical schools. Retrospective cohort study. All R01 grant-associated diversity supplements awarded to medical schools from 2005 to 2020. Diversity supplements were identified using the publicly available NIH RePORTER database. Main measures were the number of R01-associated diversity supplements awarded to medical schools each year by medical schoolNIH funding status and the number of R01-associated diversity supplements awarded to individual medical schools in the NIH top 40 by funding status. We also examined the percentage of R01 grants with an associated diversity supplement by NIH funding status and individual medical school in the NIH top 40. From 2005 to 2020, US medical school faculty received 1389 R01-associated diversity supplements. The number of diversity supplements awarded grew from 2012 to 2020, from ten to 187 for top 40 schools, and from seven to 83 for non-top 40 schools. The annual growth rate for diversity supplement awards at NIH top 40 schools (44.2%) was not significantly different than the annual growth rate among non-top 40 schools (36.2%; p = 0.68). From 2005 to 2020, the highest number of diversity supplements that an individual medical school received was 56 and the lowest number was four (mean = 24.6, SD = 11.7). The highest percentage of R01 grants with an associated diversity supplement received by a school was 4.5% and the lowest percentage was 0.79% (mean = 2.3%, SD = 0.98). Medical schools may be missing an opportunity to address the continuing shortage of individuals historically underrepresented in biomedical science and should consider additional mechanisms to enhance diversity supplement utilization.

LBSUN310 Developmental Programming: Gestational Bpa Treatment Leads To Pancreatic Beta Cell Compromise

Abstract Developmental exposure to endocrine disrupting chemicals (EDC) such as bisphenol A (BPA) have been shown to be associated with many metabolic defects in humans. Studies in animals have documented detrimental effects of fetal exposure to BPA on metabolic variables such as insulin resistance, adiposity, and cardiac function. For instance, developmental exposure of sheep to bisphenol A (BPA), a ubiquitously present EDC, causes insulin resistance and compensatory hyperinsulinemia but the underlying mechanism of it is not fully understood. To determine if pancreatic hyperplasia or hypertrophy contributes to the hyperinsulinemic status and the ontogeny of these effects, pregnant Suffolk sheep were administered daily subcutaneous injections of BPA (0. 05, 0 .5 or 5 mg/Kg BW) in corn oil from days (D) 30-90 of gestation (term 147 days). Controls received corn oil during the same period. Pancreas were taken at Day 65 and 90 of gestation from control and 0.5mg/kg BPA (environmental exposure level)-treated female fetuses, and control and prenatal BPA-treated female offspring at 2 years of age (all 3 doses) during synchronized follicular phase of the cycle. Immunohistochemistry was used to determine beta cell number, size, and islet insulin content. In addition, to determine if the pancreas was fibrotic, islet collagen content was determined by Picro Sirius red staining and whole pancreas collagen content was measured with scroll collagen assay. Data were analyzed by ANOVA (Y2) and Students's t-test (D65 and D90), and magnitude of response by Cohen's Effect Size analysis. Findings showed large magnitude reduction of islet insulin content at day 65, significant decrease in islet insulin and beta cell count at D90 along with large magnitude decrease in pancreas/fetal weight. In contrast, in the Y2 sheep prenatal BPA treatment induced a large magnitude decrease in beta cell count (0. 05mg/kg dose group), a large magnitude increase in islet insulin content (5mg/kg dose group) and large magnitude increase in islet collagen content (all 3 BPA doses). The decrease in insulin in the D65 and D90 sheep along with the decrease in beta cells and pancreas/fetal weight at D90 indicates adverse developmental impact of BPA exposure on pancreatic beta cell differentiation. Increase in collagen accumulation in Y2 sheep likely contributes to the beta cell loss reflected as decrease in beta cell number seen in 0. 05 mg/kg dose of BPA. Absence of beta cell loss in 0.5 and 5mg/kg dose in the face of increased collagen is consistent with the nonmonotonic responses these EDCs manifest. Taken together, these results highlight the risks posed by developmental exposure to BPA on beta cell function and the corresponding risk for beta cell loss as animals age. Supported by NIH R01 grants ES016541 and ES030374 Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Current Status of National Institutes of Health Research Funding for Women Surgeon-Scientists

Women have made substantial advancements in academic surgery, but research funding disparities continue to hamper their progress, and current literature on the status of National Institutes of Health (NIH) funding awarded to women surgeon-scientists appears to be conflicting. To examine gender-based differences in NIH funding awarded to surgeon-scientists by comparing total grant amounts awarded and the distribution of grants by gender and research type. This cross-sectional study was performed using a previously created database of NIH-funded surgeons from 2010 to 2020. Active physician data from the Association of American Medical Colleges were used to calculate total surgeon populations. This study was performed at the NIH using the NIH internal data platform, iSearch Grants. A total of 715 men and women surgeon-scientists funded by the NIH in 2010 and 1031 funded in 2020 were included in the analysis. The main outcome was the number of women among the total number of surgeons who received NIH grants and the total grant amounts awarded to them. Bivariate χ2 analyses were performed using population totals and substantiated by z tests of population proportions. This study included 715 physicians (n = 579 men [81.0%]) in 2010 and 1031 physicians (n = 769 men [74.6%]) in 2020. In 2020, women comprised 27.4% of the surgical workforce and 25.4% of surgeons with research funding in the US, but they received only 21.7% of total NIH research funding awarded to all surgeons. The number of funded women surgeon-scientists, however, significantly increased from 2010 to 2020 (262 [25.4%] in 2020 vs 136 [19.0%] in 2010; P < .001) as did their funding ($189.7 million [21.7%] in 2020 vs $75.9 million [12.3%] in 2010; P < .001). Furthermore, the proportion of US women surgeons overall with NIH funding significantly increased in 2020 vs 2010 (0.7% vs 0.5%; P < .001). Basic science, clinical outcomes, and clinical trial R01 grants also increased among women surgeon-scientists. Women and men K grant holders had a similar mean (SD) number of R01 application attempts before success (2.7 [3.01] vs 2.3 [3.15]; P = .60) and similar K-to-R award conversion rates (23.5% vs 26.7%; P = .55). This cross-sectional study found an increasing number of women surgeon-scientists receiving NIH funding in 2020 vs 2010 as well as increases in the median grant amounts awarded. Although these results are promising, a discrepancy remains in the proportion of women in the surgical workforce compared with those funded by the NIH and the total grant amounts awarded to them.