bluuebunny/crossref_metadata_2025 huggingface dataset:
Probabilistic truthlikeness, content elements, and meta-inductive probability optimization
Authors: Schurz Gerhard
Published: March 2021

The paper starts with the distinction between conjunction-of-parts accounts and disjunction-of-possibilities accounts to truthlikeness (Sects. 1, 2). In Sect. 3, three distinctions between kinds of truthlikeness measures (t-measures) are introduced: (i) comparative versus numeric t-measures, (ii) t-measures for qualitative versus quantitative theories, and (iii) t-measures for deterministic versus probabilistic truth. These three kinds of truthlikeness are explicated and developed within a version of conjunctive part accounts based on content elements (Sects. 4, 5). The focus lies on measures of probabilistic truthlikeness, that are divided into t-measures for statistical probabilities and single case probabilities (Sect. 4). The logical notion of probabilistic truthlikeness (evaluated relative to true probabilistic laws) can be treated as a subcase of deterministic truthlikeness for quantitative theories (Sects. 4–6). In contrast, the epistemic notion of probabilistic truthlikeness (evaluated relative to given empirical evidence) creates genuinely new problems, especially for hypotheses about single case probabilities that are evaluated not by comparison to observed frequencies (as statistical probabilities), but by comparison to the truth values of single event statements (Sect. 6). By the method of meta-induction, competing theories about single case probabilities can be aggregated into a combined theory with optimal predictive success and epistemic truthlikeness (Sect. 7).
National Bariatric Surgery Registries: an International Comparison
Authors: Akpinar Erman O. , Marang- van de Mheen Perla J. , Nienhuijs Simon W. , Greve Jan Willem M. , Liem Ronald S. L.
Published: March 2021

Introduction

Pooling population-based data from all national bariatric registries may provide international real-world evidence for outcomes that will help establish a universal standard of care, provided that the same variables and definitions are used. Therefore, this study aims to assess the concordance of variables across national registries to identify which outcomes can be used for international collaborations.

Methods

All 18 countries with a national bariatric registry who contributed to The International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) Global Registry report 2019 were requested to share their data dictionary by email. The primary outcome was the percentage of perfect agreement for variables by domain: patient, prior bariatric history, screening, operation, complication, and follow-up. Perfect agreement was defined as 100% concordance, meaning that the variable was registered with the same definition across all registries. Secondary outcomes were defined as variables having “substantial agreement” (75–99.9%) and “moderate agreement” (50–74.9%) across registries.

Results

Eleven registries responded and had a total of 2585 recorded variables that were grouped into 250 variables measuring the same concept. A total of 25 (10%) variables have a perfect agreement across all domains: 3 (18.75%) for the patient domain, 0 (0.0%) for prior bariatric history, 5 (8.2%) for screening, 6 (11.8%) for operation, 5 (8.8%) for complications, and 6 (11.8%) for follow-up. Furthermore, 28 (11.2%) variables have substantial agreement and 59 (23.6%) variables have moderate agreement across registries.

Conclusion

There is limited uniform agreement in variables across national bariatric registries. Further alignment and uniformity in collected variables are required to enable future international collaborations and comparison.

Graphical abstract
Local events-based fast RTM surface-offset gathers via dip-guided interpolation
Authors: Zhao Yang , Niu Feng-Lin , Fu Lei , Cheng Cheng , Chen Jin-Hong , Huo Shou-Dong
Published: March 2021

Reverse Time Migration (RTM) Surface Offset Gathers (SOGs) are demonstrated to deliver more superior residual dip information than ray-based approaches. It appears more powerful in complex geological settings, such as salt areas. Still, the computational cost of constructing RTM SOGs is a big challenge in applying it to 3D field data. To tackle this challenge, we propose a novel method using dips of local events as a guide for RTM gather interpolation. The residual-dip information of the SOGs is created by connecting local events from depth-domain to time-domain via ray tracing. The proposed method is validated by a synthetic experiment and a field example. It mitigates the computational cost by an order of magnitude while producing comparable results as fully computed RTM SOGs.
Being a young radiation oncologist in Poland: results of a multi-institutional survey
Authors: Pawlowska Ewa , Tomasik Bartłomiej , Spałek Mateusz , Chyrek Artur J. , Napieralska Aleksandra
Published: March 2021

In 2018, Polish Society of Radiation Oncology formed a young section (yPTRO), dedicated to radiation oncologists under the age of 40. To evaluate their current situation, an anonymous, nationwide, online survey was carried out. Thirty-two-item-based questionnaire investigated young radiation oncologists’ perception of employment, workload, education, malpractice lawsuits, scientific research, and board exam. A total of 44 physicians responded to the questionnaire, yielding a response rate of 25%. Results of the survey identified the main problematic areas. In general, young radiation oncologists in Poland are overloaded with bureaucracy. They complain on spending too much time at work and lack work-life balance. The risk of being sued for medical error is threatening two-thirds of responders in everyday work. Compensation is not satisfying for nearly half of the survey participants. Nearly all young radiation oncologists continue education and participate in national and international educational events. Forty-eight percent of responders do scientific research alongside clinical work. However, the perception of young radiation oncologists on the board exam is alarming and requires further discussion. Fifty-five percent of the survey participants think that current form of the exam is not appropriate. Hopefully, 75% of physicians feel fairly evaluated. The presented report is the first of its kind in Poland. Issues mentioned in our questionnaire will help newly formed yPTRO to develop strategic priorities for the upcoming years.
Codimension bounds for the Noether–Lefschetz components for toric varieties
Authors: Bruzzo Ugo , Montoya William D.
Published: March 2021

For a quasi-smooth hypersurface X in a projective simplicial toric variety $$\mathbb {P}_{\Sigma }$$

P
Σ

, the morphism $$i^*:H^p(\mathbb {P}_{\Sigma })\rightarrow H^p(X)$$

i
∗

:

H
p

(

P
Σ

)

→

H
p

(
X
)

induced by the inclusion is injective for $$p=\dim X$$

p
=
dim
X

and an isomorphism for $$p<\dim X-1$$

p
<
dim
X
-
1

. This allows one to define the Noether–Lefschetz locus $$\mathrm{NL}_{\beta }$$

NL
β

as the locus of quasi-smooth hypersurfaces of degree $$\beta $$
β
such that $$i^*$$

i
∗

acting on the middle algebraic cohomology is not an isomorphism. We prove that, under some assumptions, if $$\dim \mathbb {P}_{\Sigma }=2k+1$$

dim

P
Σ

=
2
k
+
1

and $$k\beta -\beta _0=n\eta $$

k
β
-

β
0

=
n
η

, $$n\in \mathbb {N}$$

n
∈
N

, where $$\eta $$
η
is the class of a 0-regular ample divisor, and $$\beta _0$$

β
0

is the anticanonical class, every irreducible component V of the Noether–Lefschetz locus quasi-smooth hypersurfaces of degree $$\beta $$
β
satisfies the bounds $$n+1\leqslant \mathrm{codim}\,Z \leqslant h^{k-1,\,k+1}(X)$$

n
+
1
⩽
codim

Z
⩽

h

k
-
1
,

k
+
1

(
X
)

.
Investigating Decadal Changes of Multiple Hydrological Products and Land-Cover Changes in the Mediterranean Region for 2009–2018
Authors: Li Wenzhao , Perera Sachi , Linstead Erik , Thomas Rejoice , El-Askary Hesham , Piechota Thomas , Struppa Daniele
Published: March 2021

Land-cover change is a critical concern due to its climatic, ecological, and socioeconomic consequences. In this study, we used multiple variables including precipitation, vegetation index, surface soil moisture, and evapotranspiration obtained from different satellite sources to study their association with land-cover changes in the Mediterranean region. Both observational and modeling data were used for climatology and correlation analysis. Famine Early Warning Systems Network (FEWS NET) Land Data Assimilation System (FLDAS) and Global Land Data Assimilation System (GLDAS) were used to extract surface soil moisture and evapotranspiration data. Intercomparing the results of FLDAS and GLDAS suggested that FLDAS data had better accuracy compared to GLDAS for its better coherence with observational data. Climate Hazards Group Infra-Red Precipitation with Station Data (version 2.0 final) (CHIRPS Pentad) were used to extract precipitation data while Moderate Resolution Imaging Spectroradiometer (MODIS) products were used to extract the vegetation indices used in this study. The land-cover change detection was demonstrated during the 2009–2018 period using MODIS Land-Cover data. Some of the barren and crop lands in Euphrates-Tigris and Algeria have converted to low-vegetated shrublands over the time, while shrublands and barren areas in Egypt’s southwestern Delta region became grasslands. These observations were well explained by changing trends of hydrological variables which showed that precipitation and soil moisture had higher values in the countries located to the east of the Mediterranean region compared to the ones on the west. For evapotranspiration, the countries in the north had lower values except for countries in Europe such as Bosnia, Romania, Slovenia, and countries in Africa such as Egypt and Libya. The enhanced vegetation index appeared to be decreasing from north to south, with countries in the north such as Germany, Romania, and Czechia having higher values, while countries in the south such as Libya, Egypt, and Iraq having lower trends. Time series analysis for selected countries was also done to understand the change in hydrological parameters, including Enhanced Vegetation Index, evapotranspiration, and soil moisture, which showed alternating drop and rise as well as stagnant values for different parameters in each country.
Identifying Novel Drug Targets by iDTPnd: A Case Study of Kinase Inhibitors
Authors: Naveed Hammad , Reglin Corinna , Schubert Thomas , Gao Xin , Arold Stefan T. , Maitland Michael L.
Published: March 2021

Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. Here, we develop iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive structural signature as well as a negative structural signature that captures the weakly conserved structural features of drug-binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We confirm the interactions of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity of 52% and a specificity of 55%. We also validate 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, and MHC class I molecules, can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein–small molecule interactions, when sufficient drug–target 3D data are available. The code for constructing the structural signatures is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.
Managing the risks and benefits of clinical research in response to a pandemic
Authors: Flume Patrick A. , Berbari Elie F. , Viera Laura , Hess Rachel , Higgins Janine , Armstrong Jennifer , Rice Linda , True Laura , Shaker Reza , Buse John B. , Panettieri Reynold A.
Published: March 2021

Introduction:

The coronavirus disease 2019 (COVID-19) created major disruptions at academic centers and healthcare systems globally. Clinical and Translational Science Awards (CTSA) fund hubs supported by the National Center for Advancing Translational Sciences provideinfrastructure and leadership for clinical and translational research at manysuch institutions.

Methods:

We surveyed CTSA hubs and received responses from 94% of them regarding the impact of the pandemic and the processes employed for the protection of research personnel and participants with respect to the conduct of research, specifically for studies unrelated to COVID-19.

Results:

In this report, we describe the results of the survey findings in the context of the current understanding of disease transmission and mitigation techniques.

Conclusions:

We reflect on common practices and provide recommendations regarding lessons learned that will be relevant to future pandemics, particularly with regards to staging the cessation and resumption of research activities with an aim to keep the workforce, research participants, and our communities safe in future pandemics.
Creating a pediatric advisory board for engaging youth in pediatric health research: A case study
Authors: Orellana Minerva , Valdez-Soto Miguel , Brockman Tabetha A. , Balls-Berry Joyce E. , Zavala Rocha Maria Guadalupe , Allyse Megan A. , DSouza Karen N. , Riggan Kirsten A. , Juhn Young , Patten Christi
Published: March 2021

Youth are an understudied population requiring additional safeguards when participating in research. Their input is necessary to facilitate participation and interest in studies. To address this, Mayo Clinic established one of the first pediatric advisory boards (PAB) comprised of 18 diverse youth aged 11–17. The PAB members participated in quarterly meetings (in person and then by video conference with the advent of COVID-19) where they provided feedback to researchers on recruitment strategies, study materials, and procedures. The PAB meetings fostered bidirectional conversations with researchers on several health research topics, including mental health. Youth advisory boards can promote engagement in pediatric research.
13109 Phosphorylation state of Myristoylated Alanine-Rich C-Kinase Substrate Effector Domain mimetics determines its cytotoxicity in glioblastoma and macrophage model
Authors: Alrefai Hasan , Eustace Nicholas J. , Anderson Joshua C. , Hicks Patricia H. , King Peter H. , Willey Christopher D.
Published: March 2021

ABSTRACT IMPACT: This study provides insight into how MED2 impacts the immune cells surrounding glioblastoma that help it to grow and spread; having a more complete understanding of how MED2 works will help us better develop therapies that may one day enter the clinic to improve patient outcomes in glioblastoma. OBJECTIVES/GOALS: The purpose of this study was to determine whether the phosphorylation state of the MED2 peptide impacts its biological activity in GBM and macrophages. MED2 variants include the phosphorylatable wild-type (MED2), pseudo-phosphorylated (MED2-PP), non-phosphorylatable (MED2-NP) and control length (CTL2) peptides. METHODS/STUDY POPULATION: MED2, MED2-NP, MED2-PP, and CTL2 were screened against a panel of molecularly characterized glioblastoma patient derived xenografts and IL4/13 stimulated M2-like THP-1 macrophages. The luminescent cell viability assay, CellTiter-Glo, was used to determine viability. RESULTS/ANTICIPATED RESULTS: The proneural lines XD456 and X1441 were highly sensitive to 5 µM MED2 and 5 µM MED2NP compared to 5 µM MED2PP (p<0.001). There was no statistically significant difference between untreated, 5 µM CTL2, and 5 µM MED2PP groups or between the MED2NP and MED2 treated groups. M2-like THP-1 macrophages were highly sensitive to 10 µM MED2NP compared to 10 µM CTL2 (p<0.01) and 10 µM MED2PP (p<0.01) No statistically significant difference was observed between untreated, 10 µM MED2, 10 µM MED2PP, and 10 µM CTL2 groups. DISCUSSION/SIGNIFICANCE OF FINDINGS: The phosphorylation state of MED2 determines its toxicity. When MED2 is phosphorylated, it is nontoxic to GBM or M2-like macrophages. The non-phosphorylatable version is toxic to both GBM and M2-like macrophages. The wild-type peptide is toxic to GBM but not M2-like macrophages, suggesting that MED2 may be phosphorylated in M2-like macrophages.
24088 Investigation of the Apelingeric System on Oxidative Imbalance within Cardiorenal Syndrome Type 4
Authors: Williams Adaysha , Kriegel Alison
Published: March 2021

ABSTRACT IMPACT: Approximately 15% of US adults have chronic kidney disease with over 700,000 of those in the end stages where treatment options are severely limited to dialysis or kidney transplant; the research presented here will help identify novel strategies that address oxidative imbalance and preserve renal function. OBJECTIVES/GOALS: Chronic Kidney Disease patients often develop secondary cardiovascular disease - Cardiorenal Syndrome Type 4. RNA sequencing data show increased apelin receptor expression in 5/6 nephrectomy rats. The Apelinergic (APJ) system is deemed beneficial in normal physiological systems. Here we explore links between stress and the APJ system in CRS4. METHODS/STUDY POPULATION: In preliminary studies performed in NRK cells, inflammatory cytokines, IL-1β and IL-6, caused increases in apelin receptor transcripts and decreased apelin transcripts, respectfully. The literature describes inflammatory processes that contribute to degradation of many organs (kidneys, heart, and liver) suggesting an oxidative imbalance. To investigate this imbalance within CRS4, three rat cell types’’ H9c2 cardiomyocytes, HII4E hepatocytes, and NRK renal epithelial cells” will be used to assess the role of exogenous apelin on pro- and anti-oxidant levels. Cells will be pretreated with apelin or vitamin E 48 hours prior to the addition of toxins or cytokines (uremic: uric acid and d-galactose or hydrogen peroxide; cytokines: IL-1β and IL-6), to assess pro- and anti-oxidant protein levels via Western Blot. RESULTS/ANTICIPATED RESULTS: We anticipate with toxin or cytokine addition (either uremic, hydrogen peroxide, IL-1β or IL-6) in all cell types, an increase in protein levels for GPX’‘ a known measure of oxidative stress’‘ should be greater than the increases in antioxidants’‘ SOD1 and Catalase. After pre-treatment of vitamin E, GPX protein levels should decrease compared to toxin/cytokine control, while SOD1 and catalase protein levels increase; this coincides with vitamin E inducing antioxidant activity in animals and humans. The anticipated results for this study after exogenous apelin addition should reveal in all three cells types reduced levels of GPX and increased levels of SOD1 and Catalase comparable to the vitamin E treatment. DISCUSSION/SIGNIFICANCE OF FINDINGS: If addition of apelin causes an antioxidant response in all three cells types, this can build on evaluation of the APJ system as a therapeutic option for those with CKD and CRS4 to minimize both inflammatory and oxidative stress. With the data gathered here, we expect to recreate the results in a CKD rat model that highlights these same manifestations.
39800 Immune Checkpoint Blockade during Periprosthetic Joint Infection
Authors: Warren Shay , Charville Greg , Amanatullah Derek
Published: March 2021

ABSTRACT IMPACT: If immune checkpoint blockade increases bacterial clearance with or without antibiotics in vitro, clinical application would be almost immediate and dramatic creating a seismic shift in the current therapeutic paradigm of periprosthetic joint infection. OBJECTIVES/GOALS: Periprosthetic joint infection (PJI) is a major cause of failure after joint replacement. Currently, the treatment of PJI relies on removing biofilm contaminated implants. Some of the bacteria within biofilm undergo a phenotypic shift becoming small colony variants (SCVs). SCVs induce local immunosuppression through PD-1/L1 signaling. METHODS/STUDY POPULATION: We will infect cultured human macrophages and bone marrow aspirate with stable Staphylococcus aureus SVCs and treat with anti-PD-1 or anti-PD-L1 monoclonal antibodies with and without antibiotics (e.g., gentamycin, cefazolin, vancomycin, rifampicin) and assess the residual bacterial viability. We will utilize multiplexed ion beam imaging to quantify PD-1/L1 expression in human tissue from patients with a chronic PJI and compare those to patients undergoing an aseptic revision. Patients with a chronic PJI are likely to have increased expression of PD-1/L1 as their tissue samples are prospectively screened. RESULTS/ANTICIPATED RESULTS: SCVs reduce the phagocytic activity of macrophages and can survive intracellularly. SCVs also induce anti-inflammatory M2-macrophage polarization and recruit a heterogeneous group of immature monocytes and granulocytes called myeloid-derived suppressor cells (MDSC) to the periprosthetic microenvironment. M2-macrophages and MDSCs then produce an immunosuppressive cytokine milieu characterized by increased IL-10 and decreased TNF-α. Clinically isolated SCVs up-regulate the expression of PD-L1 and PD-L2 on the surface of macrophages, representing a mechanism by which SCVs induce host immunosuppression and survive immune clearance. Our preliminary data show PD-L1 expression during septic PJI, but not in aseptic revisions. DISCUSSION/SIGNIFICANCE OF FINDINGS: If immune checkpoint blockade is shown to increase bacterial clearance with or without antibiotics, host immunomodulation would represent a novel class of therapeutic adjuvants to assist surgical debridement and antibiotic administration that could be superimposed on existing treatment algorithms to improve PJI related outcomes.
56371 The Signaling Axis of Tumor Suppressor LKB1 in Triple Negative Breast Cancer
Authors: Nguyen Khoa , Alzoubi Madlin , Hebert Katherine , Cheng Thomas , Elliott Steven , Burow Matthew , Collins-Burow Bridgette
Published: March 2021

ABSTRACT IMPACT: Identifying an important pathway in treatment resistant TNBC will allow for the future development of clinical therapeutics specific for this disease. OBJECTIVES/GOALS: Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer characterized by negative expression of estrogen receptor, progesterone receptor, and HER2/neu amplification. It resists therapies and has a high recurrence rate after resection. The goal of my research is to identify & characterize a TNBC pathway for future development of therapies. METHODS/STUDY POPULATION: The project uses a combination of cell lines, patient derived xenograft (PDX) models, as well as patient databases. Standard cellular and molecular biology techniques will be used including: Cell culture, qPCR, western blotting, and flow cytometry. RESULTS/ANTICIPATED RESULTS: LKB1 is a master kinase that activates 14 possible downstream kinases. The signaling pathway has been demonstrated to play a role in energy homeostasis and metabolism. Mutation of LKB1 signaling results in Peutz-Jeghers Syndrome and is associated with neoplasias of the lung, pancreas, and breast. Based on preliminary analysis, overexpression of LKB1 by shRNA in TNBC cell lines results in suppression of EMT and reduction of the cancer stem cell population. Additional studies show that LKB1 overexpression has no effect on growth rate in 2D culture while significant reduction in 3D mammosphere formations can be seen. Downstream studies using commercially available SIK1 inhibitor HG-9-91-01 is able to induce a larger fraction of CSC from reduced LKB1 overexpression as well as from baseline levels. DISCUSSION/SIGNIFICANCE OF FINDINGS: Overall, our results suggest that LKB1 acts through SIK1 to suppress EMT and the generation of cancer stem cells. This results in reduced cancer functionality, as evidenced by inhibition of mammosphere formation. These results establishes a foundation for future mechanistic studies on the LKB1 axis and its mechanisms in TNBC.
59821 Brain Mapping Addiction
Authors: Evans Brianna Brie , Ballard Sarah , Newmaster Kyra , Kim Yongsoo , Grigson Sue
Published: March 2021

ABSTRACT IMPACT: Gaining a better understanding on the role of opioids in opioid use disorder (OUD) can help us find better diagnostics, treatments, and procedures to treat the disorder. OBJECTIVES/GOALS: While we are familiar with brain areas and pathways that are implicated in opioid use disorder (OUD), we do not have a full understanding of the neural circuits activated upon drug exposure. METHODS/STUDY POPULATION: In order to identify areas of the brain most activated by opioids, we ran a pilot study using transgenic cFos-GFP mice that were injected with saline or heroin and examined the brain-wide activity patterns using a quantitative high-resolution mapping method. We observed many brain regions highly activated upon drug exposure. To examine cFos based brain activation in rats, we also ran a pilot study using a tissue clearing and 3D immunolabeling method combined with light sheet microscopy. RESULTS/ANTICIPATED RESULTS: We would expect to see higher cFos activation for brain areas in the reward pathway [including the Nucleus Accumbens (NAc), Ventral Tegmental Area (VTA), Prefrontal Cortex (PFC)] in heroin animals compared to saline animals. We can also expect higher activation in more novel areas like the lateral hypothalamus. DISCUSSION/SIGNIFICANCE OF FINDINGS: If we are able to track OUD effects through imaging in mice and rats, this can help us find better diagnostics, therapeutics, and procedures to treat the disorder. We can also eventually have a human brain atlas that outlines these affected areas as well in order to gain a better understanding on OUD particularly in the human population.
72399 Epigenetic Modification of Macrophages Contribute to Protective Memory in Against Staphylococcus aureus
Authors: Pellegrini Mateo , Chan Liana C. , Farrell Colin , Filler Scott G. , Lee Hong , Fowler Vance G. , Reed Elaine F. , Yeaman Michael R.
Published: March 2021

ABSTRACT IMPACT: This work may provide new targets for vaccine and immunotherapeutic development against MRSA infections. OBJECTIVES/GOALS: Staphylococcus aureus is the leading cause of skin and skin structure infection (SSSI), a primary portal of entry for invasive infection. Patients with SA SSSI have a high 1-year recurrence. We have shown innate memory protects mice against SA SSSI. The goal of this project is to determine epigenetic mechanisms of protective memory against SA SSSI. METHODS/STUDY POPULATION: We have shown macrophages (Mf) afford protective memory against recurrent SA SSSI in mice. Priming by prior infection reduced skin lesion size and MRSA burden, which correlated with increased Mf in abscesses and lymph nodes. Priming potentiated the opsonophagocytic killing of SA by bone-marrow derived Mf (BMDM) in vitro, and their adoptive transfer into naive skin afforded protective efficacy in vivo. Here, we investigated epigenetic mechanisms of anti-SA efficacy in BMDMs. BMDM from naive (uninfected) or primed (SA SSSI) wild-type C57Bl/6 mice were cultured ex vivo. DNA from BMDM groups were isolated and analyzed for methylation changes using reduced representation bisulfite sequencing (RRBS). Pathway analyses of methylation changes were determined with Panther. RESULTS/ANTICIPATED RESULTS: Present findings indicate the protective memory afforded by BMDM was mediated by epigenetic modifications of the DNA. Using RRBS, we profiled differentially methylated regions (DMR) in DNA from naive vs. primed BMDM. Primed BMDM exhibited significantly different DMRs as compared to naive BMDM. Proximity to known genes were mapped using GREAT. Pathway analyses revealed DMRs predominant in genes integral to immune modulation, such as integrin signaling, cytokine/chemokine networks, and growth regulation. For example, SA-primed BMDM were hypermethylated proximate to GIMAP8 versus naive BMDM, suggesting repression of this protein. Gimap family ligands are small GTPase immune-associated proteins expressed in immune cells known to regulate macrophage lysosomal fusion during parasite infection. DISCUSSION/SIGNIFICANCE OF FINDINGS: These findings reveal epigenetic mechanisms of macrophage innate memory against recurrent MRSA infection. Functional testing of these genes in response to SA infection is needed to confirm their protective role. These insights may provide new targets for vaccine and immunotherapeutic development against MRSA.
91074 Identification of monoclonal antibodies with broad reactivity against the malaria parasite variant surface antigen responsible for severe malaria
Authors: Reyes Raphael , Turner Louise , Ssewanyana Isaac , Rek John , Greenhouse Bryan , Bol Sebastiaan , Lavstsen Thomas , Bunnik Evelien M.
Published: March 2021

ABSTRACT IMPACT: This study aims to provide insight into naturally acquired immunity against severe malaria, thereby laying the foundation for the design of novel vaccine candidates to prevent severe disease as well as monoclonal antibody therapies to treat severe malaria. OBJECTIVES/GOALS: Severe malaria is caused by parasite surface antigens that contain high sequence diversity. Nevertheless, P. falciparum-exposed individuals develop antibody responses against these antigens. Our goal is to isolate antibodies with broad reactivity to understand how disease protection is acquired. METHODS/STUDY POPULATION: Our study cohort consists of Ugandan adults living in a malaria-endemic region with high transmission intensity, who are protected against severe malaria. Using fluorescently labeled probes of parasite surface antigens, we have isolated antigen-specific B cells from these donors. We then expressed the corresponding monoclonal antibodies in vitro. These antibodies were screened against a library of variant surface antigens to determine antibody breadth and potential to inhibit interaction of the parasite surface antigen with host receptors, a critical step in pathogenesis. Additionally, using a panel of variant surface antigen mutants, we have predicted the epitopes targeted by the broadest monoclonal antibodies. RESULTS/ANTICIPATED RESULTS: We have identified three monoclonal antibodies with exceptionally broad reactivity and inhibitory activity against our panel of severe disease-inducing variant surface antigens. We have identified two major sites targeted by these broadly reactive antibodies. The first site was associated with the largest breadth, but limited inhibitory potential, while the second site showed high-affinity antibody binding and inhibition of receptor binding. Interestingly, two of these three antibodies were very similar in structure, even though they were isolated from different donors. Isolation of antigen-specific B cells from additional donors will enable us to identify how common such broadly reactive antibodies are and allow the identification of additional epitopes DISCUSSION/SIGNIFICANCE OF FINDINGS: This study is the first to isolate broadly reactive antibodies that are likely to protect against severe malaria in naturally immune individuals. Further characterization of antibody-antigen interactions will inform the development of this surface antigen as a vaccine candidate for malaria.
84357 A TL1 Team Approach to Integrating Mathematical and Biological Models to Target Myeloid-Derived Immune Cells in Glioblastoma
Authors: Takacs Gregory P. , Anderson Hannah , Kreiger Christian , Luo Defang , Rong Libin , Stepien Tracy , Harrison Jeffrey K.
Published: March 2021

ABSTRACT IMPACT: Predicting therapeutic responses in GBM. OBJECTIVES/GOALS: The goal of this team approach is to integrate mathematical models of glioblastoma (GBM) infiltrating myeloid cells that contribute to the immunosuppressive phenotype in glioma with experimental data to predict therapeutic responses to combined chemokine receptor and immune checkpoint blockade. METHODS/STUDY POPULATION: Orthotopic murine KR158-luc gliomas were established in fluorescent reporter CCR2WT/RFP CX3CR1WT/GFP mice. Subsequently, an anti-CD31 injection was administered to label the vasculature. Fluorescent imaging and quantification of anti-CD3 stained sections were performed on a range of tumor sizes to acquire vasculature, tumor, T cell, and myeloid cell densities. In parallel, a system of ordinary differential equations was formulated based on biological assumptions to evaluate the change over time of tumor cells, T cells, and infiltrating myeloid cells. The model was then refined and validated by experimental results. RESULTS/ANTICIPATED RESULTS: Fluorescent imaging and quantification revealed a correlation between tumor size and abundance of (CX3CR1+, CCR2-) and (CX3CR1+, CCR2+) myeloid cell populations in the tumor microenvironment. The density of these cell populations and vasculature remained constant as the tumors increased in size. Computer simulations of the mathematical model will predict tumor, myeloid, and T cell dynamics. These simulations will be particularly useful to uncover information regarding myeloid cell dynamics, such as cell entry time into the tumor microenvironment. Parameter sensitivity analysis of the model will inform us of the biological processes driving these tumor-immune cell dynamics. DISCUSSION/SIGNIFICANCE OF FINDINGS: GBM is a challenge as current intervention are ineffective. This study improves the understanding of glioma infiltrating myeloid cells and their impact on tumor progression. The data will serve as a basis for quantitatively predicting therapeutic responses of a novel combination treatment.
44613 Plan for a Retrospective Evaluation of a Multi-Modal Weight-centric Prediabetes Intervention
Authors: Manalac Raoul , Stewart Tiffany , Ryan Donna
Published: March 2021

ABSTRACT IMPACT: By demonstrating the feasibility of a multimodal, interdisciplinary intervention for prediabetes, the current project aims to provide a template for the prevention of diabetes and associate comorbid conditions. OBJECTIVES/GOALS: To determine if a multi-modal, interdisciplinary intervention delivered to a group of prediabetic patients will result in reduced rates of diabetes progression. This project is a retrospective evaluation that will exam the feasibility and possibly efficacy of this intervention. METHODS/STUDY POPULATION: We will enroll 50 participants for the clinic, aged 21-60 inclusive. Patients will have a Body Mass Index >27kg/m2 with a diagnosis of prediabetes. Patients must be non-pregnant, using approved contraception, and agree to not become pregnant for 1 year after enrollment. After enrollment, the initial treatment period is for 1 year and includes a 12 week low calorie diet plan, a 6-month intensive behavioral and lifestyle modification plan followed by a 6 month behavior reinforcement extension. Weight management medications may be used if appropriate for the patient from a clinical perspective during the 6-month intensive behavioral/lifestyle modification. RESULTS/ANTICIPATED RESULTS: It is anticipated that there will be decreased weight with a mean weight loss goal of approximately >10%. Furthermore, it is expect that there will be improvement of other markers of metabolic disease. These include improvement of lipid values (LDL-C, HDL-C, Triglycerides, Total Cholesterol) as well as blood pressure with expected blood pressures of below 130/80 in greater than 50% of participants. Finally, It is expected that 50% or greater participants will have improvement of glycemic control. It is anticipated that greater than 50% of participants will have improvement of glycemic control and achieve normoglycemia. These values will be determined based upon fasting glucose or A1c. DISCUSSION/SIGNIFICANCE OF FINDINGS: The significance of this intervention is enormous. By demonstrating feasibility in this trial, we can work toward both assessing efficacy and possibly dissemination of this model program. If these interventions provide durable changes at scale, this could help slow the epidemic of obesity and obesity related comorbid conditions.
31115 Perimetric resilience in the retina: spatial distribution of preserved peripheral visual field loci in retinitis pigmentosa
Authors: Vongsachang Hursuong , Patel Tapan , Kong Xiangrong , Singh Mandeep S.
Published: March 2021

ABSTRACT IMPACT: We developed a novel semi-automated computational platform to quantify spatial characteristics of preserved peripheral visual field loci in retinitis pigmentosa. This work may inform future research on therapies to prevent visual field loss in retinitis pigmentosa and related diseases. OBJECTIVES/GOALS: Retinitis pigmentosa (RP) causes progressive and severe peripheral visual field (pVF) loss in some but not all patients. The characteristics of pVF in RP are incompletely understood. We developed a novel semi-automated computational platform to quantify the spatial characteristics of pVF. METHODS/STUDY POPULATION: We analyzed preserved pVF size and location in both eyes of RP patients using the Goldmann V4e isopter. We developed a custom algorithm in MATLAB to align and average the binary V4e isopter segmentations, and generated a two-dimensional probability map of the spatial distribution of preserved pVF loci along the radial and circumferential dimensions. To adjust for disease duration, cases were categorized by the time from self-reported symptom onset. Probability maps of pVF preservation were generated for categories of disease duration using unsupervised K-means clustering. Analyzing cases with longitudinal data, we identified loci of stable pVF over time. RESULTS/ANTICIPATED RESULTS: A total of 152 patients were included (N=304 eyes). The mean age was 46.7 years and 49.3% were male. Disease duration was categorized as <20 years (N=72, 47.4%), 20-40 years (N=60, 39.5%), or >40 years (N=20, 13.2%). Longitudinal data (3.2 -5.7 years of follow-up) were available in 65 patients (42.8%). Probability plots of preserved pVF loci in the cross-sectional dataset showed that the median percentage of preserved pVF loci were located between 50 ºand 80 ºeccentricity and between the 30 ºto 50 ºmeridians, with highly concordant inter-ocular symmetry. Probability plots in the longitudinal dataset showed that inferotemporal pVF loci were most likely to be preserved over time. DISCUSSION/SIGNIFICANCE OF FINDINGS: Semi-automated quantification of pVF loci is a useful platform to analyze spatial characteristics of the visual field in RP. Certain portions of the pVF may be relatively resistant to functional decline. Understanding the molecular basis of pVF resilience will inform further research on RP therapy.
21614 Use of an Outcomes Continuum to Describe Disparities in CVOID-19: Data from the OneFlorida Research Consortium
Authors: Dasa Osama , Cohen Scott , Sajdeya Ruba , Zheng Yi , Taha Mohamad B. , Pearson Thomas A.
Published: March 2021

ABSTRACT IMPACT: Identifying differential COVID-19 progression across the disease continuum may help policymakers and service providers better identify or predict gaps in services and resources and develop precision strategies to support COVID-19 patients where the need is mostly needed. OBJECTIVES/GOALS: Single institution studies have documented COVID-19 disproportionally affected US racial and ethnic minority groups compared to Whites. However, few population-wide data studied severity and death in multiracial populations. We aim to examine the current disparity in the COVID-19 continuum, including hospitalizations, severity, and death. METHODS/STUDY POPULATION: Data on 67,094 laboratory documented COVID-19 cases nested from the state-wide ‘OneFlorida’ research consortium through August 3, 2020, were assessed to decide differences and disparities in COVID-19 outcomes. A COVID-19 outcome continuum outlining the proportions of cases transitioning from diagnosis to death was constructed (Figure 1). OneFlorida partners provide health care to more than 40% of Floridians in the nation’s third-largest and very diverse state. OneFlorida partners encompass hospitals, practice/clinic settings, and physicians, which provide care for 15 million patients across all of Florida’s 67 counties. It is part of the Patient-Centered Outcomes Research Institute (PCORI). RESULTS/ANTICIPATED RESULTS: Among cases, 25,443 (37.9%) were non-Hispanic Whites, 11,709 (17.5%) were non-Hispanic Blacks, and 16,119 (24.0%) were Hispanics. Among COVID-19 patients, Blacks and Hispanics had a higher frequency of emergency department (ED) visits (45.7% and 46.0%, respectively), whereas admission rates were higher in Blacks (15.6%) and Whites (15.9%) than in Hispanics (11.5%). Blacks had the highest rates of intubation (3.6%) and in-hospital deaths (2.7%) compared to Whites (2.5% and 2.3%, respectively) and Hispanics (1.3% and 1.4%, respectively), Figure 1. When rates were indexed to the state census data, Blacks had the worst rates across the disease continuum (infection to death). In comparison, Hispanics had higher rates of ED visits but lower rates of intubation and death, Table 1. DISCUSSION/SIGNIFICANCE OF FINDINGS: Outcomes continuum is a useful tool at an individual-level to assess care outcomes and at population-level as a framework to analyze the proportion of population with COVID-19 that progress to each successive disease stage. This will help policymakers to better identify gaps in services and develop precision strategies to support COVID-19 patients.
11010 The diagnostic accuracy of procalcitonin for urinary tract infection in hospitalized older adults
Authors: Choi Justin , Meltzer Kerry , Cornelius-Schecter Anna , Jabri Assem , Simon Matthew , McCarthy Matthew , Westblade Lars , Mehta Saurabh , Zhao Zhen , Glesby Marshall
Published: March 2021

ABSTRACT IMPACT: This work seeks to improve the diagnostic accuracy of urinary tract infection among hospitalized older adults and mitigate antibiotic overuse in this population. OBJECTIVES/GOALS: Primary objective: To determine the diagnostic accuracy of serum procalcitonin (PCT) for the diagnosis of symptomatic urinary tract infection (UTI) in hospitalized older adults. Secondary objectives: (1) To develop a predictive model for the diagnosis of UTI; (2) To determine the ability of PCT in discriminating between lower and upper UTI. METHODS/STUDY POPULATION: We performed a prospective observational cohort study of 228 participants from a single institution. The study population included older adults (age 65 or older) who were hospitalized on the general medicine wards with a possible or suspected urinary tract infection (UTI). Upon obtaining informed consent, serum procalcitonin (PCT) was processed on remnant blood samples collected from the emergency department. We performed additional data collection through the electronic health record to obtain demographic information, clinical characteristics, and other laboratory and imaging results. Clinicians were surveyed for the diagnosis of UTI and charts were adjudicated by independent reviews of the medical record by infectious diseases experts to determine the primary endpoint of symptomatic UTI. RESULTS/ANTICIPATED RESULTS: We anticipate that serum procalcitonin predicts the presence of symptomatic urinary tract infection (UTI) by demonstrating an area under the receiver operating characteristic curve of at least 0.85. A predictive model developed in our cohort for the diagnosis of symptomatic UTI will be improved by the addition of serum PCT to the prediction model. Finally, we anticipate the serum PCT will accurately discriminate between upper and lower UTI. DISCUSSION/SIGNIFICANCE OF FINDINGS: Diagnosis of symptomatic UTI in hospitalized older adults is challenging and may lead to overuse of antibiotics and the development of antibiotic resistance in this vulnerable patient population. Serum procalcitonin offers a novel diagnostic strategy in the diagnosis of symptomatic UTI to enable more appropriate antibiotic therapy.
75200 Fecal Microbiota Transplantation to Prevent Infections in Patients with Acute Myeloid Leukemia: A Double-Blind Randomized Placebo-Controlled Phase 2 Clinical Trial
Authors: Ebadi Armin Rashidiryam , Ur Rehman Tauseef , Nalluri Harika , Kaiser Thomas , Holtan Shernan G. , Khoruts Alexander , Weisdorf Daniel J. , Staley Christopher
Published: March 2021

ABSTRACT IMPACT: By restoring the gut microbiota in patients with acute myeloid leukemia exposed to antibiotics, we will reduce infections during and after curative-intent chemotherapy. OBJECTIVES/GOALS: Infection is a leading cause of death in acute myeloid leukemia (AML). Antibiotics disrupt the gut microbiota, promoting secondary infections. Through a double-blind randomized placebo-controlled phase 2 trial, we will determine whether microbiota restoration using fecal microbiota transplantation (FMT) prevents infections in AML patients. METHODS/STUDY POPULATION: 72 intensively treated AML patients at our institution are randomized in a 2:1 ratio to FMT (arm A) or placebo (arm B). After completing each course of antibacterial antibiotics, patients receive one study treatment. Up to 3 study treatments are administered over 3 months. FMT is delivered as a third-party oral product containing microbiota (˜5x10^11 bacteria) in 4-6 capsules. Stool samples are collected before and after each study treatment. The primary endpoint is 4-month overall infection rate. 16S rRNA gene sequencing of stool samples is used to determine specific taxa that are under- or over-represented in samples preceding infections and compare the two arms for key microbiome features including diversity and composition. Bloodstream infection within 7 days after FMT counts towards stopping rule. RESULTS/ANTICIPATED RESULTS: Five patients have been enrolled: 4 have received 1 dose and 1 received 2 doses. The only adverse event (possibly related to study treatment) has been grade 1 abdominal pain in 1 patient. Notably, no bloodstream infection has occurred. All planned samples have been collected and are sequenced in batches. We expect arm A patients to experience fewer infections and fewer intestinal blooms of pathobionts, and both arms to experience intestinal blooms before specific infections. An interim efficacy analysis will be performed at half total enrollment. DISCUSSION/SIGNIFICANCE OF FINDINGS: Current supportive care during intensive chemotherapy is fundamentally anti-microbial and results in dysbiosis, with detrimental consequences. We will establish the evidence for FMT as a restorative strategy in AML patients. This is the first randomized placebo-controlled trial of repeated FMT, with potential implications to other cancers.