2022 ICTS Symposium Poster Abstracts

2022 ICTS Symposium graphic
Early Stage
Poster #Poster Details
1Ali, Lina
Washington University in St. Louis
Characterizing the Genetic Factors Driving Rheumatoid Arthritis Inflammatory Interactions Using an SF-Chondrocyte Co-Culture Model
Ali L, Patel P, Vakaki M, Kremitzki C, Waligorski J, Chadrasekaran V, Kelley K, Bachman G, Buchser W
  • Introduction: Rheumatoid arthritis (RA) is an autoimmune joint-debilitating disease caused by genetic and environmental factors and affects more than 1 million Americans today. Studies have characterized several mechanisms for RA onset, identifying cytokines like IL-1, IL-2, and IL-6, as well as different receptors, as important in guiding the degrading cellular interactions in the articular microenvironment. Additionally, chondrocytes and synovial fibroblasts (SFs) have been gaining more interest for their unique morphologies and interactions with each other, however, there is yet to be a study on the genetic basis of these cell-cell interactions. This project aims to create a two-cell model of chondrocytes and RA SFs in an inflamed articular environment, as well as to examine how genetic perturbations affect SF-chondrocyte cellular interactions.
  • Methods: CRISPRi, will be used to knock down implicated genes on SFs in a co-culture. This is followed by confocal microscopy and cellular image analysis to determine the functional effect of genes of interest on cell-cell interactions that may affect RA articular inflammation.
  • Results: We anticipate to identify a number of genetic mutations which we observe to have a significant effect on the cellular interaction of SFs with chondrocytes in our co-cultures. These mutations will be examined in the presence of inhibitory drugs to verify their stimulatory inflammatory effect in an articular RA microenvironment.
  • Impact: Identifying the genes whose mutations we observe and verify have significant effects on the SF-chondrocyte intercellular interaction is important in guiding more targeted RA research and therapy.
2Cifarelli, Vincenza PhD
Washington University in St. Louis
PET Imaging Cardiac Inflammation in CD36-deficient Individuals
Cifarelli V, Liu Y, Abumrad NA, Gropler RJ
  • Introduction: Our study will assess myocardial inflammation in individuals with dysfunctional lipid metabolism using a novel non-invasive positron emission tomography (PET) imaging approach. Fatty acid (FA) translocase CD36 regulates myocardial FA uptake, remodeling and inflammation. CD36 deletion in rodents associates with atrioventricular block and bradycardia; and risk of sudden death following prolonged fasting. In humans, reduced or absent myocardial FA uptake is reported in people with CD36 variants that reduces protein levels. However, CD36 role in myocardial inflammation and remodeling, its contribution to heart disease, and whether preventive treatment strategies should be used in this population remain controversial due to lack of clinical studies.
  • Methods: Our studies will focus on carriers of the CD36 variants exclusive to African Americans. Targeted imaging of CCR2 positive proinflammatory monocytes/macrophages using PET/CT will be used. Freshly isolated circulating monocytes will be analyzed by flow cytometry.
  • Results: We hypothesize that partial or total CD36-deficient individuals are at higher risk of myocardial inflammations as compared to BMI-matched non-carrier individuals.
  • Impact: The study presents basic, translational and public health impact.
    Biological Factors and products: This will be the first molecular imaging study assessing myocardial inflammation in obese individuals with CD36-deficiency and will provide a more integrative understanding of how immune cell subsets, CCR2 positive, drive myocardial inflammation during dysfunctional lipid metabolism. 
    Biomedical Technology: Targeted PET tracer is a non-invasive imaging tool with the great potential to assess real-time trafficking of immune cells in the heart and to help identify immune-modulatory therapies.
    Disease prevention and reduction: Establish risk stratification for cardiac inflammation based on genetically determined CD36 deficiency.
    Public Health Practices: The proposed molecular imaging studies will be the first one conducted in CD36-deficient African Americans, who are at a higher risk of developing cardiovascular abnormalities from metabolic diseases.
3Detering, Lisa MS
Washington University in St. Louis
Assessment of CCR2 PET for Abdominal Aortic Aneurysm Rupture Prediction and Determination of Treatment Response
Detering LM, Sastriques S, Heo GS, Sultan DH, Luehmann HP, Arif B, Benedetto SE, Lin C, Laforest R, Gropler RJ, Zayed M, English S, Liu Y
  • Introduction: Abdominal aortic aneurysms (AAA) are a life-threatening degenerative vascular disease without any effective medical therapy or imaging approach to predict the risk of rupture. AAAs occur later in life and are especially prevalent in men over the age of 65, but are more likely to rupture in women. Previously, we evaluated the efficiency of chemokine receptor 2 (CCR2) targeting tracer Cu-DOTA-ECL1i for imaging the AAA expansion and rupture in male rats. Here, we established an AAA rupture model in rats, and evaluated how sensitive our CCR2 tracer can predict AAA expansion and rupture.
  • Methods: A surgical AAA induction model in rats of intra-aortic exposure to pressurized PPE was used. AAA rupture was stimulated by the administration BAPN. CCR2 antagonist was given via oral gavage at day 3 post AAA induction. Dynamic CCR2 PET/CT scans were performed in both antagonist treated and untreated AAA rats. Histopathology, immunostaining, tissue zymography, and ELISA techniques were used to evaluate AAA tissue post-mortem.
  • Results: Compared to rats with non-ruptured AAAs, CCR2 tracer uptake was significantly higher in ruptured male and female AAAs with no difference determined in the diameter of aneurysms. CCR2 inhibition significantly decreased the rupture rate for all the AAA rats at day 14 post treatment, as well as the CCR2 PET signals. Histopathology of treated AAA rats showed reduced inflammation, preserved elastic layers, minimal VSMC loss, and compensatory medial hypertrophy. Immunostaining showed decreased CD68+ macrophages and CCR2 expression. In AAA patients, Cu-DOTA-ECL1i PET/CT showed significant uptake in the aneurysm while low tracer retention was determined in healthy volunteers. Ex vivo human AAA tissue characterization demonstrated the elevated expression of CCR2.
  • Impact: This project is diagnostic and investigative. CCR2 PET/CT signal appears to predict AAA risk of rupture in both sexes of rats, and may provide a basis of enhanced AAA surveillance in human patients with AAAs that are prone to rupture. The sensitive detection of CCR2 indicates the potential of Cu-DOTA-ECL1i for AAA theranostics.
4Djune Yemeli, Linda
Washington University in St. Louis
Immunologic Response to Ivermectin Treatment of Loiasis
Djune Yemeli L, Nana-Djeunga HC, Rush A, Kamgno J, Budge P
  • Introduction: Loiasis related post-ivermectin (IVM) adverse events (AEs) hinder lymphatic filariasis (LF)/onchocerciasis elimination in co-endemic areas. Findings from LF suggest that post-IVM AEs might be the result of immune responses to filarial or Wolbachia antigens released by dying microfilariae (Mf). The aim of this study was to determine whether IVM treatment of loiasis, devoid of Wolbachia, generates similar immunologic responses and to assess if specific loa antigens are involved in this process.
  • Methods: Thirty-nine loiasis infected patients with daytime Mf counts between 3,720-16,020 (median: 8,600; IQR 5,580-11,980), were enrolled in Central Cameroon. After receiving 150µg/Kg IVM, they were followed-up daily for seven days. Blood was collected before treatment and 8, 16-, 32-, 40-, and 56-hours post-treatment for Mf count, circulating filarial antigen (CFA) quantification/identification and measurement of serum immune mediators. CFA levels were quantified using in-house direct sandwich ELISA and cytokines levels measured using the Bio-Plex Pro Human Cytokine 27-plex Assay.
  • Results: Daytime L. loa Mf counts decreased post-treatment by ~75% (median: 1,860, IQR: 1,155-2,910) by 56hrs. A subset of participants developed detectable CFA post-treatment, with the highest levels at 56hrs. Fifteen of 27 assayed cytokines significantly increased post-treatment (MIP-1b, MIP-1a, Eotaxin, FGF-b, MCP-1, TNF-a, INF-g, G-CSF, GM-CSF, IP-10, IL-1ra, IL-8, IL-10, IL-13, and IL-17), with a peak level at 32hrs. Conversely, RANTES, PDGF-BB, IL-2, IL-4 and IL-7 transiently increased post-treatment but then decreased lower than baseline levels by 56hrs. Unlike previous findings from LF, no significant association was found between cytokines levels and baseline Mf counts. No serious treatment-emergent AEs were observed; in fact, participants reported fewer AEs post-treatment that at baseline, despite baseline Mf counts much higher than those typically seen in LF.
  • Impact: These data suggest that different mechanisms may be involved in the immune response to IVM treatment of loiasis vs. LF, and are consistent with a role for Wolbachia antigens in initiating treatment-emergent AEs in LF.
5Joshi, Trupti MBBS, PhD
University of Missouri – Columbia
Integrative Analysis of DNA Methylation and RNA-seq Data for Biomarker Detection of Endometriosis
Joshi T, Akter S, Bromfield J, Pelch K, Wilshire G, Crowder S, Schust D, Barrier B, Davis W, Nagel S
  • Introduction: Endometriosis, a complex and common gynecological disorder affecting 5-10% of reproductive-age women, is characterized by the growth of endometrial tissues outside of the uterine cavity. About 176 million women worldwide suffer from endometriosis. The current diagnostic process is laparoscopy, which is a risk-associated and costly invasive procedure. On average it takes 10 years to reach a diagnosis of endometriosis. As such, early intervention is crucial to manage the disease and reduce adverse effects.
  • Methods: Both DNA-methylation data and RNA-seq data have the potential to uncover molecular mechanisms of diseases. Tissue samples were collected from 80 patients consisting of control and endometriosis patients. The tissues were processed for enrichment-based DNA methylation and RNA-seq data collection. We used the generalized linear model for Differentially Methylated Region (DMR) and Differentially Expressed Gene (DEG) detection. The read count data from DNA-methylation and RNA-seq were concatenated into one big data matrix for predictive analytics. We used the Biosigner and the Decision Tree algorithm for integrative multi-omics analysis. Accuracy, sensitivity, and specificity were calculated to demonstrate the predictive performance and leave-one-out cross validation approach was used for this purpose.
  • Results: The Biosigner algorithm identified KBDBD2 as a biomarker that was previously reported to be associated with the endometrial cancer. The Decision Tree identified NOTCH3, STXBP5 as biomarker of endometriosis. The integrative model using Decision Tree outperformed both the models that were created using DNA methylation data and RNA-seq data, independently. The accuracy, sensitivity and specificity of the integrative model are 86.21%, 76.92% and 93.75%, consequently.
  • Impact: Application of multi-omics data integration methods allowed translation of the identification of biomarkers that are associated with endometriosis, but also show susceptibility to other diseases such as endometrial cancers.
6Li, Xiaowei PhD
Washington University in St. Louis
Antithrombogenic Sutureless Vaso-Lock for Vascular Anastomosis
Li X, Moritz W, Meade R, Kang S, Zayed M, Sacks J
  • Introduction: Micro- and macrovascular anastomoses involve suturing together of blood vessels, which is a critical foundational surgical skill. However, it is costly, time-consuming, and prone to complications. Our team has created a unique anastomotic device, Vaso-Lock, as a sutureless coupler. Vaso-Lock is intraluminal, holding free vascular ends together with traction by anchors. In terms of its clinical application, we will devise methods to provide long-term patency. We aim to characterize a surface-functionalization method for Vaso-Locks to facilitate endothelial cell affinity and antithrombogenicity; and test anastomotic and antithrombogenic efficacy of Vaso-Locks in a swine carotid-jugular arteriovenous loop model.
  • Methods: We utilized 3D-printing to prototype Vaso-Locks with quick design adjustments. We apply plasma treatment to modify Vaso-Locks to conjugate peptides or polysaccharides. Endothelial cell and platelet adhesion assays will be implemented to evaluate biocompatibility and hemocompatibility. Angiography and Doppler ultrasound will be used longitudinally to assess patency, blood flow velocities, and lumen preservation in a swine model. Histological studies will be performed for endothelialization and device-vessel interface biocompatibility.
  • Results: Vaso-Locks can be deployed in porcine carotid arteries within 1 minute in comparison to handsewn anastomosis for 1 hour. The Vaso-Lock displayed higher tensile strength than that of handsewn anastomosis. Surface-modified with adhesive peptides encouraged greater endothelial cell attachment. Anastomosis was successfully achieved in the arterio-venous anastomosis. Doppler ultrasonography confirmed venous and arterial blood mixing throughout Vaso-Locks. Survival studies are underway to assess long-term patency.
  • Impact: This project will not only develop a new device for vascular anastomosis, but establish an effective surface modification approach for antithrombogenicity and endothelium formation. Our unique framework can potentially be applied to all luminal structures, which will simplify complex surgical techniques, improve patient outcomes and safety, and make anastomosis more globally available and feasible.
7Nguyen, Andrew PhD
Saint Louis University
Developing Antisense Oligonucleotides Targeting MiR-29b Binding Site to Increase Progranulin Protein Levels for Frontotemporal Dementia
Nguyen AD, Aggarwal G, Banerjee S, Jones SA, Smith DM, Benchaar Y, Belanger J, Sevigny M, Pavlack M, Niehoff ML, de Vera IMS, Petkau TL, Leavitt BR, Ling K, Jafar-Nejad P, Rigo F, Morley JE, Farr SA, Dutchak PA, Sephton CF
  • Introduction: Frontotemporal dementia (FTD) is a devastating neurological disease with no approved treatment or cure. One common cause of FTD is heterozygous loss-of-function GRN mutations, which result in progranulin haploinsufficiency. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but ASO-based strategies for increasing target protein levels are limited. Several microRNAs (miRs), including miR-29b, negatively regulate progranulin protein levels. Here, we tested if ASOs that sterically block the miR-29b binding site in the GRN mRNA can increase progranulin levels.
  • Methods: We designed 48 ASOs targeting the miR-29b binding site in the 3′ UTR of the human GRN mRNA. We treated H4 neuroglioma cells and iPSC-derived neurons with these ASOs and subsequently measured progranulin protein levels by western blot and ELISA. We performed further studies to determine the ASOs’ mechanism of action using qPCR, ribosomal profiling, metabolic labeling, and FRET assays. Lastly, we tested the ASOs in vivo using a humanized GRN mouse model.
  • Results: We found 16 ASOs that increase progranulin protein levels in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin levels in iPSC-derived neurons and in the brains of mice. Ribosomal profiling experiments revealed that the ASOs increase progranulin translation. Consistent with this, ASO treatment increased levels of newly synthesized progranulin protein. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3′ UTR RNA. Together, our results demonstrate that ASOs can be used to increase target protein levels by partially blocking miR binding sites.
  • Impact: The results of our translational project suggest this ASO strategy may be a therapeutically feasible method for increasing CNS progranulin levels for progranulin-deficient FTD. This ASO strategy could also be applicable for other diseases of haploinsufficiency. The impact of this project may include enabling development of a drug for treatment of progranulin-deficient FTD, improving quality of life, and reducing societal and financial cost of illness.
8Parrow, Nermi PhD
Saint Louis University
Development of an HPLC-based Method for the Separation of Transferrin Forms in Murine Serum
Parrow NL, Violet PC, George NA, Levine M, Fleming RE
  • Introduction: Transferrin (Tf) is the primary iron binding protein in serum. It has two homologous lobes, N and C, that can each bind one iron molecule. Thus, Tf exists in four forms, apo-, monoferric N, monoferric C and holo-Tf. At physiologic Tf saturations, the monoferric Tfs are the predominant forms. Using mice genetically engineered to block iron binding in either the N or C lobe of Tf, we have shown that the monoferric Tfs differentially influence erythropoietin (Epo) responsiveness depending on which lobe contains iron. Anemia is a common comorbidity in chronic kidney disease (CKD). It is characterized by Epo hypo-responsiveness, which may be influenced by the specific lobe distribution of iron in Tf. Clinical analyses to investigate this possibility are pending. However, large-scale investigation has been difficult because only suboptimal techniques are available to separate the Tf isoforms from serum. We developed and are in the process of validating an HPLC-based assay for the separation of the four Tf forms from human serum. Parallel investigations using mouse models would be ideal. However, the methodology utilized to separate human Tfs does not provide adequate resolution for mouse Tfs. We hypothesize that murine Tf forms can be adequately resolved with modification of the HPLC assay developed for resolution of human isoforms.
  • Methods: To test this hypothesis, we investigated the effects of altering the pH of Buffer A in a strong anion exchange HPLC protocol on the resolution of the murine Tf forms.
  • Results: Results indicate progressively longer retention times with increasing pH, with improved resolution at pH 7.5 producing four discernable peaks corresponding to the four forms of Tf in mouse serum. Tentative peak identification has been assigned by comparing the retention times of the Tfs with serum from wild-type and each of the monoferric mutant mice. Although increased pH improves resolution, additional optimization is required for full resolution of peaks.
  • Impact: Once achieved, this assay will provide a technique to investigate the influence of the monoferric Tfs on pathology in murine models of CKD and other conditions characterized by alterations in Epo responsiveness.

9Phillips, Charlotte PhD
University of Missouri – Columbia
Combined Inhibition of Myostatin and Activin A Enhances Femoral Microarchitecture and Strength in a Type I/IV Osteogenesis Imperfecta Mouse Model
Omosule CL, Joseph D, Weiler B, Gremminger VL, Jeong Y, Kleiner S, Phillips CL
  • Introduction: Current therapeutics for osteogenesis imperfecta (OI), a heritable connective tissue disorder characterized by skeletal fragility and impaired bone cell function, are limited to bisphosphonates. Soluble activin receptor type IIB (sActRIIB) decoy molecules, which bind transforming growth factor-β (TGF-β) ligands, including myostatin and activin A, have increased skeletal bone properties in murine models of OI, including the mild/moderate G610C mouse model of OI. However, the promiscuity of sActRIIB for multiple ligand targets resulted in adverse effects observed in clinical trials of boys with Duchenne muscular dystrophy and postmenopausal women with osteoporosis. We examined the musculoskeletal effects of inhibiting activin A alone, myostatin alone, or both in wildtype (Wt) and heterozygous G610C (+/G610C) mice using highly specific monoclonal antibodies to determine their role on postnatal musculoskeletal properties.
  • Methods: Male and female Wt and +/G610C mice were injected intraperitoneally twice weekly with monoclonal control antibody (Ctrl-Ab), anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab) or both ActA-Ab and Mstn-Ab (Combo,) from 5 to 16 weeks of age. Following euthanasia at 16 weeks of age, femoral microarchitecture and biomechanical strength was evaluated by microCT (µCT) and 3-point bend analyses.
  • Results: ActA-Ab had minimal effects on femoral microarchitecture in +/G610C mice, actually decreasing bone strength in male +/G610C mice, although Wt male mice exhibited increases in trabecular microarchitecture with ActA-Ab treatment. Mstn-Ab, as previously reported, had minimal skeletal impact in +/G610C mice. Conversely, the Combo treatment out-performed inhibition by ActA-Ab alone or Mstn-Ab alone, consistently improving femoral trabecular and cortical microarchitecture and strength in both male and female +/G610C and Wt mice.
  • Impact: Combinatorial inhibition of activin A and myostatin more potently increased femoral bone microarchitecture and strength relative to myostatin or activin A inhibition alone, and recaptured the skeletal improvements generated by sActRIIB treatment in +/G610C mice.
10Rai, Muhammad Farooq PhD
Washington University in St. Louis
Microgel Fabrication for Sustained Delivery of PRP to Treat Osteoarthritis
Rai MF, Choi HM, Blanco A, Duan X, Jain E, Case N, Sell S, Zustiak SP
  • Introduction: Osteoarthritis (OA) is a debilitating joint disease that affects 50+ million American adults. Current treatment options are not optimal. Platelet-rich plasma (PRP) is a promising option. However, when PRP is delivered intra-articularly, it is rapidly cleared from the joint, diminishing treatment efficacy. We hypothesize that a delivery vehicle that can sustain PRP release will improve therapy outcomes.
  • Methods: PRP-PEG microspheres were fabricated by mixing 4-arm PEG-acrylat, PEG-dithiol crosslinker, and lyophilized PRP (PRGF) in 0.3M triethanolamine. When this gel precursor solution was passed through a T-junction along with oil, PRP-PEG droplets were formed, collected in an oil bath and left to gel overnight. Microspheres were collected by centrifugation, washed and sieved through a 200 m nylon mesh. Polydispersity was calculated as % coefficient of variance (CV). Microsphere degradation was followed by measuring diameter. To gauge cumulative release, PRGF-PEG hydrogel slabs were placed in PBS and samples were taken at different time points until degradation. Chondrocytes isolated from human articular cartilage were cultured, pre-treated with TGFβ, proliferation was tested with PicoGreen and gene expression with qPCR. Powder PRP was loaded at 10% w/v. Infrared FluoroSphere-loaded PEG microspheres with or without PRP were injected into the mouse knee and retention was assessed by IVIS.
  • Results: PRP-PEG microspheres had smooth surface and narrow size distribution (7-25% CV). Microsphere diameter decreased with increased oil flow rate and decrease in PEG flow rate from 420 to 90 μm. Upon sieving, microspheres were injectable through a needle and retained structural stability upon injection. PRP was released over 11 d with 40% release. PRP-PEG releasate from hydrogel had beneficial effect on chondrocyte proliferation and expression of certain OA-related genes compared to bolus PRP. Microspheres were stable in synovial fluid for at least 72 h where degradation was faster than in PBS. Finally, PRP-loaded microspheres remained in the knee up to 42 d after injection.
  • Impact: Sustained delivery of PRP could be a transformative treatment for patients with OA.
11Shen, Hua PhD
Washington University in St. Louis
Extracellular Vesicles from Inflammation-primed Adipose Stem Cells Improve Tendon Healing Through Restoring Balanced Response Following Tendon Injury and Repair
Shen H, Lane R, Ray RB
  • Introduction: Tendon injuries are among the most common and challenging orthopedic conditions. Many patients suffer from long-term pain and reduced function primarily due to an imbalanced healing response with excessive inflammation and inadequate regeneration. We found that extracellular vesicles produced by inflammation-primed adipose stem cells (iEV) can attenuate inflammation. It remains to be determined if iEV can also promote tendon regeneration and functional recovery and the cellular and molecular mechanisms of iEV action during tendon healing. Therefore, this study investigated the mechanistic roles of iEV in tendon healing using a mouse Achilles tendon injury and repair model combined with cell-based assays.
  • Methods: iEV were prepared from conditioned medium of IFNγ-primed adipose stem cell culture and applied locally in mice subjected to 2/3 right Achilles tendon transection and repair. Tendon responses were assessed using live bioluminescence imaging, ankle function test, and gene expression and histological analyses. iEV cargos and functions were determined via RNA-seq and Taqman PCR analyses and cell-based assays.
  • Results: iEV dose-dependently reduced injury-site NF-κB activity at 1-week post-injury (wpi) and increased anti-inflammatory gene expression at 4 wpi. iEV enhanced ankle function by 64%, reduced postoperative complications by 35%, and improved repair-site collagen deposition at 4 wpi. iEV also blocked macrophage TLR4/NF-κB signaling and promoted tendon cell proliferation, anabolic gene expression, and type I collagen release. Consistently, iEV were enriched in an anti-inflammatory miRNA that blocks macrophage NF-κB activity. iEV also carried substantial mRNAs that promote cell proliferation and survival. The combined results demonstrated that iEV can both reduce inflammation and promote tendon regeneration and the effects of iEV are associated with their abilities in inhibiting macrophage inflammatory response and promoting tendon cell proliferation and collagen production via transferring regulatory miRNAs and mRNAs.
  • Impact: This is a critical proof-of-concept study toward clinical application of EV-based therapy for tendon injuries, which will benefit millions of patients.
12Wang, Yung-Chun PhD
Washington University in St. Louis
A Genome-wide Assessment of Non-coding Risk Variants in Cerebral Palsy
Wang YC, Fu PY, Wrubel M, Magee H, Liu J, Bakhtiari S, Shetty S, Norton B, Wegner DJ, Aravamuthan B, Gurnett CA, Pearson T, Baldridge D, Wambach JA, Cole FC, Kruer MC, Jin SC
  • Introduction: Cerebral palsy (CP) is the most common physical disability in childhood characterized by irreversible, non-progressive central motor dysfunction. Genetic factors, and environmental insults such as prematurity and hypoxia-ischemia, can contribute to CP. However, significant gaps in our knowledge of the genetic basis of CP impede advances in preventive, diagnostic, and therapeutic measures. We recently performed whole-exome sequencing (WES) in 250 CP trios and observed that at least 14% of CP cases could be accounted for by damaging genomic variants, and many of these CP risk genes control the wiring process of brain circuits in early development (Jin et al., Nat. Genet. 2020). Although our results revealed a strong genetic contribution to CP, the causes for most patients remain largely unknown.
  • Methods: Our objectives are to provide mechanistic insight into newly identified genetic causes and make genotype-phenotype correlations by applying an integrative, multi-dimensional omics approach to a large, well-phenotyped CP cohort. We thus hypothesize: (1) a proportion of the unexplained CP cases could be explained by de novo single nucleotide variants (SNVs), de novo copy number variations or structural variations that could only be detected by whole-genome sequencing (WGS), and (2) high-throughput functional assays can facilitate interpretation of these genetic variants.
  • Results: WGS has been completed on ~50 cerebral palsy trios in whom WES failed to identify pathogenic variants from the Undiagnosed Diseases Network and Cerebral Palsy Research Network. Our preliminary analysis of six WGS trios identified 492 de novo SNVs and small insertions/deletions. Eight were in the coding region, one of which being a CTNNB1 pathogenic mutation that was not found in the previous WES study. Other 484 DNVs were in the non-coding region, 56 of which were predicted as cis-regulatory elements. Several of these de novo cis-regulatory variants were near known disease-associated genes, including GBE1, GNA11, SPR, and SMARCA2.
  • Impact: Our finding suggested potentially disruptive cis-regulatory elements could explain a fraction of WES-negative CP patients.
13Wylie, Kristine PhD
Washington University in St. Louis
Comparison of Metagenomic Sequencing and the NanoString nCounter Analysis System for Characterization of Bacterial and Viral Communities in Vaginal Samples
Wylie KM, Schrimpf J, Gula H, Wylie TN
  • Introduction: DNA sequencing assays have been used to characterize the vaginal microbiome and identify associations with reproductive outcomes. These assays are useful but can be prohibitively expensive and time consuming. The purpose of this study was to demonstrate the utility of the NanoString nCounter platform, a more efficient assay compared to sequencing, for characterization of the vaginal microbiome and virome.
  • Methods: A panel of NanoString nCounter targets was designed to detect common vaginal bacteria and viruses with relevance to reproductive health. A defined synthetic community of microbes and 43 clinical samples were interrogated NanoString nCounter assays and compared to known values or metagenomic sequencing results.
  • Results: The NanoString nCounter platform consistently detected ~100 copies of each target, but did not consistently detect 10 copies. Results were reproducible. The nCounter probes were able to distinguish closely related microbes, including Lactobacillus species. In clinical samples, the relative abundance of bacterial species and presence of viruses determined by metagenomic sequencing were largely reproduced by the nCounter. There was occasional disagreement when bacteria or viruses were present at low copy numbers. Overall, nCounter and sequencing both captured critical elements of the microbial communities. However, nCounter assays provide results in about 30 hours with minimal hands-on time, and the nucleic acid sequencing assays used for microbiome/virome analysis require at least 138-178 hours with extensive hands-on time. Reagent cost for the two assays was similar, but overall the cost of nCounter was lower due to the minimal requirement for hands-on personnel time. We are continuing to expand and improve the nCounter assay.
  • Impact: DNA sequencing assays can be used to inform design of a targeted multiplex panel to assess the vaginal microbiome and virome, allowing for more cost-effective and rapid screening of patient samples for research studies. This assay can capture critical features of the vaginal microbiome that are associated with reproductive health. This approach has potential as a future clinical assay.
14Wylie, Todd
Washington University in St. Louis
ViroMatch: A Computational Pipeline for Detection of Viral Reads from Complex Metagenomic Data
Wylie TN, Wylie KM
  • Introduction: Next-generation sequencing (NGS) allows the comprehensive characterization of the virome and discovery of novel viruses, as it enables culture-independent, agnostic assessment of viral nucleic acid within a sample. We have produced software in the form of an automated pipeline, ViroMatch, that takes raw NGS sequencing reads as input and performs read quantification and associated virus taxonomy classification. We are extending this pipeline to include variant analysis.
  • Methods: ViroMatch is written in Python and is implemented as a DAG (Directed Acyclic Graph) workflow using Snakemake, which supports single or parallel processing modes. ViroMatch incorporates both nucleotide and translated amino acid sequence alignment against a comprehensive database of viral reference genomes, which allows us the sensitivity to detect highly conserved and divergent viral sequences. Additionally, we have pre-compiled local viral sequences from NCBI (RefSeq, nt & nr) and associated annotation. ViroMatch is available through an executable Docker image.
  • Results: The ViroMatch pipeline has been run over 10,000 times across multiple sample types with a focus on evaluating vertebrate/human viruses. Studies include the maternal and paternal virome and in vitro fertilization outcomes, maternal virome and preterm birth, the virome in patients with post-transplant lymphoproliferative disease, and the respiratory tract virome in children at risk for asthma. Thus far, variant calling tests have been focused on papillomavirus genomes from the maternal virome and preterm birth study.
  • Impact: ViroMatch is a staple in our work involving genomics-based detection and evaluation of viruses, and we anticipate this resource will be of great interest to others in the scientific and medical communities. Our databases and companion tools are extensible, and we anticipate periodic updates based on new virus data. ViroMatch is currently an active, key component of four NIH R01 funded projects.
15Xu, Lu  MS
Washington University in St. Louis
Development of a Neuronavigation-guided Sonobiopsy Device for Glioblastoma Patients
Xu L, Pacia CP, Gong Y, Chien CY, Hu Z, Yang L, Gach HM, Hao Y, Comron H, Huang J, Leuthardt EC, Chen H
  • Introduction: Focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) is an emerging technique for the noninvasive and spatial-temporally controlled diagnosis of brain cancer by inducing blood-brain barrier (BBB) disruption to release brain tumor-specific biomarkers into the blood circulation. The feasibility, safety, and efficacy of sonobiopsy were demonstrated in both small and large animal models using magnetic resonance-guided FUS devices. To accelerate the adoption of sonobiopsy in the clinic, we developed a neuronavigation-guided sonobiopsy device, evaluated its targeting accuracy in a water tank and in vivo using a pig model, and assessed its feasibility for applications in glioblastoma patients using numerical simulation.
  • Methods: The sonobiopsy device integrated a commercially available neuronavigation system (BrainSight) with a nimble, lightweight FUS transducer (aperture=65 mm and weight = 2 lbs). Its accuracy in targeting specific location was characterized in a water tank using a hydrophone. The targeting accuracy was verified with in vivo pig studies by measuring the offsets between the intended and the actual locations of BBB opening. Numerical simulation using the K-wave toolbox was performed to assess the targeting accuracy of the FUS transducer in 54 glioblastoma patients.
  • Results: It was found that the targeting accuracy of the neuronavigation-guided sonobiopsy device as measured in the water tank was 1.40 mm ± 0.70 mm. The targeting accuracy evaluated based on in vivo pig study was 0.89 mm ± 2.24 mm. The transcranial targeting accuracy of the FUS transducer in glioblastoma patients with 5.49 mm ± 4.92mm. Age and sex were found to be not correlated with the offset, but different bones of skull in FUS trajectory was found to be significantly affecting the transcranial targeting accuracy.
  • Impact: This study showed that the developed neuronavigation-guided sonobiopsy device had a high spatial targeting accuracy, paving the foundation for its translation to clinical use.
Poster #Poster Details
16Butt, Omar MD, PhD
Washington University in St. Louis
Pre-infusion Neurofilament Light Chain (NfL) Levels Predict Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS)
Butt OH, Zhou AY, Lee K, Wu GF, Caimi  PF, de Lima MJG, Campian JL, Dipersio JF, Ghobadi A, Ances BM
  • Introduction: Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy, termed immune effector cell-associated neurotoxicity syndrome (ICANS), are common and potentially devastating. We previously demonstrated that pre-infusion plasma neurofilament light chain (NfL), a well-established marker neurodegeneration, may predict subsequent development of ICANS in a small, single-center cohort. This larger, multicenter study compares pre-infusion NfL to known post-infusion risk factors for developing ICANs including white blood cell (WBC) count, platelet count, C-reactive protein (CRP), fibrinogen, and ferritin levels.
  • Methods: Inclusion criteria for this retrospective study included available pre-infusion (up to 2 weeks prior to lymphodepletion) plasma from patients treated with a CAR T cell therapy (n = 30, 36% with ICANS, ASTCT consensus ICANS grade range 1-4). Exclusion criteria included confounding diagnoses that are known to elevate NfL (dementia, multiple sclerosis, recent stroke). Plasma NfL was assayed using a Simoa HD-1/HD-X kit (QuanterixTM). Post-infusion (within 24hrs) WBC, Platelet, CRP, fibrinogen, and ferritin were obtained from the medical record. Group comparisons were done using log-rank tests with a Bonferroni-derived significance threshold, followed by receiver operating characteristic (ROC) curve classification.
  • Results: Prior to infusion, individuals who developed ICANS had elevations in NfL (p = 0.00004) with excellent classification (AUC 0.96), sensitivity (0.91) and specificity (0.95). Post-transfusion differences in known post-infusion risk factors were only observed for ferritin (p = 0.003) with an inferior classification (AUC 0.88, sensitivity 0.78, specificity 0.86). Similar results were observed for WBC (AUC 0.77), platelet count (AUC 0.80), CRP (AUC 0.79), and fibrinogen (AUC 0.62).
  • Impact: Basic: ICANS risk after cellular therapy may reflect latent neural injury in addition to known endothelial and vascular factors.
    Translational: Pre-infusion plasma NfL levels are a robust marker for ICANS development.
    Clinical: Foreknowledge of ICANS development of may permit early (preemptive/prophylaxis) ICANS-directed therapies, improving patient outcomes.
17Cortez, Samuel MD
Washington University in St. Louis
Effectiveness, Safety, and Tolerability of Different Estradiol Replacement Therapy Presentations in Transgender Females
Cortez S, Moog D, Nicol G, Baranski T
  • Introduction: A typical regimen for transgender females includes estrogen to provide feminizing effects in conjunction antiandrogens. There is no data to indicate if a single daily dose vs divided daily doses vs continuous subcutaneous dosing of estradiol is more effective at suppressing endogenous testosterone production. The lack of research on gender affirming hormone therapy represents a gap in knowledge that precludes the delivery of safe and appropriate care. The overarching goal of this study is to evaluate the effectiveness and safety of the different estradiol dosing regimens in transgender females. The results will guide the design and implementation of larger clinical trials.
  • Methods: This is a pilot, open label, randomized clinical trial conducted at the Washington University Transgender Center. Participants are transgender females between the ages of 18 to 45 years. Exclusion criteria includes cigarette smoking, GnRH agonist use, history of blood clot. Participants were randomized to once daily sublingual, twice daily sublingual, or transdermal estradiol. All groups used spironolactone as antiandrogen. Hormone levels were checked monthly, and dose of estradiol and spironolactone were increased until testosterone level was <50 ng/dL.
  • Results: Study is ongoing. We have recruited 25 participants: 7 in the transdermal group, 9 in the daily sublingual, and 9 in the twice daily sublingual. Baseline characteristics were similar among the three groups. Within the transdermal group, the mean testosterone level was 497.4 ng/dL, 59.1 ng/dL and 37.4 ng/dL at baseline, 4 weeks, and 8 weeks respectively. On the daily sublingual estradiol, the mean testosterone level was 578.3 ng/dL, 390 ng/dL, 146.3 ng/dL at baseline, 4 weeks, 8 weeks, and 12 weeks respectively. On the twice daily sublingual estradiol, the mean testosterone level was 522.8 ng/dL, 398.1 ng/dL, 332.75 ng/dL, and 188 ng/dL at baseline, 4 weeks, 8 weeks, and 12 weeks respectively.
  • Impact: Preliminary data reflects a better testosterone suppression with the transdermal estradiol route. Further studies are needed to determine if route of administration affects the feminization process.
18Durkin, Michael MD, MPH
Washington University in St. Louis
Biological and Chemical Characterization of Aerosols Emitted During Dental Procedures in Real World Settings
Durkin MJ, Choudhary S, Wallace M, Stoeckel DC, Thornhill MH, Lockhart PB, Kwon JH, Liang SY, Burnham CA, Biswas P, Steinkamp HM
  • Introduction: The composition of real world dental aerosols remained poorly understood. Previous studies have used in vitro experimental designs and/or indirect measures to evaluate bacteria and viruses from dental splatter. However, these findings may overestimate the occupational health risks for dental healthcare personnel (DHCP). The purpose if this study is to directly measure dental aerosol composition to better assess the health risks for DHCPs.
  • Methods: We used a variety of aerosol instruments to capture and measure the bacterial, viral, and inorganic composition of aerosols during a variety of common dental procedures and in a variety of dental clinic layouts. Equipment was placed in close approximation of dentists and during each procedure to best capture the health risk hazards from the perspective of the DHCP. Devices used to capture aerosols were set at physiologic respiration rates. Aerosol mitigation was per the discretion of the dentist.
  • Results: We detected very few bacteria and no viruses in dental aerosols – regardless of clinic layout. The bacteria identified were most consistent with either environment or standard oral flora, suggesting a low risk of transmission of viable pathogens from patients to DHCPs. Our team captured elements consistent with amalgam fillings in aerosols, when analyzing revisions of restorations.
  • Impact: Aerosols generated from dental procedures are generally a low risk occupational health risk for bacterial and viral pathogens when common dental aerosol mitigation interventions were employed. DHCPs who use standard aerosol migration interventions should not worry about the risk of bacterial or viral pathogens.
19Harris-Hayes, Marcie DPT, MSCI
Washington University in St. Louis
Musculoskeletal Impairments Among Women with Urinary Urgency/Frequency
Harris-Hayes M, Foster Sn, Spitznagle TM, Tuttle LJ, Sutcliffe S, Steger-May K, Lowder JL, Meister MR, Ghetti C, Wang J, Burlis T, Mueller MJ
  • Introduction: Urgency and frequency are common lower urinary tract symptoms (UFLUTS) in women. There is limited evidence to guide physical therapist-led treatment. The focus of this project was to understand how pelvic floor muscle (PFM) strength and endurance, PFM mobility, and hip muscle strength differ between women with and without UFLUTS.
  • Methods: Women with (n=21) and without UFLUTS (n=21) were matched on age, body mass index, and vaginal parity. An examiner measured participants’ (1) hip external rotator and abductor strength via dynamometry (maximum voluntary effort against fixed resistance), (2) pelvic floor muscle strength (peak squeeze pressure) and endurance (squeeze pressure over a 10-second hold) via vaginal manometry, and (3) PFM mobility using transperineal ultrasound (TPUS). TPUS videos were obtained during 3 conditions: rest, PFM contraction, and bearing down. Levator plate angle (LPA) and puborectalis length (PR length), were measured for each condition. Values were compared between cases and controls with paired-sample t tests or Wilcoxon signed rank tests.
  • Results: Hip external rotation [67.0 (SD 19.00) N vs 83.6 (SD 21.5) N; P = .005] and hip abduction strength [163.1 (SD 48.1) N vs 190.1 (SD 53.1) N; P = .04] were significantly lower in women with UFLUTS than in those without. There was no significant difference in pelvic floor strength [36.8 (SD 19.9) cmH2O vs 41.8 (SD 21.0) cmH2O; P = .40] or endurance [234.0 (SD 149.6) cmH2O × seconds vs 273.4 (SD 149.1) cmH2O × seconds; P = .24]. Women with UFLUTS demonstrated greater LPA at rest [66.8 (SD 13.2) degrees vs 54.9 (SD 9.8) degrees; P=0.006], and less PR lengthening from rest to bearing down [0.2 (SD 3.1) mm vs 2.1 (SD 2.9) mm; P=.03].
  • Impact: Women with UFLUTS had weaker hip external rotator and abductor muscles, but similar pelvic floor strength and endurance compared with controls. Women with UFLUTS demonstrated more elevated (cranioventral) position of the PFM at rest and less PR muscle lengthening with bearing down. These findings highlight the importance of a comprehensive PFM examination and possible treatment for women with UF-LUTS to include PFM position and mobility and hip muscle strength.
20Keenoy, Katie MA, LPC
Washington University in St. Louis
Coming Up with a COVID (Cure?): Using eConsent and National Recruitment in a Fully-Remote Clinical Trial
Keenoy K, Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, Miller JP, Yang L, Yingling M, Avidan MS, Powderly WJ, Reiersen AM
  • Introduction: The STOP COVID Trials were innovative, fully-remote randomized controlled trials of fluvoxamine (a sigma1 receptor agonist with anti-inflammatory properties) vs placebo for treatment of outpatients with early COVID-19 who were self-isolating at home.
  • Methods: The trials used eConsent and an electronic data capture system with integrated recruitment from the Epic electronic health record system. The trials reduced participant burden and prevented spread of infection by allowing patients to participate from home. The trials also ensured equity in research participation by encouraging participation of individuals from racial and ethnic groups that are disproportionately affected by severe COVID-19.
  • Results: STOP COVID 1 screened 1337 individuals, randomized 181, and included 152 in the main analysis, including 25% of participants identifying as Black. STOP COVID 2 screened 2475, randomized 670, and included 547 in the main analysis, including 13% of participants identifying as Hispanic. Enrollment for STOP COVID 2 ended early due to low event rates and difficulty with recruitment after the COVID-19 vaccine rollout; however, the trial is still adequately powered for some important secondary and long-term follow up analyses.
  • Impact: It is possible to recruit a diverse sample for participation in a fully-remote clinical trial during a pandemic. Reference: Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, Miller JP, Yang L, Yingling M, Avidan MS, Angela M Reiersen AM. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA 2020 Dec 8;324(22):2292-2300.
21Leo, Ashwin MD, MPHS Candidate
Washington University in St. Louis
Digital Mental Health Intervention for Musculoskeletal Patients with Co-existing Depression and/or Anxiety
Leo AJ, Schuelke MJ, Armbrecht MA, Hunt DM, Miller JP, Cheng AL
  • Introduction: Although depression and anxiety negatively impact patients’ responses to standard orthopedic treatment, mental health is not routinely addressed in orthopedic care. Digital mental health interventions may be a feasible, effective way to address mental health in orthopedic care settings, but recent literature calls for more comparison data between digital interventions and other treatment arms. This study compared changes in mental and physical health between orthopedic patients who received usual orthopedic care, patients who received usual care plus in-person psychological counseling, and patients who received usual care plus a digital mental health intervention.
  • Methods: In this study of adults who presented for subspecialty orthopedic care and reported symptoms of depression and/or anxiety, 51 received usual orthopedic care, 51 received usual care plus in-person psychological counseling, and 51 received usual care plus a digital mental health intervention. Outcomes were between-group differences in two-month longitudinal changes in PROMIS Depression and Anxiety scores (primary) and PROMIS Pain Interference and Physical Function scores (secondary).
  • Results: Compared to patients who just received usual orthopedic care, those who also received the digital mental health intervention reported meaningfully greater improvements in PROMIS Depression (-4.8 points), Pain Interference (-2.6), and Physical Function (2.7) (all P≤.04). Compared to patients who received in-person counseling plus usual care, those who received the digital mental health intervention plus usual care reported meaningfully greater improvement in PROMIS Physical Function (2.4, P=.04) and equivalent improvements in PROMIS Depression, Anxiety, and Pain Interference.
  • Impact: Incorporation of a digital mental health intervention into orthopedic care improved mental and physical health to a greater degree than usual orthopedic care alone and to at least a comparable degree as incorporation of in-person counseling. This novel implementation of software technology may improve healthcare quality and patient quality of life in a cost-effective manner for orthopedic patients with coexisting symptoms of depression and/or anxiety.
22Liang, Stephen MD, MPHS
Washington University in St. Louis
Pathogen and Size Characterization of Aerosols Produced during Aerosol-generating Procedures in COVID-19 Positive Patient Intensive Care Units
Choudhary S, Habrock Bach T, Wallace M, Burnham CA, Durkin M, Kwon J, Babcock H, Liang SY, Biswas P
  • Introduction: Airborne transmission of SARS-CoV-2 is thought to be greatest during aerosol-generating procedures (AGP) in the hospital. The true risk posed by AGPs is not well understood.
  • Methods: Aerosol capture and real-time particle size characterization were performed in the medical intensive care unit (MICU) during mechanical ventilation, bi-level positive airway pressure (BiPAP) ventilation, high-flow nasal cannula (HFNC), nasal high-flow oxygen (Optiflow™), and bronchoscopy. Both SKC BioSampler and BioSpot viable virus aerosol sampler (VIVAS) were used to capture air samples during a 15 min period for bacterial culture and molecular respiratory virus detection (including SARS-CoV-2). Particle size characterization was performed using the TSI SidePak personal aerosol monitor, which measures particle mass concentration (PM 10, PM 2.5, PM 1.0), and the GRIMM portable aerosol spectrometer, which measures particle size distribution (0.25 to 35.15 µm). Instruments were positioned 3 ft from the patient.
  • Results: AGPs sampled included mechanical ventilation by endotracheal tube (n=10) or by tracheostomy (n=3), BiPAP ventilation (n=1), HFNC (n=6), Optiflow™ (n=5), and bronchoscopy (n=2). In addition, transition from HFNC to BiPAP (n=1) and from BIPAP to humidified nasal high-flow oxygen (Airvo™)(n=1) were also sampled. Bacterial cultures yielded a wide range of organisms, likely originating from the patient airway. No SARS-CoV-2 was detected. Bronchoscopy yielded the greatest number of aerosols in the size range of 10 nm to 1µm; PM2.5 was 800 times higher than the baseline. Other AGPs including HFNC, Optiflow™, and transitioning from BiPAP to Airvo™ yielded increases in particles in the size range of 20 to 100nm and 200 to 500 nm.
  • Impact: In a real-world sample of AGPs involving COVID-19 MICU patients, viable bacteria and fungi were isolated from air samples obtained within 3 ft of the patient. No respiratory viruses, including SARS-CoV-2, were detected. An increase in number concentration of aerosols was greatest with bronchoscopy. The risk of aerosol generation during other common AGPs may be less than previously thought.
23Liang, Stephen MD, MPHS
Washington University in St. Louis
Real-time Monitoring for Aerosol Generation in the Emergency Department using Low-cost PM Sensors during the COVID-19 Pandemic
Choudhary S, Marks L, Lauer J, Kumawat H, Babcock Hi, Durkin Mi, Liang SY, Biswas P
  • Introduction: Emergency department (ED) healthcare personnel (HCP) provide acute medical care to the ill and injured. The day-to-day burden of aerosol exposure posed to ED HCP during patient care is not well understood, but remains a concern during the COVID-19 pandemic.
  • Methods: Baseline air quality and aerosol characterization during routine ED patient care and emergent aerosol-generating procedures (AGP) were performed over an 8-month period in the ED trauma/critical care area. This area is comprised of 6 open treatment bays with no doors, each accommodating 2 patient beds separated by a curtain. Particle concentrations were measured in real-time using a network of low-cost particulate matter (PM) sensors. The APT MINIMA PM sensor estimates concentrations of particles (PM 10, PM 2.5, PM 1.0) capable of depositing in the alveolar region of the human lung. One sensor was placed within 3 ft of the head of each patient bed in the treatment bay; a sensor was also worn by a respiratory therapist during AGPs to determine personal exposure. Particle mass concentrations for the following AGPs were determined: administration of nebulized medication, supplemental oxygenation via nasal cannula, non-invasive positive pressure ventilation (NIPPV), and endotracheal intubation.
  • Results: Distribution of mass concentration during different AGPs followed a Poisson distribution. Administration of nebulized medications generated large concentrations of aerosols compared to endotracheal intubation, NIPPV, or supplemental oxygenation via nasal cannula. However, aerosols generated on one side of the treatment bay were found to travel distances ≥5 feet to the other side of the bay despite appropriate ventilation.
  • Impact: Aerosol generation during ED patient care was greatest with administration of nebulized medication. While ED HCP should continue to don appropriate respiratory personal protective equipment when performing AGPs, overall risk of generating aerosol during supplemental oxygenation via nasal cannula, NIPPV, and endotracheal intubation may be less than previously thought.
24Michelson, Andrew MD
Washington University in St. Louis
An Integrated Machine Learning Model to Predict Respiratory Failure for COVID-19 Tested Patients in the Emergency Department:  A Silent Prospective Trial
Yu SC, Guo X, Haber G, Gupta A, Kannampallil T, Lai A, Payne PRO, Kollef M, Michelson AP
  • Introduction: Acute hypoxemic respiratory failure (RF) is the hallmark symptom of COVID-19 infection that can lead to escalating oxygenation requirements and critical care utilization. Early identification of patients at risk for respiratory decompensation can facilitate timely resource deployment and mitigate care delays. To facilitate resource alignment with patient needs, a machine learning (ML) model designed to predict RF for COVID-19 tested patients who present to the emergency department (ED) was developed, integrated, and prospectively validated.
  • Methods: All patients ≥18 years of age presenting to any BJC ED with a COVID-19 PCR/antigen test performed ≤ 14 days before or 7 days after the visit were included (time criteria for model development). RF was defined by use of high humidity nasal cannula, non-invasive or invasive mechanical ventilation within 48 hours of ED arrival. The model was developed using encounter data from 3/6/20-6/8/20. Features were narrowed using a lasso regression. A logistic regression was trained using a 75%:25% test: train split with 5-fold cross validation. The model was implemented within Epic and prospectively ran from 12/23/20-4/8/21.
  • Results: Of the 11,558 patients in the development cohort, 566(4.9%) developed RF. These patients were more likely to be older (66.1[54.5-74.2] vs. 55.2[36.7-69.3], p<0.01), male (331[58.5%] vs. 5,183[47.2%], p<0.01) and have a higher BMI (34.9[27.0-40.9] vs. 28.1[23.6-34.0], p<0.01). Twelve features were selected by lasso regression and the retrospective area under the receiver operating curve ([AU]ROC) and AU the precision recall curve (AUPRC) was 0.80(0.794-0.811) and 0.28(0.26-0.29), respectively. Prospectively, the AUROC and AUPRC were 0.76 and 0.13, respectively. Patients exceeding the risk threshold were 3.5x and 3.9x more likely to develop RF (165[13.6%] vs. 401[3.9%], p<0.01) and require ICU transfer (238[19.6%] vs. 520[5.0%], p<0.01) within 48 hours.
  • Impact: Integration of simple ML-based prediction models within the EHR is feasible and yields relatively accurate, real-time predictions. Changes in prevalence, population and treatment may require ongoing algorithm monitoring and updating.
25Morgan, Kerri PhD
Washington University in St. Louis
Development and Testing of a Mobile Phone Text Messaging Intervention Based on Patient Activation to Manage Fatigue for People with MS, SCI and Stroke
Morgan K, Newland P, Heeb R, Walker K, Stowe L, Tomazin R, Wong AWK
  • Introduction: Fatigue significantly impacts daily functioning for people with disabilities (PwD). Self-management programs targeting fatigue have shown promising effects for PwD. However, current satisfaction with fatigue self-management programs is low for PwD. Tailoring a self-management intervention based on patient activation may overcome this issue. This study aimed to describe the development of a mobile phone-based fatigue self-management text message intervention targeting patient activation for persons with multiple sclerosis (MS), spinal cord injury (SCI) and stroke.
  • Methods: The research team collaborated with a consumer advisory board (CAB) and a neurologist to develop the intervention content and delivery process. The CAB reviewed all messages developed from evidence-based resources and provided input on the content and format. We tested the intervention over a 12-week period with messages being sent to 25 participants with MS (n=9), SCI (n=9), and stroke (n=7) based on their patient activation levels (measured by the Patient activation Measure (PAM-13)). The participants completed a pre- and post-intervention assessment with fatigue as the primary outcome. Following the intervention, participants rated their satisfaction with the intervention.
  • Results: Six CAB members rated 61 messages covering nine areas of fatigue self-management with good clarity (mean ratings = 3.5 to 5 out of 5) and relevance (mean ratings = 3.2 to 5 out of 5). The final set consisted of 48 messages programmed into a digital platform with a predefined schedule to deliver messages. We found moderate effects for fatigue and mild-to-moderate effects for social satisfaction and sleep (Partial eta2 = 0.04 to 0.12). Participant satisfaction with the intervention was rated high (mean ratings = 2.88 to 3.4 out of 5).
  • Impact: This intervention has the potential to increase the reach and access of PwD at different levels of activation. For PwD, whose access to health services are often limited, this intervention may provide an alternative delivery model to increase access to health services. A patient activation approach allows content to be delivered that matches with the person’s readiness and needs.
26Morris, Gabriela MD
Saint Louis University
The Role of Patch Testing for the Evaluation of Adult Patients with Hand Dermatitis: A Retrospective Cohort Study
Morris GM, Ong SK, Li Y, Bauman TM, Chrusciel T, Burkemper NM
  • Introduction: Hand dermatitis is a common dermatologic condition with a lifetime prevalence estimated to be 20%. The objective of this study was to assess the demographics and patch test positivity in adult patients who underwent patch testing at our institution with a focus on patients with hand dermatitis. We hypothesize that tobacco smoking is a risk factor for
    hand dermatitis.
  • Methods: After IRB approval, a retrospective analysis was performed of subjects who underwent patch testing between May 2015-May 2020 at Saint Louis University’s Department of Dermatology using the North American Comprehensive patch testing series. Demographic information, location of rash, duration of rash before initial presentation, patch test results, tobacco smoking history, and occupation were obtained from chart review and collected using a REDCap database. Three subgroups were analyzed including subjects with hand only involvement of their dermatitis, subjects with hand plus other body site involvement, and subjects with no hand involvement. Chi-square test was used for statistical analysis.
  • Results: The most commonly positive allergens overall at our institution were nickel (31%), Balsam of Peru (30.6%), cobalt (29.5%), methylisothiazolinone (28.3%), and hydroperoxides of linalool (25.6%). Patients with hand only dermatitis were more likely to have patch positive tests to methylisothiazolinone (37.3%; p=0.03), Cl+Me-isothiazolinone (Kathon CG, 100ppm) (25.3%; p=0.03), 2-hydroxyethyl methacrylate (HEMA) (10.7%; p=0.05), and 4-chloro 3,5-xylenol (PCMX).
  • Impact: The results from this study will be important for counseling patients with allergic contact dermatitis as tobacco use may be a modifiable risk factor for their condition. The results will also aid providers in counseling their patients with hand dermatitis regarding chemicals and products to avoid that may improve their dermatitis.
27Newcomer, Erin
Washington University in St. Louis
Pseudomonas Aeruginosa Establish Reservoirs in New Hospital Sink Drains and Show High Relatedness to Isolates Recovered From Clinical Blood Cultures
Newcomer EP, Sukhum KV, Cass C, Wallace MA, Johnson C, Fine J, Sax S, Barlet MH, Burnham CD, Dantas G, Kwon JH
  • Introduction: Healthcare-associated infections acutely threaten intensive care units (ICUs) with studies indicating that Pseudomonas aeruginosa (PSAR) reservoirs in hospital built-environments can lead to infections and outbreaks. Despite this, it is unclear how pervasively antibiotic resistant organisms (AROs) like PSAR colonize ICU surfaces. We sampled surfaces in a newly-built stem cell transplant and oncology ICU before and for one year after establishment and found close associations between surface and patient blood isolates. This led us to expand our investigation to PSAR patient blood isolates across the Barnes-Jewish Hospital system.
  • Methods: Surface and patient fecal samples were selectively cultured to enrich for AROs. PSAR blood culture isolates were recovered in the clinical laboratory for diagnostic purposes. Isolate lineages were established with shotgun whole-genome sequencing and pairwise whole-genome SNP analysis, which will also be conducted on the additional patient blood isolates. Hybrid genomes of select PSAR isolates were created using long-read sequencing data. Time-measured phylogenetic analysis was conducted using core genome alignment.
  • Results: PSAR was the most frequently identified species, comprising 156/696 of all isolates initially cultured and formed several clades with highly related sink drain isolates. Notably, 52/156 PSAR isolates were of ST1894, and this ST was recovered from the same sink drain before patient occupancy, for the full year of collection, and from 3 blood cultures. SNP analysis revealed no more than 11 SNPs between isolates within this ST. Time-measured phylogenetic analysis indicated a time since most recent common ancestor of 778 days for 40/52 isolates. We expect to find this lineage in patient blood isolates from across the hospital system, as well as other recurrent lineages.
  • Impact: ARO colonization of hospital sink drains has the potential to function as a reservoir for ARO transmission to patients. Specific strains of PSAR were found with high frequency and longitudinally in the environment and caused blood stream infections. This study highlights the need for effective and standardized sink decontamination strategies to prevent outbreaks.
28Olsen, Margaret PhD, MPH
Washington University in St. Louis
Changes in the Local Skin Microbiota in Women with Breast Cancer after Mastectomy
Olsen MA, Myckatyn TM, Tenenbaum MM, Brandt KE, Wallace MA, Habrock-Bach T, Nickel KB, Johnson C, Warren DK, Burnham CD
  • Introduction: The late onset and unusual microbiology of some breast-implant associated infections suggests local skin microbiota as a possible source of infecting bacteria.
  • Methods: Breast and axillary skin swabs, antibiotics, and skin product use were collected from women planning to undergo mastectomy with immediate implant reconstruction during the preoperative and up to four postoperative clinic visits. Skin specimens were cultured using an extensive array of growth media, and organisms were identified by MALDI-TOF mass spectrometry. Bacterial diversity was determined using Shannon’s diversity index based on the relative abundance of organisms isolated in culture (primarily genera), and richness as the number of different species at a given time point. Diversity and richness were summarized using the mean and standard deviation (SD). Comparisons between the pre- and first post-postoperative visit were performed using paired Student’s t-tests and repeated-measures ANOVA.
  • Results: Skin swabs were collected during the preoperative and at least one postoperative clinic encounter from 28 women. Bacterial diversity was significantly reduced at the first postoperative visit compared to the preoperative visit on breast skin (mean ± SD; 0.84 ± 0.48 vs. 1.27 ± 0.51, respectively, p = 0.005) but not on axillary skin (0.74 ± 0.50 vs. 0.90 ± 0.60, p = 0.21), as was species richness (breast mean ± SD; 3.39 ± 1.42 vs. 5.11 ± 2.04, respectively, p = 0.001; axillary 3.04 ± 1.64 vs. 3.46 ± 2.01, p = 0.33). There were no significant changes in diversity or richness in subsequent postoperative breast skin specimens and no significant differences associated with change in use of deodorant, antibacterial soap, type of intraoperative antibiotic or oral antibiotic used after surgery.
  • Impact: In this pilot study we found significantly reduced bacterial diversity and species richness on breast skin after mastectomy with implant reconstruction compared to the preoperative clinic visit. Future studies are needed to determine whether use of post-discharge oral antibiotics is associated with the reduction in diversity and species richness.
29Olumba, Frank MD
Washington University in St. Louis
RESTORE Declined Livers Study; A Single Center Prospective Non-randomized Trial
Olumba F, Zhou F, Xu M, Ahmed O, Kim JS, Khan A, Doyle MB, Chapman W
  • Introduction: There is a severe shortage of available liver transplants to meet the needs of patients on the waiting list. There are many factors contributing to this shortage and poor organ utilization is a significant one. A large proportion (~20-35%) of livers are discarded based on subjective assessment and concern for organ quality. Objective criteria are needed for assessing these marginal organs. A new technology called normothermic machine perfusion (NMP) has been extensively studied as the optimal method to recondition and reclaim marginal livers for transplant. NMP is a machine device that allows the delivery of oxygenated blood and nutrients to a liver at body temperature, enabling the function of the organ to be tested before it is transplanted. This study uses a commercial NMP device (OrganOx Metra) to treat previously discarded human livers for transplantation.
  • Methods: Single center, prospective non-randomized trial (NCT04483102). Trial endpoint is 25 NMP treated liver transplantations. Primary objective is the successful transplant of NMP livers based on patient and graft survival at 6 months. Secondary objectives are assessment of liver graft function and associated recipient morbidity of NMP treated organs with measurement of several liver and patient specific outcomes such as proportion of rescued livers.
  • Results: Fifteen livers accepted for placement and testing on NMP device. Eleven out of 15 livers passed viability testing and were transplanted contributing to a 73.3% rescue rate for marginal livers. Currently, six patients at 6-month time point with 66.7% graft and patient survival.
  • Impact: Over the last two decades, the demands for liver transplantation have outpaced the available organ supply. This translational study offers the most immediate solution to this problem. It will allow transplant centers to increase their utilization rate by providing reliable safety and viability criteria for the selection of marginal organs. Use of this technology will help increase the availability of organs to patients previously unlikely to receive a liver transplant.
30Pusic, Iskra MD, MSCI
Washington University in St. Louis
Use of Belimumab for Prophylaxis of Chronic Graft-Versus-Host Disease
Pusic I, Johanns T, Sarantopoulos S, Westervelt P,  Cashen A, Uy G, Abboud C, DiPersio J
  • Introduction: Belimumab (BEL) is a monoclonal antibody which inhibits binding of B-cell-activating factor (BAFF) to its receptors on B cells, thus inhibiting the survival of alloreactive B cells. Given the role of B cells and BAFF in chronic Graft-versus-Host Disease (cGvHD) pathophysiology, BEL might have a role in prevention of cGvHD. We hypothesized that targeting BAFF early after allogeneic hematopoietic cell transplantation (alloHCT) would be well-tolerated and have a favorable effect on the incidence and severity of cGvHD.
  • Methods: We are presenting data on the first 9 Pts. All Pts were adults in complete remission after alloHSCT, using mobilized peripheral blood grafts from matched related or unrelated donors, after any conditioning. cGvHD prophylaxis was with tacrolimus and methotrexate. BEL was administered i.v. at 10 mg/kg Q2W for 3 doses followed by 4 monthly doses, for a total of 7 doses, starting 50-80 days after alloHCT. Pts who received ≥1 dose of BEL were evaluable for safety and ≥2 doses for efficacy assessment. cGvHD was diagnosed using the NIH criteria. All analyses are descriptive.
  • Results: BEL was well tolerated. There were no reported grade >3 treatment-related AEs, no significant infections or myelosuppression, and no infusion reactions. 8/9 Pts received all 7 doses of BEL. Of those 8 Pts, 5/8 Pts have no evidence of cGvHD and are completely off immunosuppression > 20 mo after completing BEL. 2/8 Pts developed cGvHD: 1 Pt developed moderate cGvHD of skin, eye, mouth and liver around cycle 5 of BEL and improved with therapy; 1 Pt developed cGvHD of skin, eye, liver 7 mo after completing BEL and died of complications of pneumonia and liver failure (also Hx of hemochromatosis). 1/8 relapsed with AML 1 mo after completing BEL; now in remission after further treatment. 1/9 Pts stopped BEL after only 3 doses, due to thrombocytopenia and insurance issues. He was found to have relapsed lymphoma 3 mo later, achieved remission with further treatment and has no evidence of cGvHD 20 mo after stopping BEL. One additional Pt is being enrolled. Immune reconstitution studies are showing that B-cell counts remain low 1 yr out of alloHCT in all Pts.
  • Impact: This data describes for the first time the use of BEL for cGvHD prophylaxis. Absence of severe infections and myelosupression is reassuring. While more Pts are needed to further assess the impact of prophylactic BEL on the incidence of cGvHD, these preliminary results are encouraging.
31Rammaha, Thue MS
Washington University in St. Louis
Emerging Evidence of Behavior Change Associated with Fully Remote Delivery of a Genetically Informed Smoking Cessation Intervention
Rammaha TB, Salyer P, Chang Y, Bourdon J, Chen LS, Bierut L, Ramsey AT
  • Introduction: Genetic variation in nicotinic receptor subunits explains differences in smoking behaviors and risk of smoking-related diseases. Still, it remains unknown whether returning genetic susceptibility results can motivate smoking cessation and personalize treatment. Therefore, the aim of this trial is to investigate the effects of a genetically informed smoking cessation intervention on a) smoking quantity and medication treatment seeking and b) potential behavior change mechanisms leading to smoking cessation.
  • Methods: To date, we have enrolled 81 adult participants who smoke in a fully remote randomized controlled trial including genetic testing via 23andMe, Zoom-based delivery of a genetically informed risk feedback tool (RiskProfile) or active comparator (brief cessation advice), and 30-day and 6-month follow-ups. Each personalized RiskProfile is generated using two components: genetic risk propensity and phenotypic risks via cigarettes per day (CPD).
  • Results: As hypothesized, interim analyses (n=61 with completed 30-day follow-up) using repeated-measures ANOVA controlling for baseline CPD yield promising effect size estimations (partial eta-squared=.032, small-to-medium effect size). This indicates clinically meaningful behavior change characterized by reductions in CPD of 2.6 in the RiskProfile intervention group versus 1.1 in the active comparator group. Importantly, 42% in the intervention group versus 17% in the comparator group sought medication treatment for smoking. Increases in perceived importance of tobacco treatment and decreases in perceived self-stigma appear to be particularly promising mechanisms of behavior change.
  • Impact: Through this ongoing fully remote trial, we have significantly advanced the following clinical, community, and economic benefits: 1) translated polygenic risk scores into a behavioral intervention via RiskProfile (biological factors and products), 2) reduced access barriers via remote delivery (accessibility/delivery), 3) protected the health and safety of participants and research staff by avoiding COVID exposures (disease prevention/reduction), and 4) reduced the social and economic burden of cigarette smoking among participants (cost of illness).
32Shahi, Jeevin MD, FRCPC, DABR
Saint Louis University
Survival in Metastatic Renal Cell Carcinoma Treated with Immunotherapy and Stereotactic Radiation Therapy or Immunotherapy Alone
Shahi J, Al-Hammadi N, Hamilton Z, Dombrowski JJ
  • Introduction: Preclinical evidence suggests that responses to IO may be enhanced through the immunomodulatory effects of stereotactic radiation therapy (SRT). We hypothesized that clinical outcomes from the National Cancer Database (NCDB) would demonstrate improved overall survival (OS) in mRCC patients receiving IO+SRT versus IO alone.
  • Methods: Patients with mRCC diagnosed from 2012-2016 and receiving first-line IO±SRT were identified from the NCDB. The definition of SRT was ≥10 Gy in 1 fraction, ≥20 Gy in 2 fractions, ≥24 Gy in 3 fractions, or ≥25 Gy in 5 fractions. Conventional radiation therapy was allowed in the IO alone cohort. The primary endpoint was OS stratified by the receipt of SRT (IO+SRT versus IO alone). Secondary endpoints were OS stratified by the presence of brain metastases (BM) and timing of SRT (before or after IO). Events beyond 24 months were censored. Survival was estimated using Kaplan-Meier methodology and compared via the log-rank test. Adjustments for multiple comparisons were performed.
  • Results: Of 644 eligible patients, 63 (9.8%) received IO+SRT and 581 (90.2%) received IO alone. The median follow-up time was 17.7 months (range, 2-24 months). Baseline characteristics were similar between cohorts, although SRT+IO patients were more frequently <60 years old (57.1% vs 40.3%, P=0.010) and had higher rates of BM (71.4% vs 11.2%, P<0.001). There was no difference in metastatic tumor burden between cohorts (P=0.48). Sites treated with SRT included brain (71.4%), lung/chest (6.4%), spine (6.4%), bones (3.2%), and other (12.6%). While there was no significant difference in OS for patients receiving IO+SRT vs IO alone (log-rank P=0.11), OS was consistently higher at 1-year (74.4% vs 65.0%) and 2-years (71.0% vs 58.4%). In patients with BM, 1-year survival rates were 73.0% (95% CI, 57.4-83.7) with IO+SRT and 54.7% (95% CI, 41.8-65.9) with IO alone (P=<0.026). The timing of SRT (before or after IO) did not influence OS (P=0.32).
  • Impact: Patients with BM secondary to mRCC had prolonged OS with the addition of SRT to IO. Prospective clinical trials are warranted to better identify mRCC populations which may benefit from combined modality therapy.
33Tague, Laneshia MD, MSCI
Washington University in St. Louis
Clonal Hematopoiesis in Lung Transplant Recipients is Associated with Adverse Clinical Outcomes
Tague LK, Oetjen K, Mahadev A, Link DC, Gelman AE
  • Introduction: Cellular stressors play an important role in the emergence of clonal hematopoiesis (CH). Cytotoxic chemotherapy is associated with CH due to mutations in DNA damage response (DDR) genes, such as TP53, ATM, and PPMID. Lung transplant (LTx) recipients receive lifelong immunosuppression therapy and are known to be at increased risk for a broad spectrum of adverse hematologic events. We hypothesized that, similar to cytotoxic chemotherapy, the inflammatory and genotoxic stress of lung transplantation likewise drives the development of CH.
  • Methods: We performed a prospective cross-sectional cohort study of 85 adult lung transplant recipients (LTx) and 33 healthy controls (HC) to 1) characterize CH prevalence and 2) identify associations with transplant outcomes. We evaluated CH frequency and burden with chi-square and Poisson regression, associations between clinical and demographic variables and CH using logistic regression, and between clinical outcomes and CH using Cox regression.
  • Results: CH in DDR genes was more prevalent among LTx (24/85 LTx vs. 0/33 HC, aOR 12.9 (1.7-100.3), p=0.0002). Age [OR 1.13 (1.03-1.25), p=0.014], ILD diagnosis [OR 3.6 (0.9-15.5), p=0.083], pre-transplant smoking (OR 4.25 (1.02-17.82), p=0.048], and mycophenolate intolerance [OR 3.8 (1.3-12.9), p=0.031] were associated with DDR CH. Non-DDR CH was associated with non-minimal acute cellular rejection [aHR 13.9 (3.5-56.2), p=0.0002] and moderate to severe neutropenia [aHR 8.9 (1.2-64.7), p=0.03]. DDR CH was strongly associated with CMV viremia [aHR 4.1 (1.02-16.2), p=0.046].
  • Impact: Our findings of CH amongst lung transplant recipients represents a potential paradigm shift in how adverse clinical outcomes in solid organ recipients are screened for, evaluated, and possibly treated in the post-transplant population. The potential applications include assessing risk for common hematologic complications, evaluating the potential response to immunosuppressive therapy, risk stratification for the development of rejection and possibly novel immunosuppression agents and therapeutic targets. Future studies are needed to confirm these findings and investigate the underlying mechanisms of these relationships.
34Wang, Leyao PhD, MPH
Washington University in St. Louis
In-utero Exposure to a Devastating Hurricane is Associated with Altered Infant Nasal Microbiome
Wang L, Rosario N, Zhang A, Cao L
  • Introduction: Prenatal maternal exposures to environmental or psychological stressors increase the risks for developing respiratory diseases, including wheezing and asthma, in children. With the increasing frequency and intensity of extreme weather events worldwide, which poses dramatic environmental and psychological burdens in affected regions, it is essential to evaluate the risks of developing respiratory diseases among children who are exposed in utero to devastating climate events. The infant nasal microbiome is an important mechanism and indicator of infant respiratory health.
  • Methods: We examined the impact of maternal prenatal exposures to a devastating hurricane on the offspring’s nasal microbiome, leveraging the natural experiment of Hurricane Maria (September 2017 in Puerto Rico). We recruited 63 vaginally born infants, in which n=29 were exposed in utero to this devastating hurricane, and n=34 were conceived at least five months after the Hurricane as controls. Nasal swab samples were collected and analyzed using 16S ribosomal RNA gene sequencing at the community and taxa level respectively.
  • Results: Infants in the exposure group were more likely to harbor a Staphylococcus-Streptococcus dominant microbial community in the nose, which indicated an increased risk of developing wheezing and asthma. The richness and diversity of the microbiome was significantly higher in the exposure group compared to the control group. The bacterial genera Rhodocista, Azospirillum, Massilia, Herbaspirillum, Aquabacterium, and Pseudomonas were enriched, while Corynebacterium and Ralstonia were depleted in the exposure group. Food insecurity due to the hurricane was associated with the increase of Pseudomonas in the infant nasal microbiome.
  • Impact: Our study, for the first time, showed that infants who were exposed to Hurricane Maria during gestation had an altered nasal microbiome with a higher prevalence of environmental bacteria. More research is needed to evaluate and understand how prenatal exposures to an extreme weather event may impact the infant nasal microbiome and the development of respiratory diseases in children.
35Zhang, Xiangyu PhD 
Washington University in St. Louis
Dietary Protein Elicits a Leucine-mediated Threshold Effect on Monocyte/Macrophage mTORC1-autophagy Signaling Resulting in Elevated Cardiovascular Risk
Zhang XY, Kapoor D, Jeong SJ, Stitham J, Fappi A, Rodriguez-Velez A, Yeh YS, Mittendorfer B, Razani B
  • Introduction: High-protein intake is common in Western societies and generally considered healthy. However, results from studies on both participants and mice suggest elevated protein intake is associated with increased risk for cardiovascular diseases, although the dose at which protein intake can trigger mTOR activation and reach unhealthy levels and the specific amino acid(s) responsible for it are unknown.
  • Methods: In order to determine the effects of high protein intake on mTORC1-autophagy signaling in human circulating monocytes, we conducted two distinct clinical studies. In the first study, we evaluated extremes of protein intake by comparing the effects of liquid protein meals that contained either 10% or 50% kcal protein on monocyte mTORC1 activation in a cohort of participants. In the second study, we utilized a more “real-world” scenario, by evaluating these outcomes in participants who consumed either a 15% kcal or a 22% kcal protein meal. Circulating monocytes were isolated from blood at different time points after consuming these meals. Meanwhile, serum was also collected for detailed plasma amino acid analysis.
  • Results: We describe the presence of a threshold effect of high protein intake on this deleterious signaling pathway wherein protein content greater than about 22% kcal acutely activates mTORC1 signaling in human monocytes/macrophages. Furthermore, we identify leucine as the critical amino acid modulator and threshold indicator, capable of the dose-dependent mTORC1 activation and downstream effects. Finally, by designing specific mouse diets with protein contents mimicking graded levels of protein ingestion in our study participants, we demonstrate the presence of a dietary protein threshold effect in driving atherosclerosis in mouse models.
  • Impact: The results from the present study help explain the increased cardiovascular disease
    mortality associated with high protein and provide a direct mechanistic link for this association. This has important clinical and public health implications in suggesting high protein intake should be considered with caution and under corresponding guidelines.
36Zheng, Jie PhD
Washington University in St. Louis
Myocardial Oxygen Extraction Fraction Imaging with MRI
Zheng J, Eldeniz C, Schindler TH, Li R, Peterson LR, Woodard PM
  • Introduction: Imbalance of myocardial oxygen supply and demand precipitates a cascade of physiological changes resulting in ischemic pathology. Myocardial oxygen extraction fraction (mOEF) may provide accurate assessment of this balance. Current non-invasive reference method to quantify mOEF is positron emission tomography (PET), but the low spatial resolution, high cost, and ionizing radiation discourage the widespread use of this method. Hence, the objective of this preliminary study is to develop and evaluate a new magnetic resonance imaging (MRI) technique for fast quantification of mOEF in vivo. Two specific aims will be addressed: 1) the reproducibility of this MRI method in vivo; 2) the diagnosis utility in patients with hibernating myocardium.
  • Methods: A new MRI acquisition method was recently developed for the quantification of mOEF with good image quality. Ten healthy adults will undergo cardiac MRI exams at two different days. Field inhomogeneity and motion correction will be two key components to address. We will then evaluate 10 patients with hibernating myocardial disease who are routinely diagnosed using 18F-FDG-PET for features of preserved glucose uptake (viable myocardium) and reduced blood flow. The mOEF will provide direct measurement of oxygen utilization, with hypothesis of increased mOEF for viable myocardium and reduced mOEF for non-viable myocardium.
  • Results: First, we expect our new imaging technique to allow consistent and reproducible good image quality and obtain correct global resting mOEF (coefficient of variation < 5%). Second, our hypothesis is confirmed in patients with hibernating myocardium.
  • Impact: This T1 work uses non-invasive and non-irradiation MRI to measure myocardial oxygenation for the fast diagnosis of oxygen deficiency in patients with cardiac ischemia. The finding could potentially guide therapy for functional recovery of myocardial contractility. The technique could improve health care quality by providing direct myocardial oxygenation assessment and monitoring treatment efficacy. Without using any exogenous tracers, this method can be combined with other cardiac MRI exams for “one-stop-shopping” test, thereby reducing healthcare costs.
Health Services/Population Health
Poster #Poster Details
37Andersen, Stephanie MPA
Washington University in St. Louis
Translating for Impact: A New Toolkit for Demonstrating the Larger Impact of Your Work
Andersen SM, Combs T, Brossart L, Luke D
  • Introduction: Historically, researchers have focused on linking research to scientific outputs like publications and grants. But policymakers, the public, and funders care about the larger impact of research (e.g., lives saved, improved cost-effectiveness). Developed in 2017, the Translational Science Benefits Model offers a new approach for evaluating and disseminating the impact of scientific activities on downstream public health, clinical, and societal benefits. Interest in the TSBM has grown rapidly, though researchers often lack training in translation and dissemination. To meet this need, we developed a set of implementation tools to help researchers plan, track, and demonstrate impact. Here we describe the Translating for Impact Toolkit, its components, and plans for pilot testing.
  • Methods: Toolkit development included 3 phases: 1) review of existing tools, 2) development and review of tool prototypes, and 3) pilot testing by participants in a 2021 Implementation Research Institute. Participants applied select tools to their work and gave feedback on design, usability, and content. Future phases will include robust pilot testing of the full toolkit, review for equity and inclusion, and development of interactive formats.
  • Results: The Toolkit includes nine easy-to-use tools to integrate impact throughout the research process. The tools are designed to be used by individuals or teams of clinical and public health researchers working together on a specific project or within a program or center. Initial pilot testing indicated that PDF usability was challenging. Web-based tools may be more functional for researchers.
  • Impact: Training the next generation of clinical scientists to prioritize and promote translational impact in their work now is essential. The TSBM and Translating for Impact Toolkit provide a structure and language for this process. The Toolkit guides researchers in preparing impact statements for the public, future grants, promotion and tenure, and more. Earlier and greater focus on impact will help normalize consideration of translational impact along with traditional metrics such as publications and grants when evaluating individuals, projects, and programs.
38Ballatori, Sarah MD
Washington University in St. Louis
The Impact on Families of Congenital Upper Extremity Differences
Ballatori SE, Wall LB
  • Introduction: Congenital upper extremity differences often carry inherent functional limitations, aesthetic concerns, and the need for surgical treatment. We hypothesize that 1) caregivers of children with these differences will report a significant impact on family life, and 2) this impact would vary based on certain variables, such as insurance status.
  • Methods: Caregivers of patients age 0-18 years enrolled in the multi-institutional CoULD (Congenital Upper Limb Difference) registry were contacted. Survey questions included demographics, variables of interest, and the Impact on Family Scale (IOFS) questionnaire. Data were analyzed using Tukey post-hoc tests and linear regressions. Historical survey instrument results available through the CoULD registry, including PODCI and PROMIS, were also analyzed.
  • Results: 285 caregivers participated. 42% female patients; 88% female caregivers. Factors with significantly increased family impact included: household income $20,000-40,000 vs $80,000-100,000; public vs private insurance; bilateral vs unilateral involvement; syndrome association; and 1 adult caregiver vs 2. Additionally, all categories of PODCI (upper extremity, mobility, sports, pain, happiness, global) demonstrated a negative correlation with IOFS. PROMIS upper extremity and peer relations demonstrated an inverse relationship with IOFS; PROMIS pain interference had a positive correlation with IOFS. Although not significant for the IOFS-Overall, there was significantly increased sub-category of IOFS-Finance for distant vs local travel to see the surgeon. The IOFS-Overall for this cohort was significantly lower than the IOFS for other childhood illnesses cited in the literature.
  • Impact: Caregivers of children with congenital upper extremity differences report an impact on family life. However, this impact is less than that of other childhood illnesses. Several factors correlate with family impact, which represent opportunities to identify at-risk families and underscore the importance of caring for the whole family through a multidisciplinary approach.
39Carothers, Bobbi PhD
Washington University in St. Louis
We’re All Running on Empty: ICTS Membership Engagement and Productivity in the COVID Era
Carothers BJ, Combs TB, Palombo E, Sarli CC, Suiter AM, Buckel C, Keath EJ, Vogel M, Luke DA
  • Introduction: COVID-19 swept through the United States beginning in March 2020, leading to transitions from in-person to online collaboration and teaching, overhauled lab safety protocols and schedules, and overwhelming clinical responsibilities for physicians. This study examines changes in ICTS members’ engagement with ICTS activities and productivity. Specific aims are to 1) document changes in activity and productivity with administrative data, and 2) examine reasons for and feelings about changes in productivity via survey data.
  • Methods: Administrative data on ICTS member engagement (core service use, training, internal funding, leadership) and productivity (grants, publications) were collected annually from 2007-2020 for all 3349 members. Impact of COVID-19 was collected as part of the annual ICTS Member Satisfaction Survey for 2020. These data include 223 early-career (fellows, residents, instructors, and assistant professors) members (113 men, 101 women, 9 no response) from the WUSTL School of Medicine.
  • Results: Engagement with ICTS showed a steep decline from 2019 to 2020, largely driven by a sharp drop in core service use. Declines were also seen in the number of Research Forum reviewers, Mock Study Section presenters, and CRTC mentees. Internal funding (JIT and Pilot) showed a greater number of recipients from 2019 to 2020. For productivity, the number of members with publications and grant awards declined from 2019 to 2020, though members with grant submissions showed a slight increase. Survey data confirmed that 66% of early-career members reported a decrease in research productivity since March 2020. Top reasons cited were childcare and homeschooling, pandemic-related feelings of distress, additional administrative tasks, and extra clinical work. Only 36% of responses indicated not taking on additional administrative tasks during COVID-19; 42% of men and 31% of women indicated no additional tasks. Almost 70% of respondents reported moderate/high anxiety about their productivity.
  • Impact: COVID-19 was detrimental to ICTS engagement and productivity. Anxiety regarding productivity was widespread. Short- and long-term translational deficits are likely as a result.
40Combs, Todd PhD
Washington University in St. Louis
If You Build It, Will They Come? Linking ICTS Researcher Engagement and Scientific Productivity
Combs TB, Carothers BJ, Liu Y, Brossart LB, Evanoff B, Luke DA
  • Introduction: The NIH Clinical and Translational Science Awards (CTSA) Program supports the creation of program infrastructure promoting scientific collaboration and improvement in translational research. While most evaluations of these and similar programs focus on scientific outcomes such as grants and publications, few studies investigate the underlying mechanisms through which large infrastructure grants produce scientific or translational benefits. This study investigated how engagement – researchers’ interactions with CTSA-funded resources – can help to increase scientific productivity.
  • Methods: Authors 1) developed process indicators to define engagement in the CTSA infrastructure at Washington University in St. Louis in four general categories (core service use, internal funding, mentor-mentee opportunities, and leadership roles); 2) explored the relationship between CTSA engagement and scholarly productivity; and 3) compared the relationships between engagement and productivity across gender and race/ethnicity. Mixed effects Poisson regressions modeled productivity outcomes on engagement, controlling for demographic and academic characteristics.
  • Results: CTSA members who were engaged were more likely to publish papers and submit grants when compared to others. They were more likely to receive external grant awards – 10% to 20% percent more – than those who were not engaged. Productivity disparities between men and women and to a lesser extent across categories of race and ethnicity persisted even in samples matched on previous productivity levels.
  • Impact: CTSAs could see larger growth in scientific productivity by increasing researcher engagement and addressing demographic disparities – possibly through focused communications to raise awareness of opportunities – and dissemination of case studies and success stories of engagement to membership.
41Hoyt, Catherine PhD, OTD
Washington University in St. Louis
Parent and Provider Perspectives on a Developmental Screening and Therapy Referral Program for Children 0-3 years with Sickle Cell Disease
Hoyt CR, Erickson JE, Luo L, Housten AH, King AH
  • Introduction: Sickle cell disease (SCD) is an inherited blood disorder affecting approximately 100,000 people in the United States. Children with SCD experience severe pain and stroke. A lesser-known side effect can be developmental deficits. Early intervention (EI) can help reduce the impact of deficits. Screening for deficits in the first years of life can support early detection and referral to therapy services. Prior studies suggest that home-based EI can improve outcomes, yet few with SCD are referred to or use these beneficial services. The purpose of this study was to examine strategies to increase participation in screening and EI for children with SCD.
  • Methods: EI providers and caregivers of children 3-5 years with SCD completed a semi-structured interview and survey. Caregivers completed the Knowledge of Infant Development Inventory (KIDI); EI Providers completed the Implementation Climate Scale (ICS). Thematic analysis identified major themes of the interviews. A follow-up survey asked EI providers to rank order incentives to increase the adoption of EI for SCD.
  • Results: Eleven caregivers and eight EI providers participated. Three main themes were identified: 1) high acceptability of a screening and referral program, 2) access to services, and 3) need for caregiver buy-in. All participants described a need to support caregiver buy-in and SCD specific education. Knowledge related to child development is limited among caregivers (KIDI; mean = 79%, SD = 9%). EI providers expressed high interest in increasing EI use, yet ICS scores indicated very low incentive (mean = 0.08, SD = 0.22) for implementing evidence-based practices. The most preferred incentive was the ability to make a decision about something (e.g., topic of meeting).
  • Impact: The findings from this study add to our understanding of what is important to caregivers and would help participation in EI services. This study also identified that leaders in EI are open to new programming that includes SCD, however, there is little programmatic support. These findings indicate that greater support is needed for children with SCD, with a focus on caregiver engagement and child development.
42Kapp, Julie PhD, MPH
University of Missouri – Columbia
Collecting Early Childhood Obesity Measurements Through a Home Visiting Program: A Proof-of-Concept Study
Kapp JM, Hall B, Kemner A
  • Introduction: Community-based home visiting programs are recommended vehicles for early life-course interventions to prevent childhood obesity. We developed and implemented a proof-of-concept protocol for collecting child weight and length or height data for children aged 6 months to 5 years through Parents as Teachers (PAT) affiliates that were geographically dispersed throughout the United States.
  • Methods: We implemented our protocol with 1 affiliate in each of 4 states. We assessed formative measures of the implementation from parent educators and site leaders and reviewed delivery process measures.
  • Results: Findings suggest that collecting data on child measurements through an existing home visiting program is 1) feasible (91% of estimated measurements achieved); 2) does not require much time (median, 0.5 hours spent per child); 3) is a positive experience for families (71% of parent educators indicated that families enjoyed the experience); and 4) is fairly accurate (82% of collected data met eligibility and quality standards).
  • Impact: The program is easily implemented, requires minimal time from program staff, and has positive engagement by parents. Opportunities include practical considerations of more equipment, ease of equipment portability, engaging hesitant children, and enhanced training.
43Lewis, Melissa PhD
University of Missouri – Columbia
The Indigenous Health Toolkit: Results of a Pilot Test from Two Sites
Lewis ME
  • Introduction: Compared to all other racial/ethnic groups in the United States (US), Indigenous People (IP) suffer from the largest mental health, substance use, and physical health disparities. Ethnicity and race play a role in the quality of care and treatment patients receive within the medical system. Specifically, discrimination and bias are associated with health disparities for racial and ethnic minorities. Providers working with Indigenous patients engage in unconscious bias, microaggressions, and discriminatory practices. Biased beliefs have consequences for Indigenous patients’ health outcomes.
  • Methods: A group of experts created an Indigenous Health Toolkit (IHT) to reduce bias and improve care to Indigenous patients. The IHT was piloted at two sites within the United States: The first site is a medical training university in the southwest (hybrid delivery model) and the second site is an Indigenous-serving clinic in the upper Midwest (online). Data collection occurred via online survey pre and post intervention. Students (n=35) and providers (n=14) were asked about their knowledge, skills, beliefs, and bias around Indigenous populations. T-tests were conducted to assess change over time.
  • Results: Results indicate that students had statistically significant improvements in the areas of social justice beliefs, compassion, culture intelligence, ethnocultural beliefs, Indigenous health knowledge, and Indigenous health skills. Healthcare providers had statistically significant improvements in the areas of culture intelligence, Indigenous health knowledge, and Indigenous health skills.
  • Impact: The Indigenous Health Toolkit intervention is feasible and acceptable to both students and healthcare providers. In line with previous research, results indicate that providers gain knowledge and skills to provide appropriate care to Indigenous populations. Feedback from participants and providers will be applied to the intervention for improvement and will continue to be tested at additional sites. This intervention could have a positive impact on the care that Indigenous people receive, as well as improved health outcomes.
44Lineback, Kristen
Washington University in St. Louis
Latinx Ethnicity is Associated with Nutrition Literacy as Barrier to Lifestyle Changes in an Uninsured Urban Population
Lineback K, Ramesh R, Li J, Change R, Walker K, Linares N, Shi V, Payne C, Kesaraju R, Gaona-Romero A, Naceanceno K, Cruz-Bravo P
  • Introduction: Patients of low socioeconomic status (SES) are disproportionately affected by chronic disease, which can often be prevented or treated with healthy lifestyle interventions. Identifying factors preventing healthy lifestyle changes for low SES patients could facilitate the provision of effective counseling to lower their disease burden.
  • Methods: Undergraduate students at the Washington University in St. Louis trained in motivational interviewing and nutrition counseled uninsured clinic patients on healthy lifestyle changes. The students documented the patients’ perceived barriers to making healthy lifestyle changes, and transtheoretical model (TTM) stage of change for making lifestyle changes. The primary barriers perceived by patients were categorized and analyzed for differences in demographics and TTM stages of change.
  • Results: Barriers to lifestyle change fell into three categories: health-related, structural (i.e., related to cost, time, or transportation), and information limitations (i.e., limited understanding of healthy diet or how to prepare healthy meals). Overall, the patients (n=64) were most likely to report structural factors; however, Latinx patients were more likely to report information limitations than other patients (OR = 4.2273, 95% CI 1.37-13.07). Patients with information limitations were more likely to be in an earlier TTM stage of change (OR = 3.257, 95% CI 1.012 – 10.485).
  • Impact: Uninsured clinic patients most often perceived structural factors as their main barrier to making healthy lifestyle change, but Latinx patients were more likely to report informational limitations. Provision of educational nutrition resources to Latinx communities, including Spanish-translated information and healthy culturally relevant foods, should be explored.
45Meyer, Dixie PhD
Saint Louis University
The Relationship Between Health Habits and Global Health Status in Couples Facing Pandemic Stress
Meyer DD, Ferribly-Ferber M, Chen S, Keyvan S, Samanta J, Stratman H, Wang W
  • Introduction: When individuals are in duress, they often neglect health habits. Research shows romantic partners often adopt similar health habits. This study sought to examine the relationship between health habits and current health status in stressed couples during the winter (2020-21) peak of the COVID-19 pandemic.
  • Methods: Different gender couples (i.e., male/female; N=228, n=114) completed this ecological momentary assessment study over a two-week period. Couples selected two work days and two weekend days to complete daily surveys about their day to day activities (e.g. exercise, alcohol use, sleep, diet) and general health habit patterns (e.g., sleep quality, tobacco use, health).
  • Results: Regression analysis tested the relationship between physical health status and health habits including healthy week day eating, weekend emotional eating, exercise, sleep quality, troubled sleep, tobacco use, and alcohol use. Tobacco and alcohol use were not significant and all other predictors were significant. We tested actor partner effects between physical health status and health habits using the significant predictors from the regression model. Weekday healthy eating and sleep quality were related to physical health status for men and women. Weekend emotional eating was related to health status for women. Exercise showed actor effects for women only and partner effects for men only. Sleep quality showed partner effects for men only.
  • Impact: We demonstrated that health habits, when under chronic stress, are related to physical health status. Findings show women’s health habits (i.e., exercise and sleep quality) helped bolster men’s health status. This adds to the growing body of research showing a regulatory effect for women to men in different-gender relationships. These results add detail to our understanding about the impact of health habits during times of chronic stress. These results could be used to develop partner-based interventions to help reduce stress within couples to improve each partner’s health habits with the hope of individuals emerging from the stressful time in a healthier state.
46Pilar, Meagan PhD, MPH
Washington University in St. Louis
Implementation Outcomes and Strategies to Promote the Uptake of COVID-19 Vaccines
Pilar MP, Elwy AR, Lushniak L, Huang G, McLoughlin GM, Hooley C, Nadesan-Reddy N, Sandler B, Moshabela M, Alonge O, Geng E, Proctor EK
  • Introduction: COVID-19 has infected millions to date, resulting in significant morbidity and mortality worldwide. Despite the development of several COVID-19 vaccines, the availability, acceptability, distribution, and uptake of these vaccines has not been sufficient for reaching the 70% vaccination rate required globally to end the pandemic. Implementation science is well-suited to address these issues, and recent articles have highlighted the importance of incorporating implementation science concepts into pandemic-related research. However, limited research has examined implementation outcomes that may be unique to COVID-19 vaccinations and explored how to utilize implementation strategies to address vaccine program-related implementation challenges.
  • Methods: To address these gaps, we established a global implementation science workgroup in January 2021 and met weekly for over a year to review both current and past literature regarding vaccine acceptability, adoption, feasibility, and more. We developed a hierarchy to prioritize the applicability of “lessons learned” from the vaccination-related implementation literature. Building on a well-known implementation science framework, we also collated applications of existing implementation outcomes. Finally, we identified specific implementation strategies to overcome common challenges related to the implementation of vaccination programs, which may ensure future vaccine program success.
  • Results: Our efforts provide rationale for the utility of using implementation science methods to better understand pandemic-related research. Furthermore, we identified three additional outcomes to better evaluate the implementation of COVID-19 vaccine programs-availability, health equity, and scale-up. Results also include a list of COVID-19 relevant implementation strategies mapped to the implementation outcomes, which can be applied at multiple levels to increase vaccine uptake.
  • Impact: Through the identification of three additional implementation outcomes and a compilation of specific implementation strategies that can be applied to increase vaccine uptake, the ultimate goal of this work is to prevent and reduce disease through the uptake of the COVID-19 vaccines.
47Turner, Austin PhD
Saint Louis University
Willingness to Respond to Radiological Disasters Among First Responders in St. Louis, MO
Turner JA, Rebmann T, Charney RL, Loux TM
  • Introduction: During radiological disasters, firefighters and emergency medical services (EMS) personnel are expected to report to work and engage in response activities; however, prior research exploring willingness to respond (WTR) to radiological disasters among first responders has only considered radiological terrorism scenarios and not non-terrorism radiological scenarios. The goal of this study was to compare WTR to terrorism and non-terrorism radiological disaster scenarios among first responders in St. Louis, MO, and to explore determinants of WTR.
  • Methods: Firefighters and EMS personnel were surveyed about their WTR to a dirty bomb detonation (terrorism) and a radioactive landfill fire (non-terrorism). McNemar’s tests were used to assess differences in individual WTR between the two scenarios and if requested versus required to respond. Chi-square tests were used to identify significant individual predictors of WTR.  Multivariate logistic regressions were used to determine final models of WTR for both scenarios.
  • Results: WTR was lower for the dirty bomb scenario than the landfill scenario if requested (68.4% vs. 73.0%; p<.05). For both scenarios, WTR was lower if requested vs. required to respond (dirty bomb:  68.4% vs. 85.2%, p<.001; landfill:  73.0% vs. 87.3%, p<.001). Normative beliefs, perceived susceptibility, self-efficacy, and perceived barriers were significant predictors of WTR in the final models.
  • Impact: WTR among first responders differed significantly between terrorism and non-terrorism radiological disasters, and if requested vs. required to respond. WTR may be increased through interventions targeting significant attitudinal and belief predictors, and by establishing organizational policies that define expectations of employee response during disasters. Community resiliency can be strengthened through implementation of these public health practices.