2023 ICTS Symposium Poster Abstracts

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Early Stage

Poster #	Poster Details
1	Bachman, Graham MS Washington University in St. Louis Massively Parallel Imaging Assay Elucidates Subtle Pathogenic Phenotypes of Mitochondrial Gene Variants Bachman GW, Kremitzki C, Waligorski J, Patel P, Bramley J, Vakaki M, Chandrasekaren V, Ali L, Elia S, Grigore D, Wright M, Mitra R, Milbrandt J, Buchser W Introduction: Mutations in mitochondrial genes underlie numerous neurodegenerative diseases, yet the significance of most variants is uncertain concerning disease phenotypes. Many pathogenic mutations cause visibly distinct morphological differences in afflicted cells, allowing human cells to serve as proxies for patients when studying the genetic basis of disease. This postulate provides the basis for a pooled functional screening platform called “Raft-Seq” that maps cellular phenotypes to specific variants with high-throughput, enabling n-of-1 patient genetic diagnosis in precision medicine. Methods: The Raft-Seq pipeline uses a library of gene knock-out gRNAs introduced to cells by CRISPR/Cas9. Cells are plated onto microraft arrays, stained, imaged, and traced to generate training data for machine learning classifiers. These models identify cells-of-interest, which are isolated, expanded, and sequenced. Cell sequence and feature data are compiled and analyzed to identify pathogenic variants, which are validated in an arrayed assay. Results: We (FIVE@MGI, an ICTS core GESC@MGI affiliate) used Raft-Seq to target numerous mitochondrial genes and investigate their impact on cellular mitochondrial pathology in human cells. Of the 1,102 screened genes, 32 were identified as pathogenic variants and are currently being validated. We also endeavored to identify variants of interest within a library of 225 knock-out gRNAs targeting the ATAD3A and SLC25A19 gene, both of which are implicated in clinical neuropathologies related to mitochondria. Impact: Identifying the cause of a patient’s idiopathic disease can end their diagnostic odyssey. Raft-Seq goes beyond bioinformatic imputation of possible pathogenicity by functionally screening patient variants to determine their impact on disease, causally linking thousands of gene edits to complex and subtle cellular phenotypes. We have used this platform to elucidate novel genes implicated in mitochondrial neuropathologies and to clarify the pathogenicity and phenotype of hundreds of ATAD3A and SLC25A19 variants. These studies set the stage for new genomic diagnostics and therapeutic discovery.
2	Chen, Alan Washington University in St. Louis Translational Evidence Associating NADPH Oxidase and Heparan Sulfate Proteoglycan Activity with Cerebral Amyloid Angiopathy in Alzheimer Patient Biopsies Chen AX, Mostafa AF, Dillon M, Mehla J, Diwan D, Hussein AE, Oloomi K, Meron B, Vissa U, Zipfel G Introduction: Most dementia patients have co-existing vascular contributions to cognitive impairment and dementia (VCID). Cerebral amyloid angiopathy (CAA), a form of vascular dementia, bridges the interplay between VCID and Alzheimer’s Disease (AD) pathology and cooccurs in 90% of patients with AD. The hallmark pathology of CAA is characterized by amyloid-ß deposition in cerebrovasculature. Reactive oxidative species (ROS) promotes vascular oxidative stress (VOS) in CAA. It is now known that NADPH oxidase-derived VOS is a critical mediator of cerebrovascular dysfunction in CAA. Further, Heparan sulfate proteoglycans (HSPGs) are understood to be responsible for the upstream molecular initiation governing Aß induced oxidative stress and vessel dysfunction. Translational evidence does not yet exist associating these molecular markers with CAA. Methods: This study correlated HSPG expression and NADPH oxidase activity with each other, as well as VOS, and CAA in cerebral vessels of AD and non-AD patients, which were all hypothesized at a statistically significant positive correlation. These biopsies were digested for western blot expression analysis of NADPH oxidase, HSPG, and LRP1. Vasculature was isolated from parenchyma to study CAA specifically. Results: Significant correlation was found between NADPH Oxidase markers for NOX2, HSPG markers for glypicans and syndecans, and impaired LRP1 signal intensity with amyloid-ß signal intensity. Further, a synergistic interplay between several oxidative stress markers was found. Impact: These confirm the proof of concept hypothesis that Aß species upregulate HSPG expression, leading to increased NADPH oxidase expression, the primary molecular source of CAA-induced VOS, in human patients. Ultimately, this complements the studies investigating cerebral vessel dysfunction in AD and CAA development. Elucidating how these druggable targets, HSPG and NADPH oxidase, independently or more likely synergistically promote CAA pathogenesis has further provided a powerful platform for developing novel CAA-targeted therapies.
3	Koller, Gretchen Washington University in St. Louis Effect of Germinal Matrix Hemorrhage-Intraventricular Hemorrhage on Neonatal Rat Brain Development: A Time Course Study Koller GM, Pan S, Strahle JM Introduction: Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) is a pathologic condition which preferentially effects premature neonates, some of which later develop posthemorrhagic hydrocephalus (PHH). To date, no study has attempted to provide a head-to-head comparison of structural alterations which occur based on age of hemorrhagic insult. This study aims to provide a time course of age-dependent alterations in neonatal rat brain development as a result of GMH-IVH/PHH through pathology simulation and analysis of 2D high-resolution imaging. Methods: To induce IVH, 20uL of 150mg/mL hemoglobin (HB) dissolved in artificial cerebrospinal fluid (aCSF) was injected into the right lateral ventricle of rat pups on post-natal days 1, 7, or 15. Injection of aCSF alone was used as a control. High-resolution MRI was used to evaluate ventricular, hippocampal, and whole brain volumes on post-injection day 3, 7, and 21. Results: No cerebral areas were significantly different in size between P1 aCSF and HB cohorts overtime. Injection of HB at P7 and P15 has an effect on ventricle and hippocampal volumes that is statistically significant from the effect seen with aCSF injection at these same timepoints. Rats injected with HB at P7 and P15 have significantly larger ventricles over time than rats injected with aCSF (p<0.001), while rats treated with HB at P7 and P15 have significantly smaller hippocampal volumes over time than rats treated with aCSF (p=0.0028 (P7); p=0.0139 (P15)). Animals are currently undergoing behavior testing. We anticipate animals with larger ventricles and smaller hippocampal volumes will achieve lower scores than those with normal volumes. Impact: Data obtained from this study could help us better understand the development of GMH-IVH/PHH neurological sequelae as they relate to structural alterations. The ability to relate previously known cognitive and physical functions to specific physical grey and white matter changes documented through imaging could allow for clinicians to accurately predict future manifestations of current injuries and deliver more individualized care to these neonates and older patients who experienced GMH-IVH/PHH during infancy.
4	Li, Xiaowei PhD Washington University in St. Louis Development of Sutureless Vaso-Lock for Vascular Anastomosis Li X, Young ER, Martin C, Moritz WR, Meade R, Zaghloul M, Ribaudo J, Hicks CW, Kang SH, Zayed M, Sacks JM Introduction: Micro- and macrovascular anastomoses involve suturing together of blood vessels, which is a critical foundational surgical skill. However, it faces many challenges, such as decade-long training and inherent dexterity of the surgeon. Procedures are long and expensive, require specialized operating rooms and equipment, making them prohibitive in many hospitals. Our team has created a unique anastomotic device, Vaso-Lock, as a sutureless coupler. Vaso-Lock is intraluminal, holding free vessel ends together with traction by anchors. We aim to apply Vaso-Lock to change the paradigm of surgical training and practice, and improve technical capabilities for vascular anastomosis. Methods: We have utilized 3D-printing to prototype Vaso-Locks with quick design adjustments. Vaso-Lock maintained its intact structure after ethylene oxide sterilization, which was evaluated by scanning electron microscope. Vaso-Lock was deployed in a porcine model for anastomosis of common carotid artery and internal jugular vein. Doppler ultrasound was used to longitudinally assess patency, blood flow velocities, and lumen preservation. Histological studies were performed to evaluate endothelialization and device-vessel interface biocompatibility. Results: Vaso-Lock maintained anastomosis of common carotid artery to internal jugular vein in 3 porcine, with no evidence of leakage after deployment. Doppler ultrasonography demonstrated the mixture of arterial and venous blood inside the Vaso-Lock. During the extraction of Vaso-Lock, no blood clots were identified at the anastomosis site. Guidewire went through the explanted blood vessels anastomosed by the Vaso-Lock without resistance. All tissue sections with Vaso-Locks displayed open lumen at the anastomosis site. Inflammation cells, along with collagen bundles, appeared around anchors of the Vaso-Lock. Calcium was identified around the Vaso-Lock at 2-week. Intimal growth occurred under the Vaso-Lock at 6-week. We are evaluating surface-modified Vaso-Locks in terms of their long-term patency. Impact: We believe our novel device can dramatically reduce operating time and complications so that surgical anastomotic techniques can be more widely used. Our unique device can be further scaled to other endoluminal anastomosis including ureter, fallopian tubes, biliary trees, and many more.
5	Liu, Chang MD, PhD Washington University in St. Louis Antigen-guided Depletion of Anti-HLA Antibody-producing Cells by HLA-Fc Fusion Proteins Webber AM, Bradstreet TR, Wang X, Guo H, Nelson CA, Fremont DH, Edelson BT, Liu C Introduction: Platelet transfusion and transplantation of allogeneic stem cells and solid organs are life-saving therapies. Unwanted alloantibodies to non-self human leukocyte antigens (HLA) on donor cells increase the immunological barrier to these therapies and are important causes of platelet transfusion refractoriness and graft rejection. Although the specificities of anti-HLA antibodies can be determined at the allelic level, traditional treatments for antibody-mediated rejection non-selectively suppress humoral immunity and are not universally successful. Methods: We designed HLA-Fc fusion proteins with a bivalent targeting module derived from extracellular domains of HLA and an Fc effector module from mouse IgG2a. We characterized the biochemical properties and function of these fusion proteins in vitro and in vivo. Results: We found that HLA-Fc with A2 (A2Fc) and B7 (B7Fc) antigens lowered HLA-A2- and HLA-B7-specific reactivities, respectively, in sera from HLA-sensitized patients. A2Fc and B7Fc bound to B cell hybridomas bearing surface immunoglobulins with cognate specificities and triggered antigen-specific and Fc-dependent cytotoxicity in vitro. In immunodeficient mice carrying HLA-A2-specific hybridoma cells, A2Fc treatment lowered circulating anti-HLA-A2 levels, abolished the outgrowth of hybridoma cells, and prolonged survival compared to control groups. In an in vivo anti-HLA-A2 mediated platelet transfusion refractoriness model, A2Fc treatment mitigated refractoriness. Impact: These results support HLA-Fc as a novel strategy for antigen-specific humoral suppression to improve transfusion and transplantation outcomes. With the long-term goal of targeting HLA-specific memory B cells for desensitization, further studies of HLA-Fc’s efficacy in immune-competent animal models and human specimens are warranted.
6	Nguyen, Andrew PhD Saint Louis University ASOs Targeting the miR-29b Binding Site in the GRN mRNA Increase Translation of Progranulin: Potential Therapeutic Strategy for Progranulin-deficient 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 haploinsufficiency of progranulin. 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, have been reported to negatively regulate progranulin protein levels. Here, we tested if ASOs can increase progranulin levels by sterically blocking the miR-29b binding site in the 3′ UTR of the human GRN mRNA. 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 mechanism of action of these ASOs 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 a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3′ UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by ribosomal profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. Impact: The results of our translational project suggest that our ASO strategy may be a therapeutically feasible method for increasing CNS progranulin levels for progranulin-deficient FTD. Moreover, this strategy could be useful for development of ASO-based therapies 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.
7	Parrow, Nermi PhD Saint Louis University Lobe Specificity of Iron Binding to Transferrin Differentially Influences the Relationship Between Bone Morphogenetic Protein 6 and Hepcidin Expression in Mice Parrow NL, Ali F, George NA, Ginzburg YZ, Rivella S, Fleming RE Introduction: The mechanisms by which changes in transferrin (TF) saturation regulate hepcidin are unclear. We reported that transgenic mice expressing mutant TF that block iron binding to either N-lobe (N-bl) or C-lobe (C-bl) have differences in erythropoietin sensitivity and hepcidin regulation. To characterize the differential regulation of the gene encoding hepcidin, Hamp1, in these mice we analyzed the effects of dietary iron or exogenous administration of the iron signaling molecule, bone morphogenetic protein 6 (BMP6). Methods: Preweanling wild-type (WT), N-bl, and C-bl were gavaged with 4 mg/kg/d FeSO4 (or saline) in 2 divided doses for 3 days and sacrificed on day 4. Other 14-day old mice were administered 500 µg/kg BMP6 (or saline) IP and sacrificed 6 hours later. Results: Iron-treated mice demonstrated increased serum iron, TF saturation, and liver iron concentration in all 3 groups. The magnitude of increase in Hamp1 mRNA was greater in the C-bl mice (44-fold, p<0.01) compared to N-bl (9-fold) and WT mice (10-fold). The differential effect of iron treatment on Hamp1 was not attributable to effects on liver Bmp6 or Bmp2 expression. It was also not attributable to effects on the expression of splenic Fam132b, the gene encoding the erythroid hepcidin regulator erythroferrone. To further examine the observed increased Hamp1 relative to Bmp6 in the C-blocked mice, we assessed the effect of exogenous BMP6 on Hamp1 expression. The magnitude of the increase in Hamp1 mRNA was likewise greater in C-bl mice compared to N-bl mice and the difference was not attributable to differences in TF saturation, hepatic Bmp6, Bmp2 or splenic Fam132b expression. Impact: Iron and BMP6 treatment each effected a greater increase in liver Hamp1 expression in TF C-bl compared to N-bl mice. The responsiveness to BMP6 in the regulation of hepcidin is significantly influenced by which TF lobe iron occupies. We speculate that the differential responsiveness of the N-blocked and C-blocked TF to BMP6 and erythropoietin may have important implications in disease characterized by altered iron homeostasis and/or erythropoietin responsiveness.
8	Snoderly-Foster, Lisa PhD Saint Louis University Evolution of a Functionally Intact but Antigenically Distinct Dengue Virus Fusion Loop Snoderly-Foster LJ, Meganck RM, Zhu D, Dong S, Dalben YR, Thiono D, White L, Desilva AM, Baric RS, Tse LPV Introduction: A hallmark of Dengue virus (DENV) pathogenesis is the potential for antibody dependent enhancement (ADE), which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. ADE is linked to antibodies targeting the pre-Membrane (prM) protein and the fusion loop (FL) motif of Envelope (E) protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. It has been a commonly-held belief that the FL could not be altered due to its role in viral fusion and entry. However, we hypothesized that a DENV-FL mutant could be generated through directed evolution and that such a mutant could be a valuable tool in producing a more efficacious vaccine against DENV. Methods: Saturation mutagenesis and directed evolution were used to engineer a functional variant with a mutated FL. Downstream analysis included DENV growth kinetics, DENV thermal stability assay, and neutralization assays. Results: In the current study, we engineer a functional variant with a mutated FL (D2-FL) which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4) infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2) infected NHP. Impact: ADE of Dengue has been linked to the production of weakly-neutralizing CR antibodies against the prM and FL epitopes of DENV. Making these epitopes unrecognizable within a vaccine could reduce the production of these harmful antibodies. Our results demonstrate that the DENV-FLM mutant retains the ability to infect cells, but is insensitive to monoclonal antibodies against prM and FL. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live attenuated DENV vaccines suitable for naïve individuals and children.
9	Uner, Burcu PhD University of Health Sciences and Pharmacy A Tampon-like Xerogel Device for Non-hormonal Contraception Uner B, Pauletti GM Introduction: An unplanned pregnancy can be an emotionally devastating experience for a woman. To expand non-hormonal choices for female-controlled contraceptive methods, this research aims to develop a drug-free, tampon-like xerogel device capable of fortifying natural contraceptive mechanisms within the female reproductive tract. Methods: Xerogel devices were fabricated by lyophilization of a hydrogel comprised of Carbopol® 974P (4%, w/w), polyvinylpyrrolidone (4%, w/w), and D-mannitol (3%, w/w). Viscoelastic and mucoadhesive properties of xerogel devices following exposure to vaginal fluid simulant, pH 4.2, (VFS) and seminal fluid simulant, pH 7.7, (SFS) were quantified using the TA-XT Plus Texture Analyzer. In parallel, buffer capacity was measured using a DeltaTrak ISFET pH probe. Device porosity was estimated using volumetric displacement of n-hexane. Results: The porosity of lyophilized xerogel devices was 72-77%. Exposure of xerogel devices to VFS rapidly established a partially hydrated gel phase, which exhibited mucoadhesive properties that were 2-fold greater than those measured for the marketed contraceptive VCF® gel. Viscoelastic properties of the VFS-hydrated xerogel device dramatically increased by 160% upon exposure to SFS. Under those conditions, however, the pH value of the gel phase only moderately increased from pH 3.4 to pH 4.8. Impact: Vaginal administration of this tampon-like xerogel device fabricated by lyophilization rapidly establishes an acidic, bioresponsive gel phase that increases in viscoelastic properties upon exposure to alkaline seminal fluid. Combined with the pronounced buffer capacity of the acidic gel phase, this novel, drug-free bioengineering concept is predicted to exhibit significant contraceptive efficacy in vivo by fortifying the natural contraceptive mechanisms within the female reproductive tract.

Clinical

Poster #	Poster Details
10	Al-Hammadi, Noor MBChB, PhD, MPH Saint Louis University A Pharmacogenetic Algorithm for Days 6-21 of Warfarin Therapy Predicts the Therapeutic Warfarin Dose Al-Hammadi N, Stephenson KB, Hou J, Bass AR, Eby CS, Gage BF Introduction: Warfarin remains a commonly prescribed anticoagulant, use of which is complicated by significant inter-patient variability in the therapeutic dose and a narrow therapeutic index. Algorithms to refine the warfarin dose are needed, especially during days 6-21 of warfarin therapy, when iatrogenic hemorrhages are common. Objective: To develop clinical and genotype-guided dosing algorithms for days 6-21 of warfarin therapy. Methods: We analyzed data from the Genetic Informatics Trial of Warfarin Therapy to Prevent Deep Venous Thrombosis (GIFT). We randomly split data from the 1471 patients who achieved a therapeutic dose into training (80%) and validation (20%) datasets. We offered clinical, demographic, and laboratory variables into linear regression models. We also offered polymorphisms of the following genes VKORC1, CYP2C9, and CYP4F2 into the genetic models. We used prior research, biologic plausibility, and statistical significance (Akaike information criteria) to select variables. We quantified accuracy using correlation (R2) and mean absolute error (MAE) in the validation dataset. Results: The clinical model had an R2 of 74.0% and MAE of 0.63 mg/day; the genetic model had an R2 of 77.4% and MAE of 0.62 mg/day. The strongest predictors of therapeutic dose were the most recent warfarin doses and the current value of the International Normalized Ratio (INR). Impact: Algorithms using clinical, demographic, and laboratory variables available from the initial 6-21 days of warfarin therapy can predict the therapeutic dose. These dose-refinements may be useful in guiding warfarin dosing.
11	Arbuckle, Amanda Washington University in St. Louis A Masked, Controlled Trial of Median Nerve Stimulation for Tourette Syndrome Arbuckle AL, Iverson AM, Ueda K, Song DY, Bihun EC, Koller JM, Wallendorf M, Black KJ Introduction: A prior study showed that rhythmic, but not arrhythmic, 12 Hz stimulation of the median nerve (MNS) entrained the sensorimotor cortex EEG signal and found that 10 Hz MNS improved tics in Tourette syndrome (TS). However, no control condition was tested, and stimulation blocks lasted only 1 minute. We set out to replicate the TS results and to test whether tic improvement occurs by the proposed cortical entrainment mechanism. Preregistration was completed at ClinicalTrials.gov, under number NCT04731714. Methods: Thirty-two people with TS, age 15-64, completed two study visits with repeated MNS on and off blocks in random order, one visit for rhythmic and one for arrhythmic MNS. Subjects and staff were blind to order; a video rater was additionally blind to stimulation and to the order of visits and blocks. Results: Rhythmic MNS at 10 Hz improved tics. Both rhythmic and arrhythmic 12 Hz MNS improved tic frequency, intensity, and urges, but the two treatments did not differ significantly. Participant masking was effective, and there was no carryover effect. Several participants described a dramatic benefit. Discomfort was minimal. There was no evidence that the MNS benefit persisted after stimulation ended. Impact: These results replicate the tic benefit from MNS but show that the EEG entrainment hypothesis cannot explain that benefit. Another electrophysiological mechanism may explain the benefit; alternatively, these data do not exclude a placebo effect.
12	Benedict, Emily Washington University in St. Louis Pseudomonas Aeruginosa is Present in Sink Drains of Multiple ICU Wards at a Tertiary Medical Center Benedict EE, Newcomer EP, Sukhum KV, Cass C, Wallace MA, Johnson C, Fine J, Sax S, Bartlet MH, Burnham CD, Kwon JH, Dantas G Introduction: Healthcare-associated infections are a rising threat to hospitalized patients. Pseudomonas aeruginosa reservoirs in the hospital environment have been connected to patient infections in intensive care units (ICUs), including the stem cell transplant and oncology (SCTO) ICU in Barnes Jewish Hospital. Sink drains were identified as a consistent source of antimicrobial resistant organism (ARO) growth, including P. aeruginosa, from year-long repeated sampling in this ICU. It is unknown if sink drains in other ICU wards are similarly contaminated with AROs. Consequently, we collected and analyzed longitudinal sink drain swabs from SCTO ICU and surgical ICU (SICU) patient and non-patient rooms to identify Pseudomonas presence in these environments. Methods: Once a week for three weeks, sink drains from patient rooms, housekeeping closets, and soiled utility rooms in the SCTO ICU and SICU were sampled using moistened Eswabs. These swabs were then cultured on Cetrimide agar to enrich for Pseudomonas. All growth on each Cetrimide plate was subjected to metagenomic shotgun short-read sequencing, which enables identification of the taxa present in each sink drain sample. Results: Pseudomonas species were identified in both the SCTO ICU and SICU, with the housekeeping closets and soiled utility rooms containing Pseudomonas in all sinks across all three weeks of sampling (present in 12 of 12 samples). In the SCTO ICU, Pseudomonas was present at multiple timepoints in three rooms (present in 12 of 17 samples), while the SICU contained only one room with multiple Pseudomonas-positive timepoints (present in 8 of 16 samples). Stenotrophomonas, Serratia, and Klebsiella were also identified in all sampling locations. Impact: Pseudomonas presence in sink drains of multiple ICU wards suggests that these sink drains represent a persistent reservoir of Pseudomonas or that these sink drains are being consistently seeded with Pseudomonas, both of which warrant further exploration into the specific strains of AROs present in each sink. The presence of AROs in the SICU and non-patient rooms emphasizes the need for hospital environmental surveillance and appropriate adaptation of infection prevention measures.
13	Butler, Andrew PhD Saint Louis University Attenuated Cognitive Decline in Community-dwelling Older Adults with High Plasma Adropin Concentrations Butler AA, Aggarwal A, Morley JE, Vellas B, Nguyen AD Introduction: Adropin is highly expressed in post-mortem human brain samples relative to other tissues and correlates with RNA and protein signatures linked to cognitive decline. Increasing adropin levels in old C57BL/6J mice improves learning and memory. Whether circulating adropin levels correlate with cognitive decline in humans of advanced age is not known. Methods: We investigated the relationship between plasma adropin concentrations and cognitive decline in participants of the Multidomain Alzheimer Preventive Trial (MAPT; ClinicalTrials.gov Identifier, NCT00672685; mean age 75.8y, SD=4.5y, 60.2% female, n-452). Cognitive ability was evaluated using a composite cognitive score (CCS) that assessed four domains: memory, language, executive function, and orientation. Relationships between plasma adropin concentrations and changes in CCS (deltaCCS) during the study were examined using cox binomial regression or grouping into tertiles ranked by adropin values and controlling for age, time between baseline and final visit, baseline CCS, education and medications. Results: Increasing plasma adropin levels associated with reduced risk of cognitive decline (HR=0.873, 95% CI 0.780-0.977, P=0.018). Between adropin tertiles, deltaCCS was significantly different (estimated marginal mean andSE for the 1st, 2nd, and 3rd adropin tertiles, -0.299+/-0.057; -0.252+/-0.057; -0.107+/-0.058; n=151,152, and 149, respectively; P<0.05 between 1st and 3rd adropin tertile). Protection was observed in carriers of the APOE4 allele, while plasma Aβ42/40 ratios were significantly higher in the 3rd adropin tertile. Impact: These results suggest that the rate of cognitive decline is lower in community-dwelling older adults with higher circulating adropin levels. Further studies are needed to determine the underlying causes of the relationship and whether increasing adropin levels can delay cognitive decline.
14	Castro, AC Washington University in St. Louis Decreasing Unnecessary Urinary Catheter Usage in the ICU Castro AH, Ablordeppey EA, Rosenzweig TR Introduction: Millions of indwelling catheters are placed each year to monitor urine output. Catheter associated urinary tract infections (CAUTIs) are the most commonly hospital-acquired infections and associated with urinary catheters. Previous efforts to decrease CAUTIs in the intensive care unit (ICUs), which are more likely to use urinary catheters, have had minimal success. Despite unclear indications for use, indwelling catheters may not be removed in patients for various reasons including need for hourly urine output monitoring, limited patient mobility or concern for incontinence. This study seeks to understand the current patterns of and reasons for prolonged catheterization in the surgical ICU. The ultimate goal of the study is to identify ways to decrease urinary catheterization and CAUTIs in the ICU. Methods: We conducted a retrospective chart review of patients in a 36-bed surgical ICU from 01/01/2022-06/30/2022 who had a urinary catheter placed during admission. We defined the appropriateness of catheterization as correlation between catheter utilization indication versus evidence of such during chart review. Abstractors reviewed records for: insertion details, duration, associated acute kidney injury (AKI), severity of illness, disposition, and mortality. Inter-rater reliability will be described. Results: Results will describe current practice patterns of urinary catheterization in the ICU. Data will highlight the relationship between severity of illness, frequency of associated AKI, and urinary catheterization rates. Data will also identify most common urinary catheter placement location (Emergency Department /ICU/Operating Room), average catheter duration, key indicators identified for catheter maintenance, and occurrence of maintenance vs. chart indication. Impact: The first step to developing an implementation program to decrease unnecessary urinary catheter use is to develop comprehensive understanding of the current practices of urinary catheter utilization in the ICU. Demonstrating a protocol that decreases urinary catheter rates in the ICU would be a significant change in practice and can directly improve patient care outcomes. Decreasing the rates of CAUTIs results in disease prevention and improved health care quality and delivery, while simultaneously resulting in cost savings for the hospital system.
15	Cifarelli, Vincenza PhD Saint Louis University PET Imaging Cardiac Inflammation in CD36-deficient Individuals Cifarelli V, Abumrad NA, Liu Y, Gropler R Introduction: Fatty acid translocase CD36 regulates cardiac function, and its deletion in rodents associates with atrioventricular block and bradycardia and increasing risk of sudden death following prolonged fasting. Preclinical and clinical research show that monocyte chemotactic protein-1/chemokine (C-C motif) receptor 2 (MCP-1/CCR2) regulates myocardial remodeling and inflammation during cardiac disease. Our preliminary data, conducted with a specific CCR2 binding PET radiotracer, 64Cu-DOTA-ECL1i, show higher monocyte/macrophage (CCR2+) infiltration in CD36 null hearts at steady state as compared to age- and sex-matched wild-type mice. In African Americans, CD36 genetic variants associate with dyslipidemia, vascular stiffness, and cardiovascular disease. However, the role of CD36 in myocardial remodeling and inflammation, 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: Obese African American carriers and BMI-matched non-carriers (n=14) of the coding single nucleotide polymorphisms rs3211938, (minor allele frequency ~20%), will receive 64Cu-DOTA-ECL1i by infusion for PET/CT imaging. Results will be validated by 1) radiotracer binding profile ex vivo in isolated monocyte by autoradiography and 2) CCR2 expression in monocytes subsets by flow cytometry. Results: As compared to non-carriers, CD36 carriers present 1) increase expression of CCR2 in classical and intermediate monocytes; 2) increased level of monocytes (CD14+), and 3) increased plasma ceramides species typical of coronary heart disease and heart failure. Impact: 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, in particularly CCR2+, drive myocardial inflammation during dysfunctional lipid metabolism. Results from these studies will serve as the foundation for future investigations determining how the myocardial inflammation drives cardiac pathology and identify potential therapeutic approaches to ameliorate the process.
16	DeMarco, Elisabeth Saint Louis University Assessing the Impact of Comorbid Depressive and Anxiety Symptoms on Severity of Functional Impairment in a Nationally Representative Sample DeMarco EC, Hinyard L, Subramaniam DS Introduction: Performing self-care and domestic life tasks are key measures of functional independence for older adults. While both depression and anxiety symptoms have been correlated with increased functional limitation, these two disorders are most often studied separately, despite frequent co-occurrence and plausible interactive effects. This study examined the impact of comorbid depressive and anxiety symptoms on the severity of functional limitation in a nationally representative sample of older adults. Methods: The National Social Life, Health, and Aging Project (NSHAP) data was utilized for this study. The primary outcomes were self-reported severity with activities of daily living and instrumental activities of daily living. A composite measure of mental health was created based on reports of frequent depressive and anxiety symptoms. All analyses were weighted to account for the complex sampling design of NSHAP and conducted in R. Results: Respondents were 53.9% female, with a median age of 62 years. Approximately one-third of respondents documented either depressive or anxiety symptoms, with 11% documenting both. Those with both depressive and anxiety symptoms reported the greatest number of functional limitations, and the greatest difficulty with the tasks assessed. In a multivariate linear regression, worse mental health status, greater age, increased comorbidity burden, and reduced income significantly predicted the severity of functional limitation. Depressive symptoms with and without anxiety symptoms were significantly associated with increasing severity of functional limitation when compared to those without either depressive or anxiety symptoms. Impact: To create policy and individual-level interventions that best support functional status over the entire life course, it is vital that we understand the impact of comorbid depression and anxiety on functional status. These results build on existing literature calling for a more holistic assessment of health – both physical and mental – and further emphasizes the need for transdiagnostic mental health interventions as an avenue to increase functional independence in older adults.
17	Gupta, Aditi PhD Washington University in St. Louis Identifying Factors Associated with Preeclampsia Using Electronic Health Records Data Gupta A, Oh IY, Zhao M, Lewis A, Bhattarai K, Kernberg A, Nelson DM, Payne PRO, Lai AM Introduction: Chronic hypertension (CHTN), gestational hypertension (GHTN), preeclampsia (PE), and CHTN with superimposed PE (siPE) are hypertensive disorders of pregnancy (HDP). Criteria distinguishing HDPs are imprecise and the factors driving development of one or more HDPs and progression to PE, associated with increased risk of maternal and fetal morbidity and mortality, are unclear. Identifying more nuanced risk factors and early-warning signs of PE will improve risk stratification of patients, allowing clinicians to implement more intensive monitoring and prophylactic therapies for at-risk patients while reducing unnecessary interventions for low-risk patients. Methods: We obtained retrospective electronic health records (EHR) data from pregnancy episodes completed between June 1 2018 – August 31 2022 at Washington University/Barnes-Jewish Hospital (BJH) for patients 12-50 years of age. Univariate analyses were performed at the episode-level to identify significant variables associated with PE in individual pregnancies. Geographic information systems (GIS)-based analyses and comparisons of social vulnerability index (SVI) measures were performed at the patient-level to assess the effect of social determinants of health (SDoH) on PE risk. Results: Out of 35,653 episodes, 2,323 (6.5%) were affected by CHTN, 1,511 (4.2%) by GHTN, 1,720 (4.8%) by PE, 340 (1.0%) by siPE, and 30 (0.1%) by eclampsia. Episodes affected by PE were significantly associated with CHTN, GHTN, fetal growth restriction, diabetes, higher diastolic and systolic blood pressures, Black race, and higher rates of preterm birth and eclampsia. 22,472 patients were included in our GIS-based SDoH analyses. Patients who lived further from a prenatal clinic and in disadvantaged neighborhoods had significantly increased odds of developing PE. Impact: We established cohorts for each HDP and identified demographic, clinical, and SDoH factors that affect PE risk. These are necessary steps towards future development of machine learning models to accurately diagnose and predict development of HDPs, and pinpoint targets for intervention to prevent development of PE and improve PE-related outcomes.
18	Iverson, Ann Washington University in St. Louis Median Nerve Stimulation for Treatment of Tics: A 4-week, Open Trial with Ecological Momentary Assessment Iverson AM, Arbuckle AL, Song DY, Bihun EC and Black KJ Introduction: Current treatments for Tourette Syndrome (TS) and other chronic tic disorders (CTD) are inadequate, and patients desire new treatment options. Median nerve stimulation (MNS) at 10-12 Hz was recently proposed as a novel treatment for TS/CTD. We report on 31 people ages 15-64 with TS/CTD who participated in an open-label, comparative (within-group, several time points) study of MNS (ClinicalTrials.gov registration number NCT05016765). In this study, we aim to gather additional data on the efficacy of MNS, as well as to assess practicality and tolerability outside of a laboratory setting. Methods: Participants were recruited from completers of a randomized controlled trial (RCT) of MNS and were given a transcutaneous electrical nerve stimulation (TENS) unit to use as desired for MNS for 4 weeks. Participants were instructed to complete surveys regarding tic frequency, tic intensity, and stimulation discomfort each time they began or ended stimulation, as well as twice daily when prompted by text message at random times. Participants also completed an extensive final survey. Results: Median device use was 1.5 days per week (interquartile range [IQR] =1.4) and 50 minutes per day used (IQR= 93). Tic frequency improved during MNS (mean improvement 1.0 on a 0-5 scale, p <0.001), as did tic intensity (mean improvement 0.9, p <0.001). Mean discomfort was mild (1.2 on a 3-point scale). 21 participants (78%) reported plans to continue using the device. Participants’ results in this study did not correlate significantly with their results in the preceding blinded RCT. Impact: Although 4 participants did not complete the study, in the remainder we found MNS to improve tic frequency and intensity with minimal side effects. Thus, MNS may have promise as a potential treatment for patients with TS/CTD, although further studies are needed.
19	Laboe, Agatha Washington University in St. Louis The Relation of Food Insecurity to Eating Disorder Characteristics and Treatment among Respondents to the National Eating Disorders Association Online Screen Laboe AA, D’Adamo L, Grammer AC, McGinnis CG, Davison GM, Balantekin KN, Graham AK, Smolar L, Taylor CB, Wilfley DE, Fitzsimmons-Craft EE Introduction: Food insecurity (FI), characterized by limited or uncertain access to adequate food, has been associated with eating disorders (EDs). This study explored whether FI was associated with ED behaviors, ED diagnosis, current treatment status, and treatment-seeking intentions among adults who screened positive for probable EDs on an online ED screen. Methods: Respondents with probable EDs on the National Eating Disorders Association online screening tool self-reported demographics, FI, height and weight, past 3-month ED behaviors, and current treatment status. Respondents were also asked an optional question about treatment-seeking intentions. Hierarchical regressions evaluated relations between FI and ED behaviors, treatment status, and treatment-seeking intentions. Chi-square tests explored differences in probable ED diagnosis by FI status. Results: Of 7,517 respondents, 27% screened at risk for FI. FI was associated with greater binge eating (R2Change = .001), laxative use (R2 Change = .002), and presence of dietary restriction (R2Change = .001, OR: 1.32) beyond the effects of demographics and BMI (ps < .05). Respondents with FI more commonly met criteria for clinical/subclinical bulimia nervosa compared to those without FI (40% vs. 33%, p < .05). FI was not associated with current treatment status or treatment-seeking intentions. Impact: Findings add to existing literature supporting a relation between FI and EDs. Implications include a need to disseminate EDs screening and treatment resources to populations affected by FI and to tailor treatments to account for barriers caused by FI.
20	Luan, Zhijian MS University of Missouri – Columbia Resolving and Visualizing Irregular Heartbeats Measured by Cardiac Magnetic Resonance Zhijian L Introduction: Atrial fibrillation (AFib) is the most common irregularity of heartbeats. It can cause significant symptoms and impair heart function. Its irregular and often very rapid heart rhythm can lead to blood clots that cause stroke or heart attack, especially as the patient ages. The irregularity of heartbeats has prevented visualization of the heart using standard cardiac magnetic resonance (CMR), which usually attempts to average the beats. Real-time CMR imaging, without averaging, is better suited to visualizing irregular cardiac cycles. However, radiology lacks methods to manage the irregularity. We developed tools for easy viewing and compared heterogeneous heartbeats measured by CMR during active breathing. Methods: Our software automatically tracks the main heart motion, resolved by principal component analysis, to capture arrhythmic and normal cardiac cycles. The new approach determines the distribution of lengths of heartbeats, plots the lengths of successive pairs of beats in Poincare plots, and compares heartbeats from inspiratory and expiratory phases of respiration. Results from each subject are compared with healthy subjects, which may enable scoring of the irregularity of the AFib. Results: Per minute of scanning, the healthy cohort averaged 5 heartbeats deviating to shortened or prolonged length compared with the mean, whereas subjects with a history of AFib averaged 12 such heartbeats, a statistically significant difference (p<0.05). Specific examples will be shown. Impact: Results from each subject are compared with healthy subjects, which may enable scoring of the irregularity of the AFib.
21	Schoen, Martin MD, MPH Saint Louis University Number of Prescription Drugs and Overall Survival in Metastatic Castrate Resistant Prostate Cancer Schoen MW, Pickett CR, Eaton DB, Heiden BT, Chang SH, Yan Y, Subramanian MP, Puri V Introduction: Assessment of comorbidities is essential to clinical research and predicts adverse events and death. Prescription medications could be a tool for predicting risk independent of the Charlson Comorbidity Index (CCI). Additionally, clinicians have access to prescription medication lists, facilitating assessment of comorbidities. Methods: Retrospective study conducted of US Veterans treated for metastatic castrate resistant prostate cancer (mCRPC) May 2011-June 2017. We determined number of unique drugs and drug classes prescribed one year prior to 14 days before treatment. Multivariable logistic regression and Cox proportional hazard modeling was used to assess the association between number of drugs with 90-day mortality and overall survival (OS) while adjusting for age, CCI, body-mass index, prostate specific antigen, race, prior docetaxel, hemoglobin, albumin, bilirubin, and creatinine. Results: In 11,021 Veterans, a median of 11 (IQR, 6-18) medications and 10 (5-15) medication classes were filled in the year prior to treatment. The median age was 75 years, median CCI was 3, and 2,550 were black (23.1%). Increasing age was associated with increased CCI. Increased age was associated with decreased number of medicines. Black race was associated with increased number of mean medications compared to white race (15.5 vs. 12.0, p<0.001). After adjustment, the number of medications and drug classes were independently associated with increased 90-day mortality with adjusted OR (95% CI) of 1.021 (1.011,1.030) and 1.024 (1.012,1.036) respectively. Number of medications and drug classes were associated with decreased OS with adjusted Hazard Ratio of 1.015 (1.013,1.018) and 1.018 (1.014,1.021) respectively. Within subgroups of patients with comparable CCI, increased number of medications was associated with increased risk of death. Impact: The number of prescription medications and drug classes are independently associated with short- and long-term outcomes in patients with mCRPC, even after accounting for important covariates including age and CCI. Patient medications may provide a simple, yet reliable tool to assess comorbidities, risk of adverse events, and death.
22	VanDyke, Melanie PhD University of Health Sciences and Pharmacy Medication Hoarding: Associated Risk Factors for Older Adults with Family Caregivers in the US and Ireland VanDyke M, Ni Sheachnasaigh E, Ryan T, Lukas S Introduction: Medication hoarding is an important health risk factor (Sorenson et al., 2005). In addition, hoarding is related to falls and injuries (Wick & Zanni, 2011) and may be particularly concerning in a community-dwelling older population (Dozier, Porter, & Ayers, 2016). Individuals with complex medication regimens who require assistance from family caregivers may be at greater health risk. This project examines the relationship between Medication Saving Behaviors (MSB) and related risk factors for older adults living in the US or Ireland. Methods: In the US (n = 119) and Ireland (n = 66) caregivers providing medical management for an older family member living in the community completed an online survey. Measures included MSB; Hoarding Rating Scale (HRS); Adherence to Refills and Medication Scale (ARMS); Clinical Dementia Rating (CDR); and the number of expired medications, falls, and injuries. Results: As hypothesized, MSB scores were significantly correlated with HRS, ARMS, expired medications, and injuries (r = .24-.44; p = .001-.018). However, MSB was not related to falls nor CDR. Preliminary data from the Irish sample shows a similar pattern with each of these relationships. When the quantity of medications caused distress and mismanagement, several health risk factors were more prevalent. The majority of our participants had subclinical hoarding scores, perhaps explaining why our fall results did not match the previous literature (Ayers & Dozier, 2015). Impact: This research has important implications for identifying problematic medication saving practices, promoting medication adherence and safer medication usage, and reducing the risk of injury in community-dwelling older adults. This research demonstrates that the caregiver-rated MSB scale can help to identify higher-risk patients for intervention. For instance, Medication Therapy Management (MTM) may be particularly important to older adults with higher MSB scores who rely on family caregivers to assist with their medications.
23	Xu, Zhichen MA Washington University in St. Louis Subgroup Identification Based on Mixed Model for Repeated Measures for Alzheimer Disease Trial Xu Z, Ding J, Liu L, Su X, Wang G, Zhao Y Introduction: Many studies have shown that the progression of Alzheimer’s disease (AD) varies substantially from patient to patient. It is important to identify subpopulations who may benefit from the investigational treatment. Subgroup identification can help clinicians select patients who are most likely to have a positive response to a treatment. It may also inform the development of new therapeutic agents that can improve the treatment of AD. Methods: We propose a Mixed Model for Repeated Measures Interaction Tree (MMRM-IT), building on the assessment of the treatment-by-covariates interactions. MMRM-IT can automatically seek subgroups of individuals in whom the treatment shows heterogeneous effects. We apply this method to analyze the data from the clinical trial of “Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment”, a multicenter, randomized, double-blind, placebo-controlled, parallel-group study with a duration of 36 months. Results: Patients with a Score on Activities of Daily Living Scale less than or equal to 45 may benefit from a Vitamin E treatment. Patients with an MMSE Score less than or equal to 24 or a Score on Activities of Daily Living Scale less than or equal to 43 may benefit from a Donepezil treatment. Subsequent experiments could be conducted on these people to further verify this effect. Impact: We constructed and will release the R package for MMRM-IT. This algorithm can be used when analyzing data from a clinical trial to detect the presence of heterogeneous treatment effects and to find characteristics of the corresponding subgroups. Subsequent large-scale trials can enroll patients who meet the characteristics of these subgroups with positive effects.

Health Services/Population Health

Poster #	Poster Details
24	Ahmad, Ali MD Saint Louis University Coronary Reactivity Assessment Reduced the Healthcare-associated Cost of Patients Presenting with Angina and Non-obstructive Coronary Artery Disease Ahmad A, Corban MT, Moriarty JP, Kanaji Y, Rosedahl JK, Gulati R, Rihal CS, Prasad A, Sara JD, Toya T, Horst I, Lerman LO, Borah B, Lerman A Introduction: The financial burden linked to the diagnosis and treatment of patients with chest pain on the healthcare system is considerable. Angina and non-obstructive coronary artery disease (ANOCA) are common, associated with adverse cardiovascular events, and may lead to repeat testing or hospitalizations. Diagnostic certainty can be achieved in patients with ANOCA using coronary reactivity testing (CRT), however, its financial effect on the patient has not been studied. Methods: Patients with ANOCA who underwent diagnostic coronary angiography (CAG) and CRT (CRT group) were matched to controls who had similar presentation but only underwent a CAG without CRT (CAG-group). Standardized inflation-adjusted costs were collected and compared between the 2 groups on an annual basis for 2 years post the ‘index-date’ (CRT or CAG). Results: 252 CRT and 207 CAG patients were included in the study with an average age of 52.3±11.4 years and 75% females. The total cost was significantly higher in the CAG group as compared to the CRT group ($37,893 [$27,121 – $48,665] vs $13,794 [$10,052 – $17,536]; p<0.001). When costs are itemized and divided based on the Berenson-Eggers Type of Service (BETOS) categorization, the largest cost differences occurred in imaging (any type, including CAG) (p<0.001), procedures (e.g. PCI/CABG/thrombectomy) (p=0.001), and test (e.g. blood tests, EKG) (p<0.001). Impact: Assessment of CRT in patients with ANOCA significantly reduced costs and healthcare utilization over two years. Therefore, the study supports the proper integration of CRT into clinical practice.
25	Anderson, Elizabeth PhD, RN, CLT University of Missouri – Columbia Using Data Science Techniques to Identify Clinical Variables Associated with Negative Respiratory Outcomes in Breast Cancer Survivors Diagnosed with COVID-19 Anderson EA, Anbari AB, Baskett WI, Hulett JM, Narkthong N, Cheng AL, Armer NC, Sun Y, Shyu CR, Armer JM Introduction: Studies have shown the negative physical, psychosocial, and health system outcomes resulting from the COVID-19 pandemic. These outcomes have impacted screening, treatment, symptom management, and survivorship of breast cancer survivors. Understanding associations between breast cancer survivorship and COVID-19 outcomes is important to developing care guidelines to improve outcomes. The study goal of this reported research was to explore associations between COVID-19 and negative respiratory outcomes in breast cancer survivors using the Cerner Real-World dataset. Methods: Contrast set-mining was performed to identify variable patterns related to worse post-COVID-19 respiratory outcomes (pneumonia, respiratory failure, hypoxia, mechanical ventilation). Pearson’s chi-squared tests were applied to detect significant differences in categorical variables within and outside mined data in selected subgroups. Patterns of high statistical significance (p < .05, Growth > 2.87-10.73) were prioritized for clinical implications. Results: Breast cancer survivors diagnosed with COVID-19 who experienced a negative respiratory outcome were contrasted with survivors who did not experience a negative respiratory outcome. Analysis produced patterns of association using a base pattern of breast cancer and COVID-19 diagnoses and adding covariates of interest in a step-wise manner. Fifty highly-statistically-significant patterns associated with a negative respiratory event were observed. In addition to COVID-19 and breast cancer, the most significant patterns included the covariates of: preexisting COPD (Growth = 10.42); age > 80 (Growth = 8.17); White race (Growth = 8.13); anticoagulation (Growth = 6.11); diabetes mellitus and hypertension (Growth = 6.07). Impact: Identifying significant associations between demographic characteristics, co-morbidities, breast cancer and COVID-19 diagnosis and negative respiratory outcomes may contribute to development of screening and surveillance guidelines for high-risk cancer populations. This knowledge may increase efficiency of resource allocation in future pandemics and during eras of health system constraints.
26	Banks, Devin PhD University of Missouri – Columbia Environmental Determinants of Fatal Opioid Overdose in the Fentanyl Era: A Geospatial Analysis Considering Racial Inequities Banks DE, Scroggins S, Paschke M, Shacham E, Nance M, Cavazos-Rehg P, Winograd RP Introduction: The proliferation of illicit fentanyl and its analogues in the “third wave” of the opioid crisis has led to record overdose deaths disproportionately impacting Black individuals in the U.S.. Despite recent racialized shifts in opioid availability, little research has examined how the spatial epidemiology of opioid overdose death may have also shifted. This research has implications for providing targeted overdose-prevention services that address environmental determinants specific to fentanyl, which has eclipsed the morbidity and mortality burden of other drugs. Methods: We examined fatal opioid overdose among Black and White adult decedent residents of St. Louis City and County, Missouri (N = 4,420), derived from cause-of-death data from the Medical Examiner’s Offices from 2011-2015 (pre-fentanyl) and 2016-2021 (post-fentanyl). Hotspot analyses using Gettis-Ord Gi* statistic were conducted stratified by era and race. Results: The number of fatal opioid overdoses increased 184% between the pre-fentanyl era and fentanyl era: 350% among Black individuals and 109% among White individuals. Preliminary results indicated that fentanyl-era overdose deaths were clustered more densely than pre-fentanyl era deaths. Within the fentanyl era, deaths among Black residents were more densely clustered than those among White residents, indicating a smaller area of shared environmental characteristics contributing to fatal overdose. Hotspots were racially distinct pre-fentanyl; however, they substantially overlapped in the fentanyl era, with both Black and White deaths clustering in predominantly Black neighborhoods in North St. Louis, an area characterized by high racial and income segregation. Impact: The third wave of the opioid overdose crisis is more spatially concentrated than previous waves, pointing to the importance of identifying and intervening with environmental determinants of health and highly impacted locales. Policies and outreach programs targeting neighborhoods with high deprivation are needed to reduce the disproportionate burden of overdose on Black communities.
27	Beheshti, Mohammad MS University of Missouri – Columbia Clustering-aided Approach to Investigate the Association of Bladder Cancer Characteristics and Health-related Quality-of-life in Older Patients Beheshti M, Golzy M, Murray KS, Rosen G Introduction: Understanding factors affecting survival outcomes and quality of life is important in advising patients on treatment options for bladder cancer. We investigated whether the bladder cancer characteristics have any effect on the Health-Related Quality-of-Life (HRQoL) measures in older bladder cancer patients. This analysis improved the understanding and expectation management of these patients when making decisions on how to proceed with treatments. Methods: Data were obtained from patients with a diagnosis of BC in the SEER-MHOS database (age>=65), from 1998 through 2020. We applied unsupervised machine learning algorithms to empirically identify the homogenous clusters of elderly bladder cancer patients with similar HRQoL (measured by PCS, MCS, and ADLs). Log-rank test was used to assess the association of the clusters with survival outcomes. We investigated whether bladder cancer characteristics such as staging, surgical treatment, and time of diagnosis had any association with the identified clusters. Results: The chi-squared test indicated significant differences among clusters with respect to demographics, and socioeconomic variables (except smoking status p=0.26). We observed significant differences in outcomes such as Depression and Fall. The log-rank test from Kaplan Meier shows significant differences in survival probability among clusters. We did not find any significant difference in cancer characteristics variables such as cancer staging (P=0.12) and surgical type (P=0.07) and time from first cancer to survey (P=0.50) among the different clusters. Impact: The results indicate independency of the Health-Related Quality of Life (HRQoL) measures such as physical and mental component scores and activities of daily living of the bladder cancer patient and bladder cancer characteristics such as stages of cancer, type of surgery, and time of first cancer. This helps in better understanding the association between cancer and subsequent treatments and the emotional and physical functioning of patients and can serve as a solid foundation for urologists to better understand and counsel patients on how their functional status will impact their cancer outcomes.
28	Bello Kottenstette, Jennifer MD, MS Saint Louis University Association between Medications for Opioid Use Disorder and Pregnancy Bello Kottenstette JR, Xu K, Grucza R Introduction: Chronic opioid use reduces fertility by suppressing the hypothalamic pituitary axis. The effect of medication to treat opioid use disorder (MOUD) on women’s fertility is understudied. Using national administrative claims, we identify the impact of MOUD on odds of conception in women with OUD. Methods: We conducted a retrospective case-crossover study using Merative™ MarketScan® Commercial and Multi-State Medicaid Databases from 2006 – 2016. Dates of conception were derived from delivery codes and used as “case” days compared to all other (“control”) days of insurance enrollment. We examined 8,105 births among 6,936 women with OUD to model odds of conception on a given day as a function of MOUD exposure (buprenorphine, methadone, extended-release depot naltrexone, or oral naltrexone) using conditional logistic regression. Hormonal contraception was used as an active comparator group. Results: In the sample, 2,391 women received buprenorphine, 783 methadone, 208 extended-release depot naltrexone and 320 oral naltrexone. Mean age is 26.1 years (range: 13-45) with 60.5% having Medicaid and 39.5% commercial insurance. Days on which women used methadone (OR 0.56, 95% CI 0.47-0.68) or oral contraceptives (OR 0.42, 95% CI 0.35-0.50) compared to no medication were associated with lower odds of conception. Treatment with extended-release depot naltrexone compared to no medication was associated with higher odds of conception (OR 1.87, 95% CI 1.23-2.83). There was no difference in conception with buprenorphine (OR 0.99, 95% CI 0.89-1.11) or oral naltrexone (OR 0.85, 95% CI 0.55-1.31). Impact: The majority of treatment-seeking people with OUD who experienced pregnancy during the observation period did not receive MOUD. Those who received extended-release depot naltrexone had higher odds of conceiving compared to no treatment. Treatment with methadone was associated with lower odds of conception, whereas buprenorphine and oral naltrexone had no association. More research is needed to understand the impact of MOUD on fertility to inform prescriber counseling.
29	Fox, Daniel MD, PhD Washington University in St. Louis The Association of the UNOS Heart Allocation Policy Change with Transplant and Left Ventricular Assist Device Access and Outcomes Fox DK, Waken RJ. Wang F, Wolfe JD, Robbins K, Fanous E, Vader J, Schilling J, Maddox KE Introduction: In October 2018, the allocation policy for adult orthotopic heart transplant (OHTx) in the United States was changed, with the goal of reducing waitlist mortality and providing broader sharing of donor organs within the United States. The aim of this study was to assess the association of this policy change with changes in access to OHTx vs left ventricular assist devices (LVADs), overall and among key sociodemographic subgroups, in the US from 2016 to 2019. Methods: We identified all patients receiving OHTx or LVAD between 2016-2019 using the National Inpatient Sample. Controlling for medical comorbidities, pre-policy trends, and within hospital-year effects, we fit a dynamic logistic regression model to evaluate patient and hospital factors associated with receiving OHTx vs LVAD pre- versus post-policy change. We also examined the frequency of temporary mechanical circulatory support (tMCS) in the same fashion. Results: We identified 2264 patients who received OHTx and 3157 who received LVADs during the study period. In its first year of implementation, the UNOS policy change of 2018 was associated with no overall change utilization of OHTx vs LVAD. Among OHTx recipients, the frequency of use of tMCS changed from 15.6% in the pre period to 42.6% in the post period (p<0.001). While the policy change was associated with differences in the odds of receiving an OHTx versus LVAD between different regions of the country, there were no significant changes based on age, gender, race/ethnicity, insurance status, or rurality. Impact: The UNOS policy change on access to OHTx was associated with no overall change in OHTx vs LVAD use in its first year of implementation although we observed small changes in relative odds of transplant based on rurality. Shifts in regional allocation were not significant overall, though certain regions appeared to have a relative increase in their use of OHTx.
30	Marino, Andrew Saint Louis University Differences in Urban and Rural Implementation of Substance Misuse Recovery Programs in Illinois Marino AM, Duncan ED, Galbreath IM, van den Berk-Clark CJ Introduction: As of 2023, over 46 million Americans met DSM-5 criteria for a past year substance use disorder. Research shows that substance use disorders are chronic. However, traditional treatment approaches rely on isolated, brief treatment episodes. Recovery care models offer alternative approaches emphasizing long-term support. One promising intervention is the Recovery Oriented System of Care (ROSC), which develops recovery programs across multiple systems. The implementation of these ROSC programs in real world settings remains unclear. This study focuses on how ROSC programs are implemented in Illinois. Methods: Members of ROSC programs (N=18) were interviewed about programming, outreach, decision making and leadership structure. Data was analyzed using Atlas.ti. Grounded theory was used to generate themes. Results: The Illinois ROSC’s local county-based structure helped rural counties better coordinate services. The following themes show how counties restructured and coordinated substance treatment services and programs using the ROSC system: 1) by confronting culture – ROSCs provided support and helped confront specific themes in rural culture which stigmatized persons with substance use issues, 2) by building trust among those with lived experience – ROSCs created leadership positions and provided opportunities to meet, network, and share recovery stories, 3) by utilizing bridging social capital approaches – ROSC networks include diverse members, such as persons with lived experiences, community leaders, law enforcement, and service providers, to balance public health with public safety. Impact: ROSC programs improved care coordination by confronting culture, building trust, and utilizing bridging social capital approaches. This research showed that the implementation of local county-based ROSC programs in Illinois provided clinical and medical benefit by connecting clinicians and consumers. This occurred through promoting harm reduction activities and monthly network meetings and by reducing stigma towards substance misuse disorders. This study is limited by a small sample size and geographic area. Future studies should evaluate ROSC program implementations on a national level.
31	Okoye, Victor MD Saint Louis University Predicting Medication Adherence and Hospital Readmission Rate in Chronic Disease Patients: An AI Strategy Okoye V, Emmanuel O, Okoye G Introduction: For chronic diseases such as high blood pressure, heart failure, cancer, diabetes, and depression, more than half of these patients with prescribed medications fail to comply or refill doses as agreed with their doctor. Non-adherence to medication has contributed to increased healthcare utilization by chronic disease patients, high hospital readmission rates, and preventable medical costs globally. Methods: We explored the publicly available Medication Possession Ratio (MPR) data which looks at how often a person refills their prescription for over 600 patients from males, females, teenagers, adults, and the elderly within a 4-year period of 2016 to 2020. Data consisted of filled prescriptions, medication type, dosage form, and hospital admission. We predicted the risk of medication nonadherence and hospital readmission for the first 3 months after a patient fills their prescription. Results: Our data generated probability-based risk scores based on patients’ diagnosis codes. 33% of patients showed nonadherence due to procrastination and inattention. 39% simply forgot to complete their doses, while 9% procrastinated getting refills and 20% did not renew their prescription on time. Retrospective data from express scripts showed that 69% skipped medication and failed to complete dosages simply because of inattention and forgetfulness. 16% due to cost implication and 15% due to clinical concerns of medication not working. Impact: This research hints at the tremendous amount of work that needs to be done in order to improve medication nonadherence in chronic disease patients to further reduce hospital readmission rate, and most importantly drive health care costs to the barest minimum.
32	Pruthi, Saksham Saint Louis University Influence of Care Partner Presence on Outcomes of People with Parkinson’s Disease DeMarco EC, Pruthi S, Ravi A, DeVeydt A, Cotter A, Davids T, Subramaniam DS, Park S, Hinyard L Introduction: Parkinson’s Disease is one the most common neurodegenerative diseases, affecting millions of people worldwide. Having a combination of motor and non-motor symptoms, people with Parkinson’s Disease (PwP) are often dependent on their informal care partners (CP) to carry out vital functions. While the effect of PwP and CP characteristics on caregiver burden and outcomes has been previously reviewed, the effect of CP presence on PwP outcomes has not been synthesized. As women are less likely to have a CP and more likely to have a shorter time to paid care than men, understanding these effects is expected to highlight disparities in outcomes for those without a CP. This study aims to assess the effects of the presence of an informal CP on patient outcomes among PwP. Methods: A systematic review was conducted with the following inclusion criteria: 1) study participants are PwP 2) quantitative outcomes reported for PwP, 3) the presence or absence of a CP is noted, and 4) available in English. Databases included OVID MEDLINE, OVID PsycInfo, SCOPUS, Ebsco CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Proquest Dissertations & Theses and Web of Science Core Collection A total of 4961 unique articles were examined by 6 independent reviewers. Based on the title and abstract, 489 articles met the inclusion criteria. Upon subsequent full article review, 175 articles met study criteria. Data was extracted from each pertaining to PwP baseline demographics, PwP outcomes, and article information. Quality assessment is forthcoming. Results: The 175 articles had a total sample size of 39,764 participants from which data were extracted. Of those articles, only 4 did not have CP present. Of the included studies, the majority (103) were cross-sectional, with 32 cohorts,12 RCTs, and 4 case-controls being the next largest proportions. Outcome results like PwP motor functionality and quality of life are a part of our anticipated results. Impact: Our study aims to highlight disparities that may be present in the access and quality of care for PwP without CP. We hope this study warrants further research into improving the quality of life of PwP and those around them.
33	Robbins, Keenan MBBS, MPHS Washington University in St. Louis Bundled Payments for Care Improvement Advanced Participation Associated with Overall Savings for Medical, but not Surgical Conditions Robbins KJ, Zheng J, Orav EJ, Epstein AM, Joynt Maddox KE Introduction: The Bundled Payments for Care Improvement Advanced (BPCI-A) program is an alternative payment model (APM) which seeks to reduce spending and improve coordination of care for Medicare beneficiaries. The first model year of this program offered 32 clinical conditions from which participants could choose to enroll. It is unknown the extent to which BPCI-A participation affects care for individual conditions, or if there are differential effects on medical or surgical conditions. In this study, we compare financial and clinical outcomes between medical and surgical conditions treated at BPCI-A participating institutions during the first year of the program. Methods: We used publicly available data on BPCI-A participation. We identified control hospitals by matching on a series of hospital and market characteristics. We used Medicare claims from 2017-2019 to identify patients admitted for any of the 29 inpatient conditions in the program, and categorized them as medical or surgical/procedural. The primary predictor of interest was the three-way interaction between BPCI-A participation, time period (baseline or intervention), and the type of clinical episode (medical or surgical). The primary outcome was the change in total episode spending. Secondary findings included changes in clinical outcomes and patient complexity. Results: BPCI-A participation was associated with significantly decreased total episode spending for medical conditions ($202 per episode per quarter, p<0.001), but not for surgical conditions ($26, p=0.696, triple difference $177, p=0.024). Participation was associated with significant overall savings for five of thirteen medical conditions and two of sixteen surgical conditions. There were no differential changes in overall clinical outcomes under BPCI-A for medical or surgical conditions, including 90-day readmission, mortality, and healthy days at home. Impact: As designed, BPCI-A may not have incented optimal care delivery innovations for surgical conditions in its first year. Further research is warranted to determine if bundled payments are a viable long-term strategy to improve costs and clinical outcomes for Medicare beneficiaries.
34	Rosenzweig, Tiffany PhD Washington University in St. Louis Adaptation in an Implementation Program of POCUS Guided CVC Confirmation Rosenzweig TE, Ablordeppey AE Introduction: Ultrasound (US) guided confirmation of central venous catheters (CVC) has similar sensitivity to the traditional chest x-ray (CXR), while being less resource intensive and lowering labor cost. In spite of this data, clinicians continue to obtain CXR for CVC confirmation and have not adopted US, a new innovation, to replace CXR. A protocol was developed and a deimplementation program [DRAUP] was initiated to increase the use of US guided CVC confirmation in lieu of CXR in the ED. To be generalizable, this study aims to consider sustainability of this deimplementation program by using FRAME-IS conceptual framework to design an adapted and tailored program and rigorously document modifications to implementation strategies. We hypothesize that by using an implementation science approach to determine the types and degree of adaptions, we will determine necessary intervention changes for continued successful adoption of DRAUP. Methods: Data on the implementation of a program to decrease the use of chest x-rays in CVC confirmation was tracked for 3 years. To explore barriers to continued adoption of the protocol and areas for adaptation, participants completed a short demographics surveys and a moderator led focus group or interview. Interviews will be transcribed and analyzed for major themes using a behavioral theory addressing capacity, opportunity and motivation [COMB]. The FRAME-IS will guide selection and prioritization of adaptation strategies. Results: The completion of qualitative methods for focus groups and interviews is underway. One adaptation already underway in the program is to better understand the role of RNs in CVC placement. Analysis of the interviews with RNs and physicians in the ED will identify ways to adapt the education and training components of the program. Impact: The project focuses on changing clinical guidelines for CVC confirmation to support the reported benefits of US. The shift improves healthcare by improving efficiency and resource allocation, decreasing the amount of radiation received by patients during a hospital stay and creating cost savings for both the patient and healthcare system.
35	Schmidtke, Kelly PhD University of Health Sciences and Pharmacy The Surgical Implementation Gap: An Explanatory Mixed-methods Study describing Implementation (or lack thereof) for Six Pragmatic Randomized Controlled Trials Schmidtke KA, Evison F, Grove A, Kudrna L, Tucker O, Metcalfe A, Bradbury AW, Bhangu A, Lilford R Introduction: Every year national funding organizations invest billions of dollars in the development and evaluation of interventions to improve people’s wellbeing. Pragmatic randomized controlled trials can generate robust evidence in support of one treatment over others. However, even where such evidence is generated, practice may not change. Based on findings published in the late 20th century, only half of actionable trial findings are implemented in practice. The current study investigates whether and why practice changes according to the findings of six pragmatic randomized controlled surgical trials in England. Methods: A sequential, explanatory mixed methods study was conducted. Interrupted time-series analyses were used to assess whether actionable findings from six large, publicly funded surgical trials influenced practice. Then, qualitative interviews were performed. The Consolidated Framework for Implementation Research (CFIR) domains were used to synthesize the findings. Results: Practice changed in accordance with half of the trial findings. In one trial (patella resurfacing), change commenced after the protocol was published – before the findings were published. In another trial (percutaneous vs nasogastric tube feeding), change commenced a decade after the trial’s findings were published. In the third (abdominal aortic aneurysm repair), changes promptly tracked the evolving evidence-base in both directions. For the two varicose vein trials, the results were superseded by a further trial. For the gastric reflux trial, medical treatment overtook surgical intervention. Interview analyses find practical reasons for non-adoption in the three trials where evidence did not affect practice. Impact: Decision-makers respond to the totality of evidence. There are often good reasons for not adopting the evidence of any one trial in isolation. Trialists and funders could attend to a broader range of evidence to select what trials are conducted and to facilitate implementation where appropriate.
36	Waitman, Lemuel PhD University of Missouri – Columbia Enhancing PCORnet Clinical Research Network Data Completeness by Integrating Multistate Insurance Claims with Electronic Health Records Waitman LR, Song X Introduction: The Greater Plains Collaborative (GPC) and PCORnet Clinical Data Research Networks capture healthcare use within their health systems but may lack information on care received elsewhere in the community. Here, we describe are usable environment (GPC Reusable Observable Unified Study Environment [GROUSE]) that integrates hospital and electronic health records data in the PCORnet common data model with state-wide Medicare and Medicaid claims and assess how claims and clinical data complement each other to identify obesity and related diseases. Methods: GROUSE also allows investigators to use multiple analysis tools including SAS, R, python and natural language processing pipelines. Initially, EHR, billing, and tumor registry data from 7 healthcare systems were integrated with Center for Medicare (2011-2016) and Medicaid (2011-2012) services insurance claims to create deidentified databases in PCORnet Common Data Model formats. Trends in obesity rates for different age groups are reported, along with the relative contribution of claims and EHR data-to-data completeness and detecting common comorbidities. For PCORnet’s Third Phase starting in 2022, we have refreshed the linkages for all thirteen partner health systems (including WashU/BJC) and have requested 2018-2022 Medicare insurance claims. We are also linking hospital tumor registries from our partner health systems. Results: GROUSE contained 73 billion observations from 24 million unique patients (12.9 million Medicare; 13.9 million Medicaid; 6.6 million GPC patients with 1,674,134 patients cross-walked, 983,450 patients with body mass index (BMI) linked to claims. Impact: GROUSE provides a unified EHR-claims environment to address health system and federal privacy concerns, which enables investigators to generalize analyses across health systems integrated with multistate insurance claims.
37	Wang, Mei MS Washington University in St. Louis Using Natural Language Processing Pipeline to Extract Lab Results in Veteran Health Administration’s Electronic Health Records Wang M, Yu YC, Liu L, Schoen M, Kumar A, Colditz G, Thomas T, Chang SH Introduction: Multiple myeloma (MM) is a common hematologic malignancy. Our studies utilized electronic health record (EHR) data in the nationwide Veteran Health Administration to study the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. Disease confirmation is crucial in these studies. Relying on manual laboratory (lab) data abstraction to confirm diagnoses is labor-intensive and time-consuming, jeopardizing the feasibility of large-scale studies. With advancements in natural language processing (NLP), we developed an NLP pipeline to automate this process. Methods: We retrieved 21,106 relevant EHR documents including discrete lab records, unstructured lab comments, and surgical pathology reports from 700 randomly selected patients diagnosed with MGUS from 1999-2021. All documents were manually reviewed to abstract the values of serum monoclonal protein (M-protein), kappa/lambda (K/L) ratio, and plasma cell (PC) % and the corresponding dates. These results were served as the reference. We then developed an NLP pipeline using pattern-based rules to extract lab values, units and dates. The performance of the NLP pipeline was compared to the reference using four metrics: recall, precision, and F1 score. The difference between NLP-extracted dates and the reference was also computed. Results: The NLP pipeline achieved recall, precision and F1 score of 98, 99 and 99% for M-protein, 97, 87 and 91% for K/L ratio, and 88, 67 and 76% for PC %, respectively. 75, 99 and 100% of NLP-generated dates for M-protein, K/L ratio, and PC % results matched the reference within 7 days, respectively. On average, manual chart review required 15 minutes per patient to abstract all three lab results (excluding data loading time), whereas our NLP pipeline completed 20 patients per minute. Impact: We successfully developed an NLP pipeline to extract lab results in EHR data. This approach can replace manual review and translate unstructured information into analyzable data for diagnosis confirmation. With further adaptation, our NLP pipeline may be applied to other disease areas and assist researchers in conducting large-scale EHR database research.
38	Wilson, Lauren PhD Saint Louis University Knowledge and Confidence about Suicide Risk Reduction Wilson LE Introduction: In 2020, suicide was the 12th leading cause of death for people of all ages in the United States (US), the second leading cause of death for people, aged 10 to 34, and the fifth leading cause of death for people aged 35 to 54 (Garnett et al., 2020). Despite prevention and treatment efforts, research on healthcare contacts shows that 83% of patients saw a primary care provider (PCP) within one year of suicide death (Ahmedani et al., 2014). Considering barriers to specialty mental health services and the prevalence of PCP management of patient mental health conditions like depression, there is demand for physicians to be equipped with tools to identify, assess, and refer patients at-risk for suicide (Bono & Amendola, 2015). Behavioral health integration is a dynamic approach that seamlessly integrates both mental and physical health services such as same-day warm handoffs to behavioral health consultants, or regular consults with psychiatry (Curtis and Christian, 2012). The aim of this quantitative research study was to evaluate the relationship between level of behavioral health integration and PCPs’ self-reported beliefs about knowledge and confidence regarding suicide risk reduction activities. Methods: Primary Care Providers (n=233) in the US were invited to participate in a 35-item electronic survey adapted from the Zero Suicide Workforce Survey to assess knowledge and confidence about suicide, as well as questions about collaboration with behavioral health clinicians. Results: Differences in mean knowledge (F(2, 230), = [3.511], p=0.031) and confidence (F(2, 230), = [7.326], p=0.001) subscale scores were statistically significant among providers in coordinated (n=88, 37.8%), co-located (n=68, 29.2%), and integrated (n=77, 33.0%) levels of behavioral health integration. Impact: This project has potential community and public health benefits. Health care characteristics that promote behavioral health integration in primary care via patient-centered, collaborative teams has potential to bridge the continuity of care gap and better serve patients and families experiencing suicidality.