bluuebunny/crossref_metadata_2025_split huggingface dataset:
499. Immunotherapy with Pattern Recognition Receptor Agonists Improves Morbidity and Mortality in a Corticosteroid-Immunosuppressed Murine Model of Influenza-Associated Pulmonary Aspergillosis
Authors: Wurster Sebastian , García Jezreel Pantaleón , Albert Nathaniel D , Evans Scott , Kontoyiannis Dimiitrios P 
Published: December 2022

Abstract

Background
Corticosteroids are known to increase the incidence and worsen the outcomes of influenza-associated pulmonary aspergillosis (IAPA) in patients with severe influenza pneumonia. Adjunct immunomodulatory strategies might improve the treatment of this emerging entity, but in-vivo data in validated corticosteroid-immunosuppressed animal models of IAPA is scarce.

Methods
8-10-week-old female BALB/c mice were infected with 7.5% LD90 of a mouse-adapted influenza A/H3N2/Hong Kong/1968 strain, delivered by aerosolization on day (d) 0. On d5 and d8, mice received two intraperitoneal injections of 10 mg cortisone acetate (CA) or mock injections. On d9, mice were intranasally challenged with 50,000 Aspergillus fumigatus (AF) conidia. Infection severity was scored using the viral pneumonia score (VPS, 0 = healthy to 12 = moribund) and the murine sepsis score (MSS, 0 = healthy to 3 = moribund). For therapeutic studies, mice received a 30-minute nebulization of the toll-like receptor (TLR) 2/6/9 agonists Pam2+ODN (PMID: 34153197; 4 µM/1 µM) or PBS (mock treatment) on d8 (single-dose) or d8+12 (dual-dose). Therapeutic studies used a combined morbidity/mortality endpoint, with an event defined as either death or reaching a VPS ≥ 7.

Results
CA-immunosuppressed mice with IAPA had 64% 16-day mortality and survivors had severe morbidity (median MSS 2.7). In contrast, all non-immunosuppressed mice with IAPA survived and showed consistently low morbidity (median d16 MSS 0.5). All mock-treated CA-immunosuppressed mice with IAPA reached the combined morbidity/mortality endpoint by d11. Single-dose Pam2+ODN treatment led to universal event-free survival until d13 but all mice deteriorated by d16. Dual-dose Pam2+ODN treatment before and after AF infection led to 75% event-free survival until d21, with all survivors fully recovering (VPS = 0, p &lt; 0.001, Figure 1). Figure 1

Conclusion
Aligned with clinical evidence, we found detrimental outcomes of IAPA in CA-immunosuppressed mice. Treatment with TLR agonists significantly improved morbidity and mortality of CA-immunosuppressed mice with IAPA. Next, we will study the impact of synergistic anti-infective and immunotherapeutic interventions on the course and immunopathogenesis of IAPA.

Disclosures
Dimiitrios P. Kontoyiannis, MD, ScD, PhD (hon), AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Merck: Advisor/Consultant.
507. Peripheral blood RNA signatures associated with human babesiosis, quality of life and neurological symptoms
Authors: Marcos Luis A , Lamba Pooja , Gary Evan , Hou Wei , Spitzer Eric , Mordue Dana 
Published: December 2022

Abstract

Background
Human babesiosis is an emerging tick-borne disease in the US that is primarily caused by the protozoan Babesia microti (Bm). Although Babesiosis can cause life-threatening infections, the pathophysiology including host and parasite determinants associated with disease severity are largely unknown. The aim of this study is to identify parasite and host signatures of human babesiosis and correlate these with disease severity and long-term symptoms.

Methods
We enrolled prospectively patients with acute babesiosis (microcopy positive blood smear for Bm, confirmed by PCR) at Stony Brook University Hospital during 2020-2021. Blood samples and surveys were completed at initial diagnosis (Visit=1;V1) and at months 1, 6 and 12 (V2,V3,V4). Total RNA from whole peripheral blood was isolated using the PAXgene Blood RNA Kit from individuals infected with Bm and healthy controls. Quality of life (QOL) surveys were administered to patients.

Results
Peripheral blood transcriptome analysis of 17 patients (median age: 63 years, range 42-78; 24% female) who presented with babesiosis were distinctly different from uninfected individuals (n=9). Babesiosis was associated with a peripheral blood Type I and Type II Interferon transcriptional signature. Other dominant transcriptional signatures included those involved in activation of mononuclear cells, oxidative phosphorylation, inducible nitric oxide synthase and regulation of homeostasis as well as inducible nitric oxide synthase. Ingenuity Pathway Analysis for clinical chemistry and hematology also highlight changes associated with cardiotoxicity, hepatotoxicity, and nephrotoxicity as well as increased levels of red blood cells. Patients with babesiosis showed a persistent deterioration of QOL in cognition [mean V1=33.1; V3=36.3] and satisfaction [mean V1=28.4; V3=34]. Also a decrease in QOL over time despite effective treatment [mean at V1 82 (SD: 5.9), V2 80 (8.1), V3 76 (4.7) (p &gt;0.05).
Heat Map Summary.
Volcano Plot
Gene Pathways Analysis

Conclusion
Babesiosis is associated with a marked alteration in the peripheral blood transcriptome of patients that may also provide insight into both the pathophysiology of the disease including severity and complications. Furthermore, even after successful treatment, babesiosis may result in long-term impacts on quality of life indicators.

Disclosures
All Authors: No reported disclosures.
514. Association Between Antibiotic Exposure and Clinical Outcomes of Immune Checkpoint Inhibition
Authors: Wilson Grant , Zhang Jiajia , Spence Emma , White Maxwell , Allen Jawara , Fan Christopher , Queen Jessica , Naidoo Jarushka , Sears Cynthia L , Shaikh Fyza 
Published: December 2022

Abstract

Background
Recent studies have suggested that antibiotic (ABX) use and resulting changes in the gut microbiome alter the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment, but detailed data are lacking. We performed a retrospective analysis of the impact of ABX timeframe of administration on overall survival (OS) and progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients treated with ICIs.

Methods
We assembled a cohort of stage IV NSCLC patients treated with ICIs at Johns Hopkins Medicine between 1/1/2013 and 12/31/2019 (n=154). Patient demographics, ICI and ABX (intravenous and/or oral, n=100) treatments, tumor characteristics, and progression and survival data was extracted from the electronic medical record (EMR) and verified by chart review. Progression was defined by radiological evidence or provider notes. Univariate analysis was performed with Kaplan-Meier curves with log-rank tests and multivariate analysis was performed with Cox regression.

Results
Demographic data indicated that most patients were white (n=109), smokers (n=130), and had Eastern Cooperative Oncology Group (ECOG) performance statuses of zero to one (n=128). The median age was 67 years old and slightly under half of patients (n=65) received ICIs as first line therapy. Analysis with Kaplan-Meier curves for OS and PFS revealed significantly worse OS for patients with exposure to any ABX vs. not exposed in the 2.8 years before to 4.8 years after ICI start (Median OS: 14 vs. 21.5 months, p = 0.019; Median PFS: 4.4 vs. 7.7 months, p = 0.24). ABX exposure in the 2 months before to 2 months after ICI start also negatively impacted OS (Median OS: 7.5 vs. 17.4 months, p = 0.05; Median PFS: 3.3 vs. 5.8 months, p = 0.39). Decreased OS with any ABX use in the 2.8 years before to 4.8 years after ICI start was supported by multivariate analysis controlling for age, race, ECOG performance status, tumor histology, prior lines of therapy, and prior treatment types (Adjusted Hazard Ratio: 2.0, 95% CI: 1.3-3.3).
Kaplan-Meier survival analysis of antibiotic exposure
Overall survival (A) and progression-free survival (B) in stage IV NSCLC patients treated with ICIs, with or without exposure to ABX in the 2.8 years before to 4.8 years after ICI start. P-values calculated with log-rank tests.

Conclusion
Our study indicates a negative association of ABX on OS of ICI-treated NSCLC patients in both a broad and narrow timeframe around ICI start. Further work defining ABX impact on therapeutic outcomes in a larger cohort of patients across multiple tumor types is ongoing.

Disclosures
Grant Wilson, BS, Infectious Diseases Society of America G.E.R.M. Grant: Grant/Research Support Cynthia L. Sears, MD, Bristol Myers Squibb: Grant/Research Support Fyza Shaikh, MD, PhD, Bristol Myers Squibb: Grant/Research Support.
519. DeepLPI: A Novel Drug Repurposing Model based on Ligand-Protein Interaction Using Deep Learning
Authors: Wei Bomin , Zhang Yue , Gong Xiang 
Published: December 2022

Abstract

Background
Drug repurposing has gained increased attention because it proposes to find effective cures for new diseases from approved drugs to lower development costs and time, and computational prediction of protein-ligand interactions (PLI) can provide accurate and fast drug screening. The shortcomings of existing machine learning-based methods for PLI prediction include 1) using human-selected features leads to loss of information and therefore lower accuracy and 2) using limited 3D structure data for input leads to lower generalizability.

Methods
To address the shortcomings, I proposed DeepLPI, a novel deep learning-based model that takes as input the raw sequences of drug molecules and proteins. DeepLPI applied pre-trained embedding models to encode the raw sequences into dense vector representations, which were then fed into 1D-CNN and biLSTM to obtain predictions. BindingDB dataset was used for model training and performance evaluation that is compared with a start-of-the-art method DeepCDA. Fig 1.Principle of NLP-inspired deep learning-based methods to embed drug SMILES strings (Mol2vec) and protein sequences (ProSE). Similar drugs or proteins will be in close distance after the embedding because these methods can capture contextual information.Fig 2.Model architecture from input to output of DeepLPI.

Results
Results showed that the DeepLPI reached an overall AUROC of 0.79 based on the BindingDB internal test, 76% better than DeepCDA. DeepLPI also outperformed DeepCDA using the external Davis dataset (AUROC=0.53) and COVID-19 3CL Protease dataset (AUROC=0.61). Figure 3.A randomly reserved part of the BindingDB dataset was grouped into four cases for testing, according to whether the drug molecules or the proteins are seen in the training set. (Note that the drug-target pairs in the test set are excluded from the training set.)Fig 4.We compare with DeepCDA, a recently published DTI prediction model that reported to be better than previous models. DeepLPI is 76% better in accuracy metric AUROC in classification tasks.Fig 5.As a preliminary attempt, the model trained on BindingDB was applied to a recent COVID-19 dataset targeting the 3CL-protease, which reported 897 small molecule drugs. Our model is better than the baseline method by 25%.

Conclusion
The high performance of DeepLPI suggests that our model has the potential to identify new COVID-19 drugs when applied to approved drugs. The generalizability of the model also promises applications to diseases in a wider scope.

Disclosures
All Authors: No reported disclosures.
520. Development of Cefepime-taniborbactam MIC Antimicrobial Susceptibility Test (AST) for Enterobacterales and Pseudomonas aeruginosa on MicroScan Dried Gram-negative MIC Panels
Authors: Fernandez Enrique J , Williams Robert L , Carr Vasna , Carr Vasna , Renae Miller 
Published: December 2022

Abstract

Background
Automated AST devices are critical to inform appropriate care of patients with bacterial infections. Cefepime-taniborbactam is an investigational agent under development to treat infections due to multidrug-resistant bacteria, including carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa. Development of a cefepime-taniborbactam antimicrobial susceptibility test was completed for the MicroScan Dried Gram-negative MIC (MSDGN) Panel when compared to CLSI broth microdilution reference panels.

Methods
Development was conducted by comparing MICs obtained using the MSDGN panel to MICs using a CLSI broth microdilution reference panel. The concentration range of cefepime-taniborbactam evaluated was 0.12/4-64/4 µg/mL. A total of 1376 isolates (1256 Enterobacterales and 120 P. aeruginosa) were tested at 16, 18, and 20 hours incubation times (for visual read and autoSCAN-4). A total of 917 isolates (837 Enterobacterales and 80 P. aeruginosa) were tested at 16 and 18 hours incubation time for the WalkAway System. All isolates were tested using turbidity and Prompt® methods of inoculation. MSDGN panels were incubated at 35 ± 1°C. Reference panels, prepared according to ISO methodology, were inoculated using the turbidity inoculation method. All frozen reference panels were incubated at 35 ± 2°C and read visually. Rates of essential agreement (MicroScan MIC within ± 1 doubling dilution of reference MIC) were determined for each combination of inoculation method and read method.

Results
Essential agreement rates ranged from 93.0% to 98.8% for all isolates tested during development. Essential agreement rates for each inoculation and read method are presented in Table 1. Table 1- Results

Conclusion
Cefepime-taniborbactam MIC results obtained with the MSDGN panel correlated well with MIC results obtained using reference panels. Rates of essential agreement were ≥93.0% for all inoculation and read methods. These development data support the continued evaluation of MSDGN panel with cefepime-taniborbactam in a multicenter trial.
Pending submission and clearance by the United States Food and Drug Administration; not yet available for in vitro diagnostic use in the US. For Investigational Use Only. The performance characteristics of this product have not been established.

Disclosures
Enrique J. Fernandez, BS, Beckman Coulter, Inc.: Employee of Beckman Coulter Robert L. Williams, PhD, Beckman Coulter, Inc.: Employee of Beckman Coulter Vasna Carr, BS, Beckman Coulter, Inc.: Employee of Beckman Coulter Vasna Carr, BS, Beckman Coulter, Inc.: Employee of Beckman Coulter Miller Renae, BS, Beckman Coulter, Inc.: Employee of Beckman Coulter.
521. Investigating the Gram-Positive Selective Spectrum of Ibezapolstat, a First-in-Class DNA Polymerase IIIC (Pol IIIC) Inhibitor
Authors: Jahangir Alam M , Begum Khurshida , Karim Md Ekramul , Hu Chenlin , Basseres Eugenie , Lancaster Chris , Garey Kevin W 
Published: December 2022

Abstract

Background
Ibezapolstat (IBZ) is a non-absorbable antimicrobial currently in phase 2 clinical trials for the treatment of Clostridioides difficile infection (CDI). In vitro and human studies have shown potent activity of IBZ against C. difficile but selective activity against other beneficial Gram-positive gut microbiota shown to reduce the risk of recurrent CDI. As the target DNA Pol IIIC enzyme is present in most Gram-positive species, the reasons for this selectivity are unclear. The purpose of this study was to assess the selectivity of IBZ against Gram-positive gut microbiota.

Methods
Using stool samples and microbiome data from the phase 1 and 2 studies, changes in proportional abundance of gut microbiome species were analyzed over time in healthy volunteers or patients with CDI given IBZ. Using a separate collection of gut microbiota species, MIC determinations against a variety of Gram-positive gut species were assessed by broth microdilution.

Results
Baseline gut microbiota from healthy volunteers were primarily Firmicutes, Bacteroidetes, or Actinobacteria. Actinobacteria increased in abundance after starting IBZ (primarily Bifidobacteriales or Coriobacteriales) and persisted for the entire dosing period. In comparison to the phase 1 study, the phase 2a CDI study baseline microbiota had a lower proportion of Actinobacteria and Firmicutes and increased Bacteroidetes. In CDI patients, Actinobacteria increased in abundance after starting IBZ (primarily Coriobacteriales) followed within 2-3 days by decreased abundance of Bacteroidetes, and an increased abundance of Lachnospiraceae and Ruminococcaceae. Using isolated gut microbiota species, IBZ was inactive (MIC &gt;64 µg/mL) against representative Actinobacteria (Bifidobacteriaceae and Coriobacteriaceae) and certain Firmicutes (Lachnospiraceae and Lactobacillaceae) but highly active against strains of C. difficile (MIC&lt;2 µg/mL).

Conclusion
Microbiome changes with IBZ were dependent on underlying composition of the baseline microbiome but consistently demonstrated increased abundance of Actinobacteria after starting therapy. IBZ microbiome data coupled with in vitro MIC determinations demonstrated persistence or regrowth of healthy microbiota associated with beneficial physiologic effects.

Disclosures
Kevin W. Garey, PharmD, MS, Acurx Pharmaceuticals: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support|Summit Pharmaceuticals: Grant/Research Support.
534. Evaluation of a Rapid Multiplex PCR Diagnostic Device for the Detection of Microorganisms from Nasopharyngeal and Throat Swab Specimens in the Near Patient Setting
Authors: Bastar Jeffrey , Ky Ashley , Holmberg Kristen , Bay Hana , Drobysheva Daria , Davis Thomas , Selvarangan Rangaraj , Doran Kathryn , Sifers Laura , Cohen Daniel M , Enne Virve , Steele Mark , Andjelic Cynthia 
Published: December 2022

Abstract

Background
Limited availability of multiplex molecular tests in the near-patient setting can impact the rapid diagnosis and treatment of patients experiencing symptoms of respiratory tract infections, including pharyngitis. The BioFire® Respiratory/Sore Throat (R/ST) Panel (bioMérieux, Salt Lake City, UT), designed for use with the BioFire® SpotFire System, is a PCR-based sample-to-answer diagnostic test that identifies four bacteria and 10 viruses (including SARS-CoV-2) from nasopharyngeal swab (NPS) or throat swab (TS) specimens in about 16 minutes. This study evaluated the performance of an Investigational Use Only (IUO) version of the BioFire R/ST Panel in the near patient setting.

Methods
NPS and TS specimens were prospectively enrolled from symptomatic consented/assented volunteers of all ages, or obtained as residual leftover specimens. Enrollment was conducted between December 2020 and September 2021 at five study sites in the US and UK (adult and pediatric emergency departments or urgent care clinics) with testing performed by personnel representative of the intended users (non-laboratory professionals). Several analytes that were not circulating during the COVID-19 pandemic were supplemented with archived specimens of known analyte composition. Performance was determined for both sample types by comparison to FDA cleared multiplex PCR tests or culture and PCR followed by sequencing of isolates (Streptococcus from throat swabs).

Results
A total of 1131 NPS and 452 TS prospectively collected specimens and 542 NPS and 128 TS archived specimens were tested with the BioFire R/ST Panel. For NPS specimens (prospective and archived) overall positive percent agreement (PPA) was 98.7% and negative percent agreement (NPA) was 99.1%, and for TS specimens (prospective and archived) overall PPA was 95.9% and NPA was 99.2%.

Conclusion
The BioFire R/ST Panel is a sensitive, specific, and robust test for rapid detection of a wide range of organisms in NPS and TS specimens in the near-patient setting. This test is expected to aid in the timely diagnosis and appropriate management of pharyngitis and other respiratory infections.
Data presented are from assays that have not been cleared or approved for diagnostic use.

Disclosures
Jeffrey Bastar, PhD, MSCI, bioMerieux: Employee|bioMerieux: Stocks/Bonds Ashley Ky, MLS(ASCP), bioMérieux: Employee|bioMérieux: Stocks/Bonds Kristen Holmberg, n/a, bioMerieux: Employee Hana Bay, BS, Biomerieux: Employee|Biomerieux: Stocks/Bonds Daria Drobysheva, PhD, bioMerieux: Employee Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, F(AAM), BioFire: Grant/Research Support|Luminex: Grant/Research Support Virve Enne, BSc PhD, Biomerieux: Advisor/Consultant Cynthia Andjelic, PhD, bioMerieux: Employee.
535. Evaluation of the BioFire Blood Culture Identification (BCID2) panel for transplant recipients with a bloodstream infection
Authors: Palacios Carlo Foppiano , Peaper David , Malinis Maricar F , Malinis Maricar F , Perreault Sarah , Cohen Elizabeth A , Vogel Joshua , Azar Marwan M 
Published: December 2022

Abstract

Background
In patients with bloodstream infections (BSI), the BioFire blood culture identification (BCID2) multiplex PCR panel is associated with decreased time to organism identification and antimicrobial susceptibility results needed to guide optimal therapy. While the performance of BCID2 has been evaluated in the general population, data for transplant recipients are limited. We sought to identify the utility of the BCID2 panel in transplant recipients.

Methods
A retrospective chart review was conducted to identify all solid organ recipients (SOTR) and bone marrow transplant recipients (BMTR) within 2 years of transplantation with BSI for whom BCID2 was performed from 06/2021 to 01/2022. Demographic and microbiological data were collected. Positive blood cultures for the same patient and same organism(s) occurring within 14 days of the initial test were considered a single BSI event. Descriptive statistics were performed.

Results
A total of 29 transplant recipients with 45 positive blood cultures underwent BCID2 testing. Mean age was 54 years, 69% were BMTR and 53% of cultures were from peripheral sites. A total of 51 organisms were recovered from 45 blood cultures. Organisms identified by blood cultures included Enterobacterales (45%), Enterococcus spp (20%), Candida spp (8%), non-Enterobacterales gram negative rods (14%), Streptococcus spp (8%), and other gram positives (5%). No anaerobic organisms were isolated. BCID2 did not detect 7/51 (14%) organisms identified by blood cultures including monomicrobial (n=6/39) and polymicrobial (n=1/6) cultures. All 7 organisms not identified by BCID2 were not in the BCID2 database. All occurred in BMTR; 4 were considered pathogenic and treated with antimicrobials vs. 3 contaminants (Table 1). BCID2 detected CTX-M or Van A/B in all 15 samples with ceftriaxone (n=9) or vancomycin resistance(n=6).

Conclusion
In transplant recipients, BCID2 detected 86% of organisms and 100% of resistance markers identified by conventional testing. All 7 (14%) missed cases involved off-target organisms, of which 4 were considered pathogenic. BCID2 is a useful tool for BSI detection in transplant recipients, but providers should consider the possibility of off-target pathogens when clinically appropriate.

Disclosures
David Peaper, MD, Tangen Biosciences: Stocks/Bonds Maricar F. Malinis, MD, Aicuris: Primary Investigator of Clinical Trial at Yale Site|Takeda: Primary investigator of clinical trial at Yale Site Maricar F. Malinis, MD, Aicuris: Primary Investigator of Clinical Trial at Yale Site|Takeda: Primary investigator of clinical trial at Yale Site.