bluuebunny/crossref_metadata_2025_split huggingface dataset:
480. Redefining the Epidemiologic Profile of Histoplasmosis from 2011 to 2021 in Central Ohio
Authors: Hofmann JustIn , Sobhanie Mohammad Mahdee , Doctor Medical , Sarwar Sajed , Hebert Courtney 
Published: December 2022

Abstract

Background
Histoplasma is a common endemic mycosis in multiple Midwestern states. Most of the data defining epidemiologic risk are from 20th century outbreak investigations. A known exacerbating factor is immune suppression; but use of biologics, immunosuppressants (ISP), and chemotherapy has advanced since these investigations were conducted. This study sought to use clinical data from a tertiary care facility to address these gaps to define the evolving epidemiology of histoplasmosis in Ohio.

Methods
In a single-center retrospective cohort study, we identified adult patients with a histoplasmosis-specific diagnosis, a positive diagnostic test, and an itraconazole/amphotericin B prescription between 1/1/2012 and 10/1/2021. Prisoners were excluded. A random sample of 100 patients underwent in-depth chart review. Comorbidities, environmental risk factors, and ISP use data were collected. Cases were classified by the CDC 2017 Histoplasmosis case definition. “Confirmed” cases had culture growth, a confirmatory lab result, or histopathology plus signs and symptoms of disease, and “probable” cases had a non-confirmatory lab result plus signs and symptoms. Associations between variables were assessed using Fisher’s exact test, p &lt; 0.05.

Results
Of 100 patients, 56 had confirmed and 22 had probable histoplasmosis (Table 1). Three had confirmed blastomycosis, 15 met definitions for both histoplasmosis and blastomycosis, and 4 met neither definition. These were excluded from analysis. No environmental exposure history was documented for 23 of 78 (29.4%) patients. Of those with documented history, 15 (27.1%) had recent renovation or construction exposure; 14 (25.4%) to soil, gardening, or outdoors; 12 (21.8%) to birds, bats, and farm animals; and 25 (45.4%) had no known exposure. There were 51 (65.4%) exposed to at least one dose of ISP in the year prior to diagnosis, including 41 (52.5%) to corticosteroids. Table 1Characteristics of patient cohort

Conclusion
In this cohort, more patients with confirmed or probable histoplasmosis were exposed to ISP than had a documented traditional environmental risk factor. This study shows reliance on traditional environmental exposure history might not accurately gauge risk. Further work is needed using ISP exposure to drive appropriate diagnostic testing.

Disclosures
All Authors: No reported disclosures.
482. The modern face of esophageal candidiasis (EC) in an oncology center: Analysis of 323 cancer patients with EC
Authors: Matsuo Takahiro , Singh Ben S , Wurster Sebastian , Jiang Ying , Bhutani Manoop S , Kontoyiannis Dimiitrios P 
Published: December 2022

Abstract

Background
Historically, EC had been a common infection in the pre-azole era, and it was associated with thrush, cytopenia, chemotherapy, and debility in patients (pts) with malignancy. However, the presentation and outcomes of EC in cancer pts in the current era of new cancer treatments and frequent use of azoles as antifungal prophylaxis are scarcely studied.

Methods
We retrospectively reviewed the risk factors, clinical and laboratory features, and outcome of pathology-documented EC in pts at MD Anderson Cancer Center from January 2017 to October 2021. We followed established criteria for the endoscopy grade of EC (B E Kodsi, et al. Gastroenterology. 1976;71(5):715-9). We used a binary multivariable logistic regression model to determine independent risk factors for treatment failure (defined as relapse within 1 year from EC diagnosis) among pts who received fluconazole for EC treatment.

Results
Among 323 pts with EC, 290 pts (90%) had solid tumors; only 33 pts (10 %) had hematological malignancies. Only 7 (2%) of pts had prior antifungal prophylaxis Esophageal cancer was most common (35%), followed by lung cancer (10.8%), gastric cancer (10.2%), and colon cancer (5.9%). 229 pts (71%) received chemotherapy within 30 days prior to EC diagnosis. The most common symptoms were dysphagia (39%), nausea (20%), and odynophagia (15%); 33% of EC pts were asymptomatic. Oral thrush (2%) was uncommon. Most patients (83%) had non-ulcerative EC (endoscopic grade 1-2), 13% had grade 3, and 4% had grade 4 EC. 206 pts (64%) received antifungal treatment (oral fluconazole in 202). Among pts treated with fluconazole, 27 (13%) had treatment failure. Underlying esophageal disease was the only independent predictor of fluconazole treatment failure on multivariate analysis (adjusted odds ratio 3.88, 95%CI 1.49-10.1).

Conclusion
In a large cohort of 323 contemporary pts with EC the entity is predominantly encountered in pts with solid tumor on no antifungal prophylaxis, especially the ones with underlying esophageal pathology which is a predictor of azole treatment failure. Concomitant thrush was uncommon, and in 1/3 of pts EC was only an endoscopic finding.

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.
486. A/California/07/2009-pdm-like (H1N1) Influenza Virus Controlled Human Infection Model (CHIM) Activates Various Immune Cells Despite Induction of Mild Symptomatology
Authors: Toapanta Franklin R , Bernal Paula , Hu Jingping , Roberts Paul C , Luke Catherine J , Makhene Mamodikoe K , Ortiz Justin , Neuzil Kathleen , Sztein Marcelo 
Published: December 2022

Abstract

Background
Influenza vaccines require yearly updates due to constant antigenic drift. Improvement of current vaccines requires a deep understanding of the pathogen as well as immunity to the virus. Controlled Human Infection Models (CHIM) provide opportunities to i) test new vaccine approaches in a controlled environment and, ii) better understand host immunity. The University of Maryland School of Medicine (UMSOM) was one of four clinical sites to conduct an H1N1 influenza A virus (IAV) (A/California/07/2009-pdm-like) challenge in 2019.

Methods
Healthy adult volunteers were intranasally challenged with IAV (2 mL of ∼5x10e6 TCID50/mL). After challenge (Day 1), volunteers were assessed for the development of clinical symptoms, virus shedding, development of anti-influenza antibodies (reported elsewhere). Blood specimens were collected at Days -2, 4, 6, 8, 15 and 61 to assess changes in cellular immunity (flow cytometry and ELISpot). Our sub-study included subjects (n=20) from the UMSOM cohort only.

Results
B cell compartment, ASC (plasmablast) responses to homologous hemagglutinin (HA) and neuraminidase (NA) peaked at Day 8. Anti-HA IgG and IgA ASC responses were present in 95% and 75% participants, respectively. NA IgG and IgA ASC responses were present in 60% and 50% of participants, respectively. In the innate compartment, plasmocytoid dendritic cells (pDCs) as well as Classical (CM), intermediate (IM) and non-classical (NCM) monocytes increased in frequency at various timepoints post-challenge. Myeloid DC (mDC), pDC, CM and IM also upregulated expression of CD38 and/or HLA-DR at specific timepoints. The frequency of the CD16+CD56+ natural killer (NK) cell subset and NKT cells were also increased post-challenge. Among T cells, CD4 and CD8 T effector memory (TEM) and TEM CD45RA+ (TEMRA) were activated (CD38+ HLA-DR+) after challenge (Figure 1). CD4 T follicular helper cells (TFH)-17, TFH-1 and TFH-2 were activated (CD38+ ICOS+) at various timepoints post-challenge. Figure 1.Overview of cellular responses to Influenza CHIM.
The heat maps show changes in population frequency and/or expression of activation markers in innate (DC and monocytes) and T cells after challenge (D-2 pre-challenge). Each square displays the mean (n=20) of the population/marker. The color scale indicates the degree of change.

Conclusion
After influenza CHIM, all cell populations assessed showed signs of activation at diverse time-points. The relationship between the presence of pre-existing protective immunity (HAI &gt;40) and degree of immune activation is still under analysis.

Disclosures
Catherine J. Luke, Ph.D., GSK: Spouse is an employee of GSK Justin Ortiz, MD, Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant.
493. Defining background shared antibody sequences between unrelated healthy individuals (public clonotypes) to support future studies on specific infectious disease related conditions.
Authors: Chang Arthur , Hicar Mark D 
Published: December 2022

Abstract

Background
Public clonotypes, antibodies against specific antigens in unrelated individuals that have genetic similarities, have been shown in a variety of infections, including SARS-CoV-2 and HIV. Likely, there are shared antibody responses between individuals for many infections. To explore antibody responses that would coincide with specific infectious diseases that may set off chronic illnesses, such as Multiple Sclerosis or Alzheimer's disease, defining the background shared clonotypes is needed to differentiate disease from normal background public clonotype responses.

Methods
Heavy chain variable sequences were retrieved from public biorepositories (Bioproject PRJNA486667) composed of 43 healthy persons, and two groups of HIV infected persons; 114 with broadly neutralizing antibodies and 91 without broadly neutralizing antibodies. We utilized the Immcantation package of software run on our SUNY Buffalo computational cluster. After PRESTo annotation, duplicate sequences were collapsed and sequences of only single counts were removed. Clonal groups were determined using ChangeO requiring IGHV, IGHJ, and CDR3 amino acid sequence to be perfectly matched. Figures and statistics were generated with immcantation, excel, and graphpad prism 8.

Results
244850 heavy chain sequences from 43 healthy controls were compared for exact matches to predicted germline variable segment and CDR3 amino acid sequence and identified 0.23% as public clonotypes. Comparison to 205 HIV + individuals (a total of 1.4 million comparative sequences) showed that 2.35% of heavy chain sequences were seen in more than one individual. Generally, public clonotypes had shorter CDR3s (peak of 9 amino acids). VH 3-9, 3-30 and 4-34 were the most commonly used variable segments in public clonotypes. Common exact match CDR3 sequences using a variety of variable sequences, including an 11 amino acid CDR3 sequence motif, were also discovered.

Conclusion
This early work has identified several public clonotypes that are shared among subjects who are HIV positive and otherwise healthy people. Defining the sequences commonly seen between individuals can assist in specifying antibody responses specific to disease states from larger sequence databases.

Disclosures
All Authors: No reported disclosures.
505. Mucosal and Systemic Humoral Immunity Differences between Sexes during Influenza Vaccination and Viral Challenge
Authors: Giurgea Luca T , Bean Rachel , Han Alison , Czajkowski Lindsay , Cervantes-Medina Adriana , Gouzoulis Monica , Baus Holly Ann , Reed Susan M , Athota Rani , Mateja Allyson , Hunsberger Sally , Kash John , Taubenberger Jeffery , Memoli Matthew J 
Published: December 2022

Abstract

Background
In previous influenza challenge studies we observed that the incidence of influenza symptoms was higher in women than in men, and that women experience more symptoms overall. Women also demonstrated lower neuraminidase (NA) inhibition (NAI) antibody titers than men after challenge and regression analysis suggested that NAI titers predict clinical outcomes. We sought to evaluate this using data from a more recent challenge study with more immunologically varied volunteers, while also assessing mucosal immunity.

Methods
We obtained mucosal and serum samples from healthy adults. Half underwent intramuscular quadrivalent influenza vaccination followed by influenza A (H1N1) intranasal challenge while others just challenge alone. Antibody titers and clinical outcomes between sexes were compared.

Results
No significant differences in shedding or symptom outcomes were observed between sexes. Similarly, no differences in systemic titers against NA or hemagglutinin (HA) were seen. Serum total IgG and IgA were also similar between sexes. Prior to vaccination, mucosal IgA titers were significantly lower against HA stalk and NA in women, but these differences disappeared after vaccination. In the unvaccinated group, lower nasal IgA titers were also seen in women pre-challenge. At 7 days post-challenge, differences in mucosal titers between sexes disappeared. However, at 56 days post-challenge, mucosal IgA titers against HA, HA stalk, and NA were all significantly lower in women.

Conclusion
In contrast to our previous findings, no differences in clinical outcomes or systemic NAI titers were observed between men and women, possibly due to differences in underlying immunity between study populations or the lower sample size in this study. However, mucosal differences were noted with women having lower mucosal titers than men against HA stalk and NA at baseline. While influenza vaccination and challenge eliminated differences in the short term, they reappeared 8 weeks after challenge, with all nasal IgA antibody titers (HA, HA stalk, and NA) lower in women. Further studies are necessary to understand the differences in influenza disease and immunity between sexes.

Disclosures
All Authors: No reported disclosures.
525. A Universal ‘Day Zero’ Infectious Disease Testing Strategy Exploiting Crispr-Based Sample Depletion And Metagenomic Sequencing
Authors: Brown Keith 
Published: December 2022

Abstract

Background
The lack of preparedness for detecting the highly infectious SARS-CoV-2 pathogen — the pathogen responsible for the COVID-19 disease — caused enormous harm to the public health, the economy and society as a whole. It took ∼60 days for the first RT-PCR tests for SARS-CoV-2 infection developed by the United States Centers for Disease Control (CDC) to be made available. It then took &gt;270 days to deploy 800,000 of these tests at a time when the estimated actual testing needs required over 6 million tests per day. Testing was therefore limited to only individuals with symptoms or individuals in close contact with confirmed positive cases. Testing strategies that can be deployed on a population scale at ‘day zero’ (i.e., at the time of the first reported case) are needed. Next Generation Sequencing (NGS) has such day zero capabilities with the potential to enable feasible and broad large-scale testing strategies, however it has limited detection sensitivity for low copy numbers of pathogens which may be present. Here we demonstrate that using CRISPR-Cas9 to remove abundant sequences that do not contribute to pathogen detection, NGS detection sensitivity is equivalent to RT-PCR. In addition, we show that this assay can be used for variant strain typing, co-infection detection, and individual human host response assessment – all in a single workflow using existing open-source analysis pipelines. This NGS workflow is pathogen agnostic, and therefore has the potential to radically transform how both very large-scale pandemic response and focused clinical infectious disease testing are pursued in the future.
microbial composition at two test sites
Detection Sensitivity

Methods
Covid positive samples with RT-PCR Ct values from 16-39 were processed through the CRISRP enhanced mNGS pipeline.
Data processing workflow

Results
Sn/Sp compared to RT-PCR was 97%/100%. Strain calling concordance compared to amplicon sequencing was 100%. Co-infections from Covid positive samples were identified with high confidence. Host response signatures match the published literature.

Conclusion
Applying CRISPR enhanced metagenomic NGS at Day Zero of the next pandemic can mitigate the time gap in developing approved diagnostics at population scale and potentially save lives.

Disclosures
All Authors: No reported disclosures.
528. Bacterial vs viral etiology of fever: a prospective study to estimate a host score’s potential to support ED physicians' etiologic accuracy
Authors: Mor Meirav , Paz Meital , Amir Lisa , Levy Itzhak , Scheuerman Oded , Livni Gilat , Guetta-Oz Claire , Yochpaz Sivan , Berant Ron , Schwartz Rama , Niv Omer , Singer Dana , Ashkenazi Shai , Waisman Yehezkel 
Published: December 2022

Abstract

Background
A host-protein score (BV) combining the circulating levels of TRAIL, IP-10 and CRP was developed for distinguishing bacterial from viral infection. BV’s potential to impact decision making at the emergency department (ED) was assessed by comparing BV to physician’s etiological suspicion.

Methods
Rosetta study participants, aged 3 months to 18 years with febrile respiratory tract infection or fever without source, were prospectively recruited in a tertiary care pediatric ED. The main eligibility criteria were symptoms for less than 7 days and immunocompetence. ED physician’s initial etiological suspicion (bacterial/viral/I don’t know) and degree of confidence (low/medium/high) were recorded in a questionnaire. BV was interpreted based on pre-defined score thresholds (viral/bacterial/equivocal); the results were not available to the physician. The etiologic reference standard was based on the diagnoses (bacterial/viral/indeterminate) of 3 independent pediatricians who were provided with all available patient data but blinded to BV. BV’s potential to impact the physician’s etiologic accuracy was estimated according to alignment between BV and etiological suspicion as filled in the questionnaire (assuming full adoption of BV by the physician).

Results
Among 348 patients recruited, 290 met eligibility criteria and had requisite serum sample (Figure 1A). Median age was 1.3 years (interquartile range 1.7), 37.5% were female. 211 patients had questionnaires filled. BV matched physician’s label and reference standard in 72% of the cases (151/211; Figure 1B); of these, 52% (78/151) were labeled by the physician with low/medium confidence, i.e., BV could reinforce the physician’s suspicion. In 12% of the cases (26/211) BV aligned with the reference standard but not with the physician’s suspicion, and therefore could correct the physician's etiologic diagnosis. BV did not align with the reference standard in 7% of the cases (14/211) and was equivocal in 9% of the cases (20/211). Overall, BV could potentially correct physician diagnosis and reduce error &gt;2-fold, from 16.1% to 8.1%. Figure 1.Assessing the potential impact of BV on ED physician’s etiologic accuracy.
(A) Reference standard outcomes and BV scores. (B) BV versus adjudication-based reference standard and ED physician etiologic suspicion. Cases with missing questionnaire were omitted; n=211.

Conclusion
BV has potential to aid the diagnostic process. Future studies are warranted to assess the real-world impact of BV on ED practice.

Disclosures
Meital Paz, MD, MeMed: employee Oded Scheuerman, MD, MeMed: Grant/Research Support Ron Berant, MD, GE: Advisor/Consultant.
548. Target Enriched NGS Reveals Wide Breadth of Viruses Causing Acute Undifferentiated Fever in Thailand
Authors: Yamaguchi Julie , Berg Michael G , Phoompoung Pakpoom , Malinauskas Jenna , Cloherty Gavin , Suputtamongkol Yupin 
Published: December 2022

Abstract

Background
Despite extensive laboratory testing, infectious agents were not detected in approximately 50% of patients hospitalized for acute undifferentiated febrile illnesses (AUFI) at Siriraj Hospital, Bangkok, Thailand. Unbiased Metagenomic Next Generation Sequencing (mNGS) enables detection of any microbe present in patient samples. Target enrichment for viruses represents a highly sensitive and cost-effective approach for overcoming host background in clinical specimens. Plasma collected from 800 patients with undiagnosed AUFI between 2013-2020 were analyzed by mNGS coupled to target enrichment to identify known and novel viruses.

Methods
Plasma was pre-treated with benzonase before extraction on an Abbott m2000 instrument. mNGS libraries were prepared from double-stranded cDNA with Illumina Nextera XT reagents on an epMotion then combined in pools of 24 and hybridized to Comprehensive Viral Research Panel (CVRP; Twist Biosciences) probes covering &gt;15,000 strains of vertebrate viruses. Captured viral sequences were amplified, quantified, and sequenced together on a MiSeq. Reads were taxonomically classified by the SURPI pipeline and aligned in CLC Bio Genomics Workbench software.

Results
CVRP method optimization enabled sequencing of 24-48 libraries per MiSeq run, for which &gt;50% genome coverage was obtained with model viruses spiked into clinical specimens at 1000 cp/ml. This approach revealed an array of &gt;24 different viruses found in 26% of samples. Dengue was the most prevalent at 7.4%, with all four genotypes detected. Other common causes of AUFI such as Chikungunya, HIV-1, HAV, HBV, HCV, and CMV were present in 1.5-2.5% of cases. Less prevalent (&lt; 1%) infections included HEV, HSV-2, EBV, HHV-6, Enterovirus B&D and Parvovirus B19. We also encountered sporadic cases of Measles, Cardiovirus, West Nile, Rotavirus, Picobirnavirus, Polyomavirus 4&5, Kubovirus, and Rabies lyssavirus.

Conclusion
Target capture successfully demonstrated that viruses were important etiologies for unresolved cases of AUFI in Thailand. This data has led to a better understanding of the epidemiology of this clinical syndrome and has implications for proper management of AUFI, including lower rates of unnecessary testing and antimicrobial use.

Disclosures
Julie Yamaguchi, BS, Abbott Labs: Employee Michael G. Berg, PhD, Abbott Labs: Employee Pakpoom Phoompoung, MD, Abbott Labs: Grant/Research Support|Abbott Labs: Employee Jenna Malinauskas, MS, Abbott Labs: Employee Gavin Cloherty, PhD, Abbott: Employee|Abbott: Stocks/Bonds|Abbott Labs: Employee Yupin Suputtamongkol, MD, Abbott Labs: Grant/Research Support.