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Background Pregnant persons are at increased risk of severe coronavirus disease 2019 (COVID-19) and adverse obstetric outcomes. Understanding maternal antibody response, duration, and transplacental transfer after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination is important to inform public health recommendations. Methods This prospective observational cohort study included 351 pregnant people who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. Immunoglobulin (Ig) G and IgM to SARS-CoV-2 S1 receptor binding domain were measured in maternal and cord blood. Antibody levels and transplacental transfer ratios were compared across (1) disease severity for those with SARS-CoV-2 infection and (2) infection versus vaccination. Results There were 252 individuals with SARS-CoV-2 infection and 99 who received COVID-19 vaccination during pregnancy. Birthing people with more severe SARS-CoV-2 infection had higher maternal and cord blood IgG levels (P = .0001, P = .0001). Median IgG transfer ratio was 0.87–1.2. Maternal and cord blood IgG were higher after vaccination than infection (P = .001, P = .001). Transfer ratio was higher after 90 days in the vaccinated group (P < .001). Modeling showed higher amplitude and half-life of maternal IgG following vaccination (P < .0001). There were no significant differences by fetal sex. Conclusions COVID-19 vaccination in pregnancy leads to higher and longer lasting maternal IgG levels, higher cord blood IgG, and higher transfer ratio after 90 days compared with SARS-CoV-2 infection. Greater infection severity leads to higher maternal and cord blood antibodies. Maternal IgG decreases over time following both vaccination and infection, reinforcing the importance of vaccination, even after infection, and vaccine boosters for pregnant patients.

We evaluated changes in genetic testing for neonatal-onset epilepsy and associated short-term outcomes over an 8-year period among a cohort of patients in the neonatal intensive care unit (NICU) at a single institution before and after the introduction of sponsored genetic epilepsy testing in January 2018.Our primary outcome was a change in length of stay (LOS) after 2018. We also ascertained severity of illness with the Neonatal Sequential Organ Failure Assessment (nSOFA), type and result of genetic testing, turnaround time to molecular diagnosis (TAT), LOS, antiseizure medications (ASMs), and use of technology at discharge. We compared outcomes using nonparametric tests and difference-in-difference analysis.Fifty-three infants with genetic testing were included; 20 infants were tested after 2018. A total of 4160 infants in the NICU without genetic testing were used as reference. In the genetic testing group, LOS was 25 days (interquartile range [IQR] 5, 49) pre-2018 and 19 days (IQR 6, 19) post-2018 (P 0.001 when compared with the reference population in the difference-in-difference analysis). TAT decreased from 51 days to 17 days after 2018 (P = 0.003). ASM number decreased from 4 (IQR 2, 5) to 2 post-2018 (IQR 1, 3) (P = 0.02). Over the same time periods there was no significant change in birth weight, maximum nSOFA score, or technology dependence.In this cohort, changes in genetic testing for neonatal-onset epilepsy were associated with shorter LOS that was not explained by changes in severity of illness, birth weight, or the average LOS in the NICU over time. Validation of these results in a larger, multicenter sample size is warranted.

Background: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood. Materials and Methods: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing. Results: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast (n = 67), non-small cell lung (n = 25), colorectal (n = 18), gastroesophageal (n = 17), pancreatic (n = 11), and uterine (n = 11). The PPV of ERBB2 CNG in determining HER2 positivity by standard IHC/FISH definitions was 88% for tissue NGS (n = 57) and 80% for ctDNA (n = 47). The PPV among breast cancer patients for tissue NGS was 97% (n = 35) and ctDNA was 93% (n = 39). However, for non-breast cancer cases, the PPV of ERBB2 amplification by tissue NGS dropped to 76% (n = 22) and by ctDNA to 44% (n = 7). Conclusions: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer.

Background Pregnant people and fetuses are uniquely vulnerable to SARS-CoV-2, a driver of inflammation and immune dysregulation. Prior investigations have shown that pregnant people with SARS-CoV-2 are at higher risk of severe illness, mortality, and obstetric complications. We investigated the impact of SARS-CoV-2 infection severity and latency on maternal and infant cytokine levels. Methods We collected maternal blood and cord blood at delivery from mother-infant dyads (Chicago, IL; 3/2020-1/2022). A multiplex cytokine panel (IsoPlexis) was run on plasma from 93 SARS-CoV-2 infected dyads and 32 matched controls. Clinical data was abstracted by chart review, including latency (acute being ≤14 days and distant >14 days from SARS-CoV-2 infection to delivery) and severity (NIH criteria: asymptomatic, mild, moderate, severe/critical). Kruskal-Wallis tests with post-hoc pairwise Dunn Tests were used (α=0.05). Results SARS-CoV-2 exposed infants had lower levels of MIP-1b (p=0.037) and PDGF (p=0.008) than controls [Fig 1]. There were no differences in maternal blood cytokines at time of delivery following SARS-CoV-2 infection during pregnancy (pooled analysis of all SARS-CoV-2). Stratifying by latency, acutely exposed infants showed higher levels of MCP-1 than controls or those with distant maternal SARS-CoV-2 (p=0.016). There were no significant differences in maternal cytokines between control, acute, and distant SARS-CoV-2. In mothers with acute SARS-CoV-2, differences in levels of IL-1B (p=0.011) and IL-10 (p=0.046) were observed across severity groups, with a significant linear trend for each among severity groups (p for trend < 0.001, respectively). Severe/critical acute infection resulted in higher maternal granzyme and IL-8 than mild infection (p=0.037 and 0.047) [Fig 2]. There were no differences across severity groups in 1) mothers with distant infection, 2) infants with acute maternal infection, or 3) infants with distant maternal infection. Maternal and infant cytokine levels in acute SARS-CoV-2 infection across severity Conclusion Cytokine levels in SARS-CoV-2 positive dyads were altered only in the setting of acute or more severe infection and demonstrated anti-inflammatory, anti-viral, and anti-angiogenic responses. In acute infection, greater severity drives higher levels of both a pro- and anti-inflammatory cytokine in pregnant people. Disclosures All Authors: No reported disclosures.

Introduction: Previously reported data from our group and others have demonstrated an increase in genomic complexity and number of alterations over the course of treatment in MBC. Our study aims to categorize the pathogenicity of genomic aberrations found on serial ctDNA evaluations in MBC to explore the relevance of emerging mutations. Methods: Patients with MBC and ctDNA next-generation sequencing (NGS) analysis by Guardant360 (Guardant Health, Redwood City, CA) completed from 2015 to 2019 were retrospectively identified with an IRB-approved protocol. Clinical-pathologic features and time point for progression of disease were abstracted from review of the electronic medical record. Among the 255 patients with ctDNA analysis, 85 patients had serial ctDNA analysis from baseline and at subsequent progression of disease (PD1) and 27 had repeat ctDNA analysis at next progression (PD2). Genomic alterations were classified as oncogenic, likely oncogenic, predictive oncogenic, likely benign, inconclusive, unknown significance, and synonymous based on categorization by OncoKB.org (Chakravarty et al, JCO PO 2017). Oncogenic, likely oncogenic, and predicted oncogenic were considered ‘pathogenic’ while the remainder were ‘not known pathogenic’. Two-sample t-tests for difference of means (α = 0.05) was used for analysis of changes in pathogenic proportions and mutant allele frequencies (MAF). Results: The median age was 53.8 years, 41 patients had hormone receptor positive (HR+) HER2-negative, 22 had HER2+, and 22 had triple negative (TN) MBC. The median and interquartile range (IQR) of the time of MBC diagnosis to first ctDNA collection was 10 mo (0.3-23.1 mo), from baseline ctDNA to analysis at the time of disease progression (PD1) was 6.7 mo (3.6-12.5 mo), and from PD1 to second progression (PD2) was 4.6 mo (3.1-8.5 mo). At baseline 66% of alterations were pathogenic (38.4% oncogenic, 27.6% likely oncogenic, 26.5% unknown significance). The proportion of pathogenic variants did not significantly change over time: 62% at PD1 (p=0.41) and 56% at PD2 (p=0.19). The percent of pathogenic alterations by disease subtype at baseline and PD1 was 66% and 60% in HR+ HER2-, 73% and 57% in HER2+, and 62% and 71% in TN. 57% and 70% of patients had a new pathogenic alteration at PD1 and PD2, respectively. The most frequently detected new pathogenic alterations at the time of disease progression were TP53, PIK3CA, ESR1, FGFR1, and MYC, which occurred in 28%, 18%, 15%, 12%, and 11% of patients, respectively. Among genes that were altered in at least 10% of patients, the aberrations were very likely to be pathogenic (>75% of alterations pathogenic) for TP53, PIK3CA, ESR1, MYC, BRAF, FGFR1, often pathogenic (50-75% of alterations pathogenic) for NF1, KIT, GATA3, ERBB2, EGFR, CCNE1, PDGFRA, and often not known pathogenic ( Citation Format: Ami N Shah, Andrew A Davis, Saya Jacob, Lorenzo Gerratana, Brian Finkelman, Shruti Chandra, Neelima Katam, Firas Wehbe, Jeeven Srivastava, Ashwin Sunderraj, Qiang Zhang, Leonidas Platanias, Amir Behdad, William Gradishar, Massimo Cristofanilli. Evaluating the pathogenicity of emerging genomic aberrations detected by circulating tumor DNA over the course of metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-26.

Pregnant persons are at increased risk of severe COVID-19 and adverse obstetric outcomes. Understanding maternal antibody response, duration, and transplacental transfer after SARS-CoV-2 infection and COVID-19 vaccination is important to inform public health recommendations.This prospective observational cohort study included 351 pregnant people who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. IgG and IgM to SARS-CoV-2 S1 receptor binding domain were measured in maternal and cord blood. Antibody levels and transplacental transfer ratios were compared across 1) disease severity for those with SARS-CoV-2 infection and 2) infection versus vaccination.There were 252 individuals with SARS-CoV-2 infection and 99 who received COVID-19 vaccination during pregnancy. Birthing people with more severe SARS-CoV-2 infection had higher maternal and cord blood IgG levels (p = 0.0001, p = 0.0001). Median IgG transfer ratio was 0.87-1.2. Maternal and cord blood IgG were higher after vaccination than infection (p = 0.001, p = 0.001). Transfer ratio was higher after 90 days in the vaccinated group (p 0.001). Modeling showed higher amplitude and half-life of maternal IgG following vaccination (p 0.0001). There were no significant differences by fetal sex.COVID-19 vaccination in pregnancy leads to higher and longer lasting maternal IgG levels, higher cord blood IgG, and higher transfer ratio after 90 days compared to SARS-CoV-2 infection. Greater infection severity leads to higher maternal and cord blood antibodies. Maternal IgG decreases over time following both vaccination and infection, reinforcing the importance of vaccination, even after infection, and vaccine boosters for pregnant patients.

BackgroundPregnant persons are at increased risk of severe COVID-19 and adverse obstetric outcomes. Understanding maternal antibody response and transplacental transfer after SARS-CoV-2 infection and COVID-19 vaccination is important to inform public health recommendations.MethodsThis prospective observational cohort study included 351 birthing individuals who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. IgG and IgM to SARS-CoV-2 S1 receptor binding domain were measured in maternal and cord blood. Antibody levels and transplacental transfer ratios were compared across 1) disease severity for those with SARS-CoV-2 infection and 2) infection versus vaccination.FindingsThere were 252 individuals with SARS-CoV-2 infection and 99 who received COVID-19 vaccination during pregnancy. Birthing people with more severe SARS-CoV-2 infection category had higher maternal and cord blood IgG levels (p=0.0001, p=0.0001). Median IgG transfer ratio was 0.87-1.2. Maternal and cord blood IgG were higher after vaccination than infection (p=0.001, p=0.001). Transfer ratio was higher after 90 days in the vaccinated group (pInterpretationCOVID-19 vaccination in pregnancy leads to higher and longer lasting maternal IgG levels, higher cord blood IgG, and higher transfer ratio after 90 days compared to SARS-CoV-2 infection. Greater infection severity leads to higher maternal and cord blood antibodies. Maternal IgG decreases over time following both vaccination and infection, reinforcing the importance of vaccination, even after infection, and vaccine boosters for pregnant patients.

Bacterial ATP-binding cassette transporters are a superfamily of transport systems involved in the import of various molecules including amino acids, ions, sugars, and peptides. In the lactic acid bacteria Lactococcus lactis, the oligopeptide-binding protein A (OppA) binds peptides for import to support nitrogen metabolism and cell growth. The OppA protein is of great interest because it can bind peptides over a broad variety of lengths and sequences; however, current methods to study peptide binding have employed low throughput, endpoint, or low dynamic range techniques. Therefore, in this study, we developed a fluorescence anisotropy-based peptide-binding assay that can be readily employed to quantify OppA function. To test the utility of our assay, we characterized the pH dependence of oligopeptide binding because L. lactis is commonly used in fermentation and often must survive in low pH environments caused by lactic acid export. We determined that OppA affinity increases as pH or temperature decreases, and circular dichroism spectroscopy further indicated that acidic conditions increase the thermal stability of the protein, increasing the unfolding transition temperature by 10 °C from pH 8 to pH 6. Thus, our fluorescence anisotropy assay provides an easy technique to measure peptide binding, and it can be used to understand molecular aspects of OppA function under stress conditions experienced during fermentation and other biotechnology applications.