153. AYA Subspecialty Patient and Parent Views on COVID-19 Vaccination

This article is made available for unrestricted research re-use and secondary analysis in any form or be any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Purpose: Adolescents/young adults (AYA) with hematologic and oncologic (heme-onc) conditions are important targets for vaccine outreach because they are at increased risk for complications from COVID-19. AYA patients may also need additional support, as they are transitioning from parent to independent vaccine decision-making. AYA with sickle cell disease (SCD) are of particular concern because a high proportion are African American and experience structural racism in addition to their illness. Our objective was to examine AYA and parent attitudes regarding the COVID-19 vaccine among heme-onc populations. Methods: As part of a larger IRB-approved study, we recruited vaccine decision-makers in pediatric SCD and oncology survivor clinics, including parents of adolescents under 18 years (n=35), AYA patients 18-21 years old (n=21), and parents of AYA patients 18-21 years old (n=14). After informed consent, participants completed a demographic survey and a semi-structured interview regarding their vaccine decision-making process. Example questions included “What do you see as the benefits of the COVID-19 vaccine?” and “What are your concerns about the COVID-19 vaccine?”. Saturation was reached. Interviews were audio recorded, transcribed, and analyzed using thematic analysis. Codes were developed from the literature and early interviews. Examples included “attitudes against vaccine,” “medical mistrust,” “hesitancy,” “vaccine side effects,” and “vaccine interactions with disease process.” Fisher exact statistical tests were performed to analyze quantitative data. Results: In SCD clinic, we recruited 31 index patients (mean age: 15.1±3.5 years; 30 African American and 1 Other or Mixed), yielding 11 AYA and 26 parent interviews. In survivor clinic, we recruited 26 index patients (mean age: 16.0±3.4 years; 20 White, 2 Hispanic or Latinx; 2 Other or Mixed, 1 African American, and 1 Asian), yielding 10 AYA and 23 parent interviews. Out of the total index patients, 8 had already received the vaccine, 13 were planning to receive it, 27 were considering it, and 9 had declined it. There was no clear relationship between patients’ diagnosis (SCD or cancer) and their vaccine decisions nor between the index patient’s age (under or over 18) and their vaccine decisions. A high proportion of participants saw benefits to vaccination, such as lowering personal risk, community benefits of preventing the spread of COVID-19, and a possible return to “normal.” However, many AYA and parent participants also had concerns toward the vaccine, including concerns about short-term side effects and the potential for unknown, long-term effects. Concerns were also voiced about how rapidly the vaccine was developed and misconceptions about the vaccine were common, namely the vaccine causing infertility or increasing one’s susceptibility to contracting COVID-19. Medical mistrust toward either the vaccine or providers was explicitly stated by several participants, the majority of whom were from minoritized groups. Conclusions: COVID-19 vaccines have the potential to protect medically and socially vulnerable AYA, however patient and parent concerns, misconceptions, and mistrust are still prevalent. These data provide insights into the design and implementation of vaccine counseling interviews for AYA subspecialty patients and families

Experimental annotation of post-translational features and translated coding regions in the pathogen Salmonella Typhimurium

<p>Abstract</p> <p>Background</p> <p>Complete and accurate genome annotation is crucial for comprehensive and systematic studies of biological systems. However, determining protein-coding genes for most new genomes is almost completely performed by inference using computational predictions with significant documented error rates (> 15%). Furthermore, gene prediction programs provide no information on biologically important post-translational processing events critical for protein function.</p> <p>Results</p> <p>We experimentally annotated the bacterial pathogen <it>Salmonella </it>Typhimurium 14028, using "shotgun" proteomics to accurately uncover the translational landscape and post-translational features. The data provide protein-level experimental validation for approximately half of the predicted protein-coding genes in <it>Salmonella </it>and suggest revisions to several genes that appear to have incorrectly assigned translational start sites, including a potential novel alternate start codon. Additionally, we uncovered 12 non-annotated genes missed by gene prediction programs, as well as evidence suggesting a role for one of these novel ORFs in <it>Salmonella </it>pathogenesis. We also characterized post-translational features in the <it>Salmonella </it>genome, including chemical modifications and proteolytic cleavages. We find that bacteria have a much larger and more complex repertoire of chemical modifications than previously thought including several novel modifications. Our <it>in vivo </it>proteolysis data identified more than 130 signal peptide and N-terminal methionine cleavage events critical for protein function.</p> <p>Conclusion</p> <p>This work highlights several ways in which application of proteomics data can improve the quality of genome annotations to facilitate novel biological insights and provides a comprehensive proteome map of <it>Salmonella </it>as a resource for systems analysis.</p

Activation of Human Monocytes by Live Borrelia burgdorferi Generates TLR2-Dependent and -Independent Responses Which Include Induction of IFN-β

It is widely believed that innate immune responses to Borrelia burgdorferi (Bb) are primarily triggered by the spirochete's outer membrane lipoproteins signaling through cell surface TLR1/2. We recently challenged this notion by demonstrating that phagocytosis of live Bb by peripheral blood mononuclear cells (PBMCs) elicited greater production of proinflammatory cytokines than did equivalent bacterial lysates. Using whole genome microarrays, we show herein that, compared to lysates, live spirochetes elicited a more intense and much broader transcriptional response involving genes associated with diverse cellular processes; among these were IFN-β and a number of interferon-stimulated genes (ISGs), which are not known to result from TLR2 signaling. Using isolated monocytes, we demonstrated that cell activation signals elicited by live Bb result from cell surface interactions and uptake and degradation of organisms within phagosomes. As with PBCMs, live Bb induced markedly greater transcription and secretion of TNF-α, IL-6, IL-10 and IL-1β in monocytes than did lysates. Secreted IL-18, which, like IL-1β, also requires cleavage by activated caspase-1, was generated only in response to live Bb. Pro-inflammatory cytokine production by TLR2-deficient murine macrophages was only moderately diminished in response to live Bb but was drastically impaired against lysates; TLR2 deficiency had no significant effect on uptake and degradation of spirochetes. As with PBMCs, live Bb was a much more potent inducer of IFN-β and ISGs in isolated monocytes than were lysates or a synthetic TLR2 agonist. Collectively, our results indicate that the enhanced innate immune responses of monocytes following phagocytosis of live Bb have both TLR2-dependent and -independent components and that the latter induce transcription of type I IFNs and ISGs

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Pediatric hematology/oncology physician and nurse practitioner attitudes towards the COVID-19 vaccines: A qualitative study

As of 05/28/2021, SARS-CoV-2 (COVID-19) had caused 3.9 million infections in the United States (US) pediatric population since its discovery in December of 2019. The development and expansion of vaccination has markedly changed the shape of the epidemic. In this qualitative study, we report on pediatric hematology/oncology provider views on the COVID-19 vaccine prior to approval in the adolescent population <16 years of age. Results from interviews with 20 providers across the state of Indiana showed that most were supportive of the COVID-19 vaccine for healthy adults. However, the majority also expressed a need to see more data on the safety and effectiveness of COVID-19 vaccinations in pediatric hematology/oncology populations. While they recognized the public health importance of vaccination, their duty to protect their patients led to a need for more specific safety and efficacy data

Pediatric hematology and oncology physician and nurse practitioner views of the HPV vaccine and barriers to administration

Rates of Human papilloma virus (HPV) vaccination among pediatric survivors of cancer and patients with sickle cell disease are lower than the national average. While recent attention has focused on patient HPV vaccine hesitancy and refusal, less is known about provider-level and system-level barriers to vaccinations in pediatric hematology/oncology (PHO) populations. Applying thematic analysis to qualitative interviews with 20 pediatric hematology/oncology physicians and nurse practitioners, we examine their views regarding HPV vaccination, with a focus on access and barriers to providing HPV vaccination in PHO practices. Results demonstrated that despite 90% of interviewees supporting HPV vaccination in their population, the number of pediatric hematology/oncology providers who reported that they counsel about HPV or provide HPV vaccination was 45%, even in stem cell and sickle cell clinics, where other childhood vaccines are commonly provided. Clinicians identified provider-level, clinic-level, and system-level barriers to giving the HPV vaccination, including but not limited to time/flow constraints, lack of resources, and continued education regarding the HPV vaccine. These barriers impede the ability for pediatric hematology/oncology providers to counsel and provide HPV vaccination to this specialized population

Insulinotropic treatments exacerbate metabolic syndrome in mice lacking MeCP2 function

Rett syndrome (RTT), an X-linked postnatal disorder, results from mutations in Methyl CpG-binding protein 2 (MECP2). Survival and breathing in Mecp2NULL/Y animals are improved by an N-terminal tripeptide of insulin-like growth factor I (IGF-I) treatment. We determined that Mecp2NULL/Y animals also have a metabolic syndrome and investigated whether IGF-I treatment might improve this phenotype. Mecp2NULL/Y mice were treated with a full-length IGF-I modified with the addition of polyethylene glycol (PEG-IGF-I), which improves pharmacological properties. Low-dose PEG-IGF-I treatment slightly improved lifespan and heart rate in Mecp2NULL/Y mice; however, high-dose PEG-IGF-I decreased lifespan. To determine whether insulinotropic off-target effects of PEG-IGF-I caused the detrimental effect, we treated Mecp2NULL/Y mice with insulin, which also decreased lifespan. Thus, the clinical benefit of IGF-I treatment in RTT may critically depend on the dose used, and caution should be taken when initiating clinical trials with these compounds because the beneficial therapeutic window is narrow