Different decay of antibody response and VOC sensitivity in naïve and previously infected subjects at 15 weeks following vaccination with BNT162b2

Background COVID-19 vaccines have demonstrated effectiveness in reducing SARS-CoV-2 mild and severe outcomes. In vaccinated subjects with SARS-CoV-2 history, RBD-specific IgG and pseudovirus neutralization titers were rapidly recalled by a single BTN162b2 vaccine dose to higher levels than those in naïve recipients after the second dose, irrespective of waning immunity. In this study, we inspected the long-term kinetic and neutralizing responses of S-specific IgG induced by two administrations of BTN162b2 vaccine in infection-naïve subjects and in subjects previously infected with SARS-CoV-2. Methods Twenty-six naïve and 9 previously SARS-CoV-2 infected subjects during the second wave of the pandemic in Italy were enrolled for this study. The two groups had comparable demographic and clinical characteristics. By means of ELISA and pseudotyped-neutralization assays, we investigated the kinetics of developed IgG-RBD and their neutralizing activity against both the ancestral D614G and the SARS-CoV-2 variants of concern emerged later, respectively. The Wilcoxon matched pair signed rank test and the Kruskal–Wallis test with Dunn’s correction for multiple comparison were applied when needed. Results Although after 15 weeks from vaccination IgG-RBD dropped in all participants, naïve subjects experienced a more dramatic decline than those with previous SARS-CoV-2 infection. Neutralizing antibodies remained higher in subjects with SARS-CoV-2 history and conferred broad-spectrum protection. Conclusions These data suggest that hybrid immunity to SARS-CoV-2 has a relevant impact on the development of IgG-RBD upon vaccination. However, the rapid decay of vaccination-elicited antibodies highlights that the administration of a third dose is expected to boost the response and acquire high levels of cross-neutralizing antibodies.

Acute Myocardial Infarction During the COVID-19 Pandemic: An Update on Clinical Characteristics and Outcomes

The outbreak of coronavirus disease 2019 (COVID-19) has rapidly become a worldwide pandemic. On top of respiratory complications, COVID-19 is associated with major direct and indirect cardiovascular consequences, with the latter probably being even more relevant, especially in the setting of time-dependent cardiovascular emergencies. A growing amount of data suggests a dramatic decline in hospital admissions for acute myocardial infarction (AMI) worldwide during the COVID-19 pandemic, mostly since patients did not activate emergency medical systems because hospitals were perceived as dangerous places regarding the infection risk. Moreover, during the COVID-19 pandemic, patients with AMI had a significantly higher in-hospital mortality compared to those admitted before COVID-19, potentially due to late arrival to the hospital. Finally, no consensus has been reached regarding the most adequate healthcare management pathway for AMI and shared guidance on how to handle patients with AMI during the pandemic is still needed. In this review, we will provide an update on epidemiology, clinical characteristics, and outcomes of patients with AMI during the COVID-19 pandemic, with a special focus on its collateral cardiac impact.

Morphological Traits and Capture Depth of the Norwegian Skate (Dipturus nidarosiensis (Storm, 1881)) from Two Mediterranean Populations

The Norwegian skate Dipturus nidarosiensis (Storm, 1881) has only recently been recorded in the western-central Mediterranean Sea. It was hypothesized a more ancient presence of the species, which has not been detected due to a misidentification with other species of the same genus. This situation could lead to underestimate the risk of a dramatic decline of the spawning stock. In the IUCN Red List, the species is listed as near threatened and considered rare in both the northeast Atlantic and the Mediterranean areas. In the Mediterranean Sea, Norwegian skates were repeatedly caught mostly in two areas between 2005 and 2020: Sardinia Seas and Adriatic-Ionian Seas. In total, 58 specimens were caught, and 28 morphological length measurements were taken on all specimens. The Canonical Discriminant Analysis proved the presence of significant differences only for assemblages made on the basis of the specimen’s area of capture, but not on the basis of sex or ontogenetic development. This analysis could be the first step to highlight the differences between the populations of Norwegian skate in the Mediterranean basin. Moreover, a preliminary analysis of depth of capture was performed as a first step to study this species vertical distribution.

Current knowledge about cardiomyocytes maturation and endogenous myocardial regeneration. Background to apply this potential in humans with end-stage heart failure

Heart failure (HF) is a clinical status defined as a final stage of many cardiac diseases featured by severely impaired systolic myocardial performance in a result of dramatic decline in a number of properly functioning cardiomyocytes. Currently, the available therapeutic options for HF patients are not applicable in all of them. Up to now, many strategies to increase a number of normal cardiomyocytes have been proposed. One of them, the most physiological one at glance, seems to be a stimulation of post-mitotic cardiomyocytes to proliferate/or cardiac stem cells to differentiate. In this review article, detailed background of such method of myocardial regeneration, including the physiological processes of cardiomyocyte transformation and maturation, is presented. Moreover, the latest directions of basic research devoted to develop sufficient and safe cardiomyocyte-based therapies of the end-stage HF individuals are discussed. Concluding, this direction of further research seems to be justified particularly in a view of human population aging, an increased prevalence of HF and higher expectations of improved efficiency of patients’ care.

The Condensin II Complex Subunit NCAPH2 Is Essential for Erythropoiesis and Regulates Erythroid Gene Expression

Erythropoiesis requires dramatic changes in gene expression in a cell that is rapidly proliferating and undergoing progressive nuclear condensation in anticipation of enucleation. Disruption of this process is associated with myelodysplastic syndromes and congenital anemias. Our lab has demonstrated that Setd8, the sole histone methyltransferase that can generate H4K20me1, plays an essential role in this process (Malik 2019). H4K20me1 accumulates during terminal erythroid maturation (Murphy Blood 2021) and can regulate chromatin structure and gene expression through interaction with multiple partners, including the Condensin II Complex. The Condensin II complex is a ring-like structure composed of two conserved SMC components (SMC2 and SMC4), two HEAT subunits (NCAPG2 and NCAPD3), and a kleisin subunit NCAPH2. The Condensin II complex plays an important role in chromatin condensation during mitosis, and establishing higher-order chromatin interactions in interphase cells, with some studies suggesting it also regulates gene expression (Yuen Science Adv 2017; Iwasaki Nature Comm 2019). Similar to Setd8, many subunits of the Condensin II complex are highly expressed in erythroid cells compared to most other cell types (biogps.org). We hypothesized that the Condensin II complex, in conjunction with Setd8 and H4K20me1, is important for establishing appropriate patterns of chromatin architecture and gene expression in maturing erythroblasts. To address this hypothesis, we deleted the NCAPH2 subunit in erythroid cells by crossing mice with floxed alleles of NCAPH2 with mice expressing cre-recombinase under the direction of the Erythropoietin receptor promotor (EpoRCre). Homozygous disruption of NCAPH2 was embryonic lethal by E13.5. NCAPH2 mutant embryos were similar in appearance to littermate controls until E12.5 when they developed notable pallor and a dramatic decline in the number of benzidine positive cells. Cell cycle analyses demonstrated that an accumulation of cells in G2/M preceded the dramatic decline in erythroblast numbers at E12.5. In contrast to cells from littermate controls, the NCAPH2 mutant cells were very heterogenous in cell and nuclear size and morphology. Surpisingly, most NCAPH2 mutant cells appeared to be hemoglobinized, suggesting sufficient iron accumulation and heme synthesis. In vitro cultures derived from primitive erythroid progenitors replicated in vivo findings, including normal early erythropoeisis, with significant abnormalities during mid- to late- maturation. Western blot in cycloheximide treated primitive erythroid cultures revealed that NCAPH2 has a long half-life, which likely contributes to the relative normalicy of early primitive erythoproesis. NCAPH2 mutant embryos also had a dramatic failure of definitive erythropoiesis, as evidenced by loss of mature erythroblasts in the fetal liver at E13.5. To gain insights into the mechanisms underlying these findings, we performed RNA-seq of NCAPH2 mutant, NCAPH2 het, and NCAPH2 WT erythroblasts from E11.5 embryos. Comparing NCAPH2 mutant and NCAPH2 WT erythroblasts there were 1121 down regulated genes and 743 upregulated genes (adj p-value <0.05). As expected, the downregulated genes were enriched for pathways related to cell cycle, such as Mitotic Spindle Organization (adj pvalue 5e-42). The upregulated genes were enriched for a variety of pathways including p53 transcriptional network (adj pvalue 4e-10), neutrophil mediated immunity (2e-9), DNA-binding transcription factor (adj pvalue 7e-5), and regulation of erythrocyte differentiation (adj pvalue 5e-4). Intriguingly, 91/340 genes differentially expressed in Setd8 mutant erythroblats were also differentially expressed in NCAPH2 mutant cells, including genes typically repressed early in erythroid commitment, such as GATA2 and SPI1. Cut&Tag in CD34+ derived erythroblasts demonstrated occupancy of H4K20me1 at these loci. Mass spectrometry of proteins isolated via mono-mehtylated H4K20 peptides in erythroid extracts identified Condensin II components, supporting a model where the Condensin II complex directly interacts with H4K20me1. Together, these results demonstrate that the Condensin II complex is essential for erythropoiesis, and may work in conjunction with Setd8 and H4K20me1 to establish appropriate patterns of gene expression in maturing erythroblasts. Disclosures No relevant conflicts of interest to declare.

515. Evolution of Treatment Patterns for Patients Hospitalized with COVID-19 in the United States

Background COVID-19 remains a threat to public health, with over 30 million cases in the US alone. As understanding of optimal patient care has improved, treatment guidelines have continued to evolve. This study characterized real-world trends in treatment for US patients hospitalized with COVID-19, stratified by whether patients required invasive ventilation. Methods US patients diagnosed and hospitalized with COVID-19 between March 23 and December 31, 2020, in the Optum de-identified COVID-19 electronic health record (EHR) data set were identified. Both drug and procedure codes were used to ascertain medications, and both procedure and diagnostic codes were used to detect invasive ventilation during hospitalization. Medication trends were estimated by computing proportions of hospitalized patients receiving each drug weekly during the study period. Results In this cohort of 71,366 hospitalized patients, the largest observed change in care was related to chloroquine/hydroxychloroquine (HCQ) (Figure). HCQ usage peaked at 87% of patients receiving invasive ventilation (54% without ventilation) in the first week of this study (March 23-29), but declined to < 5% of patients, regardless of ventilation status, by the end of May. In contrast, dexamethasone usage was 10% at baseline in patients receiving ventilation (1% without ventilation) and increased to a steady state of >85% of patients receiving ventilation ( >50% without ventilation) by the end of June. Similarly, remdesivir usage increased sharply from a baseline of 2% of patients and continued to rise to a peak of 79% of patients receiving invasive ventilation (44% without ventilation) in November before declining. Conclusion Meaningful shifts in treatments for US patients hospitalized with COVID-19 were observed from March through December 2020. A dramatic decline was observed for HCQ use, likely owing to safety concerns, while usage of dexamethasone and remdesivir increased as evidence of their efficacy mounted. Across medications, usage was substantially more prevalent among patients requiring invasive ventilation compared with patients with less severe cases. Disclosures Kelly Zalocusky, PhD, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Shemra Rizzo, PhD, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Devika Chawla, PhD MSPH, F. Hoffmann-La Roche Ltd. (Shareholder)Genentech, Inc. (Employee) Yifeng Chia, PhD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee) Tripthi Kamath, PhD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee) Larry Tsai, MD, F. Hoffmann-La Roche Ltd (Shareholder)Genentech, Inc. (Employee)

490 Hiflex Delivery: How Do You Turn It Around When Things Go Bad?

Upon return to classrooms in Fall 2020, University policy required every class delivered in person also offer an online option, resulting in hiflex delivery of a careers preparation course that traditionally relied on student interaction and in-person opportunities for knowledge application to teach soft skills. Early in the semester, the class experienced a dramatic decline in physical attendance as well as engagement across all platforms, resultantly substantial real-time changes were necessary. The first step in increasing student engagement was to dedicate a single course period to candidly discuss the decline in class quality and invite participants to take an active role in improving the course and facilitating learning. Concurrently, an anonymous survey was administered to gauge interest in remaining topics, anticipated method of attendance, and incentives to engagement. Student feedback was used to adapt lesson plans and class structure moving forward. These plans were shared with students, implemented, and resulted in increased engagement and performance. Active curriculum adjustment based upon honest feedback and increased student agency improved content retention and application based upon assessment. This presentation will provide an overview of methods utilized including: student surveys, transparency of course scaffolding, small stakes assignments, adaptation of a group project to focus on application, scheduled instructor interaction and feedback on assignments and discussion boards, and intentional creation of an online learning community. Adaptations were effective for improving performance toward course learning outcomes – every student that completed all small stakes assignments and remained actively engaged in class material for the remainder of the semester earned a high scoring grade. Acknowledging a lack of success with implementation of traditional teaching strategies in a non-traditionally delivered course was necessary and enabled the instructor to engage in active dialogue with students, which created opportunities for student-supported and informed adjustments for achievement of learning outcomes.

The paradox of the COVID-19 pandemic: the impact on patient demand in Japanese hospitals

Analyzing data from a large, nationally distributed group of Japanese hospitals, we found a dramatic decline in both inpatient and outpatient volumes over the three waves of the COVID-19 pandemic in Japan from February-December 2020. We identified three key reasons for this fall in patient demand. First, COVID-19-related hygiene measures and behavioral changes significantly reduced non-COVID-19 infectious diseases. Second, consultations relating to chronic diseases fell sharply. Third, certain medical investigations and interventions were postponed or cancelled. Despite the drop in hospital attendances and admissions, COVID-19 is said to have brought the Japanese health care system to the brink of collapse. In this context, we explore longstanding systematic issues, finding that Japan's abundant supply of beds and current payment system may have introduced a perverse incentive to overprovide services, creating a mismatch between patient needs and the supply of health care resources. Poor coordination among health care providers and the highly decentralized governance of the health care system have also contributed to the crisis. In order to ensure the long-term sustainability of the Japanese health care system beyond COVID-19, it is essential to promote specialization and differentiation of medical functions among hospitals, to strengthen governance, and to introduce appropriate payment reform.