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Background Treating patients with multiple myeloma (MM) is a complex endeavor that requires effective clinical decision-making from a team of specialists and supporting clinicians. Additionally, treatment with chimeric antigen receptor (CAR) T-cell therapy presents unique challenges, requiring communication and collaboration between the oncology clinic and CAR T-cell treatment centers. To improve collaborative MM care, we conducted a quality improvement (QI) study, bringing together community and academic oncology centers to assess current practice patterns and develop strategies to overcome barriers in the treatment of patients with MM across the continuum of care. Methods This QI initiative is comprised of baseline provider surveys (Community n = 21; Academic n = 18) and pre- and post-surveys of providers (n = 31) participating in small-group, team-based audit-feedback (AF) sessions (Table 1). Survey questions were designed to assess knowledge, confidence, and experiences in keeping up with the latest clinical evidence and guideline recommendations and collaboration and communication practices between centers. Care teams from each clinic, along with a nationally renowned expert MM physician, participated in audit and feedback sessions to (a) assess system-specific practice gaps identified via the provider surveys, (b) prioritize areas for improvement, and (c) develop action plans for addressing root causes. Results Provider Surveys: When asked their top challenge encountered in managing patients with MM, community-based providers reported keeping up with clinical evidence for new and emerging therapies (48%), whereas academic-based providers reported knowing how to optimally sequence therapies (50%). Further differences between community and academic clinicians were evident in their self-reported confidence in their ability to stay up-to-date with new data on CAR T-cell therapies and other MM treatment (high/very high confidence: 84% academic; 24% community; p < .001), ability to align clinical practices with evidence-based guidelines (high/very high confidence: 72% academic; 34% community; p = .018), and ability to sequence lines of therapy and differentiate between novel therapies for MM (high/very high confidence: 72% academic; 29% community; p = .007). Despite these differences, care teams from both settings reported low percentages of eligible patients have received CAR T-cell therapy for MM, citing patient resistance, cost and difficulty gaining insurance approval as top barriers (Figure 1). When asked to rate the level of communication and collaboration between academic and community centers, 44% of academic providers and 35% of community providers rated very good/excellent. The top barrier among providers not indicating very good/excellent communication from both settings was lack of time for our clinic's staff to communicate. AF Sessions: Providers participating in the small group AF sessions reported gaining access to newer therapies (55%) as their biggest challenge regarding MM management. Clinicians indicated gains in moderate/high/very high confidence in their ability to align treatment decisions with guidelines and clinical evidence for MM (78% to 92%) and ability to sequence treatment options across multiple lines of therapy for patients with MM (80% to 100%). Care teams set goals to enhance knowledge of clinical efficacy and safety of new and emerging therapies for MM. Action plans to achieve these goals include developing a hematology disease specific tumor board to collaborate on patient care plans, further train designated staff members focused on CAR T-cell/MM, discuss relevant new data to improve the team's confidence in therapy sequencing and early referrals to CAR T-cell centers. Conclusions Through this QI initiative, clinical teams identified barriers to optimal MM care, creating and implementing specific action plans to increase knowledge of current and emerging therapies for MM to enhance individualized treatment plans. While meaningful confidence gains were demonstrated, these data underscore clinical practice gaps to address in future initiatives to support evidence-based, collaborative care plans for patients with MM. Study Sponsor Statement The study reported in this abstract was funded by educational grants from Bristol Myers Squibb. The grantors had no role in the study design, execution, analysis, or reporting.

(1) Background: Telemetry units allow the continuous monitoring of vital signs and ECG of patients. Such physiological indicators work as the digital signatures and biomarkers of disease that can aid in detecting abnormalities that appear before cardiac arrests (CAs). This review aims to identify the vital sign abnormalities measured by telemetry systems that most accurately predict CAs. (2) Methods: We conducted a systematic review using PubMed, Embase, Web of Science, and MEDLINE to search studies evaluating telemetry-detected vital signs that preceded in-hospital CAs (IHCAs). (3) Results and Discussion: Out of 45 studies, 9 met the eligibility criteria. Seven studies were case series, and 2 were case controls. Four studies evaluated ECG parameters, and 5 evaluated other physiological indicators such as blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature. Vital sign changes were highly frequent among participants and reached statistical significance compared to control subjects. There was no single vital sign change pattern found in all patients. ECG alarm thresholds may be adjustable to reduce alarm fatigue. Our review was limited by the significant dissimilarities of the studies on methodology and objectives. (4) Conclusions: Evidence confirms that changes in vital signs have the potential for predicting IHCAs. There is no consensus on how to best analyze these digital biomarkers. More rigorous and larger-scale prospective studies are needed to determine the predictive value of telemetry-detected vital signs for IHCAs.

Abstract The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

Monoamine Oxidase (MAO), an outer mitochondrial enzyme, catalyzes the oxidative deamination of neurotransmitters and biological amines, and in the process, produces a reactive aldehyde and H2O2. Our lab has recently shown that MAO activity (i.e., H2O2 production) in human right atrial myocardium is associated with postoperative atrial fibrillation. Furthermore, our lab has shown that diabetic patients have higher MAO‐A and ‐B content and rates of activity in this tissue, compared to nondiabetics. While recent studies have explored the connection between MAO and cardiac dysfunction, the chamber‐specific content and activity of MAO within the heart is still unknown. Therefore, we characterized the regional enzymatic activity of MAO‐A and ‐B based upon the hypothesis that the atria would have the highest MAO activity due to the greater density of local sympathetic nerve innervation in this region. For this study, porcine hearts were isolated from domestic pigs, as this model closely recapitulates the physiology of the human heart. One group of pigs were fed a high fat, high sucrose diet for 16 weeks to induce obesity/metabolic syndrome (n=4). Three MAO substrates (dopamine, norepinephrine, serotonin) and two isoform‐selective inhibitors (clorgyline=MAO‐A, deprenyl=MAO‐B) were used to characterize MAO activities. Enzyme content was measured using ELISA and confirmed with immunoblots. Kinetic analysis showed that, across all substrates, when normalized to tissue protein, the left atrium has the highest maximal MAO‐A and –B activity while the other three chambers are similar. Furthermore, maximal MAO activity in the left ventricle of pigs with metabolic syndrome is significantly greater (P<0.05) than left ventricle of control group. Our findings suggest that MAO activity differs by location in the heart (i.e., chamber heterogeneity). This information will be useful to inform future experimental and clinical pharmacology applications where MAO inhibitors might be used. Moreover, increased MAO in left ventricle of pigs with obesity/metabolic syndrome is important as it provides a rationale for exploring MAO inhibitors as therapeutic strategy to mitigate cardiac complications of diabetes. Support or Funding Information R01HL122863

Abstract Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1. Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2′-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.

Abstract Background Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leucocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. Methods ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, paralleldesign, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to Day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥0.3 mg/dL (or 26.5 µmol/L) from presurgery baseline within 48±4 hours of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen reduced RBCs through 75 days after the last study transfusion. With ≥292 evaluable, transfused patients (>146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. Discussion RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBC.