Brian T.

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Abstract. Purpose: Significant progress has occurred in developing quantitative PET/CT biomarkers in diffuse large B-cell lymphoma (DLBCL). Total metabolic tumor volume (MTV) is the most extensively studied, enabling assessment of FDG-avid tumor burden associated with outcomes. However, prior studies evaluated the outcome of cytotoxic chemotherapy or chimeric antigen receptor T-cell without data on recently approved FDA agents. Therefore, we aimed to assess the prognosis of PET/CT-biomarkers in patients treated with loncastuximab tesirine. Patients and Methods: We centrally reviewed screening PET/CT scans of patients with relapsed/refractory DLBCL enrolled in the LOTIS-2 (NCT03589469) study. MTV was obtained by computing individual volumes using the SUV ≥4.0 threshold. Other PET/CT metrics, clinical factors, and the International Metabolic Prognostic Index (IMPI) were evaluated. Logistic regression was used to assess the association between biomarkers and treatment response. Cox regression was used to determine the effect of biomarkers on time-to-event outcomes. We estimated biomarker prediction as continuous and binary variables defined by cutpoints. Results: Across 138 patients included in this study, MTV with a cutpoint of 96ml was the biomarker associated with the highest predictive performance in univariable and multivariable models to predict failure to achieve complete metabolic response (odds ratio =5.42; P= 0.002), progression-free survival (hazard ratio (HR)= 2.68; P= 0.002), and overall survival (HR= 3.09; P<.0001). IMPI demonstrated an appropriate performance; however, not better than MTV alone. Conclusions: Pretreatment MTV demonstrated robust risk-stratification, with those patients demonstrating high-MTV achieving lower responses and survival to loncastuximab tesirine in relapsed/refractory DLBCL.

Infants of mothers with adult congenital heart disease (ACHD) are at increased risk for adverse pregnancy and neonatal outcomes. We aim to identify mediators in the relationship between ACHD and pregnancy and infant outcomes. Case-control study using linked maternal and infant hospital records. Structural equation modeling was performed to assess for potential mediators of pregnancy and infant outcomes. We showed an increased risk of multiple adverse infant and pregnancy outcomes among infants born to mothers with ACHD. Maternal placental syndrome and congestive heart failure were mediators of prematurity. Prematurity and critical congenital heart disease in the infant were mediators of infant outcomes. However, the direct effect of ACHD on outcomes beyond that explained by these mediators remained significant. While significant mediators of infant and pregnancy outcomes were identified, there was a large direct effect of maternal ACHD. Further studies should aim to identify more factors that explain these infants’ vulnerability.

Habitual physical activity (PA) impacts the plasma proteome and reduces the risk of developing type 2 diabetes (T2D). Using a large-scale proteome-wide approach

Abstract Tears within the stabilizing muscles of the shoulder, known as the rotator cuff (RC), are the most common cause of shoulder pain—often

Analysis of the pivotal phase 3 ZUMA-7 trial identifies tumor gene expression signatures that are uniquely predictive of anti-CD19 CAR T cell response and event-free survival in second-line treatment for patients with relapsed or refractory large B cell lymphoma.

Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10−8 with slope 1) and rs34743896 (p = 5 × 10−10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.

Antimicrobial resistance has emerged as one of the leading public health threats of the twenty-first century. Gram-negative pathogens have been a major contributor to the declining efficacy of antibiotics through both acquired resistance and tolerance. In this study, a pan-drug resistant (PDR), NDM-1 and CTX-M-15 co-producing isolate of K. pneumoniae, CDC Nevada, (Kp Nevada) was exposed to the clinical combination of aztreonam + ceftazidime/avibactam (ATM/CAZ/AVI) to overcome metallo-β-lactamases. Unexpectedly, the β-lactam combination resulted in long filamentous cell formation induced by PBP3 inhibition over 168 h in the hollow fiber infection model experiments with eventual reversion of the total population upon drug removal. However, the addition of imipenem to the two drug β-lactam combination was highly synergistic with suppression of all drug resistant subpopulations over 5 days. Scanning electron microscopy and fluorescence microscopy for all imipenem combinations in time kill studies suggested a role for imipenem in suppression of long filamentous persisters, via the formation of metabolically active spheroplasts. To complement the imaging studies, salient transcriptomic changes were quantified using RT-PCR and novel cassette assay evaluated β-lactam permeability. This showed significant upregulation of both spheroplast protein Y (SPY), a periplasmic chaperone protein that has been shown to be related to spheroplast formation, and penicillin binding proteins (PBP1, PBP2, PBP3) for all combinations involving imipenem. However, with aztreonam alone, pbp1, pbp3 and spy remained unchanged while pbp2 levels were downregulated by > 25%. Imipenem displayed 207-fold higher permeability as compared with aztreonam (mean permeability coefficient of 17,200 nm/s). Although the clinical combination of aztreonam/avibactam and ceftazidime has been proposed as an important treatment of MBL Gram-negatives, we report the first occurrence of long filamentous persister formation. To our knowledge, this is the first study that defines novel β-lactam combinations involving imipenem via maximal suppression of filamentous persisters to combat PDR CDC Nevada K. pneumoniae.

Abstract South Africans living in low socioeconomic areas have self-reported unusually long sleep durations (approximately 9–10 h). One

Abstract Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures