Adeno-associated virus (AAV) gene therapy has the potential to functionally cure hemophilia B by restoring factor (F)IX concentrations into the normal range. Next-generation AAV therapies express a naturally occurring gain-of-function FIX variant, FIX-Padua (R338L-FIX), that increases FIX activity (FIX:C) by approximately eightfold compared with wild-type FIX (FIX-WT). Previous studies have shown that R338L-FIX activity varies dramatically across different clinical FIX:C assays, which complicates the monitoring and management of patients. To better understand mechanisms that contribute to R338L-FIX assay discrepancies, we characterized the performance of R338L-FIX in 13 1-stage clotting assays (OSAs) and 2 chromogenic substrate assays (CSAs) in a global field study. This study produced the largest R338L-FIX assay dataset to date and confirmed that clinical FIX:C assay results vary over threefold. Both phospholipid and activating reagents play a role in OSA discrepancies. CSA generated the most divergent FIX:C results. Manipulation of FIX:C CSA kits demonstrated that specific activity gains for R338L-FIX were most profound at lower FIX:C concentrations and that these effects were enhanced during the early phases of FXa generation. Supplementing FX into CSA had the effect of dampening FIX-WT activity relative to R338L-FIX activity, suggesting that FX impairs WT tenase formation to a greater extent than R338L-FIX tenase. Our data describe the scale of R338L-FIX assay discrepancies and provide insights into the causative mechanisms that will help establish best practices for the measurement of R338L-FIX activity in patients after gene therapy.
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http://dx.doi.org/10.1182/bloodadvances.2022007435 | DOI Listing |
The Biorepository and Integrative Genomics (BIG) Initiative in Tennessee has developed a pioneering resource to address gaps in genomic research by linking genomic, phenotypic, and environmental data from a diverse Mid-South population, including underrepresented groups. We analyzed 13,152 genomes from BIG and found significant genetic diversity, with 50% of participants inferred to have non-European or several types of admixed ancestry. Ancestry within the BIG cohort is stratified, with distinct geographic and demographic patterns, as African ancestry is more common in urban areas, while European ancestry is more common in suburban regions.
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Departments of Urban Public Health, Internal Medicine, and Family Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
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January 2025
Nairobi Research Station, Nagasaki University Institute of Tropical Medicine (NUITM)-Kenya Medical Research Institute (KEMRI) Project, Nairobi, Kenya.
Background: The loop-mediated isothermal amplification for TB (TB-LAMP) assay is more cost-effective and accessible than the Xpert MTB/RIF assay. This study aimed to evaluate the diagnostic performance of the TB-LAMP assay in individuals with and without HIV infection.
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Digit Health
January 2025
Department of Health Behavior, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Objective: Digital behavior change interventions can successfully promote change in behavioral outcomes, but often suffer from steep decreases in engagement over time, which hampers their effectiveness. Providing feedback on goal performance is an established technique to promote goal attainment; however, theory indicates that sending goal-discrepant feedback messages could cause some users to respond more negatively than others. This analysis assessed whether goal-discrepant messaging was negatively associated with participant engagement, and if this relationship was exacerbated by baseline depressive symptoms within the context of a three-month weight loss pilot mHealth intervention.
View Article and Find Full Text PDFJ Cardiovasc Electrophysiol
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