ABSTRACT
Objective: Chronic fatigue significantly affects the aging population, especially individuals with chronic conditions such as diabetes mellitus (DM). Patients with DM experience a range of comorbidities and complications that may impact quality of life (QOL). Current QOL tools are not specific to problems associated with diabetes and aging. The aim of this study was to explore the impact of DM on fatigue using the Norfolk QOL-Fatigue (QOL-F), a 35-item validated questionnaire sensitive to physical, cognitive and emotional aspects of fatigue. We hypothesize that cognitive and physical measures of fatigue are increased in DM patients. Methods: Subjects 18 to 79 years old, with type 1 or 2 DM from Hampton Roads, Virginia were recruited. Participants were administered the Norfolk QOL-F questionnaire, both in person and, during the COVID pandemic, online through Redcap survey interface. The questionnaire is divided into 5 domains (physical and cognitive problems from fatigue, subjective fatigue, reduced regular activities, activities of daily life (ADLs) and depression). Demographic and clinical information were collected. Participants with DM were compared with matched healthy controls (HC). Presence of neuropathy was assessed with the validated Norfolk QOL-Diabetic Neuropathy (DN) questionnaire. Results: Four hundred DM and 80 age, gender and race matched HC subjects were included. DM subjects had higher BMI (32.23±7.77 vs. 29.02±5.17 p=0.0011). DM participants reported significantly higher QOL-F scores (50.01±28.59 vs. 25.42±19.32 p< 0.0001). These differences were observed in all domains of the QOL-F (p< 0.0001 for all comparisons). Within the DM group, participants with DN where significantly more fatigued than those without DN (59.25±26.87 vs 27.65±18.59 p< 0.0001). These differences were observed in all fatigue domains. On multivariate regression analysis, only younger age and female gender were correlated with higher fatigue scores. Subjects interviewed after COVID pandemic were significantly more fatigued than subjects interviewed before the pandemic. However, these two groups were not well matched. Discussion/Conclusion: This study shows that the Norfolk QOL-F questionnaire can identify increased levels of fatigue in patients with chronic diseases such as DM. This may be especially relevant to physicians as they address the main concerns of this patient population, including physical limitations, disruption of ADLs and depression. Paradoxically, older subjects reported better fatigue scores. Potential explanations include differences in perception of fatigue symptoms and generational differences in everyday responsibilities and life stressors. These findings warrant further investigation.
ABSTRACT
Background & Aim: A consortium of leading human mesenchymal stem/stromal cell (hMSC) therapy developers, Sentien Biotechnologies, GenCure Biomanufacturing and RoosterBio, are developing a large-scale hMSC biomanufacturing process with a deep Quality focus, culminating in a potency assay qualified with human clinical samples. Methods, Results & Conclusion: A Xeno-Free (XF), fed-batch, microcarrier-based bioreactor process for hMSC manufacturing had been developed and optimized [1], and scaled to a 50L process, with demonstrated comparability between the hMSC critical quality attributes (CQAs) from the bioreactor process and from 2D control cells of similar population doubling (PDL) [2]. Based on this previous process development, GenCure and RoosterBio are leading the first stage of biomanufacturing through upstream (2D seed train & bioreactor expansion) and downstream process (continuous counterflow centrigufation, formulation & fill, and cryopreservation). Bioreactor runs at the 50 L scale were performed using the most commonly used hMSC sources in regenerative medicine: bone marrow (BM-MSCs), umbilical cord (UC-MSCs) and adipose (AD-MSCs). Critical process parameters (CPPs) are defined and critical quality attributes (CQAs) of the harvested cell product are characterized. An initial production run produced over 33billion BM-MSCs that passed the ISCT minimal criteria for MSCs. The subsequent expansion of UC- and AD-MSCs will be presented. Sentien's proprietary platform was used to ask questions on how the MSCs reacted to different stimuli with results showing that BM-MSCs were able to sense and respond with different secretomes to inflammatory stimuli. Our data also showed that BMMSCs induced changes in CD4, CD8 and CD19 cells and significantly reduced TNF-a levels in activated PBMCs, demonstrating their immunomodulatory capabilities. The same assays will be performed using the resulting MSCs from umbilical cord and adipose tissue expanded in the 50L bioreactor. Sentien, which has treated 16 subjects with acute kidney injury (AKI, open IND) and is currently running a trial in severe COVID-19 patients with AKI, will contribute biomarker data from the clinical-scale bioreactor and patient samples. Testing the in vitro developed potency hypothesis against the clinical samples will form the basis of a true potency assay. Through this work, the consortium will develop a generalized quality framework for large scale MSC manufacturing and potency assay development for broad use in regenerative medicine.