Howe, Charles L.

Abstract Organoids, which are tiny, lab-grown 3D structures that mimic some organizational and functional properties of human organs, are slowly transforming the face of systems and developmental biology, biomedical research, pharmaceutical testing, environmental toxin testing, and healthcare. Significant investments are essential for the mass production, preservation, and distribution of organoids, with the aim to accelerate innovation and progress across multiple fields—much like the investments made in cell and biologics manufacturing over the past 2 decades.

Multiple sclerosis is characterized by CNS infiltration of autoreactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8 + antineural T cells in the neurodegeneration that underlies irreversible clinical progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8 + T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8 + T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8 + T cell–mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer–based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8 + T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8 + T cell–mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8 + T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.

Background Falls in people with multiple sclerosis (pwMS) lead to morbidity and expense. Objective Identify clinical metrics associated with falls. Methods Eighty-six pwMS completed fall surveys, timed 25-foot walk (T25FW), and motion analysis with Clario Opal devices. Logistic regression models were created. Results Median age was 54.5 years (range 21–73), 62% (53) were female. The cohort included 58% with relapsing (50) and 42% with progressive MS (36). Those who reported falling in the last year were older (median age 58 vs 52.5, p = .03) and had a higher Patient Determined Disease Step (PDDS) score (median 3 vs 1, p < .0001). Falls were associated with worse balance metrics including sway area (median 2.3 degrees 2 vs 1.2, p = .01), jerk (median 3.3 m 2 /s 5 vs 1.6, p = .005), and slower T25FW (median 11.5 s vs 8; p < .0001). A multivariable regression model based on gait aid use and T25FW time >10.8 s (c = 0.80) was derived. Having both features portended a probability of falling of 0.97, while having neither, a probability of 0.26. Conclusions Falls in pwMS are more frequent in patients who are older, have higher PDDS, slower walking, and worse balance. Gait aid use and T25FW >10.8 s were strongly associated with falls in the past year.