Moy, James N.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Abstract RATIONALE: 4G4G/4G5G SERPINE1 genotypes produce high concentrations of plasminogen activator inhibitor-1 and are associated with worse asthma outcomes. A secondary analysis of the American Lung Association (ALA) SOYA trial showed that soy isoflavones significantly reduced asthma exacerbations versus placebo among patients with 4G4G/4G5G SERPINE1 genotypes. We hypothesized that baseline characteristics predict optimal responders to soy isoflavones among this subgroup. METHODS: ALA-SOYA was a randomized controlled trial that tested the efficacy of soy isoflavones vs. placebo for reducing asthma exacerbations among adolescents and adults with symptomatic asthma. In this responder analysis among participants with 4G4G/4G5G SERPINE1 genotypes, baseline demographic and clinical characteristics were tested for effect modification of the treatment assignment (soy/placebo) on the primary outcome of annualized number of asthma exacerbations using interaction terms in negative binomial regression models, with a significance threshold of p-interaction=0.15. RESULTS: Data were available for n=168 participants. Soy reduced the annualized number of asthma exacerbations relative to placebo among patients with 4G4G/4G5G SERPINE1 genotypes (incident rate ratio (IRR)=0.37, 95% confidence interval (CI): 0.15-0.90, p=0.028). Self-reported adherence to baseline controller therapy was the only significant effect modifier of this association (interaction p=0.115), with those using inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) controller therapy at least twice weekly experiencing reductions in asthma exacerbations with soy versus placebo (IRR = 0.25, 95% CI: 0.09-0.69; p= 0.007) but not among those using ICS/LABA controller therapy less frequently (IRR = 1.33, 95% CI: 0.22-8.02; p= 0.757). CONCLUSION: Soy isoflavones reduce asthma exacerbations among patients with the 4G4G/4G5G SERPINE1 genotypes and are most effective in those with greater adherence to asthma controller therapy regimens.

Abstract The cDNA for the highly toxic eosinophil granule major basic protein (MBP) encodes a 25-kDa acidic precursor (proMBP) that is processed to form the 14-kDa mature MBP. To characterize the biochemical and biological properties of proMBP, and compare these to the known properties of MBP, we expressed recombinant proMBP in Chinese hamster ovary cells and purified the secreted form from supernatants. We developed a mAb specific for proMBP, J163-15E10, and by using a proMBP-specific RIA we found that recombinant proMBP was expressed quite efficiently at levels between 10 and 100 mg/l. By SDS-PAGE and immunoblotting analyses of bulk Chinese hamster ovary supernatants, recombinant proMBP was electrophoretically heterogeneous with an apparent molecular mass ranging from 3 x 10(4) to 1 x 10(5) daltons. Despite difficulties encountered because of the extreme molecular heterogeneity of the proform, two methods for purification of a predominant 33-kDa form of recombinant proMBP are presented. Glycosylation analysis of purified 33-kDa proMBP indicated that approximately 5 kDa is likely accounted for by the addition of one glycosaminoglycan group, three O-linked, and one N-linked complex type carbohydrate groups. Functional studies of purified recombinant proMBP were also conducted. Using amounts of proMBP determined to be optimal for MBP activity, it was shown that proMBP not only lacked the ability to inhibit protein synthesis in K562 cells, but it also lacked the ability to stimulate basophil histamine release or generate neutrophil superoxide anion release. Furthermore, proMBP inhibited in a dose-responsive manner the basophil histamine release and superoxide anion generation stimulated by MBP. The development of a mAb and RIA specific for proMBP will now make it possible to analyze biologic fluids for the presence of this protein, especially in pregnancy, when proMBP is increased.

Abstract Eosinophil granule major basic protein (MBP) and neutrophils have each been implicated in the inflammatory late phase events of allergic disease. Based on this association and flow cytometric evidence presented in this report for MBP binding to neutrophils, we examined the ability of MBP to activate human neutrophils. Incubation of neutrophils with 0.5 to 3.0 microM MBP at room temperature produced a concentration-dependent chemiluminescence (CL) response that peaked after 50 to 70 min. Reduced-and-alkylated MBP, eosinophil cationic protein, and eosinophil-derived neurotoxin did not induce CL. MBP-induced CL was abrogated in the absence of Ca2+ and was absent in neutrophils isolated from two individuals with chronic granulomatous disease. MBP also stimulated release of superoxide anion (O2-) and lysozyme but not beta-glucuronidase or lactate dehydrogenase. Additionally, 1.5 microM MBP in combination with FMLP or platelet-activating factor stimulated a synergistic increase in O2- release from cytochalasin B-treated neutrophils. The degree of synergism with FMLP or platelet-activating factor was inversely related (p less than 0.005) to the level of MBP-induced O2- release. These results indicate that MBP activates neutrophils in a noncytolytic fashion and provide evidence that eosinophil-neutrophil collaboration may contribute to the pathogenesis observed in allergic late phase reactions.