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ObjectivesPlacebo effects refer to the impact of a treatment on health outcomes that cannot be attributed to the treatment itself. The current study aimed to investigate whether a comprehensive hearing aid fitting process would induce placebo effects compared to a simple process, and whether personal attributes such as personality traits could predict susceptibility to these effects.DesignThirty adults with hearing loss completed the study. The study began with a fitting session in which the field trial hearing aid configuration (the actual fitting) was set, followed by two experimental conditions. Each condition involved a fake hearing aid fitting and a 3-week field trial. In the fake fitting, bilateral hearing aids were fitted using the Comprehensive protocol (CM) that included multiple assessments and probe-microphone verification or the Streamlined protocol (ST) that did not involve any assessments other than a hearing test. The same hearing aid amplification settings established in the actual fitting, rather than the settings from the fake fittings, were used in the field trials for both conditions. Patient outcomes were measured using the International Outcome Inventory for Hearing Aids (IOI-HA), which was administered as both retrospective self-reports and ecological momentary assessment (EMA) surveys. Personality was assessed using the NEO Five-Factor Inventory. Upon completion of the study, participants expressed their hearing aid preferences based on hearing aids' real-world performances (prefer CM, prefer ST, or no preference).ResultsFor both retrospective self-reports and EMA, the IOI-HA scores of the CM and ST conditions did not significantly differ. Among the 30 participants, 22 expressed a preference for either CM (n = 14) or ST (n = 8). Younger participants and those with higher levels of agreeableness were more likely to have a hearing aid preference.ConclusionsAt the group level, comprehensive hearing aid fitting process did not generate a placebo effect leading to better outcomes compared to a simple process. However, despite the absence of differences in hearing aid settings, most (73%) participants were affected by placebo effects, believing that one fitting process yielded better real-world outcomes than the other. Personal attributes including personality traits and age are associated with susceptibility to placebo effects.

ABSTRACTAs immunological selection for escape mutants continues to give rise to future SARS-CoV-2 variants, novel universal therapeutic strategies against ACE2-dependent viruses are needed. Here we present an IgM-based decavalent ACE2 decoy that has variant-agnostic efficacy. In immuno-, pseudovirus, and live virus assays, IgM ACE2 decoy had potency comparable or superior to leading SARS-CoV-2 IgG-based mAb therapeutics evaluated in the clinic, which were variant-sensitive in their potency. We found that increased ACE2 valency translated into increased apparent affinity for spike protein and superior potency in biological assays when decavalent IgM ACE2 was compared to tetravalent, bivalent, and monovalent ACE2 decoys. Furthermore, a single intranasal dose of IgM ACE2 decoy at 1 mg/kg conferred therapeutic benefit against SARS-CoV-2 Delta variant infection in a hamster model. Taken together, this engineered IgM ACE2 decoy represents a SARS-CoV-2 variant-agnostic therapeutic that leverages avidity to drive enhanced target binding, viral neutralization, and in vivo respiratory protection against SARS-CoV-2.

Immunoglobulin G (IgG) has served as a traditional framework for antibody-based biology, and engineering approaches for creating multispecific therapeutics have greatly expanded its applicability. Despite these developments, there are limits to the functionality of IgG with respect to effector cells that can be activated and paratope valency that can be obtained. Other Ig isotypes have distinct functions that can engage and activate different effector cells, and some can be found naturally in higher-order assemblies. In an effort to expand the repertoire of multispecific designs for other antibody isotypes, we present here engineering of the first heterodimeric IgA Fc that can be produced at high purity with native IgA-like thermal stability. The crystal structure confirmed the accuracy of the in silico model used for engineering and that the mutations introduced at the CH3 interface do not perturb the overall IgA Fc structure. Affinity measurements and on-cell neutrophil binding demonstrated that the heterodimeric IgA Fc retains the ability to bind FcαRI, an important prerequisite for IgA-based therapeutics designed to interact with effector cells, such as neutrophils. Given the ability of IgA antibodies to multimerize via interaction with the J-chain, the designs presented here could also be used to generate multispecific, multimeric scaffolds that leverage valency to increase clustering and specificity via avidity. Taken together, the newly developed heterodimeric IgA Fc platform allows for the development of novel, multifunctional, and multimeric molecules that have the potential to transform the next generation of antibody therapeutics.Abbreviations CE-SDS: capillary electrophoresis sodium dodecyl sulfate; DSC: differential scanning calorimetry; FACS: fluorescence-activated cell sorting; FSA: full-sized antibody; Her2: human epidermal growth factor receptor 2; MFI: mean fluorescent intensity; OAA: one-armed antibody; PBS: phosphate-buffered saline; PDB: Protein Data Bank; SEC: size-exclusion chromatography; prepSEC (preparative SEC); RMSD: root-mean-square deviation; RU: resonance units; SPR: surface plasmon resonance; TAA: tumor-associated antigen; WT: wild-type.