The Incidence and Effect of Adverse Events Due to COVID-19 Vaccines on Breakthrough Infections: Decentralized Observational Study With Underrepresented Groups.

BACKGROUND: Despite continuing efforts to improve the inclusion of underserved groups in clinical research, gaps in diversity remain. Participation of special populations is especially important when facing problems of unprecedented complexity such as the COVID-19 pandemic. A better understanding of factors associated with the immune response in diverse populations would advance future preventive and curative approaches. OBJECTIVE: The objective of this study was to investigate the factors potentially responsible for adverse events following COVID-19 immunization. The study population included adults from rural areas, transitional countries, and those with medically understudied conditions, across a broad age range. METHODS: The study evolved from peer support networks developed during the COVID-19 pandemic. Participants were recruited digitally through online neighborhood and health communities. Some of the participants volunteered as study investigators assisting with offline recruitment and safety monitoring. Individuals who consented to participate were asked to share their vaccination experiences either using constantly evolving web-based surveys or via one-on-one communication. Inferential statistical analysis to estimate differences between study groups was performed using parametric and nonparametric tests. RESULTS: Of 1430 participants who shared their vaccination experiences, 648 had outcome measures at their 1.5-year follow-up. Significant differences were found between age groups, types of vaccine adverse events (VAEs), incidences of breakthrough infections, and health conditions linked to the microbiome. Pairwise comparisons showed that VAEs interfering with daily activities were significantly higher in both younger (18-59 years) and older age groups (80-100 years, P<.001) than in the 60-79-year age group. Short-term VAEs were associated with lower incidence of breakthrough COVID-19 infections relative to those who reported either minimal or long-term adverse events (P<.001). A genetic origin was suggested for some adverse reactions. CONCLUSIONS: The findings of this study demonstrate that vaccine adverse reactions in older individuals are being overlooked, and the incidence of VAEs impairing immunity may be higher than previously perceived. Better preventive measures are needed for all those at risk for life-threatening and long-term adverse events due to vaccination. Supportive community-based studies focusing on these populations could add important data to the current body of knowledge. Further and more comprehensive studies should follow. TRIAL REGISTRATION: ClinicalTrials.gov NCT04832932; https://clinicaltrials.gov/ct2/show/NCT04832932. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1101/2021.06.28.21256779.

Ion channel gene expression in the inner ear.

The ion channel genome is still being defined despite numerous publications on the subject. The ion channel transcriptome is even more difficult to assess. Using high-throughput computational tools, we surveyed all available inner ear cDNA libraries to identify genes coding for ion channels. We mapped over 100,000 expressed sequence tags (ESTs) derived from human cochlea, mouse organ of Corti, mouse and zebrafish inner ear, and rat vestibular end organs to Homo sapiens, Mus musculus, Danio rerio, and Rattus norvegicus genomes. A survey of EST data alone reveals that at least a third of the ion channel genome is expressed in the inner ear, with highest expression occurring in hair cell-enriched mouse organ of Corti and rat vestibule. Our data and comparisons with other experimental techniques that measure gene expression show that every method has its limitations and does not per se provide a complete coverage of the inner ear ion channelome. In addition, the data show that most genes produce alternative transcripts with the same spectrum across multiple organisms, no ion channel gene variants are unique to the inner ear, and many splice variants have yet to be annotated. Our high-throughput approach offers a qualitative computational and experimental analysis of ion channel genes in inner ear cDNA collections. A lack of data and incomplete gene annotations prevent both rigorous statistical analyses and comparisons of entire ion channelomes derived from different tissues and organisms.

Ribosomal dynamics inferred from variations in experimental measurements.

The crystal structures of the ribosome reveal remarkable complexity and provide a starting set of snapshots with which to understand the dynamics of translation. To augment the static crystallographic models with dynamic information present in crosslink, footprint, and cleavage data, we examined 2691 proximity measurements and focused on the subset that was apparently incompatible with >40 published crystal structures. The measurements from this subset generally involve regions of the structure that are functionally conserved and structurally flexible. Local movements in the crystallographic states of the ribosome that would satisfy biochemical proximity measurements show coherent patterns suggesting alternative conformations of the ribosome. Three different types of data obtained for the two subunits display similar "mismatching" patterns, suggesting that the signals are robust and real. In particular, there is an indication of coherent motion in the decoding region within the 30S subunit and central protuberance and surrounding areas of the 50S subunit. Directions of rearrangements fluctuate around the proposed path of tRNA translocation and the plane parallel to the interface of the two subunits. Our results demonstrate that systematic combination and analysis of noisy, apparently incompatible data sources can provide biologically useful signals about structural dynamics.

Mining biochemical information: lessons taught by the ribosome.

The publication of the crystal structures of the ribosome offers an opportunity to retrospectively evaluate the information content of hundreds of qualitative biochemical and biophysical studies of these structures. We assessed the correspondence between more than 2,500 experimental proximity measurements and the distances observed in the ribosomal crystals. Although detailed experimental procedures and protocols are unique in almost each analyzed paper, the data can be grouped into subsets with similar patterns and analyzed in an integrative fashion. We found that, for crosslinking, footprinting, and cleavage data, the corresponding distances observed in crystal structures generally did not exceed the maximum values expected (from the estimated length of the agent and maximal anticipated deviations from the conformations found in crystals). However, the distribution of distances had heavier tails than those typically assumed when building three-dimensional models, and the fraction of incompatible distances was greater than expected. Some of these incompatibilities can be attributed to the experimental methods used. In addition, the accuracy of these procedures appears to be sensitive to the different reactivities, flexibilities, and interactions among the components. These findings demonstrate the necessity of a very careful analysis of data used for structural modeling and consideration of all possible parameters that could potentially influence the quality of measurements. We conclude that experimental proximity measurements can provide useful distance information for structural modeling, but with a broad distribution of inferred distance ranges. We also conclude that development of automated modeling approaches would benefit from better annotations of experimental data for detection and interpretation of their significance.