A High Threshold of Biotherapeutic Aggregate Numbers is Needed to Induce an Immunogenic Response In Vitro, In Vivo, and in the Clinic.

BACKGROUND AND PURPOSE: There is concern that subvisible aggregates in biotherapeutic drug products pose a risk to patient safety. We investigated the threshold of biotherapeutic aggregates needed to induce immunogenic responses. METHODS AND RESULTS: Highly aggregated samples were tested in cell-based assays and induced cellular responses in a manner that depended on the number of particles. The threshold of immune activation varied by disease state (cancer, rheumatoid arthritis, allergy), concomitant therapies, and particle number. Compared to healthy donors, disease state patients showed an equal or lower response at the late phase (7 days), suggesting they may not have a higher risk of responding to aggregates. Xeno-het mice were used to assess the threshold of immune activation in vivo. Although highly aggregated samples (~ 1,600,000 particles/mL) induced a weak and transient immunogenic response in mice, a 100-fold dilution of this sample (~ 16,000 particles/mL) did not induce immunogenicity. To confirm this result, subvisible particles (up to ~ 18,000 particles/mL, containing aggregates and silicone oil droplets) produced under representative administration practices (created upon infusion of a drug product through an IV catheter) did not induce a response in cell-based assays or appear to increase the rate of adverse events or immunogenicity during phase 3 clinical trials. CONCLUSION: The ability of biotherapeutic aggregates to elicit an immune response in vitro, in vivo, and in the clinic depends on high numbers of particles. This suggests that there is a high threshold for aggregates to induce an immunogenic response which is well beyond that seen in standard biotherapeutic drug products.

Contribution of high frequencies to speech recognition in quiet and noise in listeners with varying degrees of high-frequency sensorineural hearing loss.

PURPOSE: The contribution of audible high-frequency information to speech-understanding performance in listeners with varying degrees of high-frequency sensorineural hearing loss was examined. METHOD: Thirty-six elderly hearing-impaired (EHI) and 24 young normal-hearing (YNH) listeners were tested in quiet (+20 dB speech-to-noise ratio [SNR]) and noise (+5 dB SNR) and under different bandpass conditions (narrow, 200-1600 Hz; midband, 200-3200 Hz; broadband, 200-6400 Hz), both without and with spectral shaping of the stimuli. Monosyllabic word-recognition performance was examined through use of both whole-word scoring and phoneme scoring. The 36 EHI listeners were divided into 3 groups of 12 listeners each, with the groups differing in the amount of high-frequency hearing loss. The 24 YNH participants were separated into 2 groups, each serving as a reference group for either the unshaped or spectrally shaped speech listening conditions. RESULTS: Results for spectrally shaped speech, in both quiet and noise, revealed that the 3 EHI groups performed equivalently in the different bandwidth conditions and demonstrated no change (increase or decrease) in word-recognition performance between the midband and broadband conditions. The YNH groups, however, demonstrated improved speech understanding attributable to the higher frequencies for the broadband condition in both the unshaped and shaped conditions. CONCLUSIONS: Data from the EHI listeners revealed that performance for unshaped speech was correlated moderately and negatively with degree of high-frequency hearing loss. Alternatively, recognition performance for shaped speech was related to neither the performance for unshaped speech nor the amount of high-frequency hearing loss.

Effect of training on word-recognition performance in noise for young normal-hearing and older hearing-impaired listeners.

OBJECTIVE: The objective of this study was to evaluate the effectiveness of a training program for hearing-impaired listeners to improve their speech-recognition performance within a background noise when listening to amplified speech. Both noise-masked young normal-hearing listeners, used to model the performance of elderly hearing-impaired listeners, and a group of elderly hearing-impaired listeners participated in the study. Of particular interest was whether training on an isolated word list presented by a standardized talker can generalize to everyday speech communication across novel talkers. DESIGN: Word-recognition performance was measured for both young normal-hearing (n = 16) and older hearing-impaired (n = 7) adults. Listeners were trained on a set of 75 monosyllabic words spoken by a single female talker over a 9- to 14-day period. Performance for the familiar (trained) talker was measured before and after training in both open-set and closed-set response conditions. Performance on the trained words of the familiar talker were then compared with those same words spoken by three novel talkers and to performance on a second set of untrained words presented by both the familiar and unfamiliar talkers. The hearing-impaired listeners returned 6 mo after their initial training to examine retention of the trained words as well as their ability to transfer any knowledge gained from word training to sentences containing both trained and untrained words. RESULTS: Both young normal-hearing and older hearing-impaired listeners performed significantly better on the word list in which they were trained versus a second untrained list presented by the same talker. Improvements on the untrained words were small but significant, indicating some generalization to novel words. The large increase in performance on the trained words, however, was maintained across novel talkers, pointing to the listener's greater focus on lexical memorization of the words rather than a focus on talker-specific acoustic characteristics. On return in 6 mo, listeners performed significantly better on the trained words relative to their initial baseline performance. Although the listeners performed significantly better on trained versus untrained words in isolation, once the trained words were embedded in sentences, no improvement in recognition over untrained words within the same sentences was shown. CONCLUSIONS: Older hearing-impaired listeners were able to significantly improve their word-recognition abilities through training with one talker and to the same degree as young normal-hearing listeners. The improved performance was maintained across talkers and across time. This might imply that training a listener using a standardized list and talker may still provide benefit when these same words are presented by novel talkers outside the clinic. However, training on isolated words was not sufficient to transfer to fluent speech for the specific sentence materials used within this study. Further investigation is needed regarding approaches to improve a hearing aid user's speech understanding in everyday communication situations.

Longitudinal changes in hearing aid satisfaction and usage in the elderly over a period of one or two years after hearing aid delivery.

OBJECTIVE: The objective of this study was to measure hearing aid satisfaction and usage for extended periods of time, up to 2 yr after hearing aid delivery, to determine whether longitudinal changes occur in the elderly for these outcome measures. DESIGN: A longitudinal study of hearing aid satisfaction and usage was performed in a group comprised of 134 elderly hearing aid wearers with these outcome measures obtained at 1, 6, and 12 mo postfit. A total of 49 of the original 134 elderly returned 2 yr after hearing aid delivery to complete the satisfaction and usage measures again. Multiple self-report measures of hearing aid satisfaction and hearing aid usage were obtained at each follow-up session. RESULTS: Most between-interval comparisons of the various measures of satisfaction and usage failed to reveal significant changes over time. However, some significant changes were observed in both satisfaction and usage. When such changes occurred, they were always in a direction that suggested a decrease in satisfaction or usage over time. Correlations across various postfit interval pairs were found to be positive, statistically significant, and moderate to strong in strength for all measures of satisfaction and usage. CONCLUSIONS: Although there were slight declines in hearing aid usage and satisfaction over time, measures of hearing aid satisfaction obtained at 1 mo postfit and of hearing aid usage obtained at 6 mo postfit are generally stable for up to 2 yr after hearing aid delivery.

A comparison of two measures of hearing aid satisfaction in a group of elderly hearing aid wearers.

OBJECTIVE: The objective of this study was to compare the results of two measures of hearing aid satisfaction, an indirect measure (Satisfaction with Amplification in Daily Living, SADL; Cox & Alexander, 1999) and a direct measure (an expanded version of the MarkeTrak-IV survey; Kochkin, 1996), in a group of elderly hearing aid wearers. DESIGN: A total of 43 elderly hearing aid wearers completed both satisfaction measures (order counterbalanced across wearers) after 1 mo of wearing 2-channel wide dynamic range compression (WDRC) in-the-canal (ITC) hearing aids. A correlational research design was employed. RESULTS: The elderly hearing aid wearers in this study yielded results on each measure of hearing aid satisfaction that were generally consistent with those found previously in larger groups of similar samples. The correlation between each measure of satisfaction (r = 0.75) was positive, moderately strong, and significant (p < 0.01) for the global scores of the SADL and MarkeTrak-IV scales. CONCLUSIONS: Although different approaches to the measurement of satisfaction were followed in the development of the SADL (indirect approach) and the MarkeTrak-IV (direct measurement) scales, similar results were obtained with each scale. The 15-item SADL instrument, however, is much shorter than the MarkeTrak-IV instrument and, as a result, is more efficient to administer clinically.