Sources of Interindividual Variability.

The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in others. A significant source of this variability in drug response is drug metabolism, where differences in presystemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, Cmax, and/or Cmin) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is recognized that both intrinsic factors (e.g., genetics, age, sex, and disease states) and extrinsic factors (e.g., diet , chemical exposures from the environment, and the microbiome) play a significant role. For drug-metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, upregulation and downregulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less predictable and time-dependent manner. Understanding the mechanistic basis for variability in drug disposition and response is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that will improve outcomes in maintaining health and treating disease.

Expression and Function of Eicosanoid-Producing Cytochrome P450 Enzymes in Solid Tumors.

Oxylipins derived from the oxidation of polyunsaturated fatty acids (PUFAs) act as important paracrine and autocrine signaling molecules. A subclass of oxylipins, the eicosanoids, have a broad range of physiological outcomes in inflammation, the immune response, cardiovascular homeostasis, and cell growth regulation. Consequently, eicosanoids are implicated in the pathophysiology of various diseases, most notably cancer, where eicosanoid mediated signaling is involved in tumor development, progression, and angiogenesis. Cytochrome P450s (CYPs) are a superfamily of heme monooxygenases generally involved in the clearance of xenobiotics while a subset of isozymes oxidize PUFAs to eicosanoids. Several eicosanoid forming CYPs are overexpressed in tumors, elevating eicosanoid levels and suggesting a key function in tumorigenesis and progression of tumors in the lung, breast, prostate, and kidney. This review summarizes the current understanding of CYPs' involvement in solid tumor etiology and progression providing supporting public data for gene expression from The Cancer Genome Atlas.

The Effects of Static and Moving Spectral Ripple Sensitivity on Unaided and Aided Speech Perception in Noise.

Purpose: This study evaluated whether certain spectral ripple conditions were more informative than others in predicting ecologically relevant unaided and aided speech outcomes. Method: A quasi-experimental study design was used to evaluate 67 older adult hearing aid users with bilateral, symmetrical hearing loss. Speech perception in noise was tested under conditions of unaided and aided, auditory-only and auditory-visual, and 2 types of noise. Predictors included age, audiometric thresholds, audibility, hearing aid compression, and modulation depth detection thresholds for moving (4-Hz) or static (0-Hz) 2-cycle/octave spectral ripples applied to carriers of broadband noise or 2000-Hz low- or high-pass filtered noise. Results: A principal component analysis of the modulation detection data found that broadband and low-pass static and moving ripple detection thresholds loaded onto the first factor whereas high-pass static and moving ripple detection thresholds loaded onto a second factor. A linear mixed model revealed that audibility and the first factor (reflecting broadband and low-pass static and moving ripples) were significantly associated with speech perception performance. Similar results were found for unaided and aided speech scores. The interactions between speech conditions were not significant, suggesting that the relationship between ripples and speech perception was consistent regardless of visual cues or noise condition. High-pass ripple sensitivity was not correlated with speech understanding. Conclusions: The results suggest that, for hearing aid users, poor speech understanding in noise and sensitivity to both static and slow-moving ripples may reflect deficits in the same underlying auditory processing mechanism. Significant factor loadings involving ripple stimuli with low-frequency content may suggest an impaired ability to use temporal fine structure information in the stimulus waveform. Support is provided for the use of spectral ripple testing to predict speech perception outcomes in clinical settings.

Effects of hearing loss on maintaining and switching attention.

The ability to intentionally control attention based on task goals and stimulus properties is critical to communication in many environments. However, when a person has a damaged auditory system, such as with hearing loss, perceptual organization may also be impaired, making it more difficult to direct attention to different auditory objects in the environment. Here we examined the behavioral cost associated with maintaining and switching attention in people with hearing loss compared to the normal hearing population, and found a cost associated with attending to a target stream in a multi-talker environment that cannot solely be attributed to audibility issues.

Working Memory and Speech Recognition in Noise Under Ecologically Relevant Listening Conditions: Effects of Visual Cues and Noise Type Among Adults With Hearing Loss.

Purpose: This study evaluated the relationship between working memory (WM) and speech recognition in noise with different noise types as well as in the presence of visual cues. Method: Seventy-six adults with bilateral, mild to moderately severe sensorineural hearing loss (mean age: 69 years) participated. Using a cross-sectional design, 2 measures of WM were taken: a reading span measure, and Word Auditory Recognition and Recall Measure (Smith, Pichora-Fuller, & Alexander, 2016). Speech recognition was measured with the Multi-Modal Lexical Sentence Test for Adults (Kirk et al., 2012) in steady-state noise and 4-talker babble, with and without visual cues. Testing was under unaided conditions. Results: A linear mixed model revealed visual cues and pure-tone average as the only significant predictors of Multi-Modal Lexical Sentence Test outcomes. Neither WM measure nor noise type showed a significant effect. Conclusion: The contribution of WM in explaining unaided speech recognition in noise was negligible and not influenced by noise type or visual cues. We anticipate that with audibility partially restored by hearing aids, the effects of WM will increase. For clinical practice to be affected, more significant effect sizes are needed.

Output signal-to-noise ratio and speech perception in noise: effects of algorithm.

OBJECTIVE: The aims of this study were to: 1) quantify the amount of change in signal-to-noise ratio (SNR) as a result of compression and noise reduction (NR) processing in devices from three hearing aid (HA) manufacturers and 2) use the SNR changes to predict changes in speech perception. We hypothesised that the SNR change would differ across processing type and manufacturer, and that improvements in SNR would relate to improvements in performance. DESIGN: SNR at the output of the HAs was quantified using a phase-inversion technique. A linear mixed model was used to determine whether changes in SNR across HA conditions were predictive of changes in aided speech perception in noise. STUDY SAMPLE: Two groups participated: 25 participants had normal-hearing and 25 participants had mild to moderately severe sensorineural hearing loss. RESULTS: The HAs programmed for both groups changed the SNR by a small, but statistically significant amount. Significant interactions in SNR changes were observed between HA devices and processing types. However, the change in SNR was not predictive of changes in speech perception. CONCLUSION: Although observed significant changes in SNR resulting from compression and NR did not convert to changes in speech perception, these algorithms may serve other purposes.

Exploring the Relevance of Items in the Communicative Participation Item Bank (CPIB) for Individuals With Hearing Loss.

PURPOSE: The Communicative Participation Item Bank (CPIB) was developed to evaluate participation restrictions in communication situations for individuals with speech and language disorders. This study evaluated the potential relevance of CPIB items for individuals with hearing loss. METHOD: Cognitive interviews were conducted with 17 adults with a range of treated and untreated hearing loss, who responded to 46 items. Interviews were continued until saturation was reached and prevalent trends emerged. A focus group was also conducted with 3 experienced audiologists to seek their views on the CPIB. Analysis of data included qualitative and quantitative approaches. RESULTS: The majority of the items were applicable to individuals with hearing loss; however, 12 items were identified as potentially not relevant. This was largely attributed to the items' focus on speech production rather than hearing. The results from the focus group were in agreement for a majority of items. CONCLUSIONS: The next step in validating the CPIB for individuals with hearing loss is a psychometric analysis on a large sample. Possible outcomes could be that the CPIB is considered valid in its entirety or the creation of a new questionnaire or a hearing loss-specific short form with a subset of items is necessary.

The effects of frequency lowering on speech perception in noise with adult hearing-aid users.

OBJECTIVE: Frequency lowering (FL) strategies move high frequency sound into a lower frequency range. This study determined if speech perception differences are observed between some of the different frequency lowering strategies that are available. DESIGN: A cross-sectional, repeated-measures design was used to compare three hearing aids that used wide-dynamic range compression (WDRC) and either non-linear frequency compression (NFC), linear frequency transposition (LFT), or frequency translation (FT). The hearing aids were matched to prescriptive real ear targets for WDRC. The settings for each FL strategy were adjusted to provide audibility for a 6300 Hz filtered speech signal. Sentence recognition in noise, subjective measures of sound quality, and a modified version of the speech intelligibility index (SII) were measured. STUDY SAMPLE: Ten adults between the ages of 63 to 82 years with bilateral, high frequency hearing loss. RESULTS: LFT and FT led to poorer sentence recognition compared to WDRC for most individuals. No difference in sentence recognition occurred with and without NFC. The quality questionnaire and SII showed few differences between conditions. CONCLUSION: Under similar fitting and testing conditions of this study, FL techniques may not provide speech understanding benefit in certain background noise situations.

Aided Electrophysiology Using Direct Audio Input: Effects of Amplification and Absolute Signal Level.

PURPOSE: This study investigated (a) the effect of amplification on cortical auditory evoked potentials (CAEPs) at different signal levels when signal-to-noise ratios (SNRs) were equated between unaided and aided conditions, and (b) the effect of absolute signal level on aided CAEPs when SNR was held constant. METHOD: CAEPs were recorded from 13 young adults with normal hearing. A 1000-Hz pure tone was presented in unaided and aided conditions with a linear analog hearing aid. Direct audio input was used, allowing recorded hearing aid noise floor to be added to unaided conditions to equate SNRs between conditions. An additional stimulus was created through scaling the noise floor to study the effect of signal level. RESULTS: Amplification resulted in delayed N1 and P2 peak latencies relative to the unaided condition. An effect of absolute signal level (when SNR was constant) was present for aided CAEP area measures, such that larger area measures were found at higher levels. CONCLUSION: Results of this study further demonstrate that factors in addition to SNR must also be considered before CAEPs can be used to clinically to measure aided thresholds.

Aided cortical auditory evoked potentials in response to changes in hearing aid gain.

OBJECTIVE: There is interest in using cortical auditory evoked potentials (CAEPs) to evaluate hearing aid fittings and experience-related plasticity associated with amplification; however, little is known about hearing aid signal processing effects on these responses. The purpose of this study was to determine the effect of clinically relevant hearing aid gain settings, and the resulting in-the-canal signal-to-noise ratios (SNRs), on the latency and amplitude of P1, N1, and P2 waves. DESIGN & SAMPLE: Evoked potentials and in-the-canal acoustic measures were recorded in nine normal-hearing adults in unaided and aided conditions. In the aided condition, a 40-dB signal was delivered to a hearing aid programmed to provide four levels of gain (0, 10, 20, and 30 dB). As a control, unaided stimulus levels were matched to aided condition outputs (i.e. 40, 50, 60, and 70 dB) for comparison purposes. RESULTS: When signal levels are defined in terms of output level, aided CAEPs were surprisingly smaller and delayed relative to unaided CAEPs, probably resulting from increases to noise levels caused by the hearing aid. DISCUSSION: These results reinforce the notion that hearing aids modify stimulus characteristics such as SNR, which in turn affects the CAEP in a way that does not reliably reflect hearing aid gain.

Increased NR1-NR2A/B coassembly as a mechanism for rat chronic hippocampal epilepsy.

The N-methyl-D-aspartate receptors (NMDAR) produce physiologically functional channels for enhanced excitatory neurotransmission when they exist as heteromeric complexes containing the NMDAR1 subunit combined with NMDAR2. We examined the expressions of NMDAR1 and 2A/B protein in the kainic acid induced rat chronic epileptic hippocampus. Immunoreactivities of both NMDAR1 and NDMAR2A/B were increased in the inner molecular layer of the dentate gyrus, while they were decreased in the hilar and CA3/4 pyramidal zones. Immunoblot analysis demonstrated that the overall level of NMDAR1-2A/B coassembly was increased in the whole hippocampus. These results indicate that the increase of the NMDAR1-2A/B complex in the inner molecular layer is a significant cellular mechanism that contributes to focal hyperexcitability in rat chronic hippocampal epilepsy.

Time course of transient expression of GDNF protein in rat granule cells of the bilateral dentate gyri after unilateral intrahippocampal kainic acid injection.

We examined the time course of expression of glial cell line-derived neurotrophic factor (GDNF) protein in the granule cells of the dentate gyrus following unilateral intrahippocampal injection of kainic acid (KA). Recurrent behavioral seizures were observed approximately 1 h after KA injection, which lasted for 4-6 h. GDNF immunoreactivity began to increase bilaterally in the granule cells within 3 h after KA injection, continued to increase until post-injection day (PID) 4, and returned to the control level by PID 7. The results suggest that the increase of GDNF protein in the granule cells may be ascribable to seizures induced by the KA injection. The increase of GDNF protein might promote survival of the granule cells after the intrahippocampal KA injection.