Tissue-Engineered Cochlear Fibrosis Model Links Complex Impedance to Fibrosis Formation for Cochlear Implant Patients.

Cochlear implants are a life-changing technology for those with severe sensorineural hearing loss, partially restoring hearing through direct electrical stimulation of the auditory nerve. However, they are known to elicit an immune response resulting in fibrotic tissue formation in the cochlea that is linked to residual hearing loss and suboptimal outcomes. Intracochlear fibrosis is difficult to track without postmortem histology, and no specific electrical marker for fibrosis exists. In this study, a tissue-engineered model of cochlear fibrosis is developed following implant placement to examine the electrical characteristics associated with fibrotic tissue formation around electrodes. The model is characterized using electrochemical impedance spectroscopy and an increase in the resistance and a decrease in capacitance of the tissue using a representative circuit are found. This result informs a new marker of fibrosis progression over time that is extractable from voltage waveform responses, which can be directly measured in cochlear implant patients. This marker is tested in a small sample size of recently implanted cochlear implant patients, showing a significant increase over two postoperative timepoints. Using this system, complex impedance is demonstrated as a marker of fibrosis progression that is directly measurable from cochlear implants to enable real-time tracking of fibrosis formation in patients, creating opportunities for earlier treatment intervention to improve cochlear implant efficacy.

SpeedCAP: An Efficient Method for Estimating Neural Activation Patterns Using Electrically Evoked Compound Action-Potentials in Cochlear Implant Users.

OBJECTIVES: Electrically evoked compound action-potentials (ECAPs) can be recorded using the electrodes in a cochlear implant (CI) and represent the synchronous responses of the electrically stimulated auditory nerve. ECAPs can be obtained using a forward-masking method that measures the neural response to a probe and masker electrode separately and in combination. The panoramic ECAP (PECAP) analyses measured ECAPs obtained using multiple combinations of masker and probe electrodes and uses a nonlinear optimization algorithm to estimate current spread from each electrode and neural health along the cochlea. However, the measurement of ECAPs from multiple combinations of electrodes is too time consuming for use in clinics. Here, we propose and evaluate SpeedCAP, a speedy method for obtaining the PECAP measurements that minimizes recording time by exploiting redundancies between multiple ECAP measures. DESIGN: In the first study, 11 users of Cochlear Ltd. CIs took part. ECAPs were recorded using the forward-masking artifact-cancelation technique at the most comfortable loudness level (MCL) for every combination of masker and probe electrodes for all active electrodes in the users' MAPs, as per the standard PECAP recording paradigm. The same current levels and recording parameters were then used to collect ECAPs in the same users with the SpeedCAP method. The ECAP amplitudes were then compared between the two conditions, as were the corresponding estimates of neural health and current spread calculated using the PECAP method previously described by Garcia et al. The second study measured SpeedCAP intraoperatively in 8 CI patients and with all maskers and probes presented at the same current level to assess feasibility. ECAPs for the subset of conditions where the masker and probe were presented on the same electrode were compared with those obtained using the slower approach leveraged by the standard clinical software. RESULTS: Data collection time was reduced from ≈45 to ≈8 minutes. There were no significant differences between normalized root mean squared error (RMSE) repeatability metrics for post-operative PECAP and SpeedCAP data, nor for the RMSEs calculated between PECAP and SpeedCAP data. The comparison achieved 80% power to detect effect sizes down to 8.2% RMSE. When between-participant differences were removed, both the neural-health (r = 0.73) and current-spread (r = 0.65) estimates were significantly correlated ( p < 0.0001, df = 218) between SpeedCAP and PECAP conditions across all electrodes, and showed RMSE errors of 12.7 ± 4.7% and 16.8 ± 8.8%, respectively (with the ± margins representing 95% confidence intervals). Valid ECAPs were obtained in all patients in the second study, demonstrating intraoperative feasibility of SpeedCAP. No significant differences in RMSEs were detectable between post- and intra-operative ECAP measurements, with the comparison achieving 80% power to detect effect sizes down to 13.3% RMSE. CONCLUSIONS: The improved efficiency of SpeedCAP provides time savings facilitating multi-electrode ECAP recordings in routine clinical practice. SpeedCAP data collection is sufficiently quick to record intraoperatively, and adds no more than 8.2% error to the ECAP amplitudes. Such measurements could thereafter be submitted to models such as PECAP to provide patient-specific patterns of neural activation to inform programming of clinical MAPs and identify causes of poor performance at the electrode-nerve interface of CI users. The speed and accuracy of these measurements also opens up a wide range of additional research questions to be addressed.

Detection of Extracochlear Electrodes Using Stimulation-Current- Induced Non-Stimulating Electrode Voltage Recordings With Different Electrode Designs.

HYPOTHESIS: Stimulation-Current-Induced Non-Stimulating Electrode Voltage Recordings (SCINSEVs) can help detect extracochlear electrodes for a variety of Cochlear Implant (CI) devices. BACKGROUND: Extracochlear electrodes (EEs) occur in 9 to 13% of cochlear implantations and commonly go unnoticed without imaging. Electrodes on the electrode array located extracochlearly are associated with non-auditory stimulation and a decrease in speech outcomes. We have previously shown that SCINSEVs, with hardware and software from one manufacturer, could detect EEs. Here, we test the generalizability to other manufacturers. METHODS: Fresh-frozen human cadaveric heads were implanted with Cochlear Ltd. CI522 (CI-A) and MED-EL's FLEX24 (CI-B) electrodes. Contact impedances and SCIN- SEVs were measured, with Cochlear Ltd. research Custom Sound software (Transimpedance Matrix) and MED-EL's clinical MAESTRO (Impedance Field Telemetry), for full insertion and EEs in air, saline and soft tissue. An automated detection tool was optimized and tested for these implants. Intra-operative SCINSEVs with EEs were collected for clinical purposes for six patients. RESULTS: The pattern of SCINSEVs changed in the transition zone from intracochlear to extracochlear electrodes, even with low contact impedances on EEs. Automated detection in the cadaveric specimens, with two or more EEs in saline or soft tissue, showed a mean 91% sensitivity and specificity for CI-A and 100% sensitivity and specificity for CI-B. Quantification of EEs showed significant correlations of r  = 0.69 between estimated and actual EEs for CI-A and r = 0.76 for CI-B. CONCLUSION: The applicability of SCINSEVs to detect extra- cochlear electrodes could be expanded to other cochlear implant companies despite differences in electrode array design and measurement software.

Emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

Primary Disease Prevention for Southwest American Indian Families During the COVID-19 Pandemic: Camp in a Box.

The goal of the American Indian Youth Wellness Camp in a Box was to engage, educate and empower families to improve their health and overall well-being during the COVID-19 pandemic. Camp in a Box was a 9-week program, inclusive of a 1-week intensive camp component followed by an 8-week booster component with content focused on nutrition, mental health and physical activity education. The Camp in a Box is a Tribal/Urban Indian-University partnership, and materials were developed to replace an existing weeklong residential camp and to comply with social distancing guidelines. Fourteen American Indian families from Tribal/Urban Indian communities in the southwestern United States participated (36 children aged 2-18 years; 32 adults). The intensive camp week included daily materials for families to complete together, Monday through Friday. Materials were provided for approximately 4 h of activities per day. The booster sessions began after camp week and included approximately 4 h of supplementary activities designed to be completed at any time most convenient for the family over the course of the week. Activities were designed to encourage interaction among family members with materials and supplies for parents and youth to participate. Self-reported outcomes suggested that families changed their eating habits to include more vegetables, less sweets and junk food. Parents reported an increase in family physical activity and that the activities brought the family closer together. Our Camp in a Box program was feasible and well-received until school began. During camp week, 100% of recruited families participated; at Booster Week 8, ten families (71%) remained enrolled and active. Camp in a Box is a feasible alternative to residential camps for promotion of health behaviors associated with metabolic disease prevention among American Indian families. In contrast to residential camps for youth, Camp in a Box offers an opportunity to engage the entire family in health promotion activities.

The Panoramic ECAP Method: Estimating Patient-Specific Patterns of Current Spread and Neural Health in Cochlear Implant Users.

The knowledge of patient-specific neural excitation patterns from cochlear implants (CIs) can provide important information for optimizing efficacy and improving speech perception outcomes. The Panoramic ECAP ('PECAP') method (Cosentino et al. 2015) uses forward-masked electrically evoked compound action-potentials (ECAPs) to estimate neural activation patterns of CI stimulation. The algorithm requires ECAPs be measured for all combinations of probe and masker electrodes, exploiting the fact that ECAP amplitudes reflect the overlapping excitatory areas of both probes and maskers. Here we present an improved version of the PECAP algorithm that imposes biologically realistic constraints on the solution, that, unlike the previous version, produces detailed estimates of neural activation patterns by modelling current spread and neural health along the intracochlear electrode array and is capable of identifying multiple regions of poor neural health. The algorithm was evaluated for reliability and accuracy in three ways: (1) computer-simulated current-spread and neural-health scenarios, (2) comparisons to psychophysical correlates of neural health and electrode-modiolus distances in human CI users, and (3) detection of simulated neural 'dead' regions (using forward masking) in human CI users. The PECAP algorithm reliably estimated the computer-simulated scenarios. A moderate but significant negative correlation between focused thresholds and the algorithm's neural-health estimates was found, consistent with previous literature. It also correctly identified simulated 'dead' regions in all seven CI users evaluated. The revised PECAP algorithm provides an estimate of neural excitation patterns in CIs that could be used to inform and optimize CI stimulation strategies for individual patients in clinical settings.

Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

As of January of 2021, the highly transmissible B.1.1.7 variant of SARS-CoV-2, which was first identified in the United Kingdom (U.K.), has gained a strong foothold across the world. Because of the sudden and rapid rise of B.1.1.7, we investigated the prevalence and growth dynamics of this variant in the United States (U.S.), tracking it back to its early emergence and onward local transmission. We found that the RT-qPCR testing anomaly of S gene target failure (SGTF), first observed in the U.K., was a reliable proxy for B.1.1.7 detection. We sequenced 212 B.1.1.7 SARS-CoV-2 genomes collected from testing facilities in the U.S. from December 2020 to January 2021. We found that while the fraction of B.1.1.7 among SGTF samples varied by state, detection of the variant increased at a logistic rate similar to those observed elsewhere, with a doubling rate of a little over a week and an increased transmission rate of 35-45%. By performing time-aware Bayesian phylodynamic analyses, we revealed several independent introductions of B.1.1.7 into the U.S. as early as late November 2020, with onward community transmission enabling the variant to spread to at least 30 states as of January 2021. Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

Evaluating and Comparing Behavioural and Electrophysiological Estimates of Neural Health in Cochlear Implant Users.

Variations in neural health along the cochlea can degrade the spectral and temporal representation of sounds conveyed by cochlear implants (CIs). We evaluated and compared one electrophysiological measure and two behavioural measures that have been proposed as estimates of neural health patterns, in order to explore the extent to which the different measures provide converging and consistent neural health estimates. All measures were obtained from the same 11 users of the Cochlear Corporation CI. The two behavioural measures were multipulse integration (MPI) and the polarity effect (PE), both measured on each of seven electrodes per subject. MPI was measured as the difference between thresholds at 80 pps and 1000 pps, and PE as the difference in thresholds between cathodic- and anodic-centred quadraphasic (QP) 80-pps pulse trains. It has been proposed that good neural health corresponds to a large MPI and to a large negative PE (lower thresholds for cathodic than anodic pulses). The electrophysiological measure was the effect of interphase gap (IPG) on the offset of the ECAP amplitude growth function (AGF), which has been correlated with spiral ganglion neuron density in guinea pigs. This 'IPG offset' was obtained on the same subset of electrodes used for the behavioural measures. Despite high test-retest reliability, there were no significant correlations between the neural health estimates for either within-subject comparisons across the electrode array, or between-subject comparisons of the means. A phenomenological model of a population of spiral ganglion neurons was then used to investigate physiological mechanisms that might underlie the different neural health estimates. The combined experimental and modelling results provide evidence that PE, MPI and IPG offset may reflect different characteristics of the electrode-neural interface.

Validation of a multiplex genotyping platform using a novel genomic database approach.

PURPOSE: Technological advances now allow for multiplex platforms to simultaneously test many genetic conditions. Typically, such platforms are validated by assaying samples with known genotypes and/or phenotypes and/or with synthetic plasmids; however, these methods have limitations and with the inclusion of rarer diseases and mutations, we can no longer rely solely on them. We used a novel genomic database to validate an expanded genetic carrier screening platform. METHODS: Our expanded carrier screening assay uses the Illumina Infinium iSelect HD Custom genotyping platform to test for 213 genetic diseases by assaying 1,663 pathogenic mutations. We leveraged two Coriell Institute biorepositories for validation: the Subcollection of Heritable Diseases and the 1000 Genomes Project. RESULTS: We measured 12,394 mutation observations in 206 samples, resulting in 246 true positives, 12,147 true negatives, 1 false positive, and no false negatives. Results demonstrated high sensitivity (99.99%) and specificity (99.99%). CONCLUSION: We successfully validated our platform with two biorepositories, demonstrating high sensitivity and specificity. The 1000 Genomes Project samples provided both positive and negative validation for mutations in genes not available through other biorepositories, expanding the depth of validated variants. We recommend including samples from the 1000 Genomes Project in the validation of future multiplex testing platforms.Genet Med advance online publication 30 July 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.101.