Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants.

AIMS: To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate). METHODS: PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n = 12) or dabigatran 75 mg (n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment. RESULTS: After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUCinf and Cmax , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUCinf and Cmax increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUCinf and Cmax . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran Cmax with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported. CONCLUSION: Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran Cmax was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.

Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults.

AIMS: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. METHODS: Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. RESULTS: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported. CONCLUSIONS: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.

Brain-based measures of nociception during general anesthesia with remifentanil: A randomized controlled trial.

BACKGROUND: Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation. METHODS AND FINDINGS: We investigated the effects of continuous remifentanil on cortical hemodynamics during cardiac ablation under anesthesia. In a randomized, double-blinded, placebo (PL)-controlled trial, we examined 32 pediatric patients (mean age of 15.8 years,16 females) undergoing catheter ablation for cardiac arrhythmias at the Cardiology Department of Boston Children's Hospital from October 2016 to March 2020; 9 received 0.9% NaCl, 12 received low-dose (LD) remifentanil (0.25 mcg/kg/min), and 11 received high-dose (HD) remifentanil (0.5 mcg/kg/min). The hemodynamic changes of primary somatosensory and prefrontal cortices were recorded during surgery using a continuous wave fNIRS system. The primary outcome measures were the changes in oxyhemoglobin concentration (NadirHbO, i.e., lowest oxyhemoglobin concentration and PeakHbO, i.e., peak change and area under the curve) of medial frontopolar cortex (mFPC), lateral prefrontal cortex (lPFC) and primary somatosensory cortex (S1) to ablation in PL versus remifentanil groups. Secondary measures included the fNIRS response to an auditory control condition. The data analysis was performed on an intention-to-treat (ITT) basis. Remifentanil group (dosage subgroups combined) was compared with PL, and a post hoc analysis was performed to identify dose effects. There were no adverse events. The groups were comparable in age, sex, and number of ablations. Results comparing remifentanil versus PL show that PL group exhibit greater NadirHbO in inferior mFPC (mean difference (MD) = 1.229, 95% confidence interval [CI] = 0.334, 2.124, p < 0.001) and superior mFPC (MD = 1.206, 95% CI = 0.303, 2.109, p = 0.001) and greater PeakHbO in inferior mFPC (MD = -1.138, 95% CI = -2.062, -0.214, p = 0.002) and superior mFPC (MD = -0.999, 95% CI = -1.961, -0.036, p = 0.008) in response to ablation. S1 activation from ablation was greatest in PL, then LD, and HD groups, but failed to reach significance, whereas lPFC activation to ablation was similar in all groups. Ablation versus auditory stimuli resulted in higher PeakHbO in inferior mFPC (MD = 0.053, 95% CI = 0.004, 0.101, p = 0.004) and superior mFPC (MD = 0.052, 95% CI = 0.013, 0.091, p < 0.001) and higher NadirHbO in posterior superior S1 (Pos. SS1; MD = -0.342, 95% CI = -0.680, -0.004, p = 0.007) during ablation of all patients. Remifentanil group had smaller NadirHbO in inferior mFPC (MD = 0.098, 95% CI = 0.009, 0.130, p = 0.003) and superior mFPC (MD = 0.096, 95% CI = 0.008, 0.116, p = 0.003) and smaller PeakHbO in superior mFPC (MD = -0.092, 95% CI = -0.680, -0.004, p = 0.007) during both the stimuli. Study limitations were small sample size, motion from surgery, indirect measure of nociception, and shallow penetration depth of fNIRS only allowing access to superficial cortical layers. CONCLUSIONS: We observed cortical activity related to nociception during cardiac ablation under general anesthesia with remifentanil. It highlights the potential of fNIRS to provide an objective pain measure in unconscious patients, where cortical-based measures may be more accurate than current evaluation methods. Future research may expand on this application to produce a real-time indication of pain that will aid clinicians in providing immediate and adequate pain treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02703090.

Intraoperative Correction of Cochlear Implant Electrode Translocation.

INTRODUCTION: Translocation of precurved cochlear implant (CI) electrodes reduces hearing outcomes, but it is not known whether it is possible to correct scalar translocation such that all electrodes reside fully in the scala tympani (ST). METHODS: Six cadaveric temporal bones were scanned with CT and segmented to delineate intracochlear anatomy. Mastoidectomy with facial recess was performed. Precurved CI electrodes (CI532; Cochlear Limited) were implanted until scalar translocation was confirmed with postoperative CT. Then, electrodes were removed and replaced. CT scan was repeated to assess for translocation correction. Scalar position of electrode contacts, angular insertion depth (AID) of the electrode array, and M- (average distance between each electrode contact and the modiolus) were measured. An in vivo case is reported in which intraoperative translocation detection led to removal and replacement of the electrode. RESULTS: Five of 6 cadaveric translocations (83%) were corrected with 1 attempt, resulting in full ST insertions. AID averaged 285 ± 77° for translocated electrodes compared to 344 ± 28° for nontranslocated electrodes (p = 0.109). M- averaged 0.75 ± 0.18 mm for translocated electrodes and 0.45 ± 0.11 mm for nontranslocated electrodes (p = 0.016). Reduction in M- with translocation correction averaged 38%. In the in vivo case, translocation was successfully corrected in a single attempt. CONCLUSION: Scalar translocation of precurved CI electrodes can be corrected by removal and reinsertion. This significantly improves the perimodiolar positioning of these electrodes. There was a high rate of success (83%) in this cadaveric model as well as a successful in vivo attempt.

Speech recognition as a function of the number of channels for Mid-Scala electrode array recipients.

This study investigated the number of channels needed for maximum speech understanding and sound quality in 15 adult cochlear implant (CI) recipients with Advanced Bionics (AB) Mid-Scala electrode arrays completely within scala tympani. In experiment I, CI programs used a continuous interleaved sampling (CIS)-based strategy and 4-16 active electrodes. In experiment II, CI programs used an n-of-m strategy featuring 16 active electrodes with either 8- or 12-maxima. Speech understanding and sound quality measures were assessed. For CIS programs, participants demonstrated performance gains using up to 4-10 electrodes on speech measures and sound quality ratings. For n-of-m programs, there was no significant effect of maxima, suggesting 8-maxima is sufficient for this sample's maximum performance and sound quality. These results are largely consistent with previous studies using straight electrode arrays [e.g., Fishman, Shannon, and Slattery (1997). J. Speech Lang. Hear. Res. 40, 1201-1215; Friesen, Shannon, Baskent, and Wang (2001). J. Acoust. Soc. Am. 110, 1150-1163; Shannon, Cruz, and Galvin (2011). Audiol. Neurotol. 16, 113-123; Berg, Noble, Dawant, Dwyer, Labadie, and Gifford (2020). J. Acoust. Soc. Am. 147, 3646-3656] and in contrast with recent studies looking at cochlear precurved electrode arrays [e.g., Croghan, Duran, and Smith (2017). J. Acoust. Soc. Am. 142, EL537-EL543; Berg, Noble, Dawant, Dwuer, Labadie, and Gifford (2019b). J. Acoust. Soc. Am. 145, 1556-1564], which found continuous improvements up to 16 independent channels. These findings suggest that Mid-Scala electrode array recipients demonstrate similar channel independence to straight electrode arrays rather than other manufacturer's precurved electrode arrays.

Rhythmic Change of Cortical Hemodynamic Signals Associated with Ongoing Nociception in Awake and Anesthetized Individuals: An Exploratory Functional Near Infrared Spectroscopy Study.

BACKGROUND: Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain. METHODS: Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block. RESULTS: A reduction of the total fractional power in both groups-specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex-was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34). CONCLUSIONS: These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia.

Speech recognition as a function of the number of channels for an array with large inter-electrode distances.

This study investigated the number of channels available to cochlear implant (CI) recipients for maximum speech understanding and sound quality for lateral wall electrode arrays-which result in large electrode-to-modiolus distances-featuring the greatest inter-electrode distances (2.1-2.4 mm), the longest active lengths (23.1-26.4 mm), and the fewest number of electrodes commercially available. Participants included ten post-lingually deafened adult CI recipients with MED-EL electrode arrays (FLEX28 and STANDARD) entirely within scala tympani. Electrode placement and scalar location were determined using computerized tomography. The number of channels was varied from 4 to 12 with equal spatial distribution across the array. A continuous interleaved sampling-based strategy was used. Speech recognition, sound quality ratings, and a closed-set vowel recognition task were measured acutely for each electrode condition. Participants did not demonstrate statistically significant differences beyond eight channels at the group level for almost all measures. However, several listeners showed considerable improvements from 8 to 12 channels for speech and sound quality measures. These results suggest that channel interaction caused by the greater electrode-to-modiolus distances of straight electrode arrays could be partially compensated for by a large inter-electrode distance or spacing.

Speech recognition with cochlear implants as a function of the number of channels: Effects of electrode placement.

This study investigated the effects of cochlear implant (CI) electrode array type and scalar location on the number of channels available to CI recipients for maximum speech understanding and sound quality. Eighteen post-lingually deafened adult CI recipients participated, including 11 recipients with straight electrode arrays entirely in scala tympani and 7 recipients with translocated precurved electrode arrays. Computerized tomography was used to determine electrode placement and scalar location. In each condition, the number of channels varied from 4 to 22 with equal spatial distribution across the array. Speech recognition (monosyllables, sentences in quiet and in noise), subjective speech sound quality, and closed-set auditory tasks (vowels, consonants, and spectral modulation detection) were measured acutely. Recipients with well-placed straight electrode arrays and translocated precurved electrode arrays performed similarly, demonstrating asymptotic speech recognition scores with 8-10 channels, consistent with the classic literature. This finding contrasts with recent work [Berg, Noble, Dawant, Dwyer, Labadie, and Gifford. (2019). J. Acoust. Soc. Am. 145, 1556-1564] that found precurved electrode arrays well-placed in scala tympani demonstrate continuous performance gains beyond 8-10 channels. Given these results, straight and translocated precurved electrode arrays are theorized to have less channel independence secondary to their placement farther away from neural targets.

Speech recognition as a function of the number of channels in perimodiolar electrode recipients.

This study investigated the number of channels needed for maximum speech understanding and sound quality in 30 adult cochlear implant (CI) recipients with perimodiolar electrode arrays verified via imaging to be completely within scala tympani (ST). Performance was assessed using a continuous interleaved sampling (CIS) strategy with 4, 8, 10, and 16 channels and n-of-m with 16 maxima. Listeners were administered auditory tasks of speech understanding [monosyllables, sentences (quiet and +5 dB signal-to-noise ratio, SNR), vowels, consonants], spectral modulation detection, as well as subjective estimates of sound quality. Results were as follows: (1) significant performance gains were observed for speech in quiet (monosyllables and sentences) with 16- as compared to 8-channel CIS, (2) 16 channels in a 16-of-m strategy yielded significantly higher outcomes than 16-channel CIS for sentences in noise (percent correct and subjective sound quality) and spectral modulation detection, (3) 16 channels in a 16-of-m strategy yielded significantly higher outcomes as compared to 8- and 10-channel CIS for monosyllables, sentences (quiet and noise), consonants, spectral modulation detection, and subjective sound quality, (4) 16 versus 8 maxima yielded significantly higher speech recognition for monosyllables and sentences in noise using an n-of-m strategy, and (5) the degree of benefit afforded by 16 versus 8 maxima was inversely correlated with mean electrode-to-modiolus distance. These data demonstrate greater channel independence with perimodiolar electrode arrays as compared to previous studies with straight electrodes and warrant further investigation of the minimum number of maxima and number of channels needed for maximum auditory outcomes.

Evaluation of the effect of rifampin on the pharmacokinetics of the Smoothened inhibitor glasdegib in healthy volunteers.

AIMS: This study aimed to evaluate the effect of a strong CYP3A inducer, rifampin, on glasdegib pharmacokinetics in healthy volunteers. METHODS: In an open-label, fixed-sequence, two-period Phase 1 study, subjects received a single 100-mg oral dose of glasdegib alone or following once-daily pre-treatment with 600 mg rifampin. Glasdegib pharmacokinetics were calculated using a noncompartmental analysis. RESULTS: Twelve healthy male volunteers (3 whites, 5 blacks and 4 others) were enrolled in the study. Mean age, weight, height and body mass index was 37.8 years, 83.0 kg, 177.3 cm and 26.5 kg (m2 ) -1 , respectively. When dosed alone, glasdegib geometric mean (% coefficient of variation) area under the plasma concentration-time curve from time zero to infinity (AUCinf ) was 8145 ng × h ml-1 (23%) and maximum observed concentration (Cmax ) was 703.2 ng ml-1 (19%). With rifampin, glasdegib AUCinf and Cmax decreased, with an adjusted geometric mean ratio (90% confidence interval) 29.66% (26.17-33.62) for AUCinf and 64.71% (57.21-73.19) for Cmax . Mean terminal half-life decreased from 13.39 to 5.11 hours, geometric mean apparent oral clearance increased from 12.27 to 41.38 l h-1 , whereas median time to Cmax remained similar (1.50 vs. 1.25 hours) in the presence of rifampin. All adverse events (n = 29) were mild in severity and resolved by the end of the study. CONCLUSIONS: Co-administration of rifampin expectedly decreased glasdegib AUCinf and Cmax by ~70% and ~35%, respectively. These results will help to formulate recommendations for dosing strategies in combination with CYP3A inducers in situations where co-administration may be necessary. (clinicaltrials.gov identifier: NCT02430545).

Force Perception Thresholds in Cochlear Implantation Surgery.

Tissue trauma is a frequent complication of cochlear implantation (CI) surgery, but the relationship between intracochlear trauma, electrode insertion forces, and surgeons' ability to perceive these forces is poorly understood. In this study, we simulated CI surgery using a benchtop apparatus to repeatedly apply small forces to the subjects' hands while reducing the variability in their hand movements. We used a psychophysical testing procedure to estimate the force perception thresholds of 10 otologic surgeons and found a median threshold of 20.4 mN. The results suggest that surgeons have the capability to sense at least some insertion forces and are likely to perceive severe trauma such as occurs when the electrode crosses from one scala to the other.

Axitinib plasma pharmacokinetics and ethnic differences.

Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted.

Clinical evaluation of an image-guided cochlear implant programming strategy.

The cochlear implant (CI) has been labeled the most successful neural prosthesis. Despite this success, a significant number of CI recipients experience poor speech understanding, and, even among the best performers, restoration to normal auditory fidelity is rare. While significant research efforts have been devoted to improving stimulation strategies, few developments have led to significant hearing improvement over the past two decades. We have recently introduced image processing techniques that open a new direction for advancement in this field by making it possible, for the first time, to determine the position of implanted CI electrodes relative to the nerves they stimulate using computed tomography images. In this article, we present results of an image-guided, patient-customized approach to stimulation that utilizes the electrode position information our image processing techniques provide. This approach allows us to identify electrodes that cause overlapping stimulation patterns and to deactivate them from a patient's map. This individualized mapping strategy yields significant improvement in speech understanding in both quiet and noise as well as improved spectral resolution in the 68 adult CI recipients studied to date. Our results indicate that image guidance can improve hearing outcomes for many existing CI recipients without requiring additional surgery or the use of 'experimental' stimulation strategies, hardware or software.

Factors associated with recurrence of squamous cell carcinoma involving the temporal bone.

OBJECTIVE: This study aimed to better identify factors associated with recurrence of squamous cell carcinoma (SCC) involving the temporal bone. METHODS: A retrospective study was conducted at a tertiary hospital. Sixty patients who were diagnosed over a 10-year period with SCC involving the temporal bone and underwent surgical resection were analyzed. All patients were staged based on the University of Pittsburgh staging system. Demographic, intraoperative, and pathologic data were analyzed with respect to recurrence. RESULTS: Thirteen (21.7%) patients were T1, 8 (13.3%) T2, 7 (11.7%) T3, and 32 (53.3%) T4. Eighteen patients (30.0%) recurred in the study period. The mean time to recurrence was 5.8 months. Tumors originating in the skin overlying the parotid gland and the external auditory canal had higher recurrence rates than those from the auricle/postauricular skin and temporal bone (P = .05). Direct parotid and perineural spread accounted for 15.0% of all routes of temporal invasion but resulted in 22.2% of all recurrences (P = .04). Increased N stage was statistically associated with increased risk of recurrence (P = .01). Cervical, as compared to perifacial and parotid, lymph node involvement was associated with increased risk of recurrence (odds ratio = 6.91; 95% confidence interval, 1.11-42.87). CONCLUSION: We have identified multiple factors that are associated with increased recurrence of SCC involving the temporal bone.

Impedance testing on cochlear implants after electroconvulsive therapy.

OBJECTIVE: Cochlear implants (CI) are neural prostheses that restore hearing to individuals with profound sensorineural hearing loss. The surgically implanted component consists of an electrode array, which is threaded into the cochlea, and an electronic processor, which is buried under the skin behind the ear. The Food and Drug Administration and CI manufacturers contend that electroconvulsive therapy (ECT) is contraindicated in CI recipients owing to risk of damage to the implant and/or the patient. We hypothesized that ECT does no electrical damage to CIs. METHODS: Ten functional CIs were implanted in 5 fresh cadaveric human heads. Each head then received a consecutive series of 12 unilateral ECT sessions applying maximum full pulse-width energy settings. Electroconvulsive therapy was delivered contralaterally to 5 CIs and ipsilaterally to 5 CIs. Electrical integrity testing (impedance testing) of the electrode array was performed before and after CI insertion, and after the first, third, fifth, seventh, ninth, and 12th ECT sessions. Electroconvulsive therapy was performed by a staff psychiatrist experienced with the technique. Explanted CIs were sent back to the manufacturer for further integrity testing. RESULTS: No electrical damage was identified during impedance testing. Overall, there were statistically significant decreases in impedances (consistent with no electrical damage) when comparing pre-ECT impedance values to those after 12 sessions. There was no statistically significant difference (P > 0.05) in impedance values comparing ipsilateral to contralateral ECT. Manufacturer testing revealed no other electrical damage to the CIs. CONCLUSION: Electroconvulsive therapy does not seem to cause any detectable electrical injury to CIs.

The Use of Portable, Very Low-field (0.064T) MRI to Image Cochlear Implants: Metallic Image Artifact in Comparison to Traditional, Stationary 3T MRI.

Objective: To assess image artifact when imaging a cochlear implant (CI) with a conventional 3T MRI machine compared with a very low-field (0.064T) MRI. Patients: None. Intervention: Diagnostic study. Main Outcome Measure: Image artifact size associated with the CI affixed to an MRI phantom at very low-field 0.064T MRI versus 3T MRI. Results: The longest diameter of the image artifact was 125 mm for the 3T MRI and 86 mm for the 0.064T MRI, representing 45% longer image artifact generated in the 3T MRI. The actual volume of the imaging phantom was 1371 cm3. The volume of the image artifact was measured as 379 cm3 in the 3T MRI, representing a loss of 27.6% of the actual volume of the imaging phantom. The volume of image artifact was measured as 170 cm3 in the 0.064T MRI, representing a loss of 12.4% of the phantom volume. Conclusions: 3T MRI had better image quality. This result was not surprising given that larger magnetic field strength is known to provide higher resolution. There was 15% less image artifact generated in the very low-field MRI machine compared with a conventional 3T device. And there was also subjectively increased distortion of the imaging phantom at 3T MRI compared with the 0.064T MRI. With minimized safety concerns and a much lower cost than conventional 3T machines, very low-field scanners may find expanded clinical uses. This preclinical study explores the potential utility of very low-field MRI in scanning CI recipients.

Prognosis of Bilateral Sudden Sensorineural Hearing Loss: A Systematic Review and Meta-Analysis.

OBJECTIVES: To comprehensively examine the characteristics and prognosis of bilateral sudden sensorineural hearing loss (BSSHL) and its subtypes compared to unilateral sudden sensorineural hearing loss (USSHL). DATA SOURCES: PubMed, Scopus, and CINAHL. REVIEW METHODS: Databases were searched from inception to December 5, 2023, for studies reporting patient characteristics and audiometric outcomes for BSSHL and its simultaneous (Si-BSSHL) and sequential (Se-BSSHL) subtypes. Meta-analysis of continuous measures, proportions (%), mean differences (Δ), and odds ratio (OR) were performed. RESULTS: Eleven studies were included, consisting of 368 patients with BSSHL and 2,705 patients with USSHL. The pooled prevalence among all SSHL cases was 88.1% (95% CI: 81.2%-93.6%) for USSHL and 11.9% (95% CI: 6.4% to 18.8%) for BSSHL. PTA improvement following treatment with steroids was significantly worse in patients with BSSHL (Δ15.3 dB; 95% CI: 14.6 to 15.9; p < 0.0001) compared to patients with USSHL. There was no significant difference in post-treatment PTA improvement between the BSSHL subtypes. Patients with Si-BSSHL were significantly less likely to have an idiopathic etiology (OR: 0.4; 95% CI: 0.2 to 0.8; p = 0.01) and significantly more likely to have an autoimmune disease etiology (OR: 27.4; 95% CI: 2.2 to 336.1; p = 0.01), comorbid cardiovascular disease (OR: 2.3; 95% CI: 1.1 to 5.1; p = 0.03), and comorbid hypertension (OR: 2.5; 95% CI: 1.6 to 3.8; p < 0.0001) compared to patients with USSHL. CONCLUSIONS: BSSHL is a considerably rarer form of SSHL with worse prognosis compared to USSHL. BSSHL, and Si-BSSHL in particular, has significantly greater associations with systemic pathologies compared to USSHL. Laryngoscope, 134:3883-3891, 2024.

Towards inferring positioning of straight cochlear-implant electrode arrays during insertion using real-time impedance sensing.

BACKGROUND: Cochlear-implant electrode arrays (EAs) are currently inserted with limited feedback, and impedance sensing has recently shown promise for EA localisation. METHODS: We investigate the use of impedance sensing to infer the progression of an EA during insertion. RESULTS: We show that the access resistance component of bipolar impedance sensing can detect when a straight EA reaches key anatomical locations in a plastic cochlea and when each electrode contact enters/exits the cochlea. We also demonstrate that dual-sided electrode contacts can provide useful proximity information and show the real-time relationship between impedance and wall proximity in a cadaveric cochlea for the first time. CONCLUSION: The access resistance component of bipolar impedance sensing has high potential for estimating positioning information of EAs relative to anatomy during insertion. Main limitations of this work include using saline as a surrogate for human perilymph in ex vivo models and using only one type of EA.

Effect of Hepatic Impairment on the Pharmacokinetics of Nirmatrelvir/Ritonavir, the First Oral Protease Inhibitor for the Treatment of COVID-19.

Nirmatrelvir, a novel, potent, orally bioavailable severe acute respiratory syndrome coronavirus 2 main protease inhibitor, coadministered with ritonavir for pharmacokinetic (PK) enhancement is licensed for the treatment of mild to moderate COVID-19 in individuals at increased risk of progression to severe disease. Cytochrome P450 3A4 is the primary metabolic enzyme responsible for nirmatrelvir metabolism; however, when cytochrome P450 3A4 is inhibited by ritonavir, nirmatrelvir is primarily excreted, unchanged, in urine. Because of intended use of nirmatrelvir among individuals with hepatic impairment, this Phase 1 study (NCT05005312) evaluated the effects of hepatic impairment on nirmatrelvir PK parameters to assess the potential need for any dose adjustments in this population. Participants with normal hepatic function or moderate hepatic impairment (n = 8 each) were administered a single 100-mg nirmatrelvir dose, with 100 mg of ritonavir administered 12 hours before, together with, and 12 and 24 hours after nirmatrelvir. Nirmatrelvir median plasma concentrations and systemic exposure measured by area under the plasma concentration-time curve from time zero extrapolated to infinite time and maximum observed plasma concentration values were comparable in both groups. Nirmatrelvir/ritonavir had an acceptable safety profile in both groups, and no clinically significant changes in laboratory measurements, vital signs, or electrocardiogram assessments were observed. Based on these results, no dose adjustment is deemed necessary in patients with moderate hepatic impairment and, by extension, in patients with mild hepatic impairment.

Clinical Applications for Spread of Excitation Functions Obtained Via Electrically Evoked Compound Action Potentials (eCAP).

OBJECTIVES: To assess the clinical utility of spread of excitation (SOE) functions obtained via electrically evoked compound action potentials (eCAP) to 1) identify electrode array tip fold-over, 2) predict electrode placement factors confirmed via postoperative computed tomography (CT) imaging, and 3) predict postoperative speech recognition through the first year post-activation in a large clinical sample. STUDY DESIGN: Retrospective case review. SETTING: Cochlear implant (CI) program at a tertiary medical center. PATIENTS: Two hundred seventy-two ears (238 patients) with Cochlear Ltd. CIs (mean age = 46 yr, range = 9 mo-93 yr, 50% female) implanted between August 2014 and December 2022 were included. MAIN OUTCOME MEASURES: eCAP SOE widths (mm) (probe electrodes 5, 11, and 17), incidence of electrode tip fold-over, CT imaging data (electrode-to-modiolus distance, angular insertion depth, scalar location), and speech recognition outcomes (consonant-nucleus-consonant [CNC], AzBio quiet, and +5 dB SNR) through the first year after CI activation. RESULTS: 1) eCAP SOE demonstrated a sensitivity of 85.7% for identifying tip fold-over instances that were confirmed by CT imaging. In the current dataset, the tip fold-over incidence rate was 3.1% (7 patients), with all instances involving a precurved electrode array. 2) There was a significant positive relationship between eCAP SOE and mean electrode-to-modiolus distance for precurved arrays, and a significant positive relationship between eCAP SOE and angular insertion depth for straight arrays. No relationships between eCAP SOE and scalar location or cochlea diameter were found in this sample. 3) There were no significant relationships between eCAP SOE and speech recognition outcomes for any measure or time point, except for a weak negative correlation between average eCAP SOE widths and CNC word scores at 6 months post-activation for precurved arrays. CONCLUSIONS: In the absence of intraoperative CT or fluoroscopic imaging, eCAP SOE is a reasonable alternative method for identifying electrode array tip fold-over and should be routinely measured intraoperatively, especially for precurved electrode arrays with a sheath.