Acoustic Change Complex Recorded in Hybrid Cochlear Implant Users.

INTRODUCTION: Expanding cochlear implant (CI) candidacy criteria and advances in electrode arrays and soft surgical techniques have increased the number of CI recipients who have residual low-frequency hearing. Objective measures such as obligatory cortical auditory-evoked potentials (CAEPs) may help clinicians make more tailored recommendations to recipients regarding optimal listening mode. As a step toward this goal, this study investigated how CAEPs measured from hybrid CI users differ in two listening modes: acoustic alone (A-alone) versus acoustic plus electric (A + E). METHODS: Eight successful hybrid CI users participated in this study. Two CAEPs, the P1-N1-P2 and the acoustic change complex (ACC), were measured simultaneously in response to the onset and change of a series of different and spectrally complex acoustic signals, in each of the two listening modes (A-alone and A + E). We examined the effects of listening mode and stimulus type on the onset and ACC N1-P2 amplitudes and peak latencies. RESULTS: ACC amplitudes in hybrid CI users significantly differed as a function of listening mode and stimulus type. ACC responses in A + E were larger than those in the A-alone mode. This was most evident for stimuli involving a change from low to high frequency. CONCLUSIONS: Results of this study showed that the ACC varies as a function of listening mode and stimulus type. This finding suggests that the ACC can be used as a physiologic, objective measure of the benefit of hybrid CIs, potentially supporting clinicians in making clinical recommendations on individualized listening mode, or to document subjective preference for a given listening mode. Further research into this potential clinical application in a range of hybrid recipients and/or long electrode users who have residual low-frequency hearing is warranted.

A constitutively expressed fluorescent ubiquitination-based cell-cycle indicator (FUCCI) in axolotls for studying tissue regeneration.

Regulation of cell cycle progression is essential for cell proliferation during regeneration following injury. After appendage amputation, the axolotl (Ambystoma mexicanum) regenerates missing structures through an accumulation of proliferating cells known as the blastema. To study cell division during blastema growth, we generated a transgenic line of axolotls that ubiquitously expresses a bicistronic version of the fluorescent ubiquitination-based cell-cycle indicator (FUCCI). We demonstrate near-ubiquitous FUCCI expression in developing and adult tissues, and validate these expression patterns with DNA synthesis and mitosis phase markers. We demonstrate the utility of FUCCI for live and whole-mount imaging, showing the predominantly local contribution of cells during limb and tail regeneration. We also show that spinal cord amputation results in increased proliferation at least 5 mm from the site of injury. Finally, we use multimodal staining to provide cell type information for cycling cells by combining fluorescence in situ hybridization, EdU click-chemistry and immunohistochemistry on a single FUCCI tissue section. This new line of animals will be useful for studying cell cycle dynamics using in situ endpoint assays and in vivo imaging in developing and regenerating animals.

Polypharmacy, hospitalization, and mortality risk: a nationwide cohort study.

Polypharmacy is a growing and major public health issue, particularly in the geriatric population. This study aimed to examine the association between polypharmacy and the risk of hospitalization and mortality. We included 3,007,620 elderly individuals aged ≥ 65 years who had at least one routinely-prescribed medication but had no prior hospitalization within a year. The primary exposures of interest were number of daily prescribed medications (1-2, 3-4, 5-6, 7-8, 9-10, and ≥ 11) and presence of polypharmacy (≥ 5 prescription drugs per day). The corresponding comparators were the lowest number of medications (1-2) and absence of polypharmacy. The study outcomes were hospitalization and all-cause death. The median age of participants was 72 years and 39.5% were men. Approximately, 46.6% of participants experienced polypharmacy. Over a median follow-up of 5.0 years, 2,028,062 (67.4%) hospitalizations and 459,076 (15.3%) all-cause deaths were observed. An incrementally higher number of daily prescribed medications was found to be associated with increasingly higher risk for hospitalization and mortality. These associations were consistent across subgroups of age, sex, residential area, and comorbidities. Furthermore, polypharmacy was associated with greater risk of hospitalization and death: adjusted HRs (95% CIs) were 1.18 (1.18-1.19) and 1.25 (1.24-1.25) in the overall and 1.16 (1.16-1.17) and 1.25 (1.24-1.25) in the matched cohorts, respectively. Hence, polypharmacy was associated with a higher risk of hospitalization and all-cause death among elderly individuals.

3D visualization of macromolecule synthesis.

Measuring nascent macromolecular synthesis in vivo is key to understanding how cells and tissues progress through development and respond to external cues. Here we perform in vivo injection of alkyne- or azide-modified analogs of thymidine, uridine, methionine, and glucosamine to label nascent synthesis of DNA, RNA, protein, and glycosylation. Three-dimensional volumetric imaging of nascent macromolecule synthesis was performed in axolotl salamander tissue using whole-mount click chemistry-based fluorescent staining followed by light sheet fluorescent microscopy. We also developed an image processing pipeline for segmentation and classification of morphological regions of interest and individual cells, and we apply this pipeline to the regenerating humerus. We demonstrate our approach is sensitive to biological perturbations by measuring changes in DNA synthesis after limb denervation. This method provides a powerful means to quantitatively interrogate macromolecule synthesis in heterogenous tissues at the organ, cellular, and molecular levels of organization.

Cells often respond to changes in their environment by producing new molecules and building new cell components, such as proteins, which perform most tasks in the cell, or DNA and RNA, which carry genetic information. Complex tissues ­ such as limbs, which are made up of muscles, tendons, bones and cartilage ­ are difficult to see through, so studying when and where cells in these tissues produce different types of molecules is challenging. New approaches combining advanced three-dimensional microscopy and fluorescent labelling of molecules could provide a way to study these processes within whole animal tissues. One application for this is studying how salamanders regrow lost limbs. When salamanders such as axolotls regrow a limb, some cells in the limb stump form a group called the blastema. The blastema contains cells that are specialized to different purposes. Each cell in the blastema produces many new proteins as well as new DNA and RNA molecules. Fluorescently labeling particular molecules and taking images of the regenerating limb at different times can help to reveal how these new molecules control and coordinate limb regrowth. Duerr et al. developed a three-dimensional microscopy technique to study the production of new molecules in regenerating axolotl limbs. The method labeled molecules of different types with fluorescent markers. As a result, new proteins, RNA and DNA glowed under different colored lights. Duerr et al. used their method to show that nerve damage, which hinders limb regrowth in salamanders, reduces DNA production in the blastema. There are many possible applications of this microscopy method. Since the technique allows the spatial arrangement of the cells and molecules studied to be preserved, it makes it possible to investigate which molecules each cell is making and how they interact across a tissue. Not only does the technique have the potential to reveal much more about limb regrowth at all stages, but the fluorescent markers used can also be easily adapted to many other applications.

Effects of Long-Term Musical Training on Cortical Auditory Evoked Potentials.

OBJECTIVE: Evidence suggests that musicians, as a group, have superior frequency resolution abilities when compared with nonmusicians. It is possible to assess auditory discrimination using either behavioral or electrophysiologic methods. The purpose of this study was to determine if the acoustic change complex (ACC) is sensitive enough to reflect the differences in spectral processing exhibited by musicians and nonmusicians. DESIGN: Twenty individuals (10 musicians and 10 nonmusicians) participated in this study. Pitch and spectral ripple discrimination were assessed using both behavioral and electrophysiologic methods. Behavioral measures were obtained using a standard three interval, forced choice procedure. The ACC was recorded and used as an objective (i.e., nonbehavioral) measure of discrimination between two auditory signals. The same stimuli were used for both psychophysical and electrophysiologic testing. RESULTS: As a group, musicians were able to detect smaller changes in pitch than nonmusician. They also were able to detect a shift in the position of the peaks and valleys in a ripple noise stimulus at higher ripple densities than non-musicians. ACC responses recorded from musicians were larger than those recorded from non-musicians when the amplitude of the ACC response was normalized to the amplitude of the onset response in each stimulus pair. Visual detection thresholds derived from the evoked potential data were better for musicians than non-musicians regardless of whether the task was discrimination of musical pitch or detection of a change in the frequency spectrum of the ripple noise stimuli. Behavioral measures of discrimination were generally more sensitive than the electrophysiologic measures; however, the two metrics were correlated. CONCLUSIONS: Perhaps as a result of extensive training, musicians are better able to discriminate spectrally complex acoustic signals than nonmusicians. Those differences are evident not only in perceptual/behavioral tests but also in electrophysiologic measures of neural response at the level of the auditory cortex. While these results are based on observations made from normal-hearing listeners, they suggest that the ACC may provide a non-behavioral method of assessing auditory discrimination and as a result might prove useful in future studies that explore the efficacy of participation in a musically based, auditory training program perhaps geared toward pediatric or hearing-impaired listeners.

Designing of the fixed-dose gastroretentive bilayer tablet for sustained release of metformin and immediate release of atorvastatin.

Patients with type 2 diabetes mellitus have a high risk of cardiovascular disease mainly caused by dyslipidemia. Metformin and atorvastatin are preferentially used to treat type 2 diabetes mellitus and dyslipidemia, respectively. The aim of this study was to develop a once-a-day fixed-dose combination tablet containing metformin and atorvastatin. For this purpose, we designed gastroretentive bilayer tablets consisting of 500 mg metformin in a sustained release layer and 10 mg atorvastatin in an immediate release layer. In addition, we modified the formulation to maintain a dual release pattern for the kinetically different layers for once-daily dosing. The gastroretentive bilayer tablet was developed using polyethylene oxide as a swellable polymer and ammonium methacrylate copolymer as a granule-coating polymer with minimal use of excipients. In vitro release patterns of metformin and atorvastatin from the developed formulation were similar to those of the reference drugs, Glucophage XR for metformin and Lipitor for atorvastatin, with satisfactory dissolution similarity factor (f2) values. The pharmacokinetic study showed the sustained and immediate absorptions of metformin and atorvastatin, respectively, in beagle dogs. The 90% confidence intervals of the ratios of ln values of AUCs of test formulation F3 and respective reference formulations of metformin and atorvastatin were 0.93-1.12 and 0.89-1.17, respectively, compared with their respective reference drugs. This formulation could contribute to improving the compliance and therapeutic outcome of patients with metabolic diseases.

Cochlear implant users' spectral ripple resolution.

This study revisits the issue of the spectral ripple resolution abilities of cochlear implant (CI) users. The spectral ripple resolution of recently implanted CI recipients (implanted during the last 10 years) were compared to those of CI recipients implanted 15 to 20 years ago, as well as those of normal-hearing and hearing-impaired listeners from previously published data from Henry, Turner, and Behrens [J. Acoust. Soc. Am. 118, 1111-1121 (2005)]. More recently, implanted CI recipients showed significantly better spectral ripple resolution. There is no significant difference in spectral ripple resolution for these recently implanted subjects compared to hearing-impaired (acoustic) listeners. The more recently implanted CI users had significantly better pre-operative speech perception than previously reported CI users. These better pre-operative speech perception scores in CI users from the current study may be related to better performance on the spectral ripple discrimination task; however, other possible factors such as improvements in internal and external devices cannot be excluded.

Cortical Auditory Evoked Potentials Recorded From Nucleus Hybrid Cochlear Implant Users.

OBJECTIVES: Nucleus Hybrid Cochlear Implant (CI) users hear low-frequency sounds via acoustic stimulation and high-frequency sounds via electrical stimulation. This within-subject study compares three different methods of coordinating programming of the acoustic and electrical components of the Hybrid device. Speech perception and cortical auditory evoked potentials (CAEP) were used to assess differences in outcome. The goals of this study were to determine whether (1) the evoked potential measures could predict which programming strategy resulted in better outcome on the speech perception task or was preferred by the listener, and (2) CAEPs could be used to predict which subjects benefitted most from having access to the electrical signal provided by the Hybrid implant. DESIGN: CAEPs were recorded from 10 Nucleus Hybrid CI users. Study participants were tested using three different experimental processor programs (MAPs) that differed in terms of how much overlap there was between the range of frequencies processed by the acoustic component of the Hybrid device and range of frequencies processed by the electrical component. The study design included allowing participants to acclimatize for a period of up to 4 weeks with each experimental program prior to speech perception and evoked potential testing. Performance using the experimental MAPs was assessed using both a closed-set consonant recognition task and an adaptive test that measured the signal-to-noise ratio that resulted in 50% correct identification of a set of 12 spondees presented in background noise. Long-duration, synthetic vowels were used to record both the cortical P1-N1-P2 "onset" response and the auditory "change" response (also known as the auditory change complex [ACC]). Correlations between the evoked potential measures and performance on the speech perception tasks are reported. RESULTS: Differences in performance using the three programming strategies were not large. Peak-to-peak amplitude of the ACC was not found to be sensitive enough to accurately predict the programming strategy that resulted in the best performance on either measure of speech perception. All 10 Hybrid CI users had residual low-frequency acoustic hearing. For all 10 subjects, allowing them to use both the acoustic and electrical signals provided by the implant improved performance on the consonant recognition task. For most subjects, it also resulted in slightly larger cortical change responses. However, the impact that listening mode had on the cortical change responses was small, and again, the correlation between the evoked potential and speech perception results was not significant. CONCLUSIONS: CAEPs can be successfully measured from Hybrid CI users. The responses that are recorded are similar to those recorded from normal-hearing listeners. The goal of this study was to see if CAEPs might play a role either in identifying the experimental program that resulted in best performance on a consonant recognition task or in documenting benefit from the use of the electrical signal provided by the Hybrid CI. At least for the stimuli and specific methods used in this study, no such predictive relationship was found.

Automatic spinal canal detection in lumbar MR images in the sagittal view using dynamic programming.

As there is an increasing need for the computer-aided effective management of pathology in lumbar spine, we have developed a computer-aided diagnosis and characterization framework using lumbar spine MRI that provides radiologists a second opinion. In this paper, we propose a left spinal canal boundary extraction method, based on dynamic programming in lumbar spine MRI. Our method fuses the absolute intensity difference of T1-weighted and T2-weighted sagittal images and the inverted gradient of the difference image into a dynamic programming scheme and works in a fully automatic fashion. The boundaries generated by our method are compared against reference boundaries in terms of the Euclidean distance and the Chebyshev distance. The experimental results from 85 clinical data show that our methods find the boundary with a mean Euclidean distance of 3mm, achieving a speedup factor of 167 compared with manual landmark extraction. The proposed method successfully extracts landmarks automatically and fits well with our framework for computer-aided diagnosis in lumbar spine.

Metabolic activity on [18f]-fluorodeoxyglucose-positron emission tomography/computed tomography and glucose transporter-1 expression might predict clinical outcomes in patients with limited disease small-cell lung cancer who receive concurrent chemoradiation.

BACKGROUND: Limited disease small-cell lung cancer responds well to concurrent chemoradiation therapy (CCRT), but shows high relapse rate and short RFS. We aimed to evaluate tumor metabolic activities measured using FDG-PET as a prognostic factor and analyze its relationships with markers of tumor biologic behavior. PATIENTS AND METHODS: Forty-one LD-SCLC patients receiving 4 cycles of EP (etoposide 120 mg/m(2), days 1-3; cisplatin 60 mg/m(2), day 1), 2 cycles of EP (etoposide 130 mg/m(2), days 1-3; cisplatin 30 mg/m(2), day 1)-CCRT were enrolled. Maximum standardized uptake value (SUV; SUVmax) of primary tumor was revised with SUV of liver (SUVlivermax). Differences between pre-, posttreatment average SUV uptake of primary tumor, and intrathoracic lymph nodes were presented as ΔSUVliveravg. Thirty-one tumor biopsy specimens were immunostained for GLUT-1, Bcl-2, and HIF-1α. RESULTS: The median overall survival (OS), and RFS were 13.7 and 10.4 months, respectively. In multivariate analysis, pretreatment lactate dehydrogenase (LDH) and ΔSUVliveravg correlated with RFS (hazard ratio [HR], 2.8, P = .043; HR, 0.3, P = .004). Sex, LDH, objective tumor metabolic response, and SUVlivermax correlated with OS (HR, 12.1, P = .006; HR, 3.7, P = .037; HR, 10.1, P = .008; and HR, 0.2, P = .014, respectively). High GLUT-1 positivity (> 75%), and LDH level (> 400 U/L) correlated with better objective response rate (P = .012) and HIF-1α immunoreactivity score (P = .029). CONCLUSION: ΔSUVliveravg and GLUT-1 expression might predict RFS and ORR in patients with LD-SCLC treated with definitive CCRT.

Mussel-inspired green synthesis of silver nanoparticles on graphene oxide nanosheets for enhanced catalytic applications.

We report a facile green approach to the synthesis of silver nanoparticles (Ag NPs) on the surface of graphene oxide nanosheets functionalized with mussel-inspired dopamine (GO-Dopa) without additional reductants or stabilizers at room temperature. The resulting hybrid Ag/GO-Dopa exhibits good dispersity and excellent catalytic activity in the reduction of nitroarenes.

Optimizing the combination of acoustic and electric hearing in the implanted ear.

OBJECTIVES: The aim of this study was to determine an optimal approach to program combined acoustic plus electric (A+E) hearing devices in the same ear to maximize speech-recognition performance. DESIGN: Ten participants with at least 1 year of experience using Nucleus Hybrid (short electrode) A+E devices were evaluated across three different fitting conditions that varied in the frequency ranges assigned to the acoustically and electrically presented portions of the spectrum. Real-ear measurements were used to optimize the acoustic component for each participant, and the acoustic stimulation was then held constant across conditions. The lower boundary of the electric frequency range was systematically varied to create three conditions with respect to the upper boundary of the acoustic spectrum: Meet, Overlap, and Gap programming. Consonant recognition in quiet and speech recognition in competing-talker babble were evaluated after participants were given the opportunity to adapt by using the experimental programs in their typical everyday listening situations. Participants provided subjective ratings and evaluations for each fitting condition. RESULTS: There were no significant differences in performance between conditions (Meet, Overlap, Gap) for consonant recognition in quiet. A significant decrement in performance was measured for the Overlap fitting condition for speech recognition in babble. Subjective ratings indicated a significant preference for the Meet fitting regimen. CONCLUSIONS: Participants using the Hybrid ipsilateral A+E device generally performed better when the acoustic and electric spectra were programmed to meet at a single frequency region, as opposed to a gap or overlap. Although there is no particular advantage for the Meet fitting strategy for recognition of consonants in quiet, the advantage becomes evident for speech recognition in competing-talker babble and in patient preferences.

Optical switching of the Dirac point in graphene multilayer field-effect transistors functionalized with spiropyran.

A facile method for achieving optical switching of the Dirac point and conductance in reduced graphene oxide multilayer FETs that are non-covalently functionalized with a photo-responsive spiropyran derivative is presented. The photoresponsive transition from spiropyran to merocyanine induces the reversible optical switching in graphene based FETs.

Reversibly light-modulated dirac point of graphene functionalized with spiropyran.

Graphene has been functionalized with spiropyran (SP), a well-known photochromic molecule. It has been realized with pyrene-modified SP, which has been adsorbed on graphene by π-π interaction between pyrene and graphene. The field-effect transistor (FET) with SP-functionalized graphene exhibited n-doping effect and interesting optoelectronic behaviors. The Dirac point of graphene in the FET could be controlled by light modulation because spiropyran can be reversibly switched between two different conformations, a neutral form (colorless SP) and a charge-separated form (purple colored merocyanine, MC), on UV and visible light irradiation. The MC form is produced during UV light irradiation, inducing the shift of the Dirac point of graphene toward negative gate voltage. The reverse process back to the neutral SP form occurred under visible light irradiation or in darkness, inducing a shift of the Dirac point toward positive gate voltage. The change of the Dirac point by UV and visible light was reproducibly repeated. SP molecules also improved the conductance change in the FET device. Furthermore, dynamics on conversion from MC to SP on graphene was different from that in solution and solid samples with SP-grafted polymer or that on gold nanoparticles.

ERCC1 (excision repair cross-complementation group 1) expression as a predictor for response of neoadjuvant chemotherapy for FIGO stage 2B uterine cervix cancer.

OBJECTIVE: Platinum-based neoadjuvant chemotherapy for locally advanced cervical cancer has some benefits for patients responding to chemotherapy. However, no validated clinical or biologic predictor of response to this chemotherapy has been identified to date. METHODS: We employ immunohistochemical analysis to determine the expression patterns of the excision repair cross-complementation group1 (ERCC1) protein in pre-treatment cervical biopsy tissue. In total, 43 stage IIB patients had been enrolled in a previous etoposide and cisplatin neoadjuvant phase II clinical trial, allowing comparison of the effects of cisplatin-based neoadjuvant chemotherapy on response in relation to ERCC1 expression. RESULTS: Among the 43 patients studied, 34 (79.1%) were positive and 9 (20.9%) were negative for ERCC1. Response to chemotherapy (according to RECIST criteria) was observed in all patients with negative ERCC1 expression. In logistic regression analysis, ERCC1 negativity continued to be an independent predictor for responsiveness to neoadjuvant chemotherapy (p=0.021). Among the pretreatment factors, low ERCC1 expression was a significant prognostic factor of disease-free survival in multivariate analysis (p=0.046). CONCLUSIONS: The ERCC1 expression patterns in pretreatment specimens may thus facilitate the prediction of responses to cisplatin-based NAC. We propose that patients expressing low levels of ERCC1 derive the most benefit from cisplatin-based NAC.

Comparison of electrically evoked compound action potential thresholds and loudness estimates for the stimuli used to program the Advanced Bionics cochlear implant.

BACKGROUND: In the mid-1990s, Cochlear Corporation introduced a cochlear implant (CI) to the market that was equipped with hardware that made it possible to record electrically evoked compound action potentials (ECAPs) from CI users of all ages. Over the course of the next decade, many studies were published that compared ECAP thresholds with levels used to program the speech processor of the Nucleus CI. In 2001 Advanced Bionics Corporation introduced the Clarion CII cochlear implant (the Clarion CII internal device is also known as the CII Bionic Ear). This cochlear implant was also equipped with a system that allowed measurement of the ECAP. While a great deal is known about how ECAP thresholds compare with the levels used to program the speech processor of the Nucleus CI, relatively few studies have reported comparisons between ECAP thresholds and the levels used to program the speech processor of the Advanced Bionics CI. PURPOSE: To explore the relationship between ECAP thresholds and behavioral measures of perceptual dynamic range for the range of stimuli commonly used to program the speech processor of the Advanced Bionics CI. RESEARCH DESIGN: This prospective and experimental study uses correlational and descriptive statistics to define the relationship between ECAP thresholds and perceptual dynamic range measures. STUDY SAMPLE: Twelve postlingually deafened adults participated in this study. All were experienced users of the Advanced Bionics CI system. DATA COLLECTION AND ANALYSIS: ECAP thresholds were recorded using the commercially available SoundWave software. Perceptual measures of threshold (T-level), most comfortable level (M-level), and maximum comfortable level (C-level) were obtained using both "tone bursts" and "speech bursts." The relationship between these perceptual and electrophysiological variables was defined using paired t-tests as well as correlation and linear regression. RESULTS: ECAP thresholds were significantly correlated with the perceptual dynamic range measures studied; however, correlations were not strong. Analysis of the individual data revealed considerable discrepancy between the contour of ECAP threshold versus electrode function and the behavioral loudness estimates used for programming. CONCLUSION: ECAP thresholds recorded from Advanced Bionics cochlear implant users always indicated levels where the programming stimulus was audible for the listener. However, the correlation between ECAP thresholds and M-levels (the primary metric used to program the speech processor of the Advanced Bionics CI), while statistically significant, was quite modest. If programming levels are to be determined on the basis of ECAP thresholds, care should be taken to ensure that stimulation is not uncomfortably loud, particularly on the basal electrodes in the array.