Computational evaluation of cochlear implant surgery outcomes accounting for uncertainty and parameter variability

Cochlear implantation (CI) is a complex surgical procedure that restores hearing in patients with severe deafness. The successful outcome of the implanted device relies on a group of factors, some of them unpredictable or difficult to control. Uncertainties on the electrode array position and the electrical properties of the bone make it difficult to accurately compute the current propagation delivered by the implant and the resulting neural activation. In this context, we use uncertainty quantification methods to explore how these uncertainties propagate through all the stages of CI computational simulations. To this end, we employ an automatic framework, encompassing from the finite element generation of CI models to the assessment of the neural response induced by the implant stimulation. To estimate the confidence intervals of the simulated neural response, we propose two approaches. First, we encode the variability of the cochlear morphology among the population through a statistical shape model. This allows us to generate a population of virtual patients using Monte Carlo sampling and to assign to each of them a set of parameter values according to a statistical distribution. The framework is implemented and parallelized in a High Throughput Computing environment that enables to maximize the available computing resources. Secondly, we perform a patient-specific study to evaluate the computed neural response to seek the optimal post-implantation stimulus levels. Considering a single cochlear morphology, the uncertainty in tissue electrical resistivity and surgical insertion parameters is propagated using the Probabilistic Collocation method, which reduces the number of samples to evaluate. Results show that bone resistivity has the highest influence on CI outcomes. In conjunction with the variability of the cochlear length, worst outcomes are obtained for small cochleae with high resistivity values. However, the effect of the surgical insertion length on the CI outcomes could not be clearly observed, since its impact may be concealed by the other considered parameters. Whereas the Monte Carlo approach implies a high computational cost, Probabilistic Collocation presents a suitable trade-off between precision and computational time. Results suggest that the proposed framework has a great potential to help in both surgical planning decisions and in the audiological setting process

The cGMP-Dependent Protein Kinase II Is an Inhibitory Modulator of the Hyperpolarization-Activated HCN2 Channel

Opening of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is facilitated by direct binding of cyclic nucleotides to a cyclic nucleotide-binding domain (CNBD) in the C-terminus. Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated phosphorylation. Using coimmunoprecipitation and immunohistochemistry we demonstrate that cGKII and HCN2 interact and colocalize with each other upon heterologous expression as well as in native mouse brain. We identify the proximal C-terminus of HCN2 as binding region of cGKII and show that cGKII phosphorylates HCN2 at a specific serine residue (S641) in the C-terminal end of the CNBD. The cGKII shifts the voltage-dependence of HCN2 activation to 2–5 mV more negative voltages and, hence, counteracts the stimulatory effect of cGMP on gating. The inhibitory cGMP effect can be either abolished by mutation of the phosphorylation site in HCN2 or by impairing the catalytic domain of cGKII. By contrast, the inhibitory effect is preserved in a HCN2 mutant carrying a CNBD deficient for cGMP binding. Our data suggest that bidirectional regulation of HCN2 gating by cGMP contributes to cellular fine-tuning of HCN channel activity

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): And randomised, phase 3, open-label, multicentre study

Background: Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m2; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Findings: Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival was 18·7 months (95% CI 15·6-not estimable) in the carfilzomib group versus 9·4 months (8·4-10·4) in the bortezomib group at a preplanned interim analysis (hazard ratio [HR] 0·53 [95% CI 0·44-0·65]; p<0·0001). On-study death due to adverse events occurred in 18 (4%) of 464 patients in the carfilzomib group and in 16 (3%) of 465 patients in the bortezomib group. Serious adverse events were reported in 224 (48%) of 463 patients in the carfilzomib group and in 162 (36%) of 456 patients in the bortezomib group. The most frequent grade 3 or higher adverse events were anaemia (67 [14%] of 463 patients in the carfilzomib group vs 45 [10%] of 456 patients in the bortezomib group), hypertension (41 [9%] vs 12 [3%]), thrombocytopenia (39 [8%] vs 43 [9%]), and pneumonia (32 [7%] vs 36 [8%]). Interpretation: For patients with relapsed or refractory multiple myeloma, carfilzomib with dexamethasone could be considered in cases in which bortezomib with dexamethasone is a potential treatment option. Funding: Onyx Pharmaceuticals, Inc., an Amgen subsidiary

ATP-Evoked Intracellular Ca Signaling of Different Supporting Cells in the Hearing Mouse Hemicochlea

Hearing and its protection is regulated by ATP-evoked Ca2+ signaling in the supporting cells of the organ of Corti, however, the unique anatomy of the cochlea hampers observing these mechanisms. For the first time, we have performed functional ratiometric Ca2+ imaging (fura-2) in three different supporting cell types in the hemicochlea preparation of hearing mice to measure purinergic receptor-mediated Ca2+ signaling in pillar, Deiters' and Hensen's cells. Their resting [Ca2+]i was determined and compared in the same type of preparation. ATP evoked reversible, repeatable and dose-dependent Ca2+ transients in all three cell types, showing desensitization. Inhibiting the Ca2+ signaling of the ionotropic P2X (omission of extracellular Ca2+) and metabotropic P2Y purinergic receptors (depletion of intracellular Ca2+ stores) revealed the involvement of both receptor types. Detection of P2X2,3,4,6,7 and P2Y1,2,6,12,14 receptor mRNAs by RT-PCR supported this finding and antagonism by PPADS suggested different functional purinergic receptor population in pillar versus Deiters' and Hensen's cells. The sum of the extra- and intracellular Ca2+-dependent components of the response was about equal with the control ATP response (linear additivity) in pillar cells, and showed supralinearity in Deiters' and Hensen's cells. Calcium-induced calcium release might explain this synergistic interaction. The more pronounced Ca2+ leak from the endoplasmic reticulum in Deiters' and Hensen's cells, unmasked by cyclopiazonic acid, may also suggests the higher activity of the internal stores in Ca2+ signaling in these cells. Differences in Ca2+ homeostasis and ATP-induced Ca2+ signaling might reflect the distinct roles these cells play in cochlear function and pathophysiology

A Homology Model of the Pore Region of HCN channels

HCN channels are activated by membrane hyperpolarization and regulated by cyclic nucleotides, such as cyclic adenosine-mono-phosphate (cAMP). Here we present structural models of the pore region of these channels obtained by using homology modeling and validated against spatial constraints derived from electrophysiological experiments. For the construction of the models we make two major assumptions, justified by electrophysiological observations: i), in the closed state, the topology of the inner pore of HCN channels is similar to that of K(+) channels. In particular, the orientation of the S5 and S6 helices of HCN channels is very similar to that of the corresponding helices of the K(+) KcsA and K(+) KirBac1.1 channels. Thus, we use as templates the x-ray structure of these K(+) channels. ii), In the open state, the S6 helix is bent further than it is in the closed state, as suggested (but not proven) by experimental data. For this reason, the template of the open conformation is the x-ray structure of the MthK channel. The structural models of the closed state turn out to be consistent with all the available electrophysiological data. The model of the open state turned out to be consistent with all the available electrophysiological data in the filter region, including additional experimental data performed in this work. However, it required the introduction of an appropriate, experimentally derived constraint for the S6 helix. Our modeling provides a structural framework for understanding several functional properties of HCN channels: i), the cysteine ring at the inner mouth of the pore may act as a sensor of the intracellular oxidizing/reducing conditions; ii), the bending amplitude of the S6 helix upon gating appears to be significantly smaller than that found in MthK channels; iii), the reduced ionic selectivity of HCN channels, relative to that of K(+) channels, may be caused, at least in part, by the larger flexibility of the inner pore of HCN channels

Conclusions

The preceding chapters in this book address a plethora of intriguing challenges, all directed towards bridging the gap between requirements engineering and architecture. These challenges, put together, capture a large part of the problem space currently faced by architects and requirements engineers alike. We review the various challenges that have been discussed in the preceding chapters. We present an abstracted form of the emerging trends that have been identified to deal with these challenges, referring back to individual chapters in order to exemplify them

Spectroscopic ellipsometry characterization of ZnO:Sn thin films with various Sn composition deposited by remote-plasma reactive sputtering

ZnO:Sn thin films were deposited onto thermally oxidized silicon substrates using a remote plasma reactive sputtering. Their optical constants (refractive index . n and extinction coefficient k) were determined from ellipsometric data recorded over a wide spectral range (0.05-6. eV). Parametrization of ZnO:Sn complex dielectric permittivity consists of a parameterized semiconductor oscillator function describing the short wavelength absorption edge, a Drude oscillator describing free carrier absorption in near-infrared part of spectra and a Lorentz oscillator describing the long wavelength absorption edge and intra-band absorption in the ultra-violet part of the spectra. Using a Mott-Davis model, the increase in local disorder with increasing Sn doping is quantified from the short wavelength absorption edge onset. Using the Wemple-DiDomenico single oscillator model for the transparent part of the optical constants spectra, an increase in the centroid distance of the valence and conduction bands with increasing Sn doping is shown and only slight increase in intensity of the inter-band optical transition due to Sn doping occurs. The Drude model applied in the near-infrared part of the spectra revealed the free carrier concentration and mobility of ZnO:Sn. Results show that the range of transparency of prepared ZnO:Sn layers is not dramatically affected by Sn doping whereas electrical conductivity could be controlled by Sn doping. Refractive index in the transparent part is comparable with amorphous Indium Gallium Zinc Oxide allowing utilization of prepared ZnO:Sn layers as an indium-free alternative.Authors appreciate financial support from the grant CZ.1.05/4.1.00/11.0251 from the Ministry of Education, Youth and Sports of the Czech Republic