Multicenter study with a direct acoustic cochlear implant

OBJECTIVE To confirm the clinical efficacy and safety of a direct acoustic cochlear implant. STUDY DESIGN Prospective multicenter study. SETTING The study was performed at 3 university hospitals in Europe (Germany, The Netherlands, and Switzerland). PATIENTS Fifteen patients with severe-to-profound mixed hearing loss because of otosclerosis or previous failed stapes surgery. INTERVENTION Implantation with a Codacs direct acoustic cochlear implant investigational device (ID) combined with a stapedotomy with a conventional stapes prosthesis MAIN OUTCOME MEASURES Preoperative and postoperative (3 months after activation of the investigational direct acoustic cochlear implant) audiometric evaluation measuring conventional pure tone and speech audiometry, tympanometry, aided thresholds in sound field and hearing difficulty by the Abbreviated Profile of Hearing Aid Benefit questionnaire. RESULTS The preoperative and postoperative air and bone conduction thresholds did not change significantly by the implantation with the investigational Direct Acoustic Cochlear Implant. The mean sound field thresholds (0.25-8 kHz) improved significantly by 48 dB. The word recognition scores (WRS) at 50, 65, and 80 dB SPL improved significantly by 30.4%, 75%, and 78.2%, respectively, after implantation with the investigational direct acoustic cochlear implant compared with the preoperative unaided condition. The difficulty in hearing, measured by the Abbreviated Profile of Hearing Aid Benefit, decreased by 27% after implantation with the investigational direct acoustic cochlear implant. CONCLUSION Patients with moderate-to-severe mixed hearing loss because of otosclerosis can benefit substantially using the Codacs investigational device.

In vitro accuracy evaluation of image-guided robot system for direct cochlear access

HYPOTHESIS A previously developed image-guided robot system can safely drill a tunnel from the lateral mastoid surface, through the facial recess, to the middle ear, as a viable alternative to conventional mastoidectomy for cochlear electrode insertion. BACKGROUND Direct cochlear access (DCA) provides a minimally invasive tunnel from the lateral surface of the mastoid through the facial recess to the middle ear for cochlear electrode insertion. A safe and effective tunnel drilled through the narrow facial recess requires a highly accurate image-guided surgical system. Previous attempts have relied on patient-specific templates and robotic systems to guide drilling tools. In this study, we report on improvements made to an image-guided surgical robot system developed specifically for this purpose and the resulting accuracy achieved in vitro. MATERIALS AND METHODS The proposed image-guided robotic DCA procedure was carried out bilaterally on 4 whole head cadaver specimens. Specimens were implanted with titanium fiducial markers and imaged with cone-beam CT. A preoperative plan was created using a custom software package wherein relevant anatomical structures of the facial recess were segmented, and a drill trajectory targeting the round window was defined. Patient-to-image registration was performed with the custom robot system to reference the preoperative plan, and the DCA tunnel was drilled in 3 stages with progressively longer drill bits. The position of the drilled tunnel was defined as a line fitted to a point cloud of the segmented tunnel using principle component analysis (PCA function in MatLab). The accuracy of the DCA was then assessed by coregistering preoperative and postoperative image data and measuring the deviation of the drilled tunnel from the plan. The final step of electrode insertion was also performed through the DCA tunnel after manual removal of the promontory through the external auditory canal. RESULTS Drilling error was defined as the lateral deviation of the tool in the plane perpendicular to the drill axis (excluding depth error). Errors of 0.08 ± 0.05 mm and 0.15 ± 0.08 mm were measured on the lateral mastoid surface and at the target on the round window, respectively (n =8). Full electrode insertion was possible for 7 cases. In 1 case, the electrode was partially inserted with 1 contact pair external to the cochlea. CONCLUSION The purpose-built robot system was able to perform a safe and reliable DCA for cochlear implantation. The workflow implemented in this study mimics the envisioned clinical procedure showing the feasibility of future clinical implementation.

Feasibility of Using EMG for Early Detection of the Facial Nerve During Robotic Direct Cochlear Access

HYPOTHESIS Facial nerve monitoring can be used synchronous with a high-precision robotic tool as a functional warning to prevent of a collision of the drill bit with the facial nerve during direct cochlear access (DCA). BACKGROUND Minimally invasive direct cochlear access (DCA) aims to eliminate the need for a mastoidectomy by drilling a small tunnel through the facial recess to the cochlea with the aid of stereotactic tool guidance. Because the procedure is performed in a blind manner, structures such as the facial nerve are at risk. Neuromonitoring is a commonly used tool to help surgeons identify the facial nerve (FN) during routine surgical procedures in the mastoid. Recently, neuromonitoring technology was integrated into a commercially available drill system enabling real-time monitoring of the FN. The objective of this study was to determine if this drilling system could be used to warn of an impending collision with the FN during robot-assisted DCA. MATERIALS AND METHODS The sheep was chosen as a suitable model for this study because of its similarity to the human ear anatomy. The same surgical workflow applicable to human patients was performed in the animal model. Bone screws, serving as reference fiducials, were placed in the skull near the ear canal. The sheep head was imaged using a computed tomographic scanner and segmentation of FN, mastoid, and other relevant structures as well as planning of drilling trajectories was carried out using a dedicated software tool. During the actual procedure, a surgical drill system was connected to a nerve monitor and guided by a custom built robot system. As the planned trajectories were drilled, stimulation and EMG response signals were recorded. A postoperative analysis was achieved after each surgery to determine the actual drilled positions. RESULTS Using the calibrated pose synchronized with the EMG signals, the precise relationship between distance to FN and EMG with 3 different stimulation intensities could be determined for 11 different tunnels drilled in 3 different subjects. CONCLUSION From the results, it was determined that the current implementation of the neuromonitoring system lacks sensitivity and repeatability necessary to be used as a warning device in robotic DCA. We hypothesize that this is primarily because of the stimulation pattern achieved using a noninsulated drill as a stimulating probe. Further work is necessary to determine whether specific changes to the design can improve the sensitivity and specificity.

Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer

Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.

MiR-205 is progressively down-regulated in lymph node metastasis but fails as a prognostic biomarker in high-risk prostate cancer

The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.

The Science of Exoplanets and Their Systems

A scientific forum on “The Future Science of Exoplanets and Their Systems,” sponsored by Europlanet* and the International Space Science Institute (ISSI)† and co-organized by the Center for Space and Habitability (CSH)‡ of the University of Bern, was held during December 5 and 6, 2012, in Bern, Switzerland. It gathered 24 well-known specialists in exoplanetary, Solar System, and stellar science to discuss the future of the fast-expanding field of exoplanetary research, which now has nearly 1000 objects to analyze and compare and will develop even more quickly over the coming years. The forum discussions included a review of current observational knowledge, efforts for exoplanetary atmosphere characterization and their formation, water formation, atmospheric evolution, habitability aspects, and our understanding of how exoplanets interact with their stellar and galactic environment throughout their history. Several important and timely research areas of focus for further research efforts in the field were identified by the forum participants. These scientific topics are related to the origin and formation of water and its delivery to planetary bodies and the role of the disk in relation to planet formation, including constraints from observations as well as star-planet interaction processes and their consequences for atmosphere-magnetosphere environments, evolution, and habitability. The relevance of these research areas is outlined in this report, and possible themes for future ISSI workshops are identified that may be proposed by the international research community over the coming 2–3 years.

Diffusive equilibration of N2, O2 and CO2 mixing ratios in a 1.5-million-years-old ice core

In the framework of the International Partnerships in Ice Core Sciences, one of the most important targets is to retrieve an Antarctic ice core that extends over the last 1.5 million years (i.e. an ice core that enters the climate era when glacial–interglacial cycles followed the obliquity cycles of the earth). In such an ice core the annual layers of the oldest ice would be thinned by a factor of about 100 and the climatic information of a 10 000 yr interval would be contained in less than 1 m of ice. The gas record in such an Antarctic ice core can potentially reveal the role of greenhouse gas forcing on these 40 000 yr cycles. However, besides the extreme thinning of the annual layers, also the long residence time of the trapped air in the ice and the relatively high ice temperatures near the bedrock favour diffusive exchanges. To investigate the changes in the O2 / N2 ratio, as well as the trapped CO2 concentrations, we modelled the diffusive exchange of the trapped gases O2, N2 and CO2 along the vertical axis. However, the boundary conditions of a potential drilling site are not yet well constrained and the uncertainties in the permeation coefficients of the air constituents in the ice are large. In our simulations, we have set the drill site ice thickness at 2700 m and the bedrock ice temperature at 5–10 K below the ice pressure melting point. Using these conditions and including all further uncertainties associated with the drill site and the permeation coefficients, the results suggest that in the oldest ice the precessional variations in the O2 / N2 ratio will be damped by 50–100%, whereas CO2 concentration changes associated with glacial–interglacial variations will likely be conserved (simulated damping 5%). If the precessional O2 / N2 signal will have disappeared completely in this future ice core, orbital tuning of the ice-core age scale will be limited.

Impact of an abrupt cooling event on interglacial methane emissions in northern peatlands

Rapid changes in atmospheric methane (CH4), temperature and precipitation are documented by Greenland ice core data both for glacial times (the so called Dansgaard-Oeschger (D-O) events) as well as for a cooling event in the early Holocene (the 8.2 kyr event). The onsets of D-O warm events are paralleled by abrupt increases in CH4 by up to 250 ppb in a few decades. Vice versa, the 8.2 kyr event is accompanied by an intermittent decrease in CH4 of about 80 ppb over 150 yr. The abrupt CH4 changes are thought to mainly originate from source emission variations in tropical and boreal wet ecosystems, but complex process oriented bottom-up model estimates of the changes in these ecosystems during rapid climate changes are still missing. Here we present simulations of CH4 emissions from northern peatlands with the LPJ-Bern dynamic global vegetation model. The model represents CH4 production and oxidation in soils and transport by ebullition, through plant aerenchyma, and by diffusion. Parameters are tuned to represent site emission data as well as inversion-based estimates of northern wetland emissions. The model is forced with climate input data from freshwater hosing experiments using the NCAR CSM1.4 climate model to simulate an abrupt cooling event. A concentration reduction of ~10 ppb is simulated per degree K change of mean northern hemispheric surface temperature in peatlands. Peatland emissions are equally sensitive to both changes in temperature and in precipitation. If simulated changes are taken as an analogy to the 8.2 kyr event, boreal peatland emissions alone could only explain 23 of the 80 ppb decline in atmospheric methane concentration. This points to a significant contribution to source changes from low latitude and tropical wetlands to this event.

A centrifugal ice microtome for measurements of atmospheric CO₂ on air trapped in polar ice cores

For atmospheric CO2 reconstructions using ice cores, the technique to release the trapped air from the ice samples is essential for the precision and accuracy of the measurements. We present here a new dry extraction technique in combination with a new gas analytical system that together show significant improvements with respect to current systems. Ice samples (3–15 g) are pulverised using a novel centrifugal ice microtome (CIM) by shaving the ice in a cooled vacuum chamber (−27 °C) in which no friction occurs due to the use of magnetic bearings. Both, the shaving principle of the CIM and the use of magnetic bearings have not been applied so far in this field. Shaving the ice samples produces finer ice powder and releases a minimum of 90% of the trapped air compared to 50%–70% when needle crushing is employed. In addition, the friction-free motion with an optimized design to reduce contaminations of the inner surfaces of the device result in a reduced system offset of about 2.0 ppmv compared to 4.9 ppmv. The gas analytical part shows a higher precision than the corresponding part of our previous system by a factor of two, and all processes except the loading and cleaning of the CIM now run automatically. Compared to our previous system, the complete system shows a 3 times better measurement reproducibility of about 1.1 ppmv (1 σ) which is similar to the best reproducibility of other systems applied in this field. With this high reproducibility, no replicate measurements are required anymore for most future measurement campaigns resulting in a possible output of 12–20 measurements per day compared to a maximum of 6 with other systems.

The response of atmospheric nitrous oxide to climate variations during the last glacial period

Detailed insight into natural variations of the greenhouse gas nitrous oxide (N2O) in response to changes in the Earth's climate system is provided by new measurements along the ice core of the North Greenland Ice Core Project (NGRIP). The presented record reaches from the early Holocene back into the previous interglacial with a mean time resolution of about 75 years. Between 11 and 120 kyr BP, atmospheric N2O concentrations react substantially to the last glacial-interglacial transition (Termination 1) and millennial time scale climate variations of the last glacial period. For long-lasting Dansgaard/Oeschger (DO) events, the N2O increase precedes Greenland temperature change by several hundred years with an increase rate of about 0.8-1.3 ppbv/century, which accelerates to about 3.8-10.7 ppbv/century at the time of the rapid warming in Greenland. Within each bundle of DO events, the new record further reveals particularly low N2O concentrations at the approximate time of Heinrich events. This suggests that the response of marine and/or terrestrial N2O emissions on a global scale are different for stadials with and without Heinrich events.

Direct linking of Greenland and Antarctic ice cores at the Toba eruption (74 ka BP)

The Toba eruption that occurred some 74 ka ago in Sumatra, Indonesia, is among the largest volcanic events on Earth over the last 2 million years. Tephra from this eruption has been spread over vast areas in Asia, where it constitutes a major time marker close to the Marine Isotope Stage 4/5 boundary. As yet, no tephra associated with Toba has been identified in Greenland or Antarctic ice cores. Based on new accurate dating of Toba tephra and on accurately dated European stalagmites, the Toba event is known to occur between the onsets of Greenland interstadials (GI) 19 and 20. Furthermore, the existing linking of Greenland and Antarctic ice cores by gas records and by the bipolar seesaw hypothesis suggests that the Antarctic counterpart is situated between Antarctic Isotope Maxima (AIM) 19 and 20. In this work we suggest a direct synchronization of Greenland (NGRIP) and Antarctic (EDML) ice cores at the Toba eruption based on matching of a pattern of bipolar volcanic spikes. Annual layer counting between volcanic spikes in both cores allows for a unique match. We first demonstrate this bipolar matching technique at the already synchronized Laschamp geomagnetic excursion (41 ka BP) before we apply it to the suggested Toba interval. The Toba synchronization pattern covers some 2000 yr in GI-20 and AIM-19/20 and includes nine acidity peaks that are recognized in both ice cores. The suggested bipolar Toba synchronization has decadal precision. It thus allows a determination of the exact phasing of inter-hemispheric climate in a time interval of poorly constrained ice core records, and it allows for a discussion of the climatic impact of the Toba eruption in a global perspective. The bipolar linking gives no support for a long-term global cooling caused by the Toba eruption as Antarctica experiences a major warming shortly after the event. Furthermore, our bipolar match provides a way to place palaeo-environmental records other than ice cores into a precise climatic context.

Continuous Flow Analysis of labile iron in ice-cores

The important active and passive role of mineral dust aerosol in the climate and the global carbon cycle over the last glacial/interglacial cycles has been recognized. However, little data on the most important aeolian dust-derived biological micronutrient, iron (Fe), has so far been available from ice-cores from Greenland or Antarctica. Furthermore, Fe deposition reconstructions derived from the palaeoproxies particulate dust and calcium differ significantly from the Fe flux data available. The ability to measure high temporal resolution Fe data in polar ice-cores is crucial for the study of the timing and magnitude of relationships between geochemical events and biological responses in the open ocean. This work adapts an existing flow injection analysis (FIA) methodology for low-level trace Fe determinations with an existing glaciochemical analysis system, continuous flow analysis (CFA) of ice-cores. Fe-induced oxidation of N,N′-dimethyl-p-pheylenediamine (DPD) is used to quantify the biologically more important and easily leachable Fe fraction released in a controlled digestion step at pH ∼1.0. The developed method was successfully applied to the determination of labile Fe in ice-core samples collected from the Antarctic Byrd ice-core and the Greenland Ice-Core Project (GRIP) ice-core.

A reconstruction of atmospheric carbon dioxide and its stable carbon isotopic composition from the penultimate glacial maximum to the last glacial inception

The reconstruction of the stable carbon isotope evolution in atmospheric CO2 (δ13Catm), as archived in Antarctic ice cores, bears the potential to disentangle the contributions of the different carbon cycle fluxes causing past CO2 variations. Here we present a new record of δ13Catm before, during and after the Marine Isotope Stage 5.5 (155 000 to 105 000 yr BP). The dataset is archived on the data repository PANGEA® (www.pangea.de) under 10.1594/PANGAEA.817041. The record was derived with a well established sublimation method using ice from the EPICA Dome C (EDC) and the Talos Dome ice cores in East Antarctica. We find a 0.4‰ shift to heavier values between the mean δ13Catm level in the Penultimate (~ 140 000 yr BP) and Last Glacial Maximum (~ 22 000 yr BP), which can be explained by either (i) changes in the isotopic composition or (ii) intensity of the carbon input fluxes to the combined ocean/atmosphere carbon reservoir or (iii) by long-term peat buildup. Our isotopic data suggest that the carbon cycle evolution along Termination II and the subsequent interglacial was controlled by essentially the same processes as during the last 24 000 yr, but with different phasing and magnitudes. Furthermore, a 5000 yr lag in the CO2 decline relative to EDC temperatures is confirmed during the glacial inception at the end of MIS5.5 (120 000 yr BP). Based on our isotopic data this lag can be explained by terrestrial carbon release and carbonate compensation.

Independent variations of CH₄ emissions and isotopic composition over the past 160,000 years

During the last glacial cycle, greenhouse gas concentrations fluctuated on decadal and longer timescales. Concentrations of methane, as measured in polar ice cores, show a close connection with Northern Hemisphere temperature variability, but the contribution of the various methane sources and sinks to changes in concentration is still a matter of debate. Here we assess changes in methane cycling over the past 160,000 years by measurements of the carbon isotopic composition delta C-13 of methane in Antarctic ice cores from Dronning Maud Land and Vostok. We find that variations in the delta C-13 of methane are not generally correlated with changes in atmospheric methane concentration, but instead more closely correlated to atmospheric CO2 concentrations. We interpret this to reflect a climatic and CO2-related control on the isotopic signature of methane source material, such as ecosystem shifts in the seasonally inundated tropical wetlands that produce methane. In contrast, relatively stable delta C-13 values occurred during intervals of large changes in the atmospheric loading of methane. We suggest that most methane sources-most notably tropical wetlands-must have responded simultaneously to climate changes across these periods.