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Kasper Bruun Kristensen,1 Lars Christian Lund,1 Peter Bjødstrup Jensen,1 Anne Broe,1 Emelie Rotbain,2 Per Damkier,1,3,4 Anton Pottegård,1 Jacob Harbo Andersen,1 Mikkel Højlund,1,5 Morten Olesen,1 Lotte Rasmussen,1 Morten Rix Hansen,1,3,4 Martin Thomsen Ernst,1 Rikke Wesselhoeft,1,6 Daniel Pilsgaard Henriksen,3 Mette Reilev,1 Mette Bliddal,1,7 Jesper Hallas1 1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark; 6Child and Adolescent Psychiatry Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark; 7Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Jesper Hallas, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, Odense, 5000, Denmark, Tel +4565503010, Email jhallas@health.sdu.dkPurpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices.Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥ 40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables.Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883– 0.890) exceeded that of the CCI (0.871, 95% CI 0.868– 0.874) and ECI (0.866, 95% CI 0.863– 0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779– 0.784) to 0.838 (95% CI 0.834– 0.842).Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.Keywords: multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score

Si-based anodes can increase specific energy and energy density of Li ion batteries. However, the volume-induced material stress and capacity loss necessitates only a partial Si utilization within composite anodes, typically with state-of-the-art graphite, so called Si/Gr composites. In this work, various Si nanowires (SiNWs), a promising Si architecture for these composites, are investigated and modified via pre-lithiation. Though, charged pre-lithiated anodes show potentials below 0 V vs. Li|Li+ in the initial cycles, they do not show indications for metallic Li, which is likely a hint for a triggered surface Li depletion in course of a continuous "transfer-lithiation" from lithiated Gr to Si, which is indicated by decreasing LiC6 and increasing LixSiy signals via nuclear magnetic resonance (NMR), X-ray diffraction (XRD) as well as shifts in capacities of respective voltage plateaus during discharge after storage. A relevant contribution of self-discharge is unlikely as shown by a stable open-circuit-voltage during storage in charged state and similar subsequent discharge capacities, being consequently also a hint for an intra-electrode capacity shift. The process of transfer lithiation is finally validated via solid-state 7Li NMR for varied Si morphology, i.e., amorphous and crystalline, as well as during pre-lithiation with passivated lithium metal powder (PLMP)., (© 2024 Wiley‐VCH GmbH.)

The inflammatory foreign body response (FBR) following cochlear implantation (CI) can negatively impact CI outcomes, including increased electrode impedances. This study aims to investigate the long-term efficacy of dexamethasone eluting cochlear implant and locally delivered dexamethasone, a potent anti-inflammatory glucocorticoid on the intracochlear FBR and electrical impedance post-implantation in a murine model and human subjects. The left ears of CX3CR1 +/GFP Thy1 +/YFP (macrophage-neuron dual reporter) mice were implanted with dexamethasone-eluting cochlear implants (Dex-CI) or standard implant (Standard-CI) while the right ear served as unoperated control. Another group of dual reporter mice was implanted with a standard CI electrode array followed by injection of dexamethasone in the middle ear to mimic current clinical practice (Dex-local). Mouse implants were electrically stimulated with serial measurement of electrical impedance. Human subjects were implanted with either standard or Dex-CI followed by serial impedance measurements. Dex-CI reduced electrical impedance in the murine model and human subjects and inflammatory FBR in the murine model for an extended period. Dex-local in the murine model is ineffective for long-term reduction of FBR and electrode impedance. Our data suggest that dexamethasone eluting arrays are more effective than the current clinical practice of locally applied dexamethasone in reducing FBR and electrical impedance.

Aim: To investigate the effects of once-daily oral semaglutide 50 mg on energy intake, appetite, control of eating and gastric emptying., Methods: A clinical pharmacology, double-blind study was conducted in 61 adults with obesity randomized to once-daily oral semaglutide (dose-escalated to 50 mg) or placebo for 20 weeks. Energy intake was measured during an ad libitum lunch, and participant-reported appetite ratings and Control of Eating Questionnaire responses were assessed. Gastric emptying was measured using paracetamol absorption following a standardized breakfast., Results: The relative change from baseline in ad libitum energy intake at week 20 (primary endpoint) was -39.2% points (95% confidence interval -59.0%, -19.4%) with semaglutide compared with placebo. Body weight was reduced by 9.8% with semaglutide and by 1.5% with placebo. Semaglutide reduced hunger, increased fullness and satiety, and was associated with fewer food cravings and better control of eating versus placebo. No statistically significant difference in gastric emptying was observed at week 20., Conclusions: In participants with obesity, once-daily oral semaglutide 50 mg reduced energy intake, body weight and appetite, and improved control of eating. There was no evidence of delayed gastric emptying at week 20, as measured through paracetamol absorption., (© 2024 Novo Nordisk A/S. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Polymer solid-state electrolytes offer great promise for battery materials with high energy density, mechanical stability, and improved safety. However, their low ion conductivities have so far limited their potential applications. Here, it is shown for poly(ethylene oxide) block copolymers that the super-stoichiometric addition of lithium bis(trifluoromethanesulfonyl) imide (LiTFSI) as lithium salt leads to the formation of a crystalline PEO block copolymer phase with exceptionally high ion conductivities and low activation energies. The addition of LiTFSI further induces block copolymer phase transitions into bi-continuous Fddd and gyroid network morphologies, providing continuous 3D conduction pathways. Both effects lead to solid-state block copolymer electrolyte membranes with ion conductivities of up to 1·10 -1  S cm -1 at 90 °C, decreasing only moderately to 4·10 -2  S cm -1 at room temperature, and to >1·10 -3  S cm -1 at -20 °C, corresponding to activation energies as low as 0.19 eV. The co-crystallization of PEO and LiTFSI with ether and carbonate solvents is observed to play a key role to realize a super-ionic conduction mechanism. The discovery of PEO super-ionic conductivity at high lithium concentrations opens a new pathway for fabrication of solid polymer electrolyte membranes with sufficiently high ion conductivities over a broad temperature range with widespread applications in electrical devices., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Precision graphene nanoribbons (GNRs) offer distinctive physicochemical properties that are highly dependent on their geometric topologies, thereby holding great potential for applications in carbon-based optoelectronics and spintronics. While the edge structure and width control has been a popular strategy for engineering the optoelectronic properties of GNRs, non-hexagonal-ring-containing GNRs remain underexplored due to synthetic challenges, despite offering an equally high potential for tailored properties. Herein, we report the synthesis of a wavy GNR (wGNR) by embedding periodic eight-membered rings into its carbon skeleton, which is achieved by the A 2 B 2 -type Diels-Alder polymerization between dibenzocyclooctadiyne (6) and dicyclopenta[e,l]pyrene-5,11-dione derivative (8), followed by a selective Scholl reaction of the obtained ladder-type polymer (LTP) precursor. The obtained wGNR, with a length of up to 30 nm, has been thoroughly characterized by solid-state NMR, FT-IR, Raman, and UV/Vis spectroscopy with the support of DFT calculations. The non-planar geometry of wGNR efficiently prevents the inter-ribbon π-π aggregation, leading to photoluminescence in solution. Consequently, the wGNR can function as an emissive layer for organic light-emitting electrochemical cells (OLECs), offering a proof-of-concept exploration in implementing luminescent GNRs into optoelectronic devices. The fast-responding OLECs employing wGNR will pave the way for advancements in OLEC technology and other optoelectronic devices., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Micro and nanoscale patterning of surface features and biochemical cues have emerged as tools to precisely direct neurite growth into close proximity with next generation neural prosthesis electrodes. Biophysical cues can exert greater influence on neurite pathfinding compared to the more well studied biochemical cues; yet the signaling events underlying the ability of growth cones to respond to these microfeatures remain obscure. Intracellular Ca2+ signaling plays a critical role in how a growth cone senses and grows in response to various cues (biophysical features, repulsive peptides, chemo-attractive gradients). Here, we investigate the role of inositol triphosphate (IP3) and ryanodine-sensitive receptor (RyR) signaling as sensory neurons (spiral ganglion neurons, SGNs, and dorsal root ganglion neurons, DRGNs) pathfind in response to micropatterned substrates of varied geometries. We find that IP3 and RyR signaling act in the growth cone as they navigate biophysical cues and enable proper guidance to biophysical, chemo-permissive, and chemo-repulsive micropatterns. In response to complex micropatterned geometries, RyR signaling appears to halt growth in response to both topographical features and chemo-repulsive cues. IP3 signaling appears to play a more complex role, as growth cones appear to sense the microfeatures in the presence of xestospongin C but are unable to coordinate turning in response to them. Overall, key Ca2+ signaling elements, IP3 and RyR, are found to be essential for SGNs to pathfind in response to engineered biophysical and biochemical cues. These findings inform efforts to precisely guide neurite regeneration for improved neural prosthesis function, including cochlear implants., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vecchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The diagnostic accuracy of handheld ultrasound (HHUS) devices operated by newly certified operators for pneumonia is unknown. This multicenter diagnostic accuracy study included patients prospectively suspected of pneumonia from February 2021 to February 2022 in four emergency departments. The index test was a 14-zone focused lung ultrasound (FLUS) examination, with consolidation with air bronchograms as diagnostic criteria for pneumonia. FLUS examinations were performed by newly certified operators using HHUS. The reference standard was computed tomography (CT) and expert diagnosis using all medical records. The sensitivity and specificity of FLUS and chest X-ray (CXR) were compared using McNemar's test. Of the 324 scanned patients, 212 (65%) had pneumonia, according to the expert diagnosis. FLUS had a sensitivity of 31% (95% CI 26-36) and a specificity of 82% (95% CI 78-86) compared with the experts' diagnosis. Compared with CT, FLUS had a sensitivity of 32% (95% CI 27-37) and specificity of 81% (95% CI 77-85). CXR had a sensitivity of 66% (95% CI 61-72) and a specificity of 76% (95% CI 71-81) compared with the experts' diagnosis. Compared with CT, CXR had a sensitivity of 69% (95% CI 63-74) and a specificity of 68% (95% CI 62-72). Compared with the experts' diagnosis and CT diagnosis, FLUS performed by newly certified operators using HHUS devices had a significantly lower sensitivity for pneumonia when compared to CXR ( p < 0.001). FLUS had a significantly higher specificity than CXR using CT diagnosis as a reference standard ( p = 0.02). HHUS exhibited low sensitivity for pneumonia when used by newly certified operators.

Analyzing confocal microscopic data of biological samples using the Imaris software poses challenges due to its time-consuming nature involving tedious multiple steps and possibility of human errors. Here, we developed a supervised automation protocol to minimize manual input in cell and spot counting on confocal images obtained from mouse cochlear sections. The protocol increases efficiency by incorporating image recognition and object-oriented macros. Moreover, the protocol being adaptable allows scientists in diverse other fields to customize it for their specific needs.

Cochlear implants (CI) represent incredible devices that restore hearing perception for those with moderate to profound sensorineural hearing loss. However, the ability of a CI to restore complex auditory function is limited by the number of perceptually independent spectral channels provided. A major contributor to this limitation is the physical gap between the CI electrodes and the target spiral ganglion neurons (SGNs). In order for CI electrodes to stimulate SGNs more precisely, and thus better approximate natural hearing, new methodologies need to be developed to decrease this gap, (i.e., transitioning CIs from a far-field to near-field device). In this review, strategies aimed at improving the neural-electrode interface are discussed in terms of the magnitude of impact they could have and the work needed to implement them. Ongoing research suggests current clinical efforts to limit the CI-related immune response holds great potential for improving device performance. This could eradicate the dense, fibrous capsule surrounding the electrode and enhance preservation of natural cochlear architecture, including SGNs. In the long term, however, optimized future devices will likely need to induce and guide the outgrowth of the peripheral process of SGNs to be in closer proximity to the CI electrode in order to better approximate natural hearing. This research is in its infancy; it remains to be seen which strategies (surface patterning, small molecule release, hydrogel coating, etc.) will be enable this approach. Additionally, these efforts aimed at optimizing CI function will likely translate to other neural prostheses, which face similar issues., Competing Interests: MH is a co-founder with equity interest in iotaMotion, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Vecchi, Claussen and Hansen.)

Adaptation transcends scale in both natural and artificial systems, but delineating the causative factors of this phenomenon requires urgent clarification. Herein, we unravel the molecular requirements for adaptation and establish a link to rationalize adaptive behavior on a self-assembled level. These concepts are established by analyzing a model compound exhibiting both light- and pH-responsive units, which enable the combined or independent application of different stimuli. On a molecular level, adaptation arises from coupled stimuli, as the final outcome of the system depends on their sequence of application. However, in a self-assembled state, a single stimulus suffices to induce adaptation as a result of collective molecular behavior and the reversibility of non-covalent interactions. Our findings go beyond state-of-the-art (multi)stimuli-responsive systems and allow us to draw up design guidelines for adaptive behavior both at the molecular and supramolecular levels, which are fundamental criteria for the realization of intelligent matter., (© 2024. The Author(s).)

Delayed loss of residual acoustic hearing after cochlear implantation is a common but poorly understood phenomenon due to the scarcity of relevant temporal bone tissues. Prior histopathological analysis of one case of post-implantation hearing loss suggested there were no interaural differences in hair cell or neural degeneration to explain the profound loss of low-frequency hearing on the implanted side (Quesnel et al., 2016) and attributed the threshold elevation to neo-ossification and fibrosis around the implant. Here we re-evaluated the histopathology in this case, applying immunostaining and improved microscopic techniques for differentiating surviving hair cells from supporting cells. The new analysis revealed dramatic interaural differences, with a > 80 % loss of inner hair cells in the cochlear apex on the implanted side, which can account for the post-implantation loss of residual hearing. Apical degeneration of the stria further contributed to threshold elevation on the implanted side. In contrast, spiral ganglion cell survival was reduced in the region of the electrode on the implanted side, but apical counts in the two ears were similar to that seen in age-matched unimplanted control ears. Almost none of the surviving auditory neurons retained peripheral axons throughout the basal half of the cochlea. Relevance to cochlear implant performance is discussed., Competing Interests: Declaration of competing interest There are no relevant competing interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: This work received funding from iotaMotion, Inc. M.R.H. is a cofounder and director of iotaMotion; B.J.G. serves as consultant for iotaMotion, Inc. For the remaining authors, there are no conflicts of interest to report.

The durability of photografted zwitterionic hydrogel coatings on cochlear implant biomaterials was examined to determine the viability of these antifouling surfaces during insertion and long-term implant usage. Tribometry was used to determine the effect of zwitterionic coatings on the lubricity of surfaces with varying hydration levels, applied normal force, and time frame. Additionally, flexural resistance was investigated using mandrel bending. Ex vivo durability was assessed by determining the coefficient of friction between tissues and treated surfaces. Furthermore, cochlear implantation force was measured using cadaveric human cochleae. Hydrated zwitterionic hydrogel coatings reduced frictional resistance approximately 20-fold compared to uncoated PDMS, which led to significantly lower mean force experienced by coated cochlear implants during insertion compared to uncoated systems. Under flexural force, zwitterionic films resisted failure for up to 60 min of desiccation. The large increase in lubricity was maintained for 20 h under continual force while hydrated. For loosely cross-linked systems, films remained stable and lubricious even after rehydration following complete drying. All coatings remained hydrated and functional under frictional force for at least 30 min in ambient conditions allowing drying, with lower cross-link densities showing the greatest longevity. Moreover, photografted zwitterionic hydrogel samples showed no evidence of degradation and nearly identical lubricity before and after implantation. This work demonstrates that photografted zwitterionic hydrogel coatings are sufficiently durable to maintain viability before, during, and after implantation. Mechanical properties, including greatly increased lubricity, are preserved after complete drying and rehydration for various applied forces. Additionally, this significantly enhanced lubricity translates to significantly decreased force during insertion of implants which should result in less trauma and scarring.

Li 3 Y 1- x In x Cl 6 undergoes a phase transition from trigonal to monoclinic via an intermediate orthorhombic phase. Although the trigonal yttrium containing the end member phase, Li 3 YCl 6 , synthesized by a mechanochemical route, is known to exhibit stacking fault disorder, not much is known about the monoclinic phases of the serial composition Li 3 Y 1- x In x Cl 6 . This work aims to shed light on the influence of the indium substitution on the phase evolution, along with the evolution of stacking fault disorder using X-ray and neutron powder diffraction together with solid-state nuclear magnetic resonance spectroscopy, studying the lithium-ion diffusion. Although Li 3 Y 1- x In x Cl 6 with x ≤ 0.1 exhibits an ordered trigonal structure like Li 3 YCl 6 , a large degree of stacking fault disorder is observed in the monoclinic phases for the x ≥ 0.3 compositions. The stacking fault disorder materializes as a crystallographic intergrowth of faultless domains with staggered layers stacked in a uniform layer stacking, along with faulted domains with randomized staggered layer stacking. This work shows how structurally complex even the "simple" series of solid solutions can be in this class of halide-based lithium-ion conductors, as apparent from difficulties in finding a consistent structural descriptor for the ionic transport.

Objective . Cochlear implants provide auditory perception to those with severe to profound sensorineural hearing loss: however, the quality of sound perceived by users does not approximate natural hearing. This limitation is due in part to the large physical gap between the stimulating electrodes and their target neurons. Therefore, directing the controlled outgrowth of processes from spiral ganglion neurons (SGNs) into close proximity to the electrode array could provide significantly increased hearing function. Approach. For this objective to be properly designed and implemented, the ability and limits of SGN neurites to be guided must first be determined. In this work, we engineer precise topographical microfeatures with angle turn challenges of various geometries to study SGN pathfinding and use live imaging to better understand how neurite growth is guided by these cues. Main Results. We find that the geometry of the angled microfeatures determines the ability of neurites to navigate the angled microfeature turns. SGN neurite pathfinding fidelity is increased by 20%-70% through minor increases in microfeature amplitude (depth) and by 25% if the angle of the patterned turn is made obtuse. Further, we see that dorsal root ganglion neuron growth cones change their morphology and migration to become more elongated within microfeatures. Our observations also indicate complexities in studying neurite turning. First, as the growth cone pathfinds in response to the various cues, the associated neurite often reorients across the angle topographical microfeatures. Additionally, neurite branching is observed in response to topographical guidance cues, most frequently when turning decisions are most uncertain. Significance. Overall, the multi-angle channel micropatterned substrate is a versatile and efficient system to assess neurite turning and pathfinding in response to topographical cues. These findings represent fundamental principles of neurite pathfinding that will be essential to consider for the design of 3D systems aiming to guide neurite growth in vivo ., (Creative Commons Attribution license.)

Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n-acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n-acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Emulsions are indispensable in everyday life, and the demand for emulsions' diversity and control of properties is therefore substantial. As emulsions possess a high internal surface area, an understanding of the oil/water (o/w) interfaces at the molecular level is fundamental but often impaired by experimental limitations to probe emulsion interfaces in situ. Here, we have used light-responsive surfactants (butyl-AAP) that can photoisomerize between E and Z isomers by visible and UV light irradiation to tune the emulsion interfaces. This causes massive changes in the interface tension at the extended o/w interfaces in macroemulsions and a drastic shift in the surfactants' critical micelle concentration, which we show can be used to control both the stability and phase separation. Strikingly different from macroemulsions are nanoemulsions ( R H ∼90 nm) as these are not susceptible to E / Z photoisomerization of the surfactants in terms of changes in their droplet size or ζ-potential. However, in situ second-harmonic scattering and pulsed-field gradient nuclear magnetic resonance (NMR) experiments show dramatic and reversible changes in the surface excess of surfactants at the nanoscopic interfaces. The apparent differences in ζ-potentials and surface excess provide evidence for a fixed charge to particle size ratio and the need for counterion condensation to renormalize the particle charge to a critical charge, which is markedly different compared to the behavior of very large particles in macroemulsions. Thus, our findings may have broader implications as the electrostatic stabilization of nanoparticles requires much lower surfactant concentrations, allowing for a more sustainable use of surfactants.

This study aimed to test the accuracy of a magnetic resonance imaging (MRI)-based method to detect and characterise deep venous thrombosis (DVT) in the ilio-femoro-caval veins. Patients with verified DVT in the lower extremities with extension of the thrombi to the iliac veins, who were suitable for catheter-based venous thrombolysis, were included in this study. Before the intervention, magnetic resonance venography (MRV) was performed, and the ilio-femoro-caval veins were independently evaluated for normal appearance, stenosis, and occlusion by two single-blinded observers. The same procedure was used to evaluate digital subtraction phlebography (DSP), considered to be the gold standard, which made it possible to compare the results. A total of 123 patients were included for MRV and DSP, resulting in 246 image sets to be analysed. In total, 496 segments were analysed for occlusion, stenosis, or normal appearance. The highest sensitivity compared occlusion with either normal or stenosis (0.98) in MRV, while the lowest was found between stenosis and normal (0.84). Specificity varied from 0.59 (stenosis >< occlusion) to 0.94 (occlusion >< normal). The Kappa statistic was calculated as a measure of inter-observer agreement. The kappa value for MRV was 0.91 and for DSP, 0.80. In conclusion, MRV represents a sensitive method to analyse DVT in the pelvis veins with advantages such as no radiation and contrast and the possibility to investigate the anatomical relationship in the area.

Background: Data on the benefits of the once weekly GLP-1 receptor agonist semaglutide 2·4 mg for weight management in people from east Asia are insufficient. The objective of this study was to determine the efficacy and safety of once weekly semaglutide 2·4 mg versus placebo for weight management in a predominantly east Asian adult population., Methods: This randomised phase 3a, double-blind multicentre controlled trial (STEP 7) recruited participants from 23 hospitals and trial centres in China, Hong Kong, Brazil, and South Korea. Adults with overweight or obesity, with or without type 2 diabetes, were randomly assigned (2:1) to receive a subcutaneous injection of either semaglutide 2·4 mg or placebo once a week for 44 weeks, plus a diet and physical activity intervention. Randomisation was done in blocks of six with an interactive web response system and was stratified by diagnosis of type 2 diabetes. Participants, investigators, and the trial sponsor were masked to treatment allocation until after database lock. Primary endpoints were percentage change in mean bodyweight and proportion of participants having reached a weight reduction of at least 5% of bodyweight from baseline to week 44. Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04251156, and is now complete., Findings: From Dec 8, 2020, to Aug 23, 2022, 448 participants were screened, of whom 375 were randomly assigned to either the semaglutide 2·4 mg group (n=249) or the placebo group (n=126). Estimated mean percentage change in bodyweight from baseline to week 44 was -12·1% (SE 0·5) with semaglutide 2·4 mg versus -3·6% (0·7) with placebo (estimated treatment difference -8·5 percentage points [95% CI -10·2 to -6·8]; p<0·0001). At week 44, the proportion of participants who lost 5% or more of their bodyweight was higher in the semaglutide 2·4 mg group than in the placebo group (203/238 [85%] vs 36/116 [31%]); odds ratio 13·1 (95% CI 7·4-23·1; p<0·0001). Adverse events were reported by 231 (93%) of 249 participants in the semaglutide 2·4 mg group and 108 (86%) of 126 participants in the placebo group, the most common of which were gastrointestinal disorders (168/249, 67% vs 45/126, 36%)., Interpretation: The results of this study support the use of semaglutide 2·4 mg for weight management in people of east Asian ethnicity with overweight or obesity and with or without type 2 diabetes., Funding: Novo Nordisk., Translations: For the Mandarin, Portuguese and South Korean translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests YM reports having received honoraria and personal fees from Eli Lilly Diabetes, Novo Nordisk, and Sanofi outside the submitted work. XB is a full-time employee of Novo Nordisk (China) Pharmaceuticals, Beijing, China, and is a shareholder in Novo Nordisk. FGE has received clinical research grants from Novo Nordisk, Eli Lilly, AstraZeneca, Novartis, Eurofarma, and Kowa; is on advisory boards for Novo Nordisk, Eli Lilly, AstraZeneca, and Pfizer; and has given lectures for AstraZeneca, Bayer, Novo Nordisk, Eli Lilly, Sanofi, Abbot, Merck, and Novartis. MRH is a full-time employee of Novo Nordisk and shareholder in Novo Nordisk and Eli Lilly; before his current employment MRH received speaking fees from Novartis outside the submitted work. BTK has received research funding from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk for carrying out clinical trials or studies; speaker honoraria from Alvogen Korea and Novo Nordisk; all proceeds have been donated to the Ajou University Hospital to support obesity research. AK is an employee of and shareholder in Novo Nordisk. RCWM has received research funding from AstraZeneca, Bayer, Novo Nordisk, Pfizer, Roche Diagnostics Hong Kong and Tricida for carrying out clinical trials, and has received speaker honorarium or consultancy in advisory boards from AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Merck, and Kyowa Kirin; all proceeds have been donated to the Chinese University of Hong Kong to support diabetes research. NZ is an employee of and shareholder in Novo Nordisk. ML has received consulting fees from Novo Nordisk and Sanofi, and honoraria from Novo Nordisk, Sanofi, and Bayer, and is a committee member of the Chinese Society of Endocrinology. TY declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To describe the use of robotics-assisted electrode array (EA) insertion combined with intraoperative electrocochleography (ECochG) in hearing preservation cochlear implant surgery., Study Design: Prospective, single-arm, open-label study., Setting: All procedures and data collection were performed at a single tertiary referral center., Patients: Twenty-one postlingually deaf adult subjects meeting Food and Drug Administration indication criteria for cochlear implantation with residual acoustic hearing defined as thresholds no worse than 65 dB at 125, 250, and 500 Hz., Intervention: All patients underwent standard-of-care unilateral cochlear implant surgery using a single-use robotics-assisted EA insertion device and concurrent intraoperative ECochG., Main Outcome Measures: Postoperative pure-tone average over 125, 250, and 500 Hz measured at initial activation and subsequent intervals up to 1 year afterward., Results: Twenty-two EAs were implanted with a single-use robotics-assisted insertion device and simultaneous intraoperative ECochG. Fine control over robotic insertion kinetics could be applied in response to changes in ECochG signal. Patients had stable pure-tone averages after activation with normal impedance and neural telemetry responses., Conclusions: Combining robotics-assisted EA insertion with intraoperative ECochG is a feasible technique when performing hearing preservation implant surgery. This combined approach may provide the surgeon a means to overcome the limitations of manual insertion and respond to cochlear feedback in real-time., (Copyright © 2024, Otology & Neurotology, Inc.)

Cochlear implants (CI) have revolutionized the treatment of patients with severe to profound sensory hearing loss by providing a method of bypassing normal hearing to directly stimulate the auditory nerve. A further advance in the field has been the introduction of "hearing preservation" surgery, whereby the CI electrode array (EA) is carefully inserted to spare damage to the delicate anatomy and function of the cochlea. Preserving residual function of the inner ear allows patients to receive maximal benefit from the CI and to combine CI electric stimulation with acoustic hearing, offering improved postoperative speech, hearing, and quality of life outcomes. However, under the current paradigm of implant surgery, where EAs are inserted by hand, the cochlea cannot be reliably spared from damage. Robotics-assisted EA insertion is an emerging technology that may overcome fundamental human kinetic limitations that prevent consistency in achieving steady and slow EA insertion. This review begins by describing the relationship between EA insertion speed and generation of intracochlear forces and pressures. The various mechanisms by which these intracochlear forces can damage the cochlea and lead to worsened postoperative outcomes are discussed. The constraints of manual insertion technique are compared to robotics-assisted methods, followed by an overview of the current and future state of robotics-assisted EA insertion., Competing Interests: AH is an employee of iotaMotion, Inc. MH is a cofounder with equity interest in iotaMotion, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kashani, Henslee, Nelson and Hansen.)

The influence of the microstructure on the ionic conductivity and cell performance is a topic of broad scientific interest in solid-state batteries. The current understanding is that interfacial decomposition reactions during cycling induce local strain at the interfaces between solid electrolytes and the anode/cathode, as well as within the electrode composites. Characterizing the effects of internal strain on ion transport is particularly important, given the significant local chemomechanical effects caused by volumetric changes of the active materials during cycling. Here, we show the effects of internal strain on the bulk ionic transport of the argyrodite Li 6 PS 5 Br. Internal strain is reproducibly induced by applying pressures with values up to 10 GPa. An internal permanent strain is observed in the material, indicating long-range strain fields typical for dislocations. With increasing dislocation densities, an increase in the lithium ionic conductivity can be observed that extends into improved ionic transport in solid-state battery electrode composites. This work shows the potential of strain engineering as an additional approach for tuning ion conductors without changing the composition of the material itself.

Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy., (© 2023. The Author(s).)

Graphene nanoribbons (GNRs) have garnered significant interest due to their highly customizable physicochemical properties and potential utility in nanoelectronics. Besides controlling widths and edge structures, the inclusion of chirality in GNRs brings another dimension for fine-tuning their optoelectronic properties, but related studies remain elusive owing to the absence of feasible synthetic strategies. Here, we demonstrate a novel class of cove-edged chiral GNRs ( CcGNRs ) with a tunable chiral vector ( n , m ). Notably, the bandgap and effective mass of ( n ,2)-CcGNR show a distinct positive correlation with the increasing value of n , as indicated by theory. Within this GNR family, two representative members, namely, (4,2)-CcGNR and (6,2)-CcGNR , are successfully synthesized. Both CcGNRs exhibit prominently curved geometries arising from the incorporated [4]helicene motifs along their peripheries, as also evidenced by the single-crystal structures of the two respective model compounds ( 1 and 2 ). The chemical identities and optoelectronic properties of (4,2)- and (6,2)-CcGNRs are comprehensively investigated via a combination of IR, Raman, solid-state NMR, UV-vis, and THz spectroscopies as well as theoretical calculations. In line with theoretical expectation, the obtained (6,2)-CcGNR possesses a low optical bandgap of 1.37 eV along with charge carrier mobility of ∼8 cm 2 V -1 s -1 , whereas (4,2)-CcGNR exhibits a narrower bandgap of 1.26 eV with increased mobility of ∼14 cm 2 V -1 s -1 . This work opens up a new avenue to precisely engineer the bandgap and carrier mobility of GNRs by manipulating their chiral vector.

Purpose: To better characterize the frequency and patterns of hearing dysfunction in patients who have received teprotumumab to treat thyroid eye disease., Design: Noncomparative case series., Participants: Patients who underwent audiology testing before and after completion of teprotumumab infusions., Methods: A review of patients who underwent audiology testing before and after completion of teprotumumab infusions was carried out. Additional audiogram testing during treatment was included when available. Hearing function was analyzed using audiogram data measuring threshold hearing levels at specific frequencies. Basic demographic data as well as information regarding otologic symptoms also were obtained and analyzed., Main Outcome Measures: Hearing loss demonstrated by a significant change in decibel hearing thresholds or that meets criteria for ototoxicity., Results: Twenty-two patients (44 ears) were included in the study, with baseline and most recent audiology testing after treatment ranging from 84 days before to 496 days after treatment. Fifteen patients (30 ears) also underwent testing during treatment starting after the second infusion up until the day of, but before, the eighth infusion. Hearing loss after treatment met criteria for ototoxicity in 17 of the 44 ears (38.6%), with 11 of the 22 patients (50.0%) meeting criteria in at least 1 ear. The pure-tone average decibel hearing levels (HLs) across all 44 ears demonstrated hearing loss after treatment (P = 0.0029), specifically at high (P = 0.0008) and middle frequencies (P = 0.0042), but not at low frequencies (P = 0.8344). Patients who were older also were more likely to experience hearing loss after treatment (P = 0.0048)., Conclusions: Audiometric data demonstrate that teprotumumab influences hearing function, most significantly at higher frequencies and in older patients. Audiometric testing is critical for counseling patients regarding teprotumumab treatment. A protocol for monitoring hearing during treatment is needed to detect and manage hearing changes associated with teprotumumab use., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

We report a simple design strategy for wideband uniform-rate smooth truncation (WURST) pulses that enables ultrafast frequency sweeps to maximize the sensitivity of Carr-Purcell-Meiboom-Gill (CPMG) acquisition in static wideline nuclear magnetic resonance (NMR). Three compelling examples showcase the advantage of ultrafast frequency sweeps over currently employed WURST-CPMG protocols, demonstrating the potential of investigating materials that are typically inaccessible to static wideline NMR techniques, e.g., paramagnetic solids with short homogeneous transverse relaxation times.

Objective: The objective of the current study was to present the results of an international working group survey identifying perceived limitations of existing facial nerve grading scales to inform the development of a novel grading scale for assessing early postoperative facial paralysis that incorporates regional scoring and is anchored in recovery prognosis and risk of associated complications., Study Design: Survey., Setting: A working group of 48 multidisciplinary clinicians with expertise in skull base, cerebellopontine angle, temporal bone, or parotid gland surgery., Results: House-Brackmann grade is the most widely used system to assess facial nerve function among working group members (81%), although more than half (54%) agreed that the system they currently use does not adequately estimate the risk of associated complications, such as corneal injury, and confidence in interrater and intrarater reliability is generally low. Simplicity was ranked as the most important attribute of a novel postoperative facial nerve grading system to increase the likelihood of adoption, followed by reliability and accuracy. There was widespread consensus (91%) that the eye is the most critical facial region to focus on in the early postoperative setting., Conclusions: Members were invited to submit proposed grading systems in alignment with the objectives of the working group for subsequent validation. From these data, we plan to develop a simple, clinically anchored, and reproducible staging system with regional scoring for assessing early postoperative facial nerve function after surgery of the skull base, cerebellopontine angle, temporal bone, or parotid gland., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2023, Otology & Neurotology, Inc.)

This study evaluates intracochlear electrocochleography (ECochG) for real-time monitoring during cochlear implantation. One aim tested whether adjusting the recording electrode site would help differentiate between atraumatic and traumatic ECochG amplitude decrements. A second aim assessed whether associations between ECochG amplitude decrements and post-operative hearing loss were weaker when considering hearing sensitivity at the ECochG stimulus frequency compared to a broader frequency range. Eleven adult cochlear implant recipients who were candidates for electro-acoustic stimulation participated. Single-frequency (500-Hz) ECochG was performed during cochlear implantation; the amplitude of the first harmonic of the difference waveform was considered. Post-operative hearing preservation at 500 Hz ranged from 0 to 94%. The expected relationship between ECochG amplitude decrements and hearing preservation was observed, though the trend was not statistically significant, and predictions were grossly inaccurate for two participants. Associations did not improve when considering alternative recording sites or hearing sensitivity two octaves above the ECochG stimulus frequency. Intracochlear location of a moving recording electrode is a known confound to real-time interpretation of ECochG amplitude fluctuations, which was illustrated by the strength of the correlation with ECochG amplitude decrements. Multiple factors contribute to ECochG amplitude patterns and to hearing preservation; these results highlight the confounding influence of intracochlear recording electrode location on the ECochG.

Background: Cochlear implants (CIs) restore hearing to deafened patients. The foreign body response (FBR) following cochlear implantation (post-CI) comprises an infiltration of macrophages, other immune and non-immune cells, and fibrosis into the scala tympani, a space that is normally devoid of cells. This FBR is associated with negative effects on CI outcomes including increased electrode impedances and loss of residual acoustic hearing. This study investigates the extent to which macrophage depletion by an orally administered CSF-1R specific kinase (c-FMS) inhibitor, PLX-5622, modulates the tissue response to CI and neural health., Main Text: 10- to 12-week-old CX3CR1 + /GFP Thy1 + /YFP mice on C57BL/6J/B6 background was fed chow containing 1200 mg/kg PLX5622 or control chow for the duration of the study. 7 days after starting the diet, 3-channel cochlear implants were implanted in the ear via the round window. Serial impedance and neural response telemetry (NRT) measurements were acquired throughout the study. Electric stimulation began 7 days post-CI until 28 days post-CI for 5 h/day, 5 days/week, with programming guided by NRT and behavioral responses. Cochleae harvested at 10, 28 or 56 days post-CI were cryosectioned and labeled with an antibody against α-smooth muscle actin (α-SMA) to identify myofibroblasts and quantify the fibrotic response. Using IMARIS image analysis software, the outlines of scala tympani, Rosenthal canal, modiolus, and lateral wall for each turn were traced manually to measure region volume. The density of nuclei, CX3CR1 + macrophages, Thy1 + spiral ganglion neuron (SGN) numbers, and the ratio of the α-SMA + volume/scala tympani volume were calculated. Cochlear implantation in control diet subjects caused infiltration of cells, including macrophages, into the cochlea. Fibrosis was evident in the scala tympani adjacent to the electrode array. Mice fed PLX5622 chow showed reduced macrophage infiltration throughout the implanted cochleae across all time points. However, scala tympani fibrosis was not reduced relative to control diet subjects. Further, mice treated with PLX5622 showed increased electrode impedances compared to controls. Finally, treatment with PLX5622 decreased SGN survival in implanted and contralateral cochleae., Conclusion: The data suggest that macrophages play an important role in modulating the intracochlear tissue response following CI and neural survival., (© 2023. The Author(s).)

Objectives: Understanding speech-in-noise (SiN) is a complex task that recruits multiple cortical subsystems. Individuals vary in their ability to understand SiN. This cannot be explained by simple peripheral hearing profiles, but recent work by our group ( Kim et al. 2021 , Neuroimage ) highlighted central neural factors underlying the variance in SiN ability in normal hearing (NH) subjects. The present study examined neural predictors of SiN ability in a large cohort of cochlear-implant (CI) users., Design: We recorded electroencephalography in 114 postlingually deafened CI users while they completed the California consonant test: a word-in-noise task. In many subjects, data were also collected on two other commonly used clinical measures of speech perception: a word-in-quiet task (consonant-nucleus-consonant) word and a sentence-in-noise task (AzBio sentences). Neural activity was assessed at a vertex electrode (Cz), which could help maximize eventual generalizability to clinical situations. The N1-P2 complex of event-related potentials (ERPs) at this location were included in multiple linear regression analyses, along with several other demographic and hearing factors as predictors of SiN performance., Results: In general, there was a good agreement between the scores on the three speech perception tasks. ERP amplitudes did not predict AzBio performance, which was predicted by the duration of device use, low-frequency hearing thresholds, and age. However, ERP amplitudes were strong predictors for performance for both word recognition tasks: the California consonant test (which was conducted simultaneously with electroencephalography recording) and the consonant-nucleus-consonant (conducted offline). These correlations held even after accounting for known predictors of performance including residual low-frequency hearing thresholds. In CI-users, better performance was predicted by an increased cortical response to the target word, in contrast to previous reports in normal-hearing subjects in whom speech perception ability was accounted for by the ability to suppress noise., Conclusions: These data indicate a neurophysiological correlate of SiN performance, thereby revealing a richer profile of an individual's hearing performance than shown by psychoacoustic measures alone. These results also highlight important differences between sentence and word recognition measures of performance and suggest that individual differences in these measures may be underwritten by different mechanisms. Finally, the contrast with prior reports of NH listeners in the same task suggests CI-users performance may be explained by a different weighting of neural processes than NH listeners., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.)

Objective: Minimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved postoperatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) postoperatively. However, 30% to 40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. This additional hearing loss is generally not severe enough to preclude use of acoustic amplification; however, it can still impact EAS benefits. The use of electrocochleography (ECoG) measures of peripheral hair cell and neural auditory function have shed insight into the pathophysiology of postimplant loss of residual acoustic hearing. The present study aims to assess the long-term stability of ECoG measures and to establish ECoG as an objective method of monitoring residual hearing over the course of EAS CI use. We hypothesize that repeated measures of ECoG should remain stable over time for EAS CI users with stable postoperative hearing preservation. We also hypothesize that changes in behavioral audiometry for EAS CI users with loss of residual hearing should also be reflected in changes in ECoG measures., Design: A pool of 40 subjects implanted under hearing preservation protocol was included in the study. Subjects were seen at postoperative visits for behavioral audiometry and ECoG recordings. Test sessions occurred 0.5, 1, 3, 6, 12 months, and annually after 12 months postoperatively. Changes in pure-tone behavioral audiometric thresholds relative to baseline were used to classify subjects into two groups: one group with stable acoustic hearing and another group with loss of acoustic hearing. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Longitudinal linear mixed effects models were used to study trends in ECoG thresholds, slopes, and amplitudes for subjects with stable hearing and subjects with hearing loss., Results: Preoperative, behavioral audiometry indicated that subjects had an average low-frequency pure-tone average (125 to 500 Hz) of 40.88 ± 13.12 dB HL. Postoperatively, results showed that ECoG thresholds and amplitudes were stable in EAS CI users with preserved residual hearing. ECoG thresholds increased (worsened) while ECoG amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between EAS CI users with stable hearing and subjects with delayed loss of hearing., Conclusions: These results provide a new application of postoperative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss. While our measures were conducted with custom-designed in-house equipment, CI companies are also designing and implementing hardware and software adaptations to conduct ECoG recordings. Thus, postoperative ECoG recordings can potentially be integrated into clinical practice., Competing Interests: B.J.G. is a consultant for Cochlear Ltd. M.R.H. is cofounder and Chief Medical Officer for iotaMotion, Inc. V.D.T. is a consultant for iotaMotion, Inc. The remaining authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Interferons (IFN) are an assemblage of signaling proteins made and released by various host cells in response to stimuli, including viruses. Respiratory syncytial virus (RSV), influenza virus, and SARS-CoV-2 are major causes of respiratory disease that induce or antagonize IFN responses depending on various factors. In this review, the role and function of type I, II, and III IFN responses to respiratory virus infections are considered. In addition, the role of the viral proteins in modifying anti-viral immunity is noted, as are the specific IFN responses that underly the correlates of immunity and protection from disease.

Quantitative analysis of neurite growth and morphology is essential for understanding the determinants of neural development and regeneration, however, it is complicated by the labor-intensive process of measuring diverse parameters of neurite outgrowth. Consequently, automated approaches have been developed to study neurite morphology in a high-throughput and comprehensive manner. These approaches include computer-automated algorithms known as 'convolutional neural networks' (CNNs)-powerful models capable of learning complex tasks without the biases of hand-crafted models. Nevertheless, their complexity often relegates them to functioning as 'black boxes.' Therefore, research in the field of explainable AI is imperative to comprehend the relationship between CNN image analysis output and predefined morphological parameters of neurite growth in order to assess the applicability of these machine learning approaches. In this study, drawing inspiration from the field of automated feature selection, we investigate the correlation between quantified metrics of neurite morphology and the image analysis results from NeuriteNet-a CNN developed to analyze neurite growth. NeuriteNet accurately distinguishes images of neurite growth based on different treatment groups within two separate experimental systems. These systems differentiate between neurons cultured on different substrate conditions and neurons subjected to drug treatment inhibiting neurite outgrowth. By examining the model's function and patterns of activation underlying its classification decisions, we discover that NeuriteNet focuses on aspects of neuron morphology that represent quantifiable metrics distinguishing these groups. Additionally, it incorporates factors that are not encompassed by neuron morphology tracing analyses. NeuriteNet presents a novel tool ideally suited for screening morphological differences in heterogeneous neuron groups while also providing impetus for targeted follow-up studies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Viral vector gene therapy is an attractive strategy to treat hearing loss. Since hearing loss is due to a variety of pathogenic signaling cascades in distinct cells, viral vectors that can express large or multiple genes in a cell-type specific manner are needed. Helper-dependent adenoviral vectors (HdAd) are safe viral vectors with a large packaging capacity (-36 kb). Despite the potential of HdAd, its use in the inner ear is largely unexplored. Therefore, to evaluate the utility of HdAd for inner ear gene therapy, we created two HdAd vectors that use distinct cellular receptors for transduction: HdAd Serotype Type 5 (HdAd5), the Coxsackie-Adenovirus Receptor (CAR) and a chimeric HdAd 5/35, the human CD46+ receptor (hCD46). We delivered these vectors through the round window (RW) or scala media in CBA/J, C57Bl6/J and hCD46 transgenic mice. Immunostaining in conjunction with confocal microscopy of cochlear sections revealed that multiple cell types were transduced using HdAd5 and HdAd 5/35 in all mouse models. Delivery of HdAd5 via RW in the C57Bl/6 J or CBA/J cochlea resulted in transduced mesenchymal cells of the peri‑lymphatic lining and modiolar region while scala media delivery resulted in transduction of supporting cells and inner hair cells. Hd5/35 transduction was CD46 dependent and RW delivery of HdAd5/35 in the hCD46 mouse model resulted in a similar transduction pattern as HdAd5 in the peri‑lymphatic lining and modiolar region in the cochlea. Our data indicate that HdAd vectors are promising vectors for use in inner ear gene therapy to treat some causes of hearing loss., (Copyright © 2023. Published by Elsevier B.V.)

The foreign body response to implanted materials often complicates the functionality of sensitive biomedical devices. For cochlear implants, this response can reduce device performance, battery life and preservation of residual acoustic hearing. As a permanent and passive solution to the foreign body response, this work investigates ultra-low-fouling poly(carboxybetaine methacrylate) (pCBMA) thin film hydrogels that are simultaneously photo-grafted and photo-polymerized onto polydimethylsiloxane (PDMS). The cellular anti-fouling properties of these coatings are robustly maintained even after six-months subcutaneous incubation and over a broad range of cross-linker compositions. On pCBMA-coated PDMS sheets implanted subcutaneously, capsule thickness and inflammation are reduced significantly in comparison to uncoated PDMS or coatings of polymerized poly(ethylene glycol dimethacrylate) (pPEGDMA). Further, capsule thickness is reduced over a wide range of pCBMA cross-linker compositions. On cochlear implant electrode arrays implanted subcutaneously for one year, the coating bridges over the exposed platinum electrodes and dramatically reduces the capsule thickness over the entire implant. Coated cochlear implant electrode arrays could therefore lead to persistent improved performance and reduced risk of residual hearing loss. More generally, the in vivo anti-fibrotic properties of pCBMA coatings also demonstrate potential to mitigate the fibrotic response on a variety of sensing/stimulating implants. STATEMENT OF SIGNIFICANCE: This article presents, for the first time, evidence of the in vivo anti-fibrotic effect of zwitterionic hydrogel thin films photografted to polydimethylsiloxane (PDMS) and human cochlear implant arrays. The hydrogel coating shows no evidence of degradation or loss of function after long-term implantation. The coating process enables full coverage of the electrode array. The coating reduces fibrotic capsule thickness 50-70% over a broad range of cross-link densities for implantations from six weeks to one year., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests which may be considered as potential competing interests: “Durable photopolymerizable cross-linked anti-fouling coatings” as an active patent (JP7005535B2, CN109562202B, AU2017280359B2) or patent pending (CA3028732A1, US20200308440A1)., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Precise synthesis of graphene nanoribbons (GNRs) is of great interest to chemists and materials scientists because of their unique opto-electronic properties and potential applications in carbon-based nanoelectronics and spintronics. In addition to the tunable edge structure and width, introducing curvature in GNRs is a powerful structural feature for their chemi-physical property modification. Here, we report an efficient solution synthesis of the first pyrene-based GNR (PyGNR) with curved geometry via one-pot K-region oxidation and Scholl cyclization of its corresponding well-soluble tetrahydropyrene-based polyphenylene precursor. The efficient A 2 B 2 -type Suzuki polymerization and subsequent Scholl reaction furnishes up to ∼35 nm long curved GNRs bearing cove- and armchair-edges. The construction of model compound 1, as a cutout of PyGNR, from a tetrahydropyrene-based oligophenylene precursor proves the concept and efficiency of the one-pot K-region oxidation and Scholl cyclization, which is clearly revealed by single crystal X-ray diffraction analysis. The structure and optical properties of PyGNR are investigated by Raman, FT-IR, solid-state NMR, STM and UV-Vis analysis with the support of DFT calculations. PyGNR exhibits a narrow optical bandgap of ∼1.4 eV derived from a Tauc plot, qualifying as a low-bandgap GNR. Moreover, THz spectroscopy on PyGNR estimates its macroscopic charge mobility μ as ∼3.6 cm 2 V -1 s -1 , outperforming several other curved GNRs reported via conventional Scholl reaction., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

The middle fossa approach is an excellent technique for removing appropriate vestibular schwannomas in patients with serviceable hearing. Knowledge of the intricate middle fossa anatomy is essential for optimal outcomes. Gross total removal can be achieved with preservation of hearing and facial nerve function, both in the immediate and long-term periods. This article provides an overview of the background and indications for the procedure, a description of the operative protocol, and a summary of the literature on postoperative hearing outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aliovalent substitution is a common strategy to improve the ionic conductivity of solid electrolytes for solid-state batteries. The substitution of SbS 4 3- by WS 4 2- in Na 2.9 Sb 0.9 W 0.1 S 4 leads to a very high ionic conductivity of 41 mS cm -1 at room temperature. While pristine Na 3 SbS 4 crystallizes in a tetragonal structure, the substituted Na 2.9 Sb 0.9 W 0.1 S 4 crystallizes in a cubic phase at room temperature based on its X-ray diffractogram. Here, we show by performing pair distribution function analyses and static single-pulse 121 Sb NMR experiments that the short-range order of Na 2.9 Sb 0.9 W 0.1 S 4 remains tetragonal despite the change in the Bragg diffraction pattern. Temperature-dependent Raman spectroscopy revealed that changed lattice dynamics due to the increased disorder in the Na + substructure leads to dynamic sampling causing the discrepancy in local and average structure. While showing no differences in the local structure, compared to pristine Na 3 SbS 4 , quasi-elastic neutron scattering and solid-state 23 Na nuclear magnetic resonance measurements revealed drastically improved Na + diffusivity and decreased activation energies for Na 2.9 Sb 0.9 W 0.1 S 4 . The obtained diffusion coefficients are in very good agreement with theoretical values and long-range transport measured by impedance spectroscopy. This work demonstrates the importance of studying the local structure of ionic conductors to fully understand their transport mechanisms, a prerequisite for the development of faster ionic conductors.

Objective: To determine the safety and effectiveness of the middle cranial fossa (MCF) approach for spontaneous cerebrospinal fluid leak (sCSF-L) repair in class III obese patients. To also assess the need for prophylactic lumbar drain (LD) placement in this patient population., Study Design: Retrospective cohort study., Setting: Tertiary Academic Center., Patients: All patients older than 18 years undergoing sCSF-L repair with an MCF approach., Intervention: An MCF craniotomy for sCSF-L repair., Main Outcome Measure: Rate of complications and postoperative leaks., Results: There were no perioperative complications in 78.9% (56/71) of cases. The surgical complication rate was 12.5% (2/16), 10% (2/20), and 22.2% (6/27) in class I, class II, and class III obese patients. There was no statistically significant difference in complications among these three groups. The most common postoperative complication was a persistent CSF leak in the acute postoperative period with an overall rate of 9.9% (7/71) with six of the seven patients requiring postoperative LD placement. The percentage of postoperative CSF leaks in nonobese, class I, class II, and class III patients were 25% (2/8), 12.5% (2/16), 0% (0/20), and 11.1% (3/27), respectively. There was no statistically significant difference in the rate of postoperative CSF leaks among the four groups (chi-square, p = 0.48). In all cases, the acute postoperative CSF leaks resolved in the long term and did not require further surgical repair., Conclusions: We determine that MCF craniotomy repair for sCSF-Ls is safe in patients with class III obesity, and the incidence of postoperative CSF leaks did not vary among other obesity classes. We also find that prophylactic placement of LDs is not routinely needed in this population., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2023, Otology & Neurotology, Inc.)

Background: An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects., Objectives: We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention., Search Methods: We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors., Selection Criteria: We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm., Data Collection and Analysis: We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes., Main Results: We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I 2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect., Authors' Conclusions: We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objectives: We aimed to investigate the quality of evidence and the expected added clinical value of treatments recommended by the Danish Medicines Council (DMC)., Study Design: This was an observational study., Methods: The DMC prepares reports on drugs considered for possible new standard treatments in Danish hospitals. These reports evaluate the available evidence on efficacy and safety. The quality of evidence is systematically rated by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, and estimates of added clinical value are presented. The recommendations take into account expected economic implications of new treatments. The publicly available reports up until December 29, 2021, were downloaded from the DMC Web page. Reports on drugs marked "recommended" were included. Data on quality of evidence, expected clinical value, and economic implications were imputed in a Microsoft Excel spreadsheet., Results: Seventy-nine reports were included in the analysis. In 79% of these, the quality of evidence was rated low (24%) or very low (55%), whereas no recommendations were based on evidence rated as high quality. Three (5%) of recommended treatments were expected to add large clinical value., Conclusions: Most recommendations by the DMC are based on evidence formally rated as low or very low quality by GRADE, and no recommendations were based on evidence rated as high quality. The added clinical value of the treatments was often not documented and rarely large. Continued attention to improve the clinical evidence behind national recommendations is necessary., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

While phosphotellurite glasses have superior properties over SiO 2 -based glasses for many applications in optoelectronics and photonic devices, their high hydroxyl content limits their use in the mid-infrared range. This drawback can be overcome by fluoride addition to the formulation. In this work, we report the preparation, optical, and structural characterization of new glasses in the ternary system TeO 2 - x NaF-NaPO 3 having the compositions 0.8TeO 2 -0.2[ x NaF-(1 - x )NaPO 3 ] and 0.6TeO 2 -0.4[ x NaF-(1 - x )NaPO 3 ] (0 ≤ x ≤ 1) obtained by the traditional melt-quenching method and labeled as T8NN x and T6NN x , respectively. Differential scanning calorimetry (DSC) reveals high thermal stability against crystallization, with T x - T g varying from 80 to 130 °C, depending on fluoride/phosphate ratios. Raman spectroscopy suggests that the network connectivity increases with increasing phosphate concentration. 125 Te, 23 Na, 31 P, and 19 F NMR spectroscopy provides detailed structural information about Te-O-P, Te-F, Te-O-Te, P-O-P, and P-F linkages and the charge compensation mechanism for the sodium ions. The present study is the first comprehensive structural characterization of a fluorophosphotellurite glass system.

Caldendrin is a Ca 2+ binding protein that interacts with multiple effectors, such as the Ca v 1 L-type Ca 2+ channel, which play a prominent role in regulating the outgrowth of dendrites and axons (i.e., neurites) during development and in response to injury. Here, we investigated the role of caldendrin in Ca v 1-dependent pathways that impinge upon neurite growth in dorsal root ganglion neurons (DRGNs). By immunofluorescence, caldendrin was localized in medium- and large- diameter DRGNs. Compared to DRGNs cultured from WT mice, DRGNs of caldendrin knockout (KO) mice exhibited enhanced neurite regeneration and outgrowth. Strong depolarization, which normally represses neurite growth through activation of Ca v 1 channels, had no effect on neurite growth in DRGN cultures from female caldendrin KO mice. Remarkably, DRGNs from caldendrin KO males were no different from those of WT males in terms of depolarization-dependent neurite growth repression. We conclude that caldendrin opposes neurite regeneration and growth, and this involves coupling of Ca v 1 channels to growth-inhibitory pathways in DRGNs of females but not males., (© 2023. The Author(s).)

Objective: To evaluate the safety and utility of an investigational robotic-assisted cochlear implant insertion system., Study Design: Prospective, single-arm, open-label study under abbreviated Investigational Device Exemption requirements., Setting: All procedures were performed, and all data were collected, at a single tertiary referral center., Patients: Twenty-one postlingually deafened adult subjects that met Food and Drug Administration indication criteria for cochlear implantation., Intervention: All patients underwent standard-of-care surgery for unilateral cochlear implantation with the addition of a single-use robotic-assisted insertion device during cochlear electrode insertion., Main Outcome Measures: Successful insertion of cochlear implant electrode array, electrode array insertion time, postoperative implant function., Results: Successful robotic-assisted insertion of lateral wall cochlear implant electrode arrays was achieved in 20 (95.2%) of 21 patients. One insertion was unable to be achieved by either robotic-assisted or manual insertion methods, and the patient was retrospectively found to have a preexisting cochlear fracture. Mean intracochlear electrode array insertion time was 3 minutes 15 seconds. All implants with successful robotic-assisted electrode array insertion (n = 20) had normal impedance and neural response telemetry measures for up to 6 months after surgery., Conclusions: Here we report the first human trial of a single-use robotic-assisted surgical device for cochlear implant electrode array insertion. This device successfully and safely inserted lateral wall cochlear implant electrode arrays from the three device manufacturers with devices approved but he Food and Drug Administration., (Copyright © 2022, Otology & Neurotology, Inc.)