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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

Acoustic plus electric (electric-acoustic) speech processing has been successful in highlighting the important role of articulation information in consonant recognition in those adults that have profound high-frequency hearing loss at frequencies greater than 1500 Hz and less than 60% discrimination scores. Eighty-seven subjects were enrolled in an adult Hybrid multicenter Food and Drug Administration clinical trial. Immediate hearing preservation was accomplished in 85/87 subjects. Over time (3 months to 5 years), some hearing preservation was maintained in 91% of the group. Combined electric-acoustic processing enabled most of this group of volunteers to gain improved speech understanding, compared to their preoperative hearing, with bilateral hearing aids. Most have preservation of low-frequency acoustic hearing within 15 dB of their preoperative pure tone levels. Those with greater losses (>30 dB) also benefited from the combination of electric-acoustic speech processing. Postoperatively, in the electric-acoustic processing condition, loss of low-frequency hearing did not correlate with improvements in speech perception scores in quiet. Sixteen subjects were identified as poor performers in that they did not achieve a significant improvement through electric-acoustic processing. A multiple regression analysis determined that 91% of the variance in the poorly performing group can be explained by the preoperative speech recognition score and duration of deafness. Signal-to-noise ratios for speech understanding in noise improved more than 9 dB in some individuals in the electric-acoustic processing condition. The relation between speech understanding in noise thresholds and residual low-frequency acoustic hearing is significant (r = 0.62; p < 0.05). The data suggest that, in general, the advantages gained for speech recognition in noise by preserving residual hearing exist, unless the hearing loss approaches profound levels. Preservation of residual low-frequency hearing should be considered when expanding candidate selection criteria for standard cochlear implants. Duration of profound high-frequency hearing loss appears to be an important variable when determining selection criteria for the Hybrid implant. [ABSTRACT FROM AUTHOR]

Objective: For vestibular schwannomas (VSs) that require treatment, options are limited to microsurgery or irradiation (IR). Development of alternative therapies that augment or replace microsurgery or IR would benefit patients not suitable for current therapies. This study explored the ability of ErbB2 inhibitors to modulate the effects of IR on VS cells.Study Design: Prospective study using primary cultures derived from human VSs.Methods: Primary cultures of VS cells were derived from acutely resected tumors. Cultures received single escalating doses (15-40 Gy) of gamma-irradiation from a Cs gamma-irradiation source. Cell proliferation was determined by BrdU uptake and apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Trastuzumab (Herceptin) and PD158780 were independently used to inhibit ErbB2 signaling while neuregulin-1beta (NRG-1) was used to activate ErbB2.Results: IR induces VS cell cycle arrest and apoptosis in doses greater than 20 Gy, demonstrating that VS cells are relatively radioresistant. This radioresistance likely arises from their low proliferative capacity as a sublethal dose of IR (10 Gy) strongly induces deoxyribonucleic acid (DNA) damage evidenced by histone H2AX phosphorylation. Inhibition of ErbB2, which decreases VS cell proliferation, protects VS cells from radiation-induced apoptosis, while NRG-1, an ErbB2 ligand and VS cell mitogen, increases radiation-induced VS cell apoptosis.Conclusions: Compared with many neoplastic conditions, VS cells are relatively radioresistant. The radio-protective effect of ErbB2 inhibitors implies that the sensitivity of VS cells to IR depends on their proliferative capacity. These results hold important implications for current and future treatment strategies. [ABSTRACT FROM AUTHOR]

Many patients in primary care present with ear pain (otalgia). When the ear is the source of the pain (primary otalgia), the ear examination is usually abnormal. When the ear is not the source of the pain (secondary otalgia), the ear examination is typically normal. The cause of primary otalgia is usually apparent on examination; the most common causes are otitis media and otitis externa. The cause of secondary otalgia is often difficult to determine because the innervation of the ear is complex and there are many potential sources of referred pain. The most common causes are temporomandibular joint syndrome, pharyngitis, dental disease, and cervical spine arthritis. If the diagnosis is not clear from the history and physical examination, options include a trial of symptomatic treatment without a clear diagnosis; imaging studies; and consultation with an otolaryngologist. Patients who smoke, drink alcohol, are older than 50 years, or have diabetes are at higher risk of a cause of ear pain that needs further evaluation. Patients whose history or physical examination increases suspicion for a serious occult cause of ear pain or whose symptoms persist after symptomatic treatment should be considered for further evaluation, such as magnetic resonance imaging, fiberoptic nasolaryngoscopy, or an erythrocyte sedimentation rate measurement. [ABSTRACT FROM AUTHOR]

Objectives: After axotomy, Schwann cells (SCs), required for successful nerve regeneration, undergo a number of cellular changes including dedifferentiation, proliferation, expression of molecules that support axon growth, and apoptosis. This study investigated the role of p75, sortilin, and proneurotrophins in SC survival after facial nerve (FN) axotomy.Study Design: Preliminary animal study.Methods: With use of FN SCs, expression of p75 and its coreceptor sortilin were quantified by immunofluorescence on days 12, 22, and 52 after axotomy in vivo and by Western blot in vitro. Contralateral FNs served as a control. SC apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). To verify a causative role for p75 in FN SC death, cultured FN SCs were treated with pro-nerve growth factor (NGF), and apoptosis was determined by TUNEL.Results: Expression of p75 and sortilin increased in FN SCs distal (P < .05) to the axotomy compared with the contralateral controls for all time points. SC apoptosis also significantly increased in the distal segment compared with the contralateral and proximal portions (P < .05). ProNGF, a p75 ligand, increased apoptosis and p75 expression in primary FN SC cultures.Conclusion: FN axotomy increases p75 and sortilin expression in SCs, which correlates with increased apoptosis. These findings suggest roles for p75 and sortilin in SC loss after FN injury. Sortilin is a novel target in promoting FN healing after injury. [ABSTRACT FROM AUTHOR]

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.)