Virtual reality application matches the most established treatment for Mal de Debarquement Syndrome: A non-inferiority, randomized, open clinical trial.

Mal de Debarquement Syndrome (MdDS) is a debilitating neuro-otological disorder where individuals consistently feel self-motion, often triggered by motion like being on a boat (MT-MdDS). Due to the unknown pathophysiological mechanism, available treatment options for managing symptoms are limited. Our objective was to develop a virtual reality application (VRA) to simulate the full field optokinetic stimulation (OKS) booth and evaluate its efficacy compared to the standard treatment. In our randomized, open, non-inferiority clinical trial with 30 â€‹MT-MdDS patients, 15 received the OKS booth and 15 the new VRA over four consecutive days. Two 4-min treatment blocks were scheduled in the morning and afternoon, with a total of four blocks. Treatment effectiveness was evaluated through questionnaires and posturography. Our findings suggest that the choice of modality does not significantly differ in achieving an overall improvement in symptoms. We advocate that the VRA can be used as an accessible alternative to the booth method worldwide, effectively mitigating MdDS symptoms and enhancing the QoL of numerous MdDS patients.

Guideline for standardized approach in the treatment of the Mal de Debarquement syndrome.

Introduction: Mal de Debarquement Syndrome (MdDS) is a debilitating neuro-otological disorder. Patients experience almost continuously a perception of self-motion. This syndrome can be motion-triggered (MT-MdDS), such as on a boat, or occur spontaneously or have other triggers (SO-MdDS) in the absence of such motion. Because the pathophysiological mechanism is unknown, treatment options and symptom management strategies are limited. One available treatment protocol involves a readaptation of the vestibular ocular reflex (VOR). This study assesses the effectiveness of vestibulo-ocular reflex (VOR) readaptation in 131 consecutive patients with a fixed protocol. Methods: We administered 131 treatments involving optokinetic stimulation (OKS) paired with a fixed head roll at 0.167 Hz over two to five consecutive days. Each day, four-minute treatment blocks were scheduled twice in the morning and afternoon. Treatment effectiveness was evaluated through questionnaires and posturography. Results: We observed significant improvements in the visual analog scale (VAS), MdDS symptom questionnaire, and posturography measures from pre- to post-treatment. No significant differences were found in outcome variables between MT- and SO-MdDS onsets. Conclusion: Symptoms improved subjectively and objectively in patients' post-treatment. The overall success rate was 64.1%, with no significant difference between MT (64.2%) and SO (63.3%). This study supports the conclusion that VOR readaptation treatment provides relief for two-thirds of MdDS patients, irrespective of the onset type. Based on consistency in the findings, we propose a standardized method for treatment of MdDS based on the OKS with head roll paradigm.

The Need for Vestibular Implants in a Tertiary Referral Ear, Nose, and Throat Center and Its Relation to Hearing Status.

BACKGROUND: Patients with bilateral vestibulopathy (BVP) are at increased risk of falling and have poor quality of life. Several research groups are currently developing and investigating vestibular implants to treat BVP. The goal was to identify how many patients can be considered eligible for vestibular implantation. METHODS: The objective vestibular implantation criteria for research were applied to the results of the caloric irrigation test, the sinusoidal harmonic acceleration test, the video head impulse test, and the cervical and ocular vestibular evoked myogenic potential tests. RESULTS: Vestibular implant eligibility was situated between 3.6% and 15.7% (semicircular canal implant: 3.6%; otolith implant: 15.7%; combined implant: 4.8%). Only 16 out of the 29 patients (55%) eligible for a vestibular implant had bilateral severe-to-profound hearing loss. The remaining 45% (13/29) thus have better hearing in at least 1 ear. CONCLUSION: Vestibular implant eligibility in an ear, nose, and throat department was situated between 3.6% and 15.7%, depending on the type of implant that was considered. In addition, the data showed that 45% of the eligible patients had normal-to-moderate hearing in at least 1 ear. In other words, only recruiting patients with (bilateral) severe-to-profound hearing loss for vestibular implantation leads to the systematic exclusion of about half of the candidates. Structure-preserving surgical techniques are thus a major future challenge in the field of vestibular implantation.

Rapid Access to Potent Bispecific T Cell Engagers Using Biogenic Tyrosine Click Chemistry.

Bispecific antibodies as T cell engagers designed to display binding capabilities to both tumor-associated antigens and antigens on T cells are considered promising agents in the fight against cancer. Even though chemical strategies to develop such constructs have emerged, a method that readily converts a therapeutically applied antibody into a bispecific construct by a fully non-genetic process is not yet available. Herein, we report the application of a biogenic, tyrosine-based click reaction utilizing chemoenzymatic modifications of native IgG1 antibodies to generate a synthetic bispecific antibody construct that exhibits tumor-killing capability at picomolar concentrations. Control experiments revealed that a covalent linkage of the different components is required for the observed biological activities. In view of the highly potent nature of the constructs and the modular approach that relies on convenient synthetic methods utilizing therapeutically approved biomolecules, our method expedites the production of potent bispecific antibody constructs with tunable cell killing efficacy with significant impact on therapeutic properties.

Case report: Can cochlear implant stimulation lead to improved balance even after vestibular neurectomy?

Introduction: In a previous manuscript from our research group, the concept of vestibular co-stimulation was investigated in adult subjects who received a cochlear implant (CI). Despite what literature reports state, no signs of vestibular co-stimulation could be observed. Results: In this case report, it was described how a woman, who previously underwent a neurectomy of the left vestibular nerve and suffers from bilateral vestibulopathy (BVP), reported improved balance whenever her CI on the left was stimulating. Unexpectedly, the sway analyses during posturography indeed showed a clinically relevant improvement when the CI was activated. Discussion: Vestibular co-stimulation as a side effect of CI stimulation could not be the explanation in this case due to the ipsilateral vestibular neurectomy. It is more likely that the results can be attributed to the electrically restored auditory input, which serves as an external reference for maintaining balance and spatial orientation. In addition, this patient experienced disturbing tinnitus whenever her CI was deactivated. It is thus plausible that the tinnitus increased her cognitive load, which was already increased because of the BVP, leading to an increased imbalance in the absence of CI stimulation.

Generation of DAR1 Antibody-Drug Conjugates for Ultrapotent Payloads Using Tailored GlycoConnect Technology.

GlycoConnect technology can be readily adapted to provide different drug-to-antibody ratios (DARs) and is currently also evaluated in various clinical programs, including ADCT-601 (DAR2), MRG004a (DAR4), and XMT-1660 (DAR6). While antibody-drug conjugates (ADCs) typically feature a DAR2-8, it has become clear that ADCs with ultrapotent payloads (e.g., PBD dimers and calicheamicin) can only be administered to patients at low doses (<0.5 mg/kg), which may compromise effective biodistribution and may be insufficient to reach target receptor saturation in the tumor. Here, we show that GlycoConnect technology can be readily extended to DAR1 ADCs without the need of antibody re-engineering. We demonstrate that various ultrapotent, cytotoxic payloads are amenable to this methodology. In a follow-up experiment, HCC-1954 tumor spheroids were treated with either an AlexaFluor647-labeled DAR1 or DAR2 PBD-based ADC to study the effect on tumor penetration. Significant improvement of tumor spheroid penetration was observed for the DAR1 ADC compared to the DAR2 ADC at an equal payload dose, underlining the potential of a lower DAR for ADCs bearing ultrapotent payloads.

High Rates of Quinone-Alkyne Cycloaddition Reactions are Dictated by Entropic Factors.

Reaction rates of strained cycloalkynes and cycloalkenes with 1,2-quinone were quantified by stopped flow UV-Vis spectroscopy and computational analysis. We found that the strained alkyne BCN-OH 3 (k2 1824 M-1 s-1 ) reacts >150 times faster than the strained alkene TCO-OH 5 (k2 11.56 M-1 s-1 ), and that derivatization with a carbamate can lead to a reduction of the rate constant with almost half. Also, the 8-membered strained alkyne BCN-OH 3 reacts 16 times faster than the more strained 7-membered THS 2 (k2 110.6 M-1 s-1 ). Using the linearized Eyring equation we determined the thermodynamic activation parameters of these two strained alkynes, revealing that the SPOCQ reaction of quinone 1 with THS 2 is associated with ΔH≠ of 0.80 kcal/mol, ΔS≠ =-46.8 cal/K⋅mol, and ΔG≠ =14.8 kcal/mol (at 25 °C), whereas the same reaction with BCN-OH 3 is associated with, ΔH≠ =2.25 kcal/mol, ΔS≠ =-36.3 cal/K⋅mol, and ΔG≠ =13.1 kcal/mol (at 25 °C). Computational analysis supported the values obtained by the stopped-flow measurements, with calculated ΔG≠ of 15.6 kcal/mol (in H2 O) for the SPOCQ reaction with THS 2, and with ΔG≠ of 14.7 kcal/mol (in H2 O) for the SPOCQ reaction with BCN-OH 3. With these empirically determined thermodynamic parameters, we set an important step towards a more fundamental understanding of this set of rapid click reactions.

Neuroplasticity in F16 fighter jet pilots.

Exposure to altered g-levels causes unusual sensorimotor demands that must be dealt with by the brain. This study aimed to investigate whether fighter pilots, who are exposed to frequent g-level transitions and high g-levels, show differential functional characteristics compared to matched controls, indicative of neuroplasticity. We acquired resting-state functional magnetic resonance imaging data to assess brain functional connectivity (FC) changes with increasing flight experience in pilots and to assess differences in FC between pilots and controls. We performed whole-brain exploratory and region-of-interest (ROI) analyses, with the right parietal operculum 2 (OP2) and the right angular gyrus (AG) as ROIs. Our results show positive correlations with flight experience in the left inferior and right middle frontal gyri, and in the right temporal pole. Negative correlations were observed in primary sensorimotor regions. We found decreased whole-brain functional connectivity of the left inferior frontal gyrus in fighter pilots compared to controls and this cluster showed decreased functional connectivity with the medial superior frontal gyrus. Functional connectivity increased between the right parietal operculum 2 and the left visual cortex, and between the right and left angular gyrus in pilots compared to controls. These findings suggest altered motor, vestibular, and multisensory processing in the brains of fighter pilots, possibly reflecting coping strategies to altered sensorimotor demands during flight. Altered functional connectivity in frontal areas may reflect adaptive cognitive strategies to cope with challenging conditions during flight. These findings provide novel insights into brain functional characteristics of fighter pilots, which may be of interest to humans traveling to space.

Prolonged microgravity induces reversible and persistent changes on human cerebral connectivity.

The prospect of continued manned space missions warrants an in-depth understanding of how prolonged microgravity affects the human brain. Functional magnetic resonance imaging (fMRI) can pinpoint changes reflecting adaptive neuroplasticity across time. We acquired resting-state fMRI data of cosmonauts before, shortly after, and eight months after spaceflight as a follow-up to assess global connectivity changes over time. Our results show persisting connectivity decreases in posterior cingulate cortex and thalamus and persisting increases in the right angular gyrus. Connectivity in the bilateral insular cortex decreased after spaceflight, which reversed at follow-up. No significant connectivity changes across eight months were found in a matched control group. Overall, we show that altered gravitational environments influence functional connectivity longitudinally in multimodal brain hubs, reflecting adaptations to unfamiliar and conflicting sensory input in microgravity. These results provide insights into brain functional modifications occurring during spaceflight, and their further development when back on Earth.

Are Acoustic Markers of Voice and Speech Signals Affected by Nose-and-Mouth-Covering Respiratory Protective Masks?

BACKGROUND: Worldwide use of nose-and-mouth-covering respiratory protective mask (RPM) has become ubiquitous during COVID19 pandemic. Consequences of wearing RPMs, especially regarding perception and production of spoken communication, are gradually emerging. The present study explored how three prevalent RPMs affect various speech and voice sound properties. METHODS: Pre-recorded sustained [a] vowels and read sentences from 47 subjects were played by a speech production model ('Voice Emitted by Spare Parts', or 'VESPA') in four conditions: without RPM (C1), with disposable surgical mask (C2), with FFP2 mask (C3), and with transparent plastic mask (C4). Differences between C1 and masked conditions were assessed with Dunnett's t test in 26 speech sound properties related to voice production (fundamental frequency, sound intensity level), voice quality (jitter percent, shimmer percent, harmonics-to-noise ratio, smoothed cepstral peak prominence, Acoustic Voice Quality Index), articulation and resonance (first and second formant frequencies, first and second formant bandwidths, spectral center of gravity, spectral standard deviation, spectral skewness, spectral kurtosis, spectral slope, and spectral energy in ten 1-kHz bands from 0 to 10 kHz). RESULTS: C2, C3, and C4 significantly affected 10, 15, and 19 of the acoustic speech markers, respectively. Furthermore, absolute differences between unmasked and masked conditions were largest for C4 and smallest for C2. CONCLUSIONS: All RPMs influenced more or less speech sound properties. However, this influence was least for surgical RPMs and most for plastic RPMs. Surgical RPMs are therefore preferred when spoken communication is priority next to respiratory protection.

Future research directions to identify risks and mitigation strategies for neurostructural, ocular, and behavioral changes induced by human spaceflight: A NASA-ESA expert group consensus report.

A team of experts on the effects of the spaceflight environment on the brain and eye (SANS: Spaceflight-Associated Neuro-ocular Syndrome) was convened by NASA and ESA to (1) review spaceflight-associated structural and functional changes of the human brain and eye, and any interactions between the two; and (2) identify critical future research directions in this area to help characterize the risk and identify possible countermeasures and strategies to mitigate the spaceflight-induced brain and eye alterations. The experts identified 14 critical future research directions that would substantially advance our knowledge of the effects of spending prolonged periods of time in the spaceflight environment on SANS, as well as brain structure and function. They used a paired comparison approach to rank the relative importance of these 14 recommendations, which are discussed in detail in the main report and are summarized briefly below.

Ocular counter-roll is less affected in experienced versus novice space crew after long-duration spaceflight.

Otoliths are the primary gravity sensors of the vestibular system and are responsible for the ocular counter-roll (OCR). This compensatory eye torsion ensures gaze stabilization and is sensitive to a head roll with respect to gravity and the Gravito-Inertial Acceleration vector during, e.g., centrifugation. To measure the effect of prolonged spaceflight on the otoliths, we quantified the OCR induced by off-axis centrifugation in a group of 27 cosmonauts in an upright position before and after their 6-month space mission to the International Space Station. We observed a significant decrease in OCR early postflight, larger for first-time compared to experienced flyers. We also found a significantly larger torsion for the inner eye, the eye closest to the rotation axis. Our results suggest that experienced cosmonauts have acquired the ability to adapt faster after G-transitions. These data provide a scientific basis for sending experienced cosmonauts on challenging missions that include multiple g-level transitions.

Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering.

Antibody-drug conjugates (ADCs) are increasingly powerful medicines for targeted cancer therapy. Inspired by the trend to further improve their therapeutic index by generation of homogenous ADCs, we report here how the clinical-stage GlycoConnect™ technology uses the globally conserved N-glycosylation site to generate stable and site-specific ADCs based on enzymatic remodeling and metal-free click chemistry. We demonstrate how an engineered endoglycosidase and a native glycosyl transferase enable highly efficient, one-pot glycan remodeling, incorporating a novel sugar substrate 6-azidoGalNAc. Metal-free click attachment of an array of cytotoxic payloads was highly optimized, in particular by inclusion of anionic surfactants. The therapeutic potential of GlycoConnect™, in combination with HydraSpace™ polar spacer technology, was compared to that of Kadcyla® (ado-trastuzumab emtansine), showing significantly improved efficacy and tolerability.

Total ossicular chain reconstruction using a titanium prosthesis: functional results.

PURPOSE: To evaluate the efficacy and safety of a titanium total prosthesis (TORP) in ossicular chain reconstruction. METHODS: Retrospective analysis of 113 cases of total ossicular chain reconstruction performed by a single surgeon between 2006 and 2018. Follow-up lasted until January 2020. Participants were patients with chronic otitis media, cholesteatoma, or ossicular chain disruption. RESULTS: Mean preoperative air-bone gap (± standard deviation) was 32.74 dB (± 11.62). Mean postoperative air-bone gap was 21.68 (± 11.29). Mean air-bone gap improvement was 11.06 dB (± 14.99) (p < 0.001). 57 cases had a post-operative air-bone gap smaller than or equal to 20 dB (50.44%). In four cases, prosthesis dislocation was observed (12.39%). Mean prosthesis length in this group was 5.29 mm (± 0.86) versus 4.36 mm (± 1.02) in cases without prosthesis dislocation (p = 0.002). CONCLUSIONS: Total ossicular reconstruction using a titanium prosthesis yields favorable functional results, also during prolonged follow-up. Prosthesis length was significantly longer in cases with prosthesis dislocation.

The Role of Different Afferent Systems in the Modulation of the Otolith-Ocular Reflex After Long-Term Space Flights.

Background: The vestibular (otolith) function is highly suppressed during space flight (SF) and the study of these changes is very important for the safety of the space crew during SF missions. The vestibular function (particularly, otolith-ocular reflex-OOcR) in clinical and space medicine is studied using different methodologies. However, different methods and methodologies can influence the outcome results. Objective: The current study addresses the question of whether the OOcR results obtained by different methods are different, and what the role is of the different afferent systems in the modulation of the OOcR. Methods: A total of 25 Russian cosmonauts voluntarily took part in our study. They are crewmembers of long duration space missions on the International Space Station (ISS). Cosmonauts were examined in pre- and post-flight "Sensory Adaptation" and "Gaze Spin" experiments, twice before (preflight) and three times after SF (post-flight). We used two different video oculography (VOG) systems for the recording of the OOcR obtained in each experiment. Results: Comparison of the two VOG systems didn't result into significant and systematic differences in the OOcR measurements. Analysis of the static torsion otolith-ocular reflex (OOR), static torsion otolith-cervical-ocular reflex (OCOR) and static torsion otolith-ocular reflex during eccentric centrifugation (OOREC) shows that the OOREC results in a lower OOcR response compared to the OOR and OCOR (before flight and late post-flight). However, all OOcRs were significantly decreased in all cosmonauts early post-flight. Conclusion: Analysis of the results of ocular counter rolling (OCR) obtained by different methods (OOR, OCOR, and OOREC) showed that different afferent systems (tactile-proprioception, neck-cervical, visual and vestibular afferent input) have an impact on the OOcR.

Vestibular Co-stimulation in Adults with a Cochlear Implant.

BACKGROUND: Vestibular co-stimulation is a side effect of cochlear implant stimulation. The electrical currents delivered by the cochlear implant can spread toward the vestibular system and thus stimulate it. The aim of the study is to evaluate whether it is feasible to functionally restore the balance by modifying the vestibular co-stimulation. METHODS: Four adult patients, who had received a commercially available cochlear implant previously, were enrolled. Counterbalanced biphasic pulses were presented as bursts or as an amplitude-modulated biphasic pulse train (modulation frequencies ranging from 1 to 500 Hz) at the participant's upper comfortable level for electrical stimulation. Subjective sensations and vestibular-mediated eye movements were used for evaluating the possible effects of vestibular co-stimulation. RESULTS: One participant experienced a cyclic tilting of his head in response to an amplitude-modulated biphasic pulse train with a modulation frequency of 2 and 400 Hz. However, during a follow-up visit, the sensation could not be replicated. CONCLUSION: Subjective vestibular sensations or vestibular-mediated eye movements could not be electrically evoked with a commercially available cochlear implant in 4 adult patients with almost normal vestibular function. Therefore, customized design of the hard-, firm-, and/or software of the commercially available cochlear implant might be necessary in order to electrically restore vestibular performance.

The effect of prolonged spaceflight on cerebrospinal fluid and perivascular spaces of astronauts and cosmonauts.

Long-duration spaceflight induces changes to the brain and cerebrospinal fluid compartments and visual acuity problems known as spaceflight-associated neuro-ocular syndrome (SANS). The clinical relevance of these changes and whether they equally affect crews of different space agencies remain unknown. We used MRI to analyze the alterations occurring in the perivascular spaces (PVS) in NASA and European Space Agency astronauts and Roscosmos cosmonauts after a 6-mo spaceflight on the International Space Station (ISS). We found increased volume of basal ganglia PVS and white matter PVS (WM-PVS) after spaceflight, which was more prominent in the NASA crew than the Roscosmos crew. Moreover, both crews demonstrated a similar degree of lateral ventricle enlargement and decreased subarachnoid space at the vertex, which was correlated with WM-PVS enlargement. As all crews experienced the same environment aboard the ISS, the differences in WM-PVS enlargement may have been due to, among other factors, differences in the use of countermeasures and high-resistive exercise regimes, which can influence brain fluid redistribution. Moreover, NASA astronauts who developed SANS had greater pre- and postflight WM-PVS volumes than those unaffected. These results provide evidence for a potential link between WM-PVS fluid and SANS.

Brain Connectometry Changes in Space Travelers After Long-Duration Spaceflight.

Humans undergo extreme physiological changes when subjected to long periods of weightlessness, and as we continue to become a space-faring species, it is imperative that we fully understand the physiological changes that occur in the human body, including the brain. In this study, we present findings of brain structural changes associated with long-duration spaceflight based on diffusion magnetic resonance imaging (dMRI) data. Twelve cosmonauts who spent an average of six months aboard the International Space Station (ISS) were scanned in an MRI scanner pre-flight, ten days after flight, and at a follow-up time point seven months after flight. We performed differential tractography, a technique that confines white matter fiber tracking to voxels showing microstructural changes. We found significant microstructural changes in several large white matter tracts, such as the corpus callosum, arcuate fasciculus, corticospinal, corticostriatal, and cerebellar tracts. This is the first paper to use fiber tractography to investigate which specific tracts exhibit structural changes after long-duration spaceflight and may direct future research to investigate brain functional and behavioral changes associated with these white matter pathways.

Comparison between 3D SPACE FLAIR and 3D TSE FLAIR in Menière's disease.

PURPOSE: Heavily T2-weighted 3D FLAIR (hT2w-3D-FLAIR) sequence with constant flip angle (CFA) has been reported as being more sensitive to low concentrations of gadolinium (Gd) enabling endolymphatic hydrops (EH) visualization. The purpose of this study was to compare signal-to-noise (SNR) ratio, detection rate of EH, and increased perilymphatic enhancement (PE) as well as diagnostic accuracy in diagnosing definite Menière's disease (MD), using 3D-SPACE FLAIR versus conventional 3D-TSE FLAIR. METHODS: This retrospective study included 29 definite MD patients who underwent a 4-h delayed intravenous (IV) Gd-enhanced 3D-TSE FLAIR and 3D-SPACE FLAIR MRI between February 2019 and February 2020. MR images were qualitatively and quantitatively analyzed twice by 2 experienced head and neck radiologists. Qualitative assessment included grading of cochlear and vestibular EH and visual comparison of PE. Quantitative assessment of PE was performed by placing a region of interest (ROI) and ratio calculation in the basal turn of the cochlea and the brainstem. RESULTS: The intra- and inter-reader reliability for grading of EH and PE was excellent (0.7 < kappa < 0.9) for 3D-SPACE FLAIR and exceeded the values for 3D-TSE FLAIR (0.5 < kappa < 0.9) The combination of EH and visual assessment of PE has the highest diagnostic accuracy in diagnosing definite MD on 3D-SPACE FLAIR with a sensitivity of 0.91 and a specificity of 0.98 resulting in a sensitivity raise of 6% compared to 3D-TSE FLAIR. CONCLUSION: Four-hour delayed IV Gd-enhanced 3D-SPACE FLAIR sequence has a higher sensitivity and reproducibility than 3D-TSE FLAIR for the visualization of EH and increased PE in definite MD patients.