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.

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.

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.

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.

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.

Assessing the Clinical Value of Objective and Patient-Reported Audiovestibular Outcome Measures in the Risk Estimation of Systemic Cobalt Toxicity for Patients With a Metal-on-Metal Hip Implant.

OBJECTIVES: Based on limited evidence from case reports and small cohort studies of metal-on-metal (MoM) hip implant patients with presumed systemic cobalt (Co) toxicity, and a few animal studies on Co-induced damage to the otovestibular system, it was hypothesised that Co exhibits an ototoxic potential alongside other systemic manifestations. Preliminary investigations from our research group in MoM patients confirmed this assumption for the auditory system, whereas no signs of Co-induced vestibular impairment were detected, and a clear dose-response relationship between the auditory function and the blood Co levels was lacking. Therefore, the current study aimed to extend and validate these findings in a larger sample of MoM patients and control subjects, to explore the potential clinical value of audiovestibular outcome measures in the risk estimation of systemic Co toxicity in this patient population. DESIGN: Fifty patients (32 to 68 years) with a primary unilateral/bilateral MoM hip implant were matched for age, gender, and noise exposure to 50 nonimplanted control subjects. Both groups underwent the same protocol, consisting of an objective auditory [i.e., conventional and high-frequency audiometry, transient-evoked and distortion (TEOAEs and DPOAEs), auditory brainstem responses] and vestibular (i.e., cervical and ocular vestibular evoked myogenic potentials, horizontal and vertical video head impulse tests) test battery, a questionnaire inquiring auditory, balance, and general neurological symptoms, and a blood sample collection to determine the plasma Co concentration. RESULTS: The auditory test battery presented consistently higher audiometric thresholds in the MoM patient group, with group differences ranging from 2.1 to 5.7 dB in the lower frequencies (0.25 to 6.0 kHz) and from 4.6 to 9.3 dB in the high frequencies (8.0 to 14.0 kHz). Group differences at high frequencies were statistically significant ( p ≤ 0.001). Additionally, significantly lower TEOAE ( p = 0.009) and DPOAE ( p < 0.001) amplitudes were observed in the MoM patients when the better ear was included in the analysis, and more absent TEOAE and DPOAE responses were found between 1.0 and 4.0 kHz (0.008 ≤ p ≤ 0.039). Within the vestibular test battery, the MoM patients showed longer N1 and P1 ocular vestibular evoked myogenic potentials latencies for the left ear, and lower video head impulse test gains for the left anterior and right posterior semicircular canals (0.005 ≤ p ≤0.035). The patient-reported (questionnaire) outcome delivered no significant group differences ( p > 0.01). Six patients had elevated Co levels according to our local institutional threshold (>4 or 5 µg/l for unilateral or bilateral MoM hip implants, resp.), but their audiovestibular outcome measures did not differ significantly from those of the other patients. CONCLUSIONS: Corresponding to our preliminary investigations, the results indicate possibly Co-induced (predominantly high-frequency) auditory impairment, probably triggered by toxic damage to the cochlear structures. However, the low mean difference values, the lack of group differences for the patient-reported outcome measures, and the lack of any relationship with the blood Co levels strongly reduce the clinical relevance of these findings. Therefore, the risk of Co-induced ototoxic impairment is considered to be clinically negligible for the majority of MoM hip implant patients, and the use of auditory tests in the risk estimation of systemic Co toxicity should be decided on a case-by-case basis.

Brain ventricular volume changes induced by long-duration spaceflight.

Long-duration spaceflight induces detrimental changes in human physiology. Its residual effects and mechanisms remain unclear. We prospectively investigated the changes in cerebrospinal fluid (CSF) volume of the brain ventricular regions in space crew by means of a region of interest analysis on structural brain scans. Cosmonaut MRI data were investigated preflight (n = 11), postflight (n = 11), and at long-term follow-up 7 mo after landing (n = 7). Post hoc analyses revealed a significant difference between preflight and postflight values for all supratentorial ventricular structures, i.e., lateral ventricle (mean % change ± SE = 13.3 ± 1.9), third ventricle (mean % change ± SE = 10.4 ± 1.1), and the total ventricular volume (mean % change ± SE = 11.6 ± 1.5) (all P < 0.0001), with higher volumes at postflight. At follow-up, these structures did not quite reach baseline levels, with still residual increases in volume for the lateral ventricle (mean % change ± SE = 7.7 ± 1.6; P = 0.0009), the third ventricle (mean % change ± SE = 4.7 ± 1.3; P = 0.0063), and the total ventricular volume (mean % change ± SE = 6.4 ± 1.3; P = 0.0008). This spatiotemporal pattern of CSF compartment enlargement and recovery points to a reduced CSF resorption in microgravity as the underlying cause. Our results warrant more detailed and longer longitudinal follow-up. The clinical impact of our findings on the long-term cosmonauts' health and their relation to ocular changes reported in space travelers requires further prospective studies.

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.

Non-Genetic Generation of Antibody Conjugates Based on Chemoenzymatic Tyrosine Click Chemistry.

The availability of tools to generate homogeneous and stable antibody conjugates without recombinant DNA technology is a valuable asset in fields spanning from in vitro diagnostics to in vivo imaging and therapeutics. We present here a general approach for the conjugation to human IgG1 antibodies, by employing a straightforward two-stage protocol based on antibody deglycosylation followed by tyrosinase-mediated ortho-quinone strain-promoted click chemistry. The technology is validated by the efficient and clean generation of highly potent DAR2 and DAR4 antibody-drug conjugates (ADCs) with cytotoxic payloads MMAE or PBD dimer, and their in vitro evaluation.

The Antwerp Vestibular Compensation Index (AVeCI): an index for vestibular compensation estimation, based on functional balance performance.

PURPOSE: To create an index that is a measure of the amount of vestibular compensation and for which only functional balance performance is needed. METHODS: The medical charts of 62 eligible peripheral vestibular dysfunction (PVD) patients were analyzed retrospectively. To be included, the following vestibulo-ocular reflex (VOR) and balance performance data had to be available: (1) caloric and sinusoidal harmonic acceleration test (SHA) and (2) standing balance sum-eyes closed (SBS-EC), Timed Up and Go Test and Dynamic Gait Index. Patients were divided into three groups: normal caloric- and SHA test (group 1), abnormal caloric- and normal SHA test (group 2, PVD compensated) and abnormal caloric- and SHA test (group 3, PVD uncompensated). Next to the use of non-parametric tests to study the VOR and balance variables, logistic regression was used to identify the balance measures that predict whether PVD patients were compensated or uncompensated. This resulted also in the construction of a continuous measure representing the degree of compensation. RESULTS: Logistic regression identified SBS-EC and age to classify uncompensated from compensated patients with sensitivity of 83.9% and specificity of 72.4%. Then an index was created, called the Antwerp Vestibular Compensation Index, AVeCI = - 50 + age × 0.486 + SBS-EC × 0.421. A patient belongs to the uncompensated group when AVeCI < 0 and to the compensated group when AVeCI > 0, with respective group means of - 5 and 5. CONCLUSION: AVeCI stages the degree of compensation of PVD patients and can serve to evaluate rehabilitation effects.

The relationship between cochleovestibular function tests and endolymphatic hydrops grading on MRI in patients with Menière's disease.

PURPOSE: In this retrospective study the relationship between cochleovestibular function and a magnetic resonance imaging (MRI-) based classification system of endolymphatic hydrops was investigated. METHODS: Seventy-eight patients with unilateral definite Menière's disease who underwent MRI were included. The parameters of Pure Tone Audiometry (PTA), caloric irrigation test, cervical vestibular evoked myogenic potentials, and video Head Impulse Test were compared between the grades of endolymphatic hydrops (EH) and perilymphatic enhancement (PE) on MRI. RESULTS: The low-frequency PTA was significantly different between cochlear EH grades I and II (p = 0.036; Grade I: mean (Standard Deviation, SD) = 51 decibel Hearing Level (dB HL) (18 dB HL); Grade II: mean (SD) = 60 dB HL (16 dB HL)), and vestibular EH grades 0 and III (p = 0.018; Grade 0: mean (SD) = 43 dB HL (21 dB HL); Grade III: mean = 60 dB HL (10 dB HL)). The ipsilateral caloric sum of ears with vestibular EH grade I (n = 6) was increased with regards to vestibular EH grades 0 (p = 0.001), II (p < 0.001), and III (p < 0.001) (Grade 0: mean (SD) = 24°/s (15°/s); Grade I: mean (SD) = 47°/s (11°/s); Grade II: mean (SD) = 21°/s (13°/s); Grade III: mean (SD) = 16°/s (8°/s)). CONCLUSION: According to these results we can conclude that only the highest grades of cochlear and vestibular EH seem to be associated with decreased cochleovestibular functioning.

The ototoxic potential of cobalt from metal-on-metal hip implants: a pilot study on the patient-reported auditory, vestibular, and general neurological outcome.

OBJECTIVE: This study aimed to systematically investigate the ototoxic potential of cobalt in patients with a metal-on-metal (MoM) hip implant, using objective auditory and vestibular assessments and a questionnaire. The results of the objective evaluation were published previously, whereas the current study focused on the questionnaire outcome and its relationship to the blood cobalt level. Design and study sample: Twenty patients (33-65 years) with a primary MoM hip implant and 20 non-implanted control subjects, matched for age, gender, and noise exposure, received a questionnaire to evaluate the presence of several hearing and balance symptoms (part 1) and general neurological issues (part 2). RESULTS: Concerning part 1, the proportion of auditory-related symptoms in general (p = 0.022) and tinnitus (p = 0.047) was significantly higher in the MoM patient group, whereas no group difference was found for hyperacusis, increased listening effort, and decreased speech understanding. Concerning part 2, no significant group differences were detected. Within the MoM patient group, the questionnaire outcome was not significantly different between the low-exposure and high-exposure subgroups according to the blood Co level. CONCLUSIONS: In line with our previous study, these results potentially imply Co-induced impairment to the auditory system, despite the lack of a clear dose-response relationship.

Cross-cultural validation and psychometrics' evaluation of women's experience of maternity care scale in French: the ESEM.

BACKGROUND: Evaluating women's satisfaction should reflect the entire maternity care experience (antenatal, intrapartum and postnatal). The Women's Experience Maternity Care Scale (WEMCS) questionnaire enables this assessment. The purpose of this study was to translate in French, adapt and explore the psychometric properties of the WEMCS and to determine the best cut-off on the optimal satisfaction for the three scales. METHODS: Backward, forward translation and cross-cultural adaptation were processed to validate the French version of WEMCS: Échelle de Satisfaction de l'Experience des soins en Maternité (ESEM). Psychometric tests assessed the questionnaire, which includes three scales, such as construct validity, internal consistency, Cronbach's alpha coefficients and ceiling and floor effects. A receiver operating characteristic (ROC) curve was used to determine the best cut-off values for optimal satisfaction. Reproducibility was verified by test-retest reliability. RESULTS: Primiparas with uncomplicated pregnancies were recruited antenatally at the University Hospital of Geneva. Of the 229 patients who agreed to participate, 202 women (88.2%) returned the test and retest questionnaires. Principal component analysis for the antenatal, intrapartum and postnatal scales suggested the unidimensional character of the three scales; Cronbach's alpha coefficients were high for the three scales with values of > 0.85. Construct validity based on the five-point Likert scale values showed a Spearman's rho correlation of r = 0.56 for the antenatal scale (p < 0.001) and r = 0.62 for the intrapartum scale (p < 0.001), as well as a strong correlation with the postnatal scale, with r = 0.78 (p < 0.001). Optimum cut-off scores for the ROC curve of the antenatal, intrapartum and postnatal scores were equal to or higher than 48, 50 and 70, respectively. The three scales showed good sensitivity and good specificity. The stability of the ESEM questionnaire was confirmed by intra-class correlation coefficients of > 0.80. However, the three scales revealed ceiling effects. CONCLUSION: The psychometric proprieties of the ESEM demonstrate it's ability to evaluate the quality of perinatal health care. The ESEM should be tested in the context of different models of women's care and with women with different degrees of pregnancy complications to explore the validity of this scale.

The Superiority of the Otolith System.

BACKGROUND: The peripheral vestibular end organ is considered to consist of semi-circular canals (SCC) for detection of angular accelerations and the otoliths for detection of linear accelerations. However, otoliths being phylogenetically the oldest part of the vestibular sensory organs are involved in detection of all motions. SUMMARY: This study elaborates on this property of the otolith organ, as this concept can be of importance for the currently designed vestibular implant devices. Key Message: The analysis of the evolution of the inner ear and examination of clinical examples shows the robustness of the otolith system and inhibition capacity of the SCC. The otolith system must be considered superior to the SCC system as illustrated by evolution, clinical evidence, and physical principles.

The Ototoxic Potential of Cobalt From Metal-on-Metal Hip Implants: Objective Auditory and Vestibular Outcome.

OBJECTIVES: During the past decade, the initial popularity of metal-on-metal (MoM) hip implants has shown a progressive decline due to increasingly reported implant failure and revision surgeries. Local as well as systemic toxic side effects have been associated with excessive metal ion release from implants, in which cobalt (Co) plays an important role. The rare condition of systemic cobaltism seems to manifest as a clinical syndrome with cardiac, endocrine, and neurological symptoms, including hearing loss, tinnitus, and imbalance. In most cases described in the literature, revision surgery and the subsequent drop in blood Co level led to (partial) alleviation of the symptoms, suggesting a causal relationship with Co exposure. Moreover, the ototoxic potential of Co has recently been demonstrated in animal experiments. Since its ototoxic potential in humans is merely based on anecdotal case reports, the current study aimed to prospectively and objectively examine the auditory and vestibular function in patients implanted with a MoM hip prosthesis. DESIGN: Twenty patients (15 males and 5 females, aged between 33 and 65 years) implanted with a primary MoM hip prosthesis were matched for age, gender, and noise exposure to 20 non-implanted control subjects. Each participant was subjected to an extensive auditory (conventional and high-frequency pure tone audiometry, transient evoked and distortion product otoacoustic emissions [TEOAEs and DPOAEs], auditory brainstem responses [ABR]) and vestibular test battery (cervical and ocular vestibular evoked myogenic potentials [cVEMPs and oVEMPs], rotatory test, caloric test, video head impulse test [vHIT]), supplemented with a blood sample collection to determine the plasma Co concentration. RESULTS: The median [interquartile range] plasma Co concentration was 1.40 [0.70, 6.30] µg/L in the MoM patient group and 0.19 [0.09, 0.34] µg/L in the control group. Within the auditory test battery, a clear trend was observed toward higher audiometric thresholds (11.2 to 16 kHz), lower DPOAE (between 4 and 8 kHz), and total TEOAE (1 to 4 kHz) amplitudes, and a higher interaural latency difference for wave V of the ABR in the patient versus control group (0.01 ≤ p < 0.05). Within the vestibular test battery, considerably longer cVEMP P1 latencies, higher oVEMP amplitudes (0.01 ≤ p < 0.05), and lower asymmetry ratio of the vHIT gain (p < 0.01) were found in the MoM patients. In the patient group, no suggestive association was observed between the plasma Co level and the auditory or vestibular outcome parameters. CONCLUSIONS: The auditory results seem to reflect signs of Co-induced damage to the hearing function in the high frequencies. This corresponds to previous findings on drug-induced ototoxicity and the recent animal experiments with Co, which identified the basal cochlear outer hair cells as primary targets and indicated that the cellular mechanisms underlying the toxicity might be similar. The vestibular outcomes of the current study are inconclusive and require further elaboration, especially with respect to animal studies. The lack of a clear dose-response relationship may question the clinical relevance of our results, but recent findings in MoM hip implant patients have confirmed that this relationship can be complicated by many patient-specific factors.

The value of four stage vestibular hydrops grading and asymmetric perilymphatic enhancement in the diagnosis of Menière's disease on MRI.

PURPOSE: There is still a clinical-radiologic discrepancy in patients with Menière's disease (MD). Therefore, the purpose of this study was to investigate the reliability of current MRI endolymphatic hydrops (EH) criteria according to Baráth in a larger study population and the clinical utility of new imaging signs such as a supplementary fourth low-grade vestibular EH and the degree of perilymphatic enhancement (PE) in patients with Menière's disease (MD). METHODS: This retrospective study included 148 patients with probable or definite MD according to the 2015 American Academy of Otolaryngology, Head and Neck Surgery criteria who underwent a 4-h delayed intravenous Gd-enhanced 3D-FLAIR MRI between January 2015 and December 2016. Vestibular EH, vestibular PE, cochlear EH, and cochlear PE were reviewed twice by three experienced readers. Cohen's Kappa and multivariate logistic regression were used for analysis. RESULTS: The intra- and inter-reader reliability for the grading of vestibular-cochlear EH and PE was excellent (0.7 < kappa < 0.9). The two most distinctive characteristics to identify MD are cochlear PE and vestibular EH which combined gave a sensitivity and specificity of 79.5 and 93.6%. By addition of a lower grade vestibular EH, the sensitivity improved to 84.6% without losing specificity (92.3%). Cochlear EH nor vestibular PE showed added-value. CONCLUSIONS: MRI using vestibular-cochlear EH and PE grading system is a reliable technique. A four-stage vestibular EH grading system in combination with cochlear PE assessment gives the best diagnostic accuracy to detect MD.

Kinetics of the Strain-Promoted Oxidation-Controlled Cycloalkyne-1,2-quinone Cycloaddition: Experimental and Theoretical Studies.

Stimulated by its success in both bioconjugation and surface modification, we studied the strain-promoted oxidation-controlled cycloalkyne-1,2-quinone cycloaddition (SPOCQ) in three ways. First, the second-order rate constants and activation parameters (ΔH⧧) were determined of various cyclooctynes reacting with 4-tert-butyl-1,2-quinone in a SPOCQ reaction, yielding values for ΔH⧧ of 4.5, 7.3, and 12.1 kcal/mol, for bicyclo[6.1.0]non-4-yne (BCN), cyclooctyne (OCT), and dibenzoazacyclooctyne (DIBAC), respectively. Second, their reaction paths were investigated in detail by a range of quantum mechanical calculations. Single-configuration theoretical methods, like various DFT and a range of MP2-based methods, typically overestimate this barrier by 3-8 kcal/mol (after inclusion of zero-point energy, thermal, and solvation corrections), whereas MP2 itself underestimates the barrier significantly. Only dispersion-corrected DFT methods like B97D (yielding 4.9, 6.4, and 12.1 kcal/mol for these three reactions) and high-level CCSD(T) and multireference multiconfiguration AQCC ab initio approaches (both yielding 8.2 kcal/mol for BCN) give good approximations of experimental data. Finally, the multireference methods show that the radical character in the TS is rather small, thus rationalizing the use of single-reference methods like B97D and SCS-MP2 as intrinsically valid approaches.

Enzymatic strategies for (near) clinical development of antibody-drug conjugates.

Target-specific killing of tumor cells with antibody-drug conjugates (ADCs) is an elegant concept in the continued fight against cancer. However, despite more than 20 years of clinical development, only four ADC have reached market approval, while at least 50 clinical programs were terminated early. The high attrition rate of ADCs may, at least in part, be attributed to heterogeneity and instability of conventional technologies. At present, various (chemo)enzymatic approaches for site-specific and stable conjugation of toxic payloads are making their way to the clinic, thereby potentially providing ADCs with increased therapeutic window.

Differential effect of visual motion adaption upon visual cortical excitability.

The objectives of this study were 1) to probe the effects of visual motion adaptation on early visual and V5/MT cortical excitability and 2) to investigate whether changes in cortical excitability following visual motion adaptation are related to the degree of visual dependency, i.e., an overreliance on visual cues compared with vestibular or proprioceptive cues. Participants were exposed to a roll motion visual stimulus before, during, and after visual motion adaptation. At these stages, 20 transcranial magnetic stimulation (TMS) pulses at phosphene threshold values were applied over early visual and V5/MT cortical areas from which the probability of eliciting a phosphene was calculated. Before and after adaptation, participants aligned the subjective visual vertical in front of the roll motion stimulus as a marker of visual dependency. During adaptation, early visual cortex excitability decreased whereas V5/MT excitability increased. After adaptation, both early visual and V5/MT excitability were increased. The roll motion-induced tilt of the subjective visual vertical (visual dependence) was not influenced by visual motion adaptation and did not correlate with phosphene threshold or visual cortex excitability. We conclude that early visual and V5/MT cortical excitability is differentially affected by visual motion adaptation. Furthermore, excitability in the early or late visual cortex is not associated with an increase in visual reliance during spatial orientation. Our findings complement earlier studies that have probed visual cortical excitability following motion adaptation and highlight the differential role of the early visual cortex and V5/MT in visual motion processing.NEW & NOTEWORTHY We examined the influence of visual motion adaptation on visual cortex excitability and found a differential effect in V1/V2 compared with V5/MT. Changes in visual excitability following motion adaptation were not related to the degree of an individual's visual dependency.